Costanzo P, Perrone-Filardi P, Vassallo E, Paolillo S, Cesarano P, Brevetti G, Chiariello M.
Does carotid intima-media thickness regression predict reduction of cardiovascular events? A meta-analysis of 41 randomized trials.
J Am Coll Cardiol. 2010 Dec 7;56(24):2006-20. doi: 10.1016/j.jacc.2010.05.059.
Abstract/Text
OBJECTIVES: the purpose of this study was to verify whether intima-media thickness (IMT) regression is associated with reduced incidence of cardiovascular events.
BACKGROUND: Carotid IMT increase is associated with a raised risk of coronary heart disease (CHD) and cerebrovascular (CBV) events. However, it is undetermined whether favorable changes of IMT reflect prognostic benefits.
METHODS: the MEDLINE database and the Cochrane Database were searched for articles published until August 2009. All randomized trials assessing carotid IMT at baseline, at end of follow-up, and reporting clinical end points were included. A weighted random-effects meta-regression analysis was performed to test the relationship between mean and maximum IMT changes and outcomes. The influence of baseline patients' characteristics, cardiovascular risk profile, IMT at baseline, follow-up, and quality of the trials was also explored. Overall estimates of effect were calculated with a fixed-effects model, random-effects model, or Peto method.
RESULTS: forty-one trials enrolling 18,307 participants were included. Despite significant reduction in CHD, CBV events, and all-cause death induced by active treatments (for CHD events, odds ratio [OR]: 0.82, 95% confidence interval [CI]: 0.69 to 0.96, p = 0.02; for CBV events, OR: 0.71, 95% CI: 0.51 to 1.00, p = 0.05; and for all-cause death, OR: 0.71, 95% CI: 0.53 to 0.96, p = 0.03), there was no significant relationship between IMT regression and CHD events (tau(2)0.91, p = 0.37), CBV events (tau(2)-0.32, p = 0.75), and all-cause death (tau(2)-0.41, p = 0.69). In addition, subjects' baseline characteristics, cardiovascular risk profile, IMT at baseline, follow-up, and quality of the trials did not significantly influence the association between IMT changes and clinical outcomes.
CONCLUSIONS: regression or slowed progression of carotid IMT, induced by cardiovascular drug therapies, do not reflect reduction in cardiovascular events.
Published by Elsevier Inc. All rights reserved.
Lorenz MW, Polak JF, Kavousi M, Mathiesen EB, Völzke H, Tuomainen TP, Sander D, Plichart M, Catapano AL, Robertson CM, Kiechl S, Rundek T, Desvarieux M, Lind L, Schmid C, DasMahapatra P, Gao L, Ziegelbauer K, Bots ML, Thompson SG; PROG-IMT Study Group.
Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project): a meta-analysis of individual participant data.
Lancet. 2012 Jun 2;379(9831):2053-62. doi: 10.1016/S0140-6736(12)60441-3. Epub 2012 Apr 27.
Abstract/Text
BACKGROUND: Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association.
METHODS: We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis.
FINDINGS: Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02).
INTERPRETATION: The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials.
FUNDING: Deutsche Forschungsgemeinschaft.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, Engström G, Evans GW, de Graaf J, Grobbee DE, Hedblad B, Hofman A, Holewijn S, Ikeda A, Kavousi M, Kitagawa K, Kitamura A, Koffijberg H, Lonn EM, Lorenz MW, Mathiesen EB, Nijpels G, Okazaki S, O'Leary DH, Polak JF, Price JF, Robertson C, Rembold CM, Rosvall M, Rundek T, Salonen JT, Sitzer M, Stehouwer CD, Witteman JC, Moons KG, Bots ML.
Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.
JAMA. 2012 Aug 22;308(8):796-803. doi: 10.1001/jama.2012.9630.
Abstract/Text
CONTEXT: The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent.
OBJECTIVE: To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score.
DATA SOURCES: Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion.
STUDY SELECTION: Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke.
DATA EXTRACTION: Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease.
RESULTS: We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women.
CONCLUSION: The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.
福井次矢 ほか. ハイテク医療の中での身体診察. 日内会誌 1997; 86: 83-102.
van Baal J, Hubbard R, Game F, Jeffcoate W.
Mortality associated with acute Charcot foot and neuropathic foot ulceration.
Diabetes Care. 2010 May;33(5):1086-9. doi: 10.2337/dc09-1428. Epub 2010 Feb 25.
Abstract/Text
OBJECTIVE: To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFUs).
RESEARCH DESIGN AND METHODS: Data were extracted from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFUs managed from 1980. Finally, the results of all patients with acute Charcot foot and all control subjects managed between 1980 and 2007 were compared with normative mortality data for the U.K. population.
RESULTS: A total of 70 patients presented with an acute Charcot foot (mean age 57.4 +/- 12.0 years; 48 male [68.6%]) between 2001 and 2007; there were 66 matched control subjects. By 1 October 2008, 13 (eight male; 18.6%) patients with a Charcot foot had died, after a median of 2.1 years (interquartile range 1.1-3.3). Twenty-two (20 male; 33.3%) control subjects had also died after a median of 1.3 years (0.6-2.5). There was no difference in survival between the two groups (log-rank P > 0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 years (4.0-15.4) and was not significantly different from the control NFU patients (8.43 years [3.4-15.8]). When compared with normative U.K. population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively.
CONCLUSIONS: These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly high.
Iversen MM, Tell GS, Riise T, Hanestad BR, Østbye T, Graue M, Midthjell K.
History of foot ulcer increases mortality among individuals with diabetes: ten-year follow-up of the Nord-Trøndelag Health Study, Norway.
Diabetes Care. 2009 Dec;32(12):2193-9. doi: 10.2337/dc09-0651. Epub 2009 Sep 3.
Abstract/Text
OBJECTIVE: To compare mortality rates for individuals with diabetes with and without a history of foot ulcer (HFU) and with that for the nondiabetic population.
RESEARCH DESIGN AND METHODS: This population-based study included 155 diabetic individuals with an HFU, 1,339 diabetic individuals without an HFU, and 63,632 nondiabetic individuals who were all followed for 10 years with mortality as the end point.
RESULTS: During the follow-up period, a total of 49.0% of diabetic individuals with an HFU died, compared with 35.2% of diabetic individuals without an HFU and 10.5% of those without diabetes. In Cox regression analyses adjusted for age, sex, education, current smoking, and waist circumference, having an HFU was associated with more than a twofold (2.29 [95% CI 1.82-2.88]) hazard risk for mortality compared with that of the nondiabetic group. In corresponding analyses comparing diabetic individuals with and without an HFU, an HFU was associated with 47% increased mortality (1.47 [1.14-1.89]). Significant covariates were older age, male sex, and current smoking. After inclusion of A1C, insulin use, microalbuminuria, cardiovascular disease, and depression scores in the model, each was significantly related to life expectancy.
CONCLUSIONS: AN HFU increased mortality risk among community-dwelling adults and elderly individuals with diabetes. The excess risk persisted after adjustment for comorbidity and depression scores, indicating that close clinical monitoring might be warranted among individuals with an HFU, who may be particularly vulnerable to adverse outcomes.
Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman R, Kirkman MS, Lavery LA, Lemaster JW, Mills JL Sr, Mueller MJ, Sheehan P, Wukich DK; American Diabetes Association; American Association of Clinical Endocrinologists.
Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association, with endorsement by the American Association of Clinical Endocrinologists.
Diabetes Care. 2008 Aug;31(8):1679-85. doi: 10.2337/dc08-9021.
Abstract/Text
Kanji JN, Anglin RE, Hunt DL, Panju A.
Does this patient with diabetes have large-fiber peripheral neuropathy?
JAMA. 2010 Apr 21;303(15):1526-32. doi: 10.1001/jama.2010.428.
Abstract/Text
CONTEXT: Diabetic peripheral neuropathy predisposes patients to foot ulceration that heals poorly and too often leads to amputation. Large-fiber peripheral neuropathy (LFPN), one common form of diabetic neuropathy, when detected early prompts aggressive measures to prevent progression to foot ulceration and its associated morbidity and mortality.
OBJECTIVE: To systematically review the literature to determine the clinical examination findings predictive of asymptomatic LFPN before foot ulceration develops.
DATA SOURCES, STUDY SELECTION, AND DATA EXTRACTION: MEDLINE (January 1966-November 2009) and EMBASE (1980-2009 [week 50]) databases were searched for articles on bedside diagnosis of diabetic peripheral neuropathy. Included studies compared elements of history or physical examination with nerve conduction testing as the reference standard.
DATA SYNTHESIS: Of 1388 articles, 9 on diagnostic accuracy and 3 on precision met inclusion criteria. The prevalence of diabetic LFPN ranged from 23% to 79%. A score greater than 4 on a symptom questionnaire developed by the Italian Society of Diabetology increases the likelihood of LFPN (likelihood ratio [LR], 4.0; 95% confidence interval [CI], 2.9-5.6; negative LR, 0.19; 95% CI, 0.10-0.38). The most useful examination findings were vibration perception with a 128-Hz tuning fork (LR range, 16-35) and pressure sensation with a 5.07 Semmes-Weinstein monofilament (LR range, 11-16). Normal results on vibration testing (LR range, 0.33-0.51) or monofilament (LR range, 0.09-0.54) make LFPN less likely. Combinations of signs did not perform better than these 2 individual findings.
CONCLUSIONS: Physical examination is most useful in evaluating for LFPN in patients with diabetes. Abnormal results on monofilament testing and vibratory perception (alone or in combination with the appearance of the feet, ulceration, and ankle reflexes) are the most helpful signs.
Dros J, Wewerinke A, Bindels PJ, van Weert HC.
Accuracy of monofilament testing to diagnose peripheral neuropathy: a systematic review.
Ann Fam Med. 2009 Nov-Dec;7(6):555-8. doi: 10.1370/afm.1016.
Abstract/Text
PURPOSE: We wanted to summarize evidence about the diagnostic accuracy of the 5.07/10-g monofilament test in peripheral neuropathy.
METHODS: We conducted a systematic review of studies in which the accuracy of the 5.07/10-g monofilament was evaluated to detect peripheral neuropathy of any cause using nerve conduction as reference standard. Methodological quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool.
RESULTS: We reviewed 173 titles and abstracts of articles to identify 54 potentially eligible studies, of which 3 were finally selected for data synthesis. All studies were limited to patients with diabetes mellitus and showed limitations according to the QUADAS tool. Sensitivity ranged from 41% to 93% and specificity ranged from 68% to 100%. Because of the heterogenous nature of the studies, a meta-analysis could not be accomplished.
CONCLUSIONS: Despite the frequent use of monofilament testing, little can be said about the test accuracy for detecting neuropathy in feet without visible ulcers. Optimal test application and defining a threshold should have priority in evaluating monofilament testing, as this test is advocated in many clinical guidelines. Accordingly, we do not recommend the sole use of monofilament testing to diagnose peripheral neuropathy.
Perkins BA, Orszag A, Ngo M, Ng E, New P, Bril V.
Prediction of incident diabetic neuropathy using the monofilament examination: a 4-year prospective study.
Diabetes Care. 2010 Jul;33(7):1549-54. doi: 10.2337/dc09-1835. Epub 2010 Mar 31.
Abstract/Text
OBJECTIVE: To determine the specific monofilament examination score that predicts the subsequent 4-year incidence of diabetic neuropathy with the highest degree of diagnostic accuracy.
RESEARCH DESIGN AND METHODS: Longitudinal follow-up of 175 of 197 (89%) participants in the Toronto Diabetic Neuropathy Cohort without baseline neuropathy for incident neuropathy. We examined the baseline monofilament examination score (and other simple sensory screening tests) by receiver operating characteristic (ROC) curve analysis.
RESULTS: Incident diabetic neuropathy developed in 50 (29%) participants over a mean follow-up of 4.1 years (interquartile range 2.6-7.1 years). Although male sex, longer diabetes duration, taller height, and higher blood pressure at baseline were associated with incident neuropathy, the strongest association was with a lower baseline monofilament score (score out of 8 was 3.7 +/- 2.5 for incident neuropathy vs. 5.7 +/- 2.3 for those who did not develop neuropathy; P < 0.001). The optimal threshold score for risk of incident neuropathy was CONCLUSIONS: A simple threshold of
日本糖尿病学会糖尿病診断基準に関する調査検討委員会. 糖尿病の分類と診断基準に関する委員会報告（国際標準化対応版）.糖尿病 2012; 55: 485-504.
CDC：National diabetes fact sheet：national estimates and generali nformation on diabetes and prediabetes in the United States：11, 2011.
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Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group.
Lancet. 1998 Sep 12;352(9131):837-53.
Abstract/Text
BACKGROUND: Improved blood-glucose control decreases the progression of diabetic microvascular disease, but the effect on macrovascular complications is unknown. There is concern that sulphonylureas may increase cardiovascular mortality in patients with type 2 diabetes and that high insulin concentrations may enhance atheroma formation. We compared the effects of intensive blood-glucose control with either sulphonylurea or insulin and conventional treatment on the risk of microvascular and macrovascular complications in patients with type 2 diabetes in a randomised controlled trial.
METHODS: 3867 newly diagnosed patients with type 2 diabetes, median age 54 years (IQR 48-60 years), who after 3 months' diet treatment had a mean of two fasting plasma glucose (FPG) concentrations of 6.1-15.0 mmol/L were randomly assigned intensive policy with a sulphonylurea (chlorpropamide, glibenclamide, or glipizide) or with insulin, or conventional policy with diet. The aim in the intensive group was FPG less than 6 mmol/L. In the conventional group, the aim was the best achievable FPG with diet alone; drugs were added only if there were hyperglycaemic symptoms or FPG greater than 15 mmol/L. Three aggregate endpoints were used to assess differences between conventional and intensive treatment: any diabetes-related endpoint (sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous haemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hyperglycaemia or hypoglycaemia, and sudden death); all-cause mortality. Single clinical endpoints and surrogate subclinical endpoints were also assessed. All analyses were by intention to treat and frequency of hypoglycaemia was also analysed by actual therapy.
FINDINGS: Over 10 years, haemoglobin A1c (HbA1c) was 7.0% (6.2-8.2) in the intensive group compared with 7.9% (6.9-8.8) in the conventional group--an 11% reduction. There was no difference in HbA1c among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21, p=0.029) for any diabetes-related endpoint; 10% lower (-11 to 27, p=0.34) for any diabetes-related death; and 6% lower (-10 to 20, p=0.44) for all-cause mortality. Most of the risk reduction in the any diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40, p=0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin). Patients in the intensive group had more hypoglycaemic episodes than those in the conventional group on both types of analysis (both p<0.0001). The rates of major hypoglycaemic episodes per year were 0.7% with conventional treatment, 1.0% with chlorpropamide, 1.4% with glibenclamide, and 1.8% with insulin. Weight gain was significantly higher in the intensive group (mean 2.9 kg) than in the conventional group (p<0.001), and patients assigned insulin had a greater gain in weight (4.0 kg) than those assigned chlorpropamide (2.6 kg) or glibenclamide (1.7 kg).
INTERPRETATION: Intensive blood-glucose control by either sulphonylureas or insulin substantially decreases the risk of microvascular complications, but not macrovascular disease, in patients with type 2 diabetes.(ABSTRACT TRUNCATED)
Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M.
Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.
Diabetes Res Clin Pract. 1995 May;28(2):103-17. doi: 10.1016/0168-8227(95)01064-k.
Abstract/Text
To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications, we performed a prospective study of Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) treated with multiple insulin injection treatment. A total of 110 patients with NIDDM was randomly assigned to multiple insulin injection treatment group (MIT group) or to conventional insulin injection treatment group (CIT group). Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary-prevention cohort, and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary-intervention cohort. The appearance and the progression of retinopathy, nephropathy and neuropathy were evaluated every 6 months over a 6-year period. The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages (normoalbuminuria, microalbuminuria and albuminuria) for nephropathy. The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7% for the MIT group and 32.0% for the CIT group in the primary-prevention cohort (P = 0.039), and 19.2% for MIT group and 44.0% for CIT group in the secondary-intervention cohort (P = 0.049). The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7% for the MIT group and 28.0% for the CIT group in the primary-prevention cohort (P = 0.032), and 11.5% and 32.0%, respectively, for the MIT and CIT groups in the secondary-intervention cohort (P = 0.044). In neurological tests after 6 years, MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group, they deteriorated in the CIT group. In conclusion, intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy, nephropathy and neuropathy in Japanese patients with NIDDM. From this study, the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows; HbA1c < 6.5%, FBG < 110 mg/dl, and 2-h post-prandial blood glucose concentration < 180 mg/dl.
UK Prospective Diabetes Study Group.
Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.
BMJ. 1998 Sep 12;317(7160):703-13.
Abstract/Text
OBJECTIVE: To determine whether tight control of blood pressure prevents macrovascular and microvascular complications in patients with type 2 diabetes.
DESIGN: Randomised controlled trial comparing tight control of blood pressure aiming at a blood pressure of <150/85 mm Hg (with the use of an angiotensin converting enzyme inhibitor captopril or a beta blocker atenolol as main treatment) with less tight control aiming at a blood pressure of <180/105 mm Hg.
SETTING: 20 hospital based clinics in England, Scotland, and Northern Ireland.
SUBJECTS: 1148 hypertensive patients with type 2 diabetes (mean age 56, mean blood pressure at entry 160/94 mm Hg); 758 patients were allocated to tight control of blood pressure and 390 patients to less tight control with a median follow up of 8.4 years.
MAIN OUTCOME MEASURES: Predefined clinical end points, fatal and non-fatal, related to diabetes, deaths related to diabetes, and all cause mortality. Surrogate measures of microvascular disease included urinary albumin excretion and retinal photography.
RESULTS: Mean blood pressure during follow up was significantly reduced in the group assigned tight blood pressure control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P<0.0001). Reductions in risk in the group assigned to tight control compared with that assigned to less tight control were 24% in diabetes related end points (95% confidence interval 8% to 38%) (P=0.0046), 32% in deaths related to diabetes (6% to 51%) (P=0.019), 44% in strokes (11% to 65%) (P=0.013), and 37% in microvascular end points (11% to 56%) (P=0.0092), predominantly owing to a reduced risk of retinal photocoagulation. There was a non-significant reduction in all cause mortality. After nine years of follow up the group assigned to tight blood pressure control also had a 34% reduction in risk in the proportion of patients with deterioration of retinopathy by two steps (99% confidence interval 11% to 50%) (P=0.0004) and a 47% reduced risk (7% to 70%) (P=0.004) of deterioration in visual acuity by three lines of the early treatment of diabetic retinopathy study (ETDRS) chart. After nine years of follow up 29% of patients in the group assigned to tight control required three or more treatments to lower blood pressure to achieve target blood pressures.
CONCLUSION: Tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity.
Patel A; ADVANCE Collaborative Group; MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, Glasziou P, Grobbee DE, Hamet P, Heller S, Liu LS, Mancia G, Mogensen CE, Pan CY, Rodgers A, Williams B.
Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial.
Lancet. 2007 Sep 8;370(9590):829-40. doi: 10.1016/S0140-6736(07)61303-8.
Abstract/Text
BACKGROUND: Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes, and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension. We assessed the effects of the routine administration of an angiotensin converting enzyme (ACE) inhibitor-diuretic combination on serious vascular events in patients with diabetes, irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs.
METHODS: The trial was done by 215 collaborating centres in 20 countries. After a 6-week active run-in period, 11 140 patients with type 2 diabetes were randomised to treatment with a fixed combination of perindopril and indapamide or matching placebo, in addition to current therapy. The primary endpoints were composites of major macrovascular and microvascular events, defined as death from cardiovascular disease, non-fatal stroke or non-fatal myocardial infarction, and new or worsening renal or diabetic eye disease, and analysis was by intention-to-treat. The macrovascular and microvascular composites were analysed jointly and separately. This trial is registered with ClinicalTrials.gov, number NCT00145925.
FINDINGS: After a mean of 4.3 years of follow-up, 73% of those assigned active treatment and 74% of those assigned control remained on randomised treatment. Compared with patients assigned placebo, those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg. The relative risk of a major macrovascular or microvascular event was reduced by 9% (861 [15.5%] active vs 938 [16.8%] placebo; hazard ratio 0.91, 95% CI 0.83-1.00, p=0.04). The separate reductions in macrovascular and microvascular events were similar but were not independently significant (macrovascular 0.92; 0.81-1.04, p=0.16; microvascular 0.91; 0.80-1.04, p=0.16). The relative risk of death from cardiovascular disease was reduced by 18% (211 [3.8%] active vs 257 [4.6%] placebo; 0.82, 0.68-0.98, p=0.03) and death from any cause was reduced by 14% (408 [7.3%] active vs 471 [8.5%] placebo; 0.86, 0.75-0.98, p=0.03). There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline.
INTERPRETATION: Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events, including death. Although the confidence limits were wide, the results suggest that over 5 years, one death due to any cause would be averted among every 79 patients assigned active therapy.
Sano T, Hotta N, Kawamura T, Matsumae H, Chaya S, Sasaki H, Nakayama M, Hara T, Matsuo S, Sakamoto N.
Effects of long-term enalapril treatment on persistent microalbuminuria in normotensive type 2 diabetic patients: results of a 4-year, prospective, randomized study.
Diabet Med. 1996 Feb;13(2):120-4. doi: 10.1002/(SICI)1096-9136(199602)13:2<120::AID-DIA6>3.0.CO;2-F.
Abstract/Text
The beneficial effect of long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor on urinary microalbumin excretion (UAE) and renal function was investigated in a 4 year, randomized prospective study in normotensive patients with non-insulin-dependent (Type 2) diabetes mellitus. Sixty-two normotensive patients with Type 2 diabetes mellitus and microalbuminuria but normal renal function were randomized to receive either enalapril 5 mg day-1 or no treatment. In the enalapril-treated patients, UAE was reduced from 115.4 +/- 80.1 to 95.6 +/- 61.7 mg 24 h-1 after 12 months (p < 0.05) and to 75.3 +/- 44.8 mg 24 h-1 after 48 months (p < 0.001). In the untreated group, UAE increased slowly from 93.9 +/- 69.9 to 150.0 +/- 144.5 mg 24 h-1 after 48 months. No changes in creatinine clearance, blood pressure or HbA1C were seen in either group during the 4-year period. In normotensive Type 2 diabetic patients with early stage of diabetic microalbuminuria. This effect is long-lasting and probably independent of the antihypertensive action of the drug.
Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M.
Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients.
Ann Intern Med. 1993 Apr 15;118(8):577-81. doi: 10.7326/0003-4819-118-8-199304150-00001.
Abstract/Text
OBJECTIVE: To evaluate the long-term effect of angiotensin-converting enzyme inhibition on proteinuria and on the rate of decline in kidney function in patients with type II diabetes mellitus and microalbuminuria.
DESIGN: Randomized, double-blind, placebo-controlled trial. Each patient was followed for 5 years.
SETTING: Six clinics for diabetes mellitus coordinated by a department of medicine in a university hospital in Israel.
PATIENTS: Ninety-four normotensive, type II diabetic patients with microalbuminuria and normal renal function.
INTERVENTION: The patients were randomly assigned to receive enalapril, 10 mg per day, or placebo. Any increase in blood pressure was treated with long-acting nifedipine.
MEASUREMENTS: Albuminuria, blood pressure, serum creatinine, fasting blood glucose, and glycosylated hemoglobin levels, every 3 to 4 months.
RESULTS: In the patients treated with enalapril, albuminuria decreased from 143 +/- 64 (mean +/- SD) mg/24 h to 122 +/- 67 mg/24 h during the first year. Thereafter, we observed a slow increase to 140 +/- 134 mg/24 h after 5 years. In the placebo group, albuminuria increased from 123 +/- 58 mg/24 h to 310 +/- 167 mg/24 h after 5 years. (Difference in rate of change in proteinuria [P < 0.05]). Kidney function (expressed as mean reciprocal creatinine) declined by 13% in the placebo group and remained stable (-1%) in the enalapril group (P < 0.05). Control of blood glucose levels remained stable, in both groups, throughout the study. The mean blood pressure was stable in the enalapril group (initial group mean, 99 +/- 2.1 mm Hg; fifth-year mean, 100 +/- 3.2 mm Hg) and increased in the placebo group from an initial mean value of 97 +/- 3.2 mm Hg to 102 +/- 3.4 mm Hg at the end of the study period (P = 0.082).
CONCLUSIONS: In normotensive patients with diabetes mellitus type II, the institution of angiotensin-converting enzyme inhibition during early stages of diabetic nephropathy results in long-term stabilization of plasma creatinine levels and of the degree of urinary loss of albumin. These effects are probably independent of the antihypertensive action of these agents.
Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R.
Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial.
Ann Intern Med. 1998 Jun 15;128(12 Pt 1):982-8. doi: 10.7326/0003-4819-128-12_part_1-199806150-00004.
Abstract/Text
BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitors attenuate the decline in renal function in diabetic patients with microalbuminuria. However, no data are available on the use of ACE inhibitors to prevent the decrease in renal function in normotensive, normoalbuminuric patients with type 2 diabetes.
OBJECTIVE: To evaluate the effect of prolonged ACE inhibition on renal function and albuminuria in patients with type 2 diabetes.
DESIGN: Randomized, double-blind, placebo-controlled trial with 6-year follow-up.
SETTING: Eight outpatient clinics coordinated by a department of medicine in a university hospital.
PATIENTS: 156 patients in whom type 2 diabetes was diagnosed after 40 years of age who had a baseline mean blood pressure less than 107 mm Hg and albuminuria (albumin excretion < or = 30 mg/24 h).
INTERVENTION: Enalapril, 10 mg/d, or placebo.
MEASUREMENTS: Degree of albuminuria at 24 hours, creatinine clearance, blood pressure, and hemoglobin A1c values.
RESULTS: Enalapril therapy decreased albumin excretion from a mean +/- SD of 11.6 +/- 7 mg/24 h to 9.7 +/- 6 mg/24 h at 2 years. This was followed by a gradual increase to 15.8 +/- 8 mg/24 h at 6 years. In the placebo group, albumin excretion increased from 10.8 +/- 8 mg/24 h to 26.5 +/- 10 mg/24 h at 6 years (P = 0.001 for enalapril compared with placebo). Transition to microalbuminuria occurred in 15 of 79 (19%) placebo recipients and 5 of 77 (6.5%) enalapril recipients. Enalapril treatment resulted in an absolute risk reduction of 12.5% (95% CI, 2% to 23%; P = 0.042) for development of microalbuminuria. After 6 years, creatinine clearance decreased from 1.78 +/- 0.13 mL/s to 1.63 +/- 0.12 mL/s (mean decrease, 0.025 mL/s per year) in enalapril recipients and from 1.81 +/- 0.15 mL/s to 1.57 +/- 0.17 mL/s (mean decrease, 0.04 mL/s per year) in placebo recipients (P = 0.040). Hemoglobin A1c values decreased modestly in both groups. Mean blood pressure remained normal (< 107 mm Hg) in all patients.
CONCLUSIONS: Enalapril attenuated the decline in renal function and reduced the extent of albuminuria in normotensive, normoalbuminuric patients with type 2 diabetes. Further research is needed to determine whether this treatment forestalls the development of overt nephropathy.
Sano T, Kawamura T, Matsumae H, Sasaki H, Nakayama M, Hara T, Matsuo S, Hotta N, Sakamoto N.
Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients.
Diabetes Care. 1994 May;17(5):420-4. doi: 10.2337/diacare.17.5.420.
Abstract/Text
OBJECTIVE: To determine whether long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor has a beneficial effect on the urinary microalbumin excretion and renal function in non-insulin-dependent diabetes mellitus (NIDDM) patients, enalapril (5 mg/day) was administered for 48 months.
RESEARCH DESIGN AND METHODS: -Fifty-two patients with NIDDM who had persistent microalbuminuria in the range of 20-300 mg/24 h, serum creatinine < 106.1 microM (1.2 mg/dl), supine systolic blood pressure (BP) < 150 mmHg, supine diastolic BP < 90 mmHg, and HbA1c < 10% were divided into four groups. Twenty-six patients with normotension were divided at random into two groups; one group received enalapril (5 mg/day) (NE group), the other did not receive enalapril (NC group). In the same way, 26 other patients who were already well-controlled with nifedipine (30 mg/day) over a long-term period (4-6 years) were divided at random into two groups; one received enalapril (5 mg/day) (HE group), the other did not receive enalapril (HC group).
RESULTS: After 48 months, urinary albumin excretion (UAE) was markedly reduced in group NE from 102.4 x/divided by 1.3 to 55.5 x/divided by 1.3 mg/24 h (P < 0.005), whereas no significant change occurred in group NC. In the well-controlled hypertensive groups, a significant reduction in UAE occurred in group HE (P < 0.05), whereas no significant change occurred in group HC. No changes in creatinine clearance, BP, or blood glucose control were seen during the study.
CONCLUSIONS: Treatment with enalapril for 48 months may have a beneficial effect on the decline of microalbumin excretion in NIDDM patients.
Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, Joseph A, Kolkhof P, Nowack C, Schloemer P, Ruilope LM; FIGARO-DKD Investigators.
Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.
N Engl J Med. 2021 Dec 9;385(24):2252-2263. doi: 10.1056/NEJMoa2110956. Epub 2021 Aug 28.
Abstract/Text
BACKGROUND: Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear.
METHODS: In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m2 of body-surface area (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of at least 60 ml per minute per 1.73 m2 (stage 1 or 2 CKD). Patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary outcome, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome was a composite of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR, or death from renal causes. Safety was assessed as investigator-reported adverse events.
RESULTS: A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%).
CONCLUSIONS: Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD ClinicalTrials.gov number, NCT02545049.).
Copyright © 2021 Massachusetts Medical Society.
Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, Kolkhof P, Nowack C, Schloemer P, Joseph A, Filippatos G; FIDELIO-DKD Investigators.
Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes.
N Engl J Med. 2020 Dec 3;383(23):2219-2229. doi: 10.1056/NEJMoa2025845. Epub 2020 Oct 23.
Abstract/Text
BACKGROUND: Finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, reduced albuminuria in short-term trials involving patients with chronic kidney disease (CKD) and type 2 diabetes. However, its long-term effects on kidney and cardiovascular outcomes are unknown.
METHODS: In this double-blind trial, we randomly assigned 5734 patients with CKD and type 2 diabetes in a 1:1 ratio to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300, an estimated glomerular filtration rate (eGFR) of 25 to less than 60 ml per minute per 1.73 m2 of body-surface area, and diabetic retinopathy, or they had a urinary albumin-to-creatinine ratio of 300 to 5000 and an eGFR of 25 to less than 75 ml per minute per 1.73 m2. All the patients were treated with renin-angiotensin system blockade that had been adjusted before randomization to the maximum dose on the manufacturer's label that did not cause unacceptable side effects. The primary composite outcome, assessed in a time-to-event analysis, was kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes. The key secondary composite outcome, also assessed in a time-to-event analysis, was death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure.
RESULTS: During a median follow-up of 2.6 years, a primary outcome event occurred in 504 of 2833 patients (17.8%) in the finerenone group and 600 of 2841 patients (21.1%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.93; P = 0.001). A key secondary outcome event occurred in 367 patients (13.0%) and 420 patients (14.8%) in the respective groups (hazard ratio, 0.86; 95% CI, 0.75 to 0.99; P = 0.03). Overall, the frequency of adverse events was similar in the two groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone than with placebo (2.3% and 0.9%, respectively).
CONCLUSIONS: In patients with CKD and type 2 diabetes, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo. (Funded by Bayer; FIDELIO-DKD ClinicalTrials.gov number, NCT02540993.).
Copyright © 2020 Massachusetts Medical Society.
Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL.
Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial.
Lancet. 2009 Oct 10;374(9697):1252-61. doi: 10.1016/S0140-6736(09)61081-3. Epub 2009 Sep 30.
Abstract/Text
BACKGROUND: Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone.
METHODS: In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0-10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636.
FINDINGS: 45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to 5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1 to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious adverse events were recorded for any patients during the trial.
INTERPRETATION: Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain.
FUNDING: Canadian Institutes of Health Research.
Boyle J, Eriksson ME, Gribble L, Gouni R, Johnsen S, Coppini DV, Kerr D.
Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life.
Diabetes Care. 2012 Dec;35(12):2451-8. doi: 10.2337/dc12-0656. Epub 2012 Sep 18.
Abstract/Text
OBJECTIVE: Chronic diabetic peripheral neuropathic pain (DPNP) is difficult to treat, with treatment regimens often inadequate at controlling pain and limited by side effects and drug tolerance. Secondary parameters, such as quality of sleep and mood, may also be important for successful DPNP management. The objectives of this study were to compare the analgesic efficacy of pregabalin, amitriptyline, and duloxetine, and their effect on polysomnographic sleep, daytime functioning, and quality of life in patients with DPNP.
RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, parallel group investigation of type 1 and 2 diabetic subjects with DPNP. Each treatment group had a single-blind, 8-day, placebo run-in followed by 14 days of lower-dose and 14 days of higher-dose medication. At the end of each dose titration period, subjective pain, sleep, and daytime functioning were assessed during a 2-day residential period.
RESULTS: All medications reduced pain when compared with placebo, but no one treatment was superior to any other. For sleep, pregabalin improved sleep continuity (P < 0.001), whereas duloxetine increased wake and reduced total sleep time (P < 0.01 and P < 0.001). Despite negative effects on sleep, duloxetine enhanced central nervous system arousal and performance on sensory motor tasks. There were no significant safety findings; however, there was a significantly higher number of adverse events in the pregabalin treatment group.
CONCLUSIONS: There was no significant difference in analgesic efficacy between amitriptyline, duloxetine, and pregabalin. However, there were significant differences in the secondary parameters, which may be of relevance when deciding the optimal treatment for DPNP.
Freeman R, Durso-Decruz E, Emir B.
Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses.
Diabetes Care. 2008 Jul;31(7):1448-54. doi: 10.2337/dc07-2105. Epub 2008 Mar 20.
Abstract/Text
OBJECTIVE: To evaluate the efficacy, safety, and tolerability of pregabalin across the effective dosing range, to determine differences in the efficacy of three times daily (TID) versus twice daily (BID) dosage schedules, and to use time-to-event analysis to determine the time to onset of a sustained therapeutic effect using data from seven trials of pregabalin in painful diabetic peripheral neuropathy (DPN).
RESEARCH DESIGN AND METHODS: Data were pooled across seven double-blind, randomized, placebo-controlled trials using pregabalin to treat painful DPN with dosages of 150, 300, and 600 mg/day administered TID or BID. Only one trial included all three of these dosages, and TID dosing was used in four. All studies shared fundamental selection criteria, and treatment durations ranged from 5 to 13 weeks.
RESULTS: Pooled analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day administered TID vs. placebo, all P < or = 0.007). Only the 600 mg/day dosage showed efficacy when administered BID (P < or = 0.001). Pain and sleep interference reductions associated with pregabalin appear to be positively correlated with dosage; the greatest effect was observed in patients treated with 600 mg/day. Kaplan-Meier analysis revealed that the median time to onset of a sustained (> or =30% at end point) 1-point improvement was 4 days in patients treated with pregabalin at 600 mg/day, 5 days in patients treated with pregabalin at 300 mg/day, 13 days in patients treated with pregabalin at 150 mg/day, and 60 days in patients receiving placebo. The most common treatment-emergent adverse events were dizziness, somnolence, and peripheral edema.
CONCLUSIONS: Treatment with pregabalin across its effective dosing range is associated with significant, dose-related improvement in pain in patients with DPN.
Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, Feldman E, Iverson DJ, Perkins B, Russell JW, Zochodne D; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation.
Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation.
Neurology. 2011 May 17;76(20):1758-65. doi: 10.1212/WNL.0b013e3182166ebe. Epub 2011 Apr 11.
Abstract/Text
OBJECTIVE: To develop a scientifically sound and clinically relevant evidence-based guideline for the treatment of painful diabetic neuropathy (PDN).
METHODS: We performed a systematic review of the literature from 1960 to August 2008 and classified the studies according to the American Academy of Neurology classification of evidence scheme for a therapeutic article, and recommendations were linked to the strength of the evidence. The basic question asked was: "What is the efficacy of a given treatment (pharmacologic: anticonvulsants, antidepressants, opioids, others; and nonpharmacologic: electrical stimulation, magnetic field treatment, low-intensity laser treatment, Reiki massage, others) to reduce pain and improve physical function and quality of life (QOL) in patients with PDN?"
RESULTS AND RECOMMENDATIONS: Pregabalin is established as effective and should be offered for relief of PDN (Level A). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, and oxycodone controlled-release), and capsaicin are probably effective and should be considered for treatment of PDN (Level B). Other treatments have less robust evidence or the evidence is negative. Effective treatments for PDN are available, but many have side effects that limit their usefulness, and few studies have sufficient information on treatment effects on function and QOL.
Satoh J, Yagihashi S, Baba M, Suzuki M, Arakawa A, Yoshiyama T, Shoji S.
Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial.
Diabet Med. 2011 Jan;28(1):109-16. doi: 10.1111/j.1464-5491.2010.03152.x.
Abstract/Text
AIMS: To evaluate the efficacy, safety and pharmacokinetics of pregabalin in treating neuropathic pain associated with diabetic peripheral neuropathy in Japanese patients.
METHODS: A randomized, double-blind, placebo-controlled, multicentre 14 week clinical trial was conducted. Japanese patients with diabetic peripheral neuropathy (n = 317) were randomized to receive placebo or pregabalin at 300 or 600 mg/day. The primary efficacy measure was a change of mean pain score from baseline to end-point from patients' daily pain diaries.
RESULTS: Significant reductions in pain were observed in patients treated with pregabalin at 300 and 600 mg/day vs. placebo (P < 0.05). Improvements in weekly pain scores were observed as early as week 1 and were sustained throughout the study period (300 and 600 mg/day difference from placebo at study end-point, -0.63 and -0.74, respectively). Pregabalin produced significant improvements in weekly sleep interference scores, the short-form McGill Pain Questionnaire, the Medical Outcomes Study-Sleep Scale, the 36-item Short-Form Health Survey scale, and the Patient and Clinical Global Impression of Change. Patient impressions of numbness, pain and paraesthesia were also significantly improved. Regarding treatment responders, 29.1 and 35.6% of patients treated with 300 and 600 mg/day, respectively, reported ≥ 50% improvement in mean pain scores (vs. 21.5% for placebo). Pregabalin was well tolerated; somnolence (26%), dizziness (24%), peripheral oedema (13%) and weight gain (11%) were the most common adverse events and generally were reported as mild to moderate.
CONCLUSIONS: Pregabalin was effective in reducing pain and improving sleep disturbances due to pain, and was well tolerated in Japanese patients with painful DPN.
© 2010 The Authors. Diabetic Medicine © 2010 Diabetes UK.
Yasuda H, Hotta N, Nakao K, Kasuga M, Kashiwagi A, Kawamori R.
Superiority of duloxetine to placebo in improving diabetic neuropathic pain: Results of a randomized controlled trial in Japan.
J Diabetes Investig. 2011 Apr 7;2(2):132-9. doi: 10.1111/j.2040-1124.2010.00073.x.
Abstract/Text
UNLABELLED: Aims/Introduction: Duloxetine has been suggested to exert analgesic effects by activating the descending inhibitory system through inhibition of serotonin (5-HT) and noradrenaline (NA) reuptake. This randomized controlled trial investigated the efficacy and safety of duloxetine in Japanese patients with diabetic neuropathic pain (DNP).
MATERIALS AND METHODS: Duloxetine 40 or 60 mg/day or placebo was given orally once daily for 12 weeks. The primary efficacy measure was weekly mean 24-h average pain severity score on the 11-point Numerical Rating Scale.
RESULTS: At 12 weeks vs baseline, the 24-h average pain score (adjusted mean ± SE) was significantly improved in the combined duloxetine (-2.47 ± 0.18) and duloxetine 40 mg (-2.41 ± 0.21) and 60 mg groups (-2.53 ± 0.21) as compared with the placebo group (-1.61 ± 0.18). Duloxetine also exerted significant improvements over the placebo in nearly all secondary outcome measures including 24-h worst pain, night pain, Brief Pain Inventory (BPI) pain scores, Patient's Global Impression of Improvement (PGI-I) and health outcome measures, namely, various BPI interference scores. The incidence of adverse events (AE) was higher in the duloxetine groups than in the placebo group (duloxetine overall, 84.8%; duloxetine 40 mg, 84.7%; duloxetine 60 mg, 84.9%; placebo, 73.7%). Most AE were mild or moderate in severity, and resolved or relieved. There were no clinically significant safety concerns.
CONCLUSIONS: Duloxetine 40 or 60 mg/day showed superiority over the placebo at reducing pain scores in patients with DNP. Duloxetine is safe, efficacious and clinically useful in the management of DNP. This trial was registered with ClinicalTrials.gov (no. NCT-00552175). (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00073.x, 2010).
Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R.
Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy.
N Engl J Med. 1992 May 7;326(19):1250-6. doi: 10.1056/NEJM199205073261904.
Abstract/Text
BACKGROUND: Amitriptyline reduces the pain caused by peripheral-nerve disease, but treatment is often limited by side effects related to the drug's many pharmacologic actions. Selective agents might be safer and more effective.
METHODS: We carried out two randomized, double-blind, crossover studies in patients with painful diabetic neuropathy, comparing amitriptyline with the relatively selective blocker of norepinephrine reuptake desipramine in 38 patients, and comparing the selective blocker of serotonin reuptake fluoxetine with placebo in 46 patients. Fifty-seven patients were randomly assigned to a study as well as to the order of treatment, permitting comparison among all three drugs and placebo as the first treatment. The patients rated the degree of pain present each day using verbal descriptors, and they also assessed the extent of pain relief globally at the end of each treatment period.
RESULTS: After individual dose titration, the mean daily doses of the drugs were as follows: amitriptyline, 105 mg; desipramine, 111 mg; and fluoxetine, 40 mg. There was moderate or greater relief of pain in 28 of the 38 patients (74 percent) who received amitriptyline, 23 of the 38 patients (61 percent) who received desipramine, 22 of the 46 patients (48 percent) who received fluoxetine, and 19 of the 46 patients (41 percent) who received placebo. The differences in responses between amitriptyline and desipramine and between fluoxetine and placebo were not statistically significant, but both amitriptyline and desipramine were superior to placebo. Amitriptyline and desipramine were as effective in patients who were not depressed as in depressed patients, but fluoxetine was effective only in depressed patients.
CONCLUSIONS: Desipramine relieves pain caused by diabetic neuropathy with efficacy similar to that of amitriptyline, offering an alternative for patients unable to tolerate the latter. Blockade of norepinephrine reuptake is likely to mediate the analgesic effect of these antidepressant drugs in diabetic neuropathy. Fluoxetine, which blocks serotonin uptake, is no more effective than placebo for the relief of pain.
Wong MC, Chung JW, Wong TK.
Effects of treatments for symptoms of painful diabetic neuropathy: systematic review.
BMJ. 2007 Jul 14;335(7610):87. doi: 10.1136/bmj.39213.565972.AE. Epub 2007 Jun 11.
Abstract/Text
OBJECTIVE: To evaluate the effects of treatments for the symptoms of painful diabetic neuropathy.
DESIGN: Systematic review.
DATA SOURCES: Articles (English and full text) on double blind randomised trials found by searching with the key words anticonvulsant, antidepressant, non-steroidal anti-inflammatory drugs, tramadol, opioid, ion channel blocker, diabetic neuropathy, diabetic peripheral neuropathy, peripheral neuropathy, and neuropathy. The search included Medline, Embase, EMB reviews-AP Journal club, and the Cochrane central register of controlled trials.
STUDY SELECTION: Randomised controlled trials comparing topically applied and orally administered drugs with a placebo in adults with painful diabetic neuropathy.
DATA EXTRACTION: Data were extracted to examine quality of methods, characteristics of studies and patients, efficacy, and side effects. The primary outcome was dichotomous information for 50% or moderate reduction of pain. Secondary outcomes were 30% reduction of pain and withdrawals related to adverse events.
RESULTS: Odds ratios were calculated for achievement of 30%, 50%, or moderate pain relief and for withdrawals related to adverse effects. Twenty five reports were included and seven were excluded. The 25 included reports compared anticonvulsants (n=1270), antidepressants (94), opioids (329), ion channel blockers (173), N-methyl-D-aspartate antagonist (14), duloxetine (805), capsaicin (277), and isosorbide dinitrate spray (22) with placebo. The odds ratios in terms of 50% pain relief were 5.33 (95% confidence interval 1.77 to 16.02) for traditional anticonvulsants, 3.25 (2.27 to 4.66) for newer generation anticonvulsants, and 22.24 (5.83 to 84.75) for tricylic antidepressants. The odds ratios in terms of withdrawals related to adverse events were 1.51 (0.33 to 6.96) for traditional anticonvulsants, 2.98 (1.75 to 5.07) for newer generation anticonvulsants, and 2.32 (0.59 to 9.69) for tricylic antidepressants. Insufficient dichotomous data were available to calculate the odds ratios for ion channel blockers.
CONCLUSION: Anticonvulsants and antidepressants are still the most commonly used options to manage diabetic neuropathy. Oral tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants. Evidence of the long term effects of oral antidepressants and anticonvulsants is still lacking. Further studies are needed on opioids, N-methyl-D-aspartate antagonists, and ion channel blockers.
McQuay H, Carroll D, Jadad AR, Wiffen P, Moore A.
Anticonvulsant drugs for management of pain: a systematic review.
BMJ. 1995 Oct 21;311(7012):1047-52. doi: 10.1136/bmj.311.7012.1047.
Abstract/Text
OBJECTIVE: To determine effectiveness and adverse effects of anticonvulsant drugs in management of pain.
DESIGN: Systematic review of randomised controlled trials of anticonvulsants for acute, chronic, or cancer pain identified by using Medline, by hand searching, by searching reference lists, and by contacting investigators.
SUBJECTS: Between 1966 and February 1994, 37 reports were found; 20 reports, of four anticonvulsants, were eligible.
MAIN OUTCOME MEASURES: Numbers needed to treat were calculated for effectiveness, adverse effects, and drug related withdrawal from study.
RESULTS: The only placebo controlled study in acute pain found no analgesic effect of sodium valproate. For treating trigeminal neuralgia, carbamazepine had a combined number needed to treat of 2.6 for effectiveness, 3.4 for adverse effects, and 24 for severe effects (withdrawal from study). For treating diabetic neuropathy, anticonvulsants had a combined number needed to treat of 2.5 for effectiveness, 3.1 for adverse effects, and 20 for severe effects. For migraine prophylaxis, anticonvulsants had a combined number needed to treat of 1.6 for effectiveness, 2.4 for adverse effects, and 39 for severe effects. Phenytoin had no effect on the irritable bowel syndrome, and carbamazepine had little effect on pain after stroke. Clonazepam was effective in one study for temporomandibular joint dysfunction. No study compared one anticonvulsant with another.
CONCLUSIONS: Anticonvulsants were effective for trigeminal neuralgia and diabetic neuropathy and for migraine prophylaxis. Minor adverse effects occurred as often as benefit.
Tahmoush AJ, Alonso RJ, Tahmoush GP, Heiman-Patterson TD.
Cramp-fasciculation syndrome: a treatable hyperexcitable peripheral nerve disorder.
Neurology. 1991 Jul;41(7):1021-4. doi: 10.1212/wnl.41.7.1021.
Abstract/Text
We report nine patients with muscle aching, cramps, stiffness, exercise intolerance, and peripheral nerve hyperexcitability. Neurologic examination showed calf fasciculations in seven, quadriceps myokymia in two, and deltoid myokymia in one patient. Two patients had mild increase in serum creatine kinase. Muscle biopsy showed either no abnormality (three patients) or mild neurogenic changes (four patients). Fasciculations were the only abnormality on routine electrodiagnostic studies. Supramaximal stimulation of the median, ulnar, peroneal, and posterior tibial nerves at frequencies of 0.5, 1, 2, and 5 Hz produced showers of electrical potentials following the M response in at least one nerve. In three patients, the fasciculations and evoked electrical potentials were abolished by regional application of curare but not nerve block. Carbamazepine therapy caused moderate-to-marked reduction of symptoms and nerve hyperexcitability. We designate this hyperexcitable peripheral nerve disorder as the "cramp-fasciculation syndrome."
Chan JC, Wat NM, So WY, Lam KS, Chua CT, Wong KS, Morad Z, Dickson TZ, Hille D, Zhang Z, Cooper ME, Shahinfar S, Brenner BM, Kurokawa K; Asian RENAAL Study Investigators.
Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study.
Diabetes Care. 2004 Apr;27(4):874-9. doi: 10.2337/diacare.27.4.874.
Abstract/Text
OBJECTIVE: Asia is predicted to have the largest population of patients with diabetes who are at high risk for renal disease. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, approximately 17% of patients were Asians. In this subgroup analysis, we examined the characteristics, response, and adherence to treatment of the Asian population, as well as their baseline predictors of risk of renal end points.
RESEARCH DESIGN AND METHODS: A total of 252 Asian patients were enrolled in the RENAAL study, which compared losartan (50 mg titrated to 100 mg) to placebo in addition to conventional antihypertensive medications in type 2 diabetic patients with nephropathy. Mean follow-up was 3.2 years. The effect of losartan therapy on renal and cardiovascular outcomes was examined, and baseline predictors of risk were determined using a Cox proportional hazards model with prespecified baseline covariates.
RESULTS: Losartan reduced the risk of the primary composite end point composed of a doubling of serum creatinine, end-stage renal disease, or all-cause mortality in Asian patients by 35% (P = 0.02). No difference between losartan and placebo was observed for the cardiovascular composite outcomes. Losartan reduced the level of proteinuria by 47% (P < 0.001) and rate of decrease in renal function by 31% (0.0074). Discontinuations were lower in the losartan-treated patients. The strongest baseline predictors of risk of renal end points were proteinuria (hazard ratio 1.42, P < 0.0001) and low Hb (0.81, P < 0.0001).
CONCLUSIONS: In this subgroup analysis of the RENAAL study, losartan conferred significant renal benefits and was well tolerated in Asian patients with type 2 diabetes and clinical nephropathy. Baseline proteinuria and low Hb were strong predictors of risk of renal outcomes.
Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators.
Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
N Engl J Med. 2001 Sep 20;345(12):861-9. doi: 10.1056/NEJMoa011161.
Abstract/Text
BACKGROUND: Diabetic nephropathy is the leading cause of end-stage renal disease. Interruption of the renin-angiotensin system slows the progression of renal disease in patients with type 1 diabetes, but similar data are not available for patients with type 2, the most common form of diabetes. We assessed the role of the angiotensin-II-receptor antagonist losartan in patients with type 2 diabetes and nephropathy.
METHODS: A total of 1513 patients were enrolled in this randomized, double-blind study comparing losartan (50 to 100 mg once daily) with placebo, both taken in addition to conventional antihypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers, and centrally acting agents), for a mean of 3.4 years. The primary outcome was the composite of a doubling of the base-line serum creatinine concentration, end-stage renal disease, or death. Secondary end points included a composite of morbidity and mortality from cardiovascular causes, proteinuria, and the rate of progression of renal disease.
RESULTS: A total of 327 patients in the losartan group reached the primary end point, as compared with 359 in the placebo group (risk reduction, 16 percent; P=0.02). Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25 percent; P=0.006) and end-stage renal disease (risk reduction, 28 percent; P=0.002) but had no effect on the rate of death. The benefit exceeded that attributable to changes in blood pressure. The composite of morbidity and mortality from cardiovascular causes was similar in the two groups, although the rate of first hospitalization for heart failure was significantly lower with losartan (risk reduction, 32 percent; P=0.005). The level of proteinuria declined by 35 percent with losartan (P<0.001 for the comparison with placebo).
CONCLUSIONS: Losartan conferred significant renal benefits in patients with type 2 diabetes and nephropathy, and it was generally well tolerated.
Cheng J, Zhang W, Zhang X, Han F, Li X, He X, Li Q, Chen J.
Effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysis.
JAMA Intern Med. 2014 May;174(5):773-85. doi: 10.1001/jamainternmed.2014.348.
Abstract/Text
IMPORTANCE: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may have different effects on cardiovascular (CV) events in patients with diabetes mellitus (DM).
OBJECTIVE: To conduct a meta-analysis to separately evaluate the effects of ACEIs and ARBs on all-cause mortality, CV deaths, and major CV events in patients with DM. DATA SOURCES Data sources included MEDLINE (1966-2012), EMBASE (1988-2012), the Cochrane Central Register of Controlled Trials, conference proceedings, and article reference lists.
STUDY SELECTION: We included randomized clinical trials reporting the effects of ACEI and ARB regimens for DM on all-cause mortality, CV deaths, and major CV events with an observation period of at least 12 months. Studies were excluded if they were crossover trials.
DATA EXTRACTION AND SYNTHESIS: Dichotomous outcome data from individual trials were analyzed using the risk ratio (RR) measure and its 95% CI with random-effects models. We estimated the difference between the estimates of the subgroups according to tests for interaction. We performed meta-regression analyses to identify sources of heterogeneity.
MAIN OUTCOMES AND MEASURES: Primary end points were all-cause mortality and death from CV causes. Secondary end points were the effects of ACEIs and ARBs on major CV events.
RESULTS: Twenty-three of 35 identified trials compared ACEIs with placebo or active drugs (32,827 patients) and 13 compared ARBs with no therapy (controls) (23,867 patients). When compared with controls (placebo/active treatment), ACEIs significantly reduced the risk of all-cause mortality by 13% (RR, 0.87; 95% CI, 0.78-0.98), CV deaths by 17% (0.83; 0.70-0.99), and major CV events by 14% (0.86; 0.77-0.95), including myocardial infarction by 21% (0.79; 0.65-0.95) and heart failure by 19% (0.81; 0.71-0.93). Treatment with ARBs did not significantly affect all-cause mortality (RR, 0.94; 95% CI, 0.82-1.08), CV death rate (1.21; 0.81-1.80), and major CV events (0.94; 0.85-1.01) with the exception of heart failure (0.70; 0.59-0.82). Both ACEIs and ARBs were not associated with a decrease in the risk for stroke in patients with DM. Meta-regression analysis showed that the ACEI treatment effect on all-cause mortality and CV death did not vary significantly with the starting baseline blood pressure and proteinuria of the trial participants and the type of ACEI and DM.
CONCLUSIONS AND RELEVANCE: Angiotensin-converting enzyme inhibitors reduced all-cause mortality, CV mortality, and major CV events in patients with DM, whereas ARBs had no benefits on these outcomes. Thus, ACEIs should be considered as first-line therapy to limit excess mortality and morbidity in this population.
Lindholm LH, Ibsen H, Dahlöf B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristiansson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman J, Snapinn S; LIFE Study Group.
Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol.
Lancet. 2002 Mar 23;359(9311):1004-10. doi: 10.1016/S0140-6736(02)08090-X.
Abstract/Text
BACKGROUND: The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear. In prespecified analyses, we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients.
METHODS: As part of the LIFE study, in a double-masked, randomised, parallel-group trial, we assigned a group of 1195 patients with diabetes, hypertension, and signs of left-ventricular hypertrophy (LVH) on electrocardiograms losartan-based or atenolol-based treatment. Mean age of patients was 67 years (SD 7) and mean blood pressure 177/96 mm Hg (14/10) after placebo run-in. We followed up patients for at least 4 years (mean 4.7 years [1.1]). We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myocardial infarction).
FINDINGS: Mean blood pressure fell to 146/79 mm Hg (17/11) in losartan patients and 148/79 mm Hg (19/11) in atenolol patients. The primary endpoint occurred in 103 patients assigned losartan (n=586) and 139 assigned atenolol (n=609); relative risk 0.76 (95% CI 0.58-.98), p=0.031. 38 and 61 patients in the losartan and atenolol groups, respectively, died from cardiovascular disease; 0.63 (0.42-0.95), p=0.028. Mortality from all causes was 63 and 104 in losartan and atenolol groups, respectively; 0.61 (0.45-0.84), p=0.002.
INTERPRETATION: Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and LVH. Losartan seems to have benefits beyond blood pressure reduction.
Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group.
MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial.
Lancet. 2003 Jun 14;361(9374):2005-16. doi: 10.1016/s0140-6736(03)13636-7.
Abstract/Text
BACKGROUND: Individuals with diabetes are at increased risk of cardiovascular morbidity and mortality, although typically their plasma concentrations of LDL cholesterol are similar to those in the general population. Previous evidence about the effects of lowering cholesterol in people with diabetes has been limited, and most diabetic patients do not currently receive cholesterol-lowering therapy despite their increased risk.
METHODS: 5963 UK adults (aged 40-80 years) known to have diabetes, and an additional 14573 with occlusive arterial disease (but no diagnosed diabetes), were randomly allocated to receive 40 mg simvastatin daily or matching placebo. Prespecified analyses in these prior disease subcategories, and other relevant subcategories, were of first major coronary event (ie, non-fatal myocardial infarction or coronary death) and of first major vascular event (ie, major coronary event, stroke or revascularisation). Analyses were also conducted of subsequent vascular events during the scheduled treatment period. Comparisons are of all simvastatin-allocated versus all placebo-allocated participants (ie, intention to treat), which yielded an average difference in LDL cholesterol of 1.0 mmol/L (39 mg/dL) during the 5-year treatment period.
FINDINGS: Both among the participants who presented with diabetes and among those who did not, there were highly significant reductions of about a quarter in the first event rate for major coronary events, for strokes, and for revascularisations. For the first occurrence of any of these major vascular events among participants with diabetes, there was a definite 22% (95% CI 13-30) reduction in the event rate (601 [20.2%] simvastatin-allocated vs 748 [25.1%] placebo-allocated, p<0.0001), which was similar to that among the other high-risk individuals studied. There were also highly significant reductions of 33% (95% CI 17-46, p=0.0003) among the 2912 diabetic participants who did not have any diagnosed occlusive arterial disease at entry, and of 27% (95% CI 13-40, p=0.0007) among the 2426 diabetic participants whose pretreatment LDL cholesterol concentration was below 3.0 mmol/L (116 mg/dL). The proportional reduction in risk was also about a quarter among various other subcategories of diabetic patient studied, including: those with different duration, type, or control of diabetes; those aged over 65 years at entry or with hypertension; and those with total cholesterol below 5.0 mmol/L (193 mg/dL). In addition, among participants who had a first major vascular event following randomisation, allocation to simvastatin reduced the rate of subsequent events during the scheduled treatment period.
INTERPRETATION: The present study provides direct evidence that cholesterol-lowering therapy is beneficial for people with diabetes even if they do not already have manifest coronary disease or high cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rate of first major vascular events by about a quarter in a wide range of diabetic patients studied. After making allowance for non-compliance, actual use of this statin regimen would probably reduce these rates by about a third. For example, among the type of diabetic patient studied without occlusive arterial disease, 5 years of treatment would be expected to prevent about 45 people per 1000 from having at least one major vascular event (and, among these 45 people, to prevent about 70 first or subsequent events during this treatment period). Statin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations.
Pyŏrälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G.
Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. A subgroup analysis of the Scandinavian Simvastatin Survival Study (4S).
Diabetes Care. 1997 Apr;20(4):614-20. doi: 10.2337/diacare.20.4.614.
Abstract/Text
OBJECTIVE: To assess in diabetic patients with coronary heart disease (CHD) the effect of cholesterol lowering with simvastatin on mortality and the risk of CHD and other atherosclerotic events.
RESEARCH DESIGN AND METHODS: A post hoc subgroup analysis was carried out on data from 202 diabetic patients and 4,242 nondiabetic patients with previous myocardial infarction or angina pectoris, serum total cholesterol 5.5-8.0 mmol/l, and serum triglycerides < or = 2.5 mmol/l who were participating in the Scandinavian Simvastatin Survival Study (4S). Participants in the 4S were randomly assigned to double-blind treatment with simvastatin, 20 mg daily, with blinded dosage titration up to 40 mg daily, according to cholesterol response during the first 6-18 weeks, or placebo. Endpoints were 1) total mortality, 2) major CHD events (CHD death or nonfatal myocardial infarction), 3) other acute atherosclerotic events, 4) myocardial revascularization procedures.
RESULTS: Over the 5.4-year median follow-up period, simvastatin treatment produced mean changes in serum lipids in diabetic patients similar to those observed in nondiabetic patients. The relative risks (RRs) of main endpoints in simvastatin-treated diabetic patients were as follows: total mortality 0.57 (95% CI, 0.30-1.08; P = 0.087), major CHD events 0.45 (95% CI, 0.27-0.74; P = 0.002), and any atherosclerotic event 0.63 (95% CI, 0.43-0.92; P = 0.018). The corresponding RRs in nondiabetic patients were the following: 0.71 (95% CI, 0.58-0.87; P = 0.001), 0.68 (95% CI, 0.60-0.77; P < 0.0001), and 0.74 (95% CI, 0.68-0.82; P < 0.0001).
CONCLUSIONS: The results strongly suggest that cholesterol lowering with simvastatin improves the prognosis of diabetic patients with CHD. The absolute clinical benefit achieved by cholesterol lowering may be greater in diabetic than in nondiabetic patients with CHD because diabetic patients have a higher absolute risk of recurrent CHD events and other atherosclerotic events.
Naci H, Brugts J, Ades T.
Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246 955 participants from 135 randomized, controlled trials.
Circ Cardiovasc Qual Outcomes. 2013 Jul;6(4):390-9. doi: 10.1161/CIRCOUTCOMES.111.000071. Epub 2013 Jul 9.
Abstract/Text
BACKGROUND: Our objective was to estimate the comparative harms of individual statins using both placebo-controlled and active-comparator trials.
METHODS AND RESULTS: We systematically reviewed randomized trials evaluating different statins in participants with and without cardiovascular disease. We performed random-effects pairwise and network meta-analyses to quantify the relative harms of individual statins. We included 55 two-armed placebo-controlled and 80 two- or multiarmed active-comparator trials including 246,955 individuals. According to pairwise meta-analyses, individual statins were not different than control in terms of myalgia, creatine kinase elevation, cancer, and discontinuations because of adverse events. Statins as a class resulted in significantly higher odds of diabetes mellitus (odds ratio, 1.09; 95% confidence interval, 1.02-1.16) and transaminase elevations (odds ratio, 1.51; 95% confidence interval, 1.24-1.84) compared with control. When individual statins were compared in network meta-analyses, there were numerous statistically detectable differences, favoring simvastatin and pravastatin. According to dose-level comparisons, individual statins resulted in higher odds of discontinuations with higher doses of atorvastatin and rosuvastatin. Similarly, higher doses of atorvasatin, fluvastatin, lovastatin, and simvastatin were associated with higher odds of transaminase elevations. Simvastatin at its highest doses was associated with creatine kinase elevations (odds ratio, 4.14; 95% credible interval, 1.08-16.24). Meta-regression analyses adjusting for study-level age at baseline, low-density lipoprotein cholesterol level, and publication year did not explain heterogeneity. There was no detectable inconsistency in the network.
CONCLUSIONS: As a class, adverse events associated with statin therapy are not common. Statins are not associated with cancer risk but do result in a higher odds of diabetes mellitus. Among individual statins, simvastatin and pravastatin seem safer and more tolerable than other statins.
ACCORD Study Group; Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC Jr, Cushman WC, Simons-Morton DG, Byington RP.
Effects of combination lipid therapy in type 2 diabetes mellitus.
N Engl J Med. 2010 Apr 29;362(17):1563-74. doi: 10.1056/NEJMoa1001282. Epub 2010 Mar 14.
Abstract/Text
BACKGROUND: We investigated whether combination therapy with a statin plus a fibrate, as compared with statin monotherapy, would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease.
METHODS: We randomly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo. The primary outcome was the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The mean follow-up was 4.7 years.
RESULTS: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (hazard ratio in the fenofibrate group, 0.92; 95% confidence interval [CI], 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (hazard ratio, 0.91; 95% CI, 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol (P=0.057 for interaction).
CONCLUSIONS: The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes. (ClinicalTrials.gov number, NCT00000620.)
2010 Massachusetts Medical Society
Ueki K, Sasako T, Okazaki Y, Kato M, Okahata S, Katsuyama H, Haraguchi M, Morita A, Ohashi K, Hara K, Morise A, Izumi K, Ishizuka N, Ohashi Y, Noda M, Kadowaki T; J-DOIT3 Study Group.
Effect of an intensified multifactorial intervention on cardiovascular outcomes and mortality in type 2 diabetes (J-DOIT3): an open-label, randomised controlled trial.
Lancet Diabetes Endocrinol. 2017 Dec;5(12):951-964. doi: 10.1016/S2213-8587(17)30327-3. Epub 2017 Oct 24.
Abstract/Text
BACKGROUND: Limited evidence suggests that multifactorial interventions for control of glucose, blood pressure, and lipids reduce macrovascular complications and mortality in patients with type 2 diabetes. However, safe and effective treatment targets for these risk factors have not been determined for such interventions.
METHODS: In this multicentre, open-label, randomised, parallel-group trial, undertaken at 81 clinical sites in Japan, we randomly assigned (1:1) patients with type 2 diabetes aged 45-69 years with hypertension, dyslipidaemia, or both, and an HbA1c of 6·9% (52·0 mmol/mol) or higher, to receive conventional therapy for glucose, blood pressure, and lipid control (targets: HbA1c <6·9% [52·0 mmol/mol], blood pressure <130/80 mm Hg, LDL cholesterol <120 mg/dL [or 100 mg/dL in patients with a history of coronary artery disease]) or intensive therapy (HbA1c <6·2% [44·3 mmol/mol], blood pressure <120/75 mm Hg, LDL cholesterol <80 mg/dL [or 70 mg/dL in patients with a history of coronary artery disease]). Randomisation was done using a computer-generated, dynamic balancing method, stratified by sex, age, HbA1c, and history of cardiovascular disease. Neither patients nor investigators were masked to group assignment. The primary outcome was occurrence of any of a composite of myocardial infarction, stroke, revascularisation (coronary artery bypass surgery, percutaneous transluminal coronary angioplasty, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting), and all-cause mortality. The primary analysis was done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00300976.
FINDINGS: Between June 16, 2006, and March 31, 2009, 2542 eligible patients were randomly assigned to intensive therapy or conventional therapy (1271 in each group) and followed up for a median of 8·5 years (IQR 7·3-9·0). Two patients in the intensive therapy group were found to be ineligible after randomisation and were excluded from the analyses. During the intervention period, mean HbA1c, systolic blood pressure, diastolic blood pressure, and LDL cholesterol concentrations were significantly lower in the intensive therapy group than in the conventional therapy group (6·8% [51·0 mmol/mol] vs 7·2% [55·2 mmol/mol]; 123 mm Hg vs 129 mm Hg; 71 mm Hg vs 74 mm Hg; and 85 mg/dL vs 104 mg/dL, respectively; all p<0·0001). The primary outcome occurred in 109 patients in the intensive therapy group and in 133 patients in the conventional therapy group (hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·094). In a post-hoc breakdown of the composite outcome, frequencies of all-cause mortality (HR 1·01, 95% CI 0·68-1·51; p=0·95) and coronary events (myocardial infarction, coronary artery bypass surgery, and percutaneous transluminal coronary angioplasty; HR 0·86, 0·58-1·27; p=0·44) did not differ between groups, but cerebrovascular events (stroke, carotid endarterectomy, percutaneous transluminal cerebral angioplasty, and carotid artery stenting) were significantly less frequent in the intensive therapy group (HR 0·42, 0·24-0·74; p=0·002). Apart from non-severe hypoglycaemia (521 [41%] patients in the intensive therapy group vs 283 [22%] in the conventional therapy group, p<0·0001) and oedema (193 [15%] vs 129 [10%], p=0·0001), the frequencies of major adverse events did not differ between groups.
INTERPRETATION: Our results do not fully support the efficacy of further intensified multifactorial intervention compared with current standard care for the prevention of a composite of coronary events, cerebrovascular events, and all-cause mortality. Nevertheless, our findings suggest a potential benefit of an intensified intervention for the prevention of cerebrovascular events in patients with type 2 diabetes.
FUNDING: Ministry of Health, Labour and Welfare of Japan, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Kissei Pharmaceutical, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, MSD, Novartis Pharma, Novo Nordisk, Ono Pharmaceutical, Pfizer, Sanwa Kagaku Kenkyusho, Shionogi, Sumitomo Dainippon Pharma, Taisho Toyama Pharmaceutical, and Takeda.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews DR, Holman RR.
Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23).
BMJ. 1998 Mar 14;316(7134):823-8. doi: 10.1136/bmj.316.7134.823.
Abstract/Text
OBJECTIVE: To evaluate baseline risk factors for coronary artery disease in patients with type 2 diabetes mellitus.
DESIGN: A stepwise selection procedure, adjusting for age and sex, was used in 2693 subjects with complete data to determine which risk factors for coronary artery disease should be included in a Cox proportional hazards model.
SUBJECTS: 3055 white patients (mean age 52) with recently diagnosed type 2 diabetes mellitus and without evidence of disease related to atheroma. Median duration of follow up was 7.9 years. 335 patients developed coronary artery disease within 10 years.
OUTCOME MEASURES: Angina with confirmatory abnormal electrocardiogram; non-fatal and fatal myocardial infarction.
RESULTS: Coronary artery disease was significantly associated with increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, and increased triglyceride concentration, haemoglobin A1c, systolic blood pressure, fasting plasma glucose concentration, and a history of smoking. The estimated hazard ratios for the upper third relative to the lower third were 2.26 (95% confidence interval 1.70 to 3.00) for low density lipoprotein cholesterol, 0.55 (0.41 to 0.73) for high density lipoprotein cholesterol, 1.52 (1.15 to 2.01) for haemoglobin A1c, and 1.82 (1.34 to 2.47) for systolic blood pressure. The estimated hazard ratio for smokers was 1.41 (1.06 to 1.88).
CONCLUSION: A quintet of potentially modifiable risk factors for coronary artery disease exists in patients with type 2 diabetes mellitus. These risk factors are increased concentrations of low density lipoprotein cholesterol, decreased concentrations of high density lipoprotein cholesterol, raised blood pressure, hyperglycaemia, and smoking.
Cholesterol Treatment Trialists' (CTT) Collaborators; Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C.
Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.
Lancet. 2008 Jan 12;371(9607):117-25. doi: 10.1016/S0140-6736(08)60104-X.
Abstract/Text
BACKGROUND: Although statin therapy reduces the risk of occlusive vascular events in people with diabetes mellitus, there is uncertainty about the effects on particular outcomes and whether such effects depend on the type of diabetes, lipid profile, or other factors. We undertook a prospective meta-analysis to help resolve these uncertainties.
METHODS: We analysed data from 18 686 individuals with diabetes (1466 with type 1 and 17,220 with type 2) in the context of a further 71,370 without diabetes in 14 randomised trials of statin therapy. Weighted estimates were obtained of effects on clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol.
FINDINGS: During a mean follow-up of 4.3 years, there were 3247 major vascular events in people with diabetes. There was a 9% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol in participants with diabetes (rate ratio [RR] 0.91, 99% CI 0.82-1.01; p=0.02), which was similar to the 13% reduction in those without diabetes (0.87, 0.82-0.92; p<0.0001). This finding reflected a significant reduction in vascular mortality (0.87, 0.76-1.00; p=0.008) and no effect on non-vascular mortality (0.97, 0.82-1.16; p=0.7) in participants with diabetes. There was a significant 21% proportional reduction in major vascular events per mmol/L reduction in LDL cholesterol in people with diabetes (0.79, 0.72-0.86; p<0.0001), which was similar to the effect observed in those without diabetes (0.79, 0.76-0.82; p<0.0001). In diabetic participants there were reductions in myocardial infarction or coronary death (0.78, 0.69-0.87; p<0.0001), coronary revascularisation (0.75, 0.64-0.88; p<0.0001), and stroke (0.79, 0.67-0.93; p=0.0002). Among people with diabetes the proportional effects of statin therapy were similar irrespective of whether there was a prior history of vascular disease and irrespective of other baseline characteristics. After 5 years, 42 (95% CI 30-55) fewer people with diabetes had major vascular events per 1000 allocated statin therapy.
INTERPRETATION: Statin therapy should be considered for all diabetic individuals who are at sufficiently high risk of vascular events.
Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S, Kitagawa K, Kitakaze M, Kitazono T, Kurabayashi M, Miyauchi K, Murakami T, Murohara T, Node K, Ogawa S, Saito Y, Seino Y, Shigeeda T, Shindo S, Sugawara M, Sugiyama S, Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K, Yamagishi M, Yamazaki T, Yo S, Yokote K, Yoshida K, Yoshimura M, Yoshimura N, Nakao K, Nagai R; EMPATHY Investigators.
Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study.
Diabetes Care. 2018 Jun;41(6):1275-1284. doi: 10.2337/dc17-2224. Epub 2018 Apr 6.
Abstract/Text
OBJECTIVE: Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach).
RESEARCH DESIGN AND METHODS: In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524).
RESULTS: Mean follow-up was 37 ± 13 months. LDL-C at 36 months was 76.5 ± 21.6 mg/dL in the intensive group and 104.1 ± 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups.
CONCLUSIONS: We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation.
© 2018 by the American Diabetes Association.
葛谷健，中川昌一，佐藤譲ほか：糖尿病の分類と診断基準に関する委員会報告．糖尿病42：385-404,1999.
Kawasaki R, Tanaka S, Tanaka S, Yamamoto T, Sone H, Ohashi Y, Akanuma Y, Yamada N, Yamashita H; Japan Diabetes Complications Study Group.
Incidence and progression of diabetic retinopathy in Japanese adults with type 2 diabetes: 8 year follow-up study of the Japan Diabetes Complications Study (JDCS).
Diabetologia. 2011 Sep;54(9):2288-94. doi: 10.1007/s00125-011-2199-0. Epub 2011 Jun 1.
Abstract/Text
AIMS/HYPOTHESIS: The aim of this study was to determine the incidence and progression rates of diabetic retinopathy and their associations in Japanese individuals with type 2 diabetes.
METHODS: This is a part of the Japan Diabetic Complications Study (JDCS), a multi-centred randomised trial of type 2 diabetes patients aged 40-70 years with an 8 year follow-up. There were 1,221 patients without diabetic retinopathy at baseline; incidence of diabetic retinopathy was defined as the development of any diabetic retinopathy. There were 410 patients with mild non-proliferative diabetic retinopathy at baseline; progression of diabetic retinopathy was defined as the development of severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy. We used multivariate proportional Cox hazard models, and generalised additive models were also applied to identify potential threshold effect.
RESULTS: The incidence and progression rate of diabetic retinopathy was 38.3/1,000 person-years and 21.1/1,000 person-years, respectively. Higher HbA(1c) (adjusted HR [aHR] per 1% [10.9 mmol/mol] 1.36 [95% CI 1.28-1.45]), longer duration of diabetes (aHR per 5 year period 1.26 [95% CI 1.17-1.35]), higher systolic blood pressure (aHR per +10 mmHg 1.01 [95% CI 1.00-1.02]) and higher body mass index (aHR per 1 kg/m(2) 1.05 [95% CI 1.00-1.09]) were associated with incident diabetic retinopathy. The association between HbA(1c) and incident diabetic retinopathy was linear; the association with duration of diabetes increased rapidly between 5 and 10 years. Higher HbA(1c) was also associated with progression of diabetic retinopathy (aHR per 1% [10.9 mmol/mol] 1.66 [95% CI 1.41-1.96]).
CONCLUSIONS: Observed incidence and progression rates of diabetic retinopathy seemed lower than that in western populations. HbA(1c) was the only factor associated with both incidence and progression of diabetic retinopathy. The strength of the association between duration of diabetes and incidence of diabetic retinopathy increased rapidly during a period of 5 to 10 years duration of diabetes.
TRIAL REGISTRATION: C000000222 ( www.umin.ac.jp )
FUNDING: This study is supported by the Ministry of Health, Labour and Welfare, Japan.
Molitch ME, DeFronzo RA, Franz MJ, Keane WF, Mogensen CE, Parving HH; American Diabetes Association.
Diabetic nephropathy.
Diabetes Care. 2003 Jan;26 Suppl 1:S94-8. doi: 10.2337/diacare.26.2007.s94.
Abstract/Text
Ritz E, Orth SR.
Nephropathy in patients with type 2 diabetes mellitus.
N Engl J Med. 1999 Oct 7;341(15):1127-33. doi: 10.1056/NEJM199910073411506.
Abstract/Text
Kim HC, Cho YJ, Ahn CW, Park KS, Kim JC, Nam JS, Im YS, Lee JE, Lee SC, Lee HK.
Nerve growth factor and expression of its receptors in patients with diabetic neuropathy.
Diabet Med. 2009 Dec;26(12):1228-34. doi: 10.1111/j.1464-5491.2009.02856.x.
Abstract/Text
AIMS: Low serum nerve growth factor (NGF) levels have been reported in patients with diabetic peripheral neuropathy (DPN), but the role of NGF in the development of neuropathy is unclear. Thus, we investigated the associations of serum NGF level and NGF receptor activity with the presence and severity of DPN.
METHODS: One hundred and thirty-six patients with Type 2 diabetes were included in this cross-sectional study. Serum NGF levels were measured by ELISA. Expressions of NGF receptors (TrkA and p75(NTR)) were measured by immunohistochemical staining. The presence and severity of DPN were assessed by neuropathy disability score (NDS) and by corneal nerve fibre length (cNFL) and nerve branch density (cNBD) using in vivo confocal microscopy.
RESULTS: Patients with DPN had higher serum NGF levels (56-451 pg/ml) than patients without DPN (4-54 pg/ml). However, in DPN patients, serum NGF was negatively associated with neuropathy severity (mild 222 +/- 64 pg/ml; moderate 114 +/- 17 pg/ml; severe 89 +/- 20 pg/ml). This negative association was consistent in all severity indices (NDS, P < 0.001; cNFL, P < 0.001; cNBD P = 0.010) even after adjustment for age, sex, diabetes duration, insulin use, fasting glucose and glycated haemoglobin. Although NGF receptor activities had significantly (P < 0.05) negative associations with the presence and severity of neuropathy, these associations were not significant when adjusted for other factors.
CONCLUSIONS: Serum NGF level was positively associated with the presence of DPN but negatively associated with neuropathy severity in DPN patients. The change in serum NGF might be a consequence of, rather than a contributor to, the early development of DPN.
Ellrodt G, Cook DJ, Lee J, Cho M, Hunt D, Weingarten S.
Evidence-based disease management.
JAMA. 1997 Nov 26;278(20):1687-92.
Abstract/Text
Disease management is an approach to patient care that emphasizes coordinated, comprehensive care along the continuum of disease and across health care delivery systems. Evidence-based medicine is an approach to practice and teaching that integrates pathophysiological rationale, caregiver experience, and patient preferences with valid and current clinical research evidence. Using diabetes mellitus as an example, we describe the importance of evidence-based medicine to the development of disease management programs. We present a method for developing and implementing evidence-based clinical guidelines, clinical pathways, and algorithms and describe the creation of systems to measure and report processes and outcomes that could drive quality improvement in diabetes care. Multidisciplinary teams are ideally suited to develop, lead, and implement evidence-based disease management programs, since they play an essential role in the preventive, diagnostic, and therapeutic decisions for patients with diabetes throughout the course of their disease.
Ismail-Beigi F.
Clinical practice. Glycemic management of type 2 diabetes mellitus.
N Engl J Med. 2012 Apr 5;366(14):1319-27. doi: 10.1056/NEJMcp1013127.
Abstract/Text
Riddle MC, Karl DM.
Individualizing targets and tactics for high-risk patients with type 2 diabetes: practical lessons from ACCORD and other cardiovascular trials.
Diabetes Care. 2012 Oct;35(10):2100-7. doi: 10.2337/dc12-0650.
Abstract/Text
Kirkman MS, Briscoe VJ, Clark N, Florez H, Haas LB, Halter JB, Huang ES, Korytkowski MT, Munshi MN, Odegard PS, Pratley RE, Swift CS.
Diabetes in older adults.
Diabetes Care. 2012 Dec;35(12):2650-64. doi: 10.2337/dc12-1801. Epub 2012 Oct 25.
Abstract/Text
Lipska KJ, Ross JS, Wang Y, Inzucchi SE, Minges K, Karter AJ, Huang ES, Desai MM, Gill TM, Krumholz HM.
National trends in US hospital admissions for hyperglycemia and hypoglycemia among Medicare beneficiaries, 1999 to 2011.
JAMA Intern Med. 2014 Jul;174(7):1116-24. doi: 10.1001/jamainternmed.2014.1824.
Abstract/Text
IMPORTANCE: The increasing intensity of diabetes mellitus management over the past decade may have resulted in lower rates of hyperglycemic emergencies but higher rates of hospital admissions for hypoglycemia among older adults. Trends in these hospitalizations and subsequent outcomes are not known.
OBJECTIVE: To characterize changes in hyperglycemia and hypoglycemia hospitalization rates and subsequent mortality and readmission rates among older adults in the United States over a 12-year period, and to compare these results according to age, sex, and race.
DESIGN, SETTING, AND PATIENTS: Retrospective observational study using data from 33,952,331 Medicare fee-for-service beneficiaries 65 years or older from 1999 to 2011.
MAIN OUTCOMES AND MEASURES: Hospitalization rates for hyperglycemia and hypoglycemia, 30-day and 1-year mortality rates, and 30-day readmission rates.
RESULTS: A total of 279,937 patients experienced 302,095 hospitalizations for hyperglycemia, and 404,467 patients experienced 429,850 hospitalizations for hypoglycemia between 1999 and 2011. During this time, rates of admissions for hyperglycemia declined by 38.6% (from 114 to 70 admissions per 100,000 person-years), while admissions for hypoglycemia increased by 11.7% (from 94 to 105 admissions per 100,000 person-years). In analyses designed to account for changing diabetes mellitus prevalence, admissions for hyperglycemia and hypoglycemia declined by 55.2% and 9.5%, respectively. Trends were similar across age, sex, and racial subgroups, but hypoglycemia rates were 2-fold higher for older patients (≥75 years) when compared with younger patients (65-74 years), and admission rates for both hyperglycemia and hypoglycemia were 4-fold higher for black patients compared with white patients. The 30-day and 1-year mortality and 30-day readmission rates improved during the study period and were similar after an index hospitalization for either hyperglycemia or hypoglycemia (5.4%, 17.1%, and 15.3%, respectively, after hyperglycemia hospitalizations in 2010; 4.4%, 19.9%, and 16.3% after hypoglycemia hospitalizations).
CONCLUSIONS AND RELEVANCE: Hospital admission rates for hypoglycemia now exceed those for hyperglycemia among older adults. Although admissions for hypoglycemia have declined modestly since 2007, rates among black Medicare beneficiaries and those older than 75 years remain high. Hospital admissions for severe hypoglycemia seem to pose a greater health threat than those for hyperglycemia, suggesting new opportunities for improvement in care of persons with diabetes mellitus.
Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N.
Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials.
Lancet. 2009 May 23;373(9677):1765-72. doi: 10.1016/S0140-6736(09)60697-8.
Abstract/Text
BACKGROUND: Whether intensive control of glucose reduces macrovascular events and all-cause mortality in individuals with type 2 diabetes mellitus is unclear. We undertook a meta-analysis of randomised controlled trials to determine whether intensive treatment is beneficial.
METHODS: We selected five prospective randomised controlled trials of 33 040 participants to assess the effect of an intensive glucose-lowering regimen on death and cardiovascular outcomes compared with a standard regimen. We gathered information about events of non-fatal myocardial infarction, coronary heart disease (fatal and non-fatal myocardial infarction), stroke, and all-cause mortality, and did a random-effects meta-analysis to obtain summary effect estimates for the clinical outcomes with use of odds ratios calculated from the raw data of every trial. Statistical heterogeneity across trials was assessed with the chi(2) and I(2) statistics.
FINDINGS: The five trials provided information on 1497 events of non-fatal myocardial infarction, 2318 of coronary heart disease, 1127 of stroke, and 2892 of all-cause mortality during about 163 000 person-years of follow-up. The mean haemoglobin A(1c) concentration (HbA(1c)) was 0.9% lower for participants given intensive treatment than for those given standard treatment. Intensive glycaemic control resulted in a 17% reduction in events of non-fatal myocardial infarction (odds ratio 0.83, 95% CI 0.75-0.93), and a 15% reduction in events of coronary heart disease (0.85, 0.77-0.93). Intensive glycaemic control had no significant effect on events of stroke (0.93, 0.81-1.06) or all-cause mortality (1.02, 0.87-1.19).
INTERPRETATION: Overall, intensive compared with standard glycaemic control significantly reduces coronary events without an increased risk of death. However, the optimum mechanism, speed, and extent of HbA(1c) reduction might be different in differing populations.
FUNDING: None.
Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassaï B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C.
Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials.
BMJ. 2011 Jul 26;343:d4169. doi: 10.1136/bmj.d4169. Epub 2011 Jul 26.
Abstract/Text
OBJECTIVE: To determine all cause mortality and deaths from cardiovascular events related to intensive glucose lowering treatment in people with type 2 diabetes.
DESIGN: Meta-analysis of randomised controlled trials.
DATA SOURCES: Medline, Embase, and the Cochrane database of systematic reviews.
STUDY SELECTION: Randomised controlled trials that assessed the effect of intensive glucose lowering treatment on cardiovascular events and microvascular complications in adults (≥ 18 years) with type 2 diabetes.
DATA EXTRACTION: Primary end points were all cause mortality and death from cardiovascular causes. Secondary end points were severe hypoglycaemia and macrovascular and microvascular events. Synthesis of results Results are reported as risk ratios with 99% confidence intervals. Statistical heterogeneity between trials was assessed with χ(2), τ(2), and I(2) statistics. A fixed effect model was used to assess the effect on the outcomes of intensive glucose lowering versus standard treatment. The quality of clinical trials was assessed by the Jadad score.
RESULTS: 13 studies were included. Of 34,533 patients, 18,315 received intensive glucose lowering treatment and 16,218 standard treatment. Intensive treatment did not significantly affect all cause mortality (risk ratio 1.04, 99% confidence interval 0.91 to 1.19) or cardiovascular death (1.11, 0.86 to 1.43). Intensive therapy was, however, associated with reductions in the risk of non-fatal myocardial infarction (0.85, 0.74 to 0.96, P<0.001), and microalbuminuria (0.90, 0.85 to 0.96, P<0.001) but a more than twofold increase in the risk of severe hypoglycaemia (2.33, 21.62 to 3.36, P<0.001). Over a treatment period of five years, 117 to 150 patients would need to be treated to avoid one myocardial infarction and 32 to 142 patients to avoid one episode of microalbuminuria, whereas one severe episode of hypoglycaemia would occur for every 15 to 52 patients. In analysis restricted to high quality studies (Jadad score >3), intensive treatment was not associated with any significant risk of reductions but resulted in a 47% increase in risk of congestive heart failure (P<0.001).
CONCLUSIONS: The overall results of this meta-analysis show limited benefits of intensive glucose lowering treatment on all cause mortality and deaths from cardiovascular causes. We cannot exclude a 9% reduction or a 19% increase in all cause mortality and a 14% reduction or a 43% increase in cardiovascular death. The benefit:risk ratio of intensive glucose lowering treatment in the prevention of macrovascular and microvascular events remains uncertain. The harm associated with severe hypoglycaemia might counterbalance the potential benefit of intensive glucose lowering treatment. More double blind randomised controlled trials are needed to establish the best therapeutic approach in people with type 2 diabetes.
Nathan DM, McGee P, Steffes MW, Lachin JM; DCCT/EDIC Research Group.
Relationship of glycated albumin to blood glucose and HbA1c values and to retinopathy, nephropathy, and cardiovascular outcomes in the DCCT/EDIC study.
Diabetes. 2014 Jan;63(1):282-90. doi: 10.2337/db13-0782. Epub 2013 Aug 29.
Abstract/Text
The association of chronic glycemia, measured by HbA(1c), with long-term complications of type 1 diabetes has been well established in the Diabetes Control and Complications Trial (DCCT) and other studies. The role of intermediate-term and acute glycemia and of glucose variability on microvascular and cardiovascular disease (CVD) is less clear. In order to examine the interrelationships among long-term, intermediate-term, and acute measures of glucose and its daily variability, we compared HbA(1c), glycated albumin (GA), and seven-point glucose profile concentrations measured longitudinally in a case-cohort subpopulation of the DCCT. HbA(1c) and GA were closely correlated with each other and with the mean blood glucose (MBG) calculated from the seven-point profile. The associations of glucose variability and postprandial concentrations with HbA(1c) and GA were relatively weak and were further attenuated when MBG was included in multivariate models. In the case-cohort analyses, HbA(1c) and GA had similar associations with retinopathy and nephropathy, which were strengthened when both measures were considered together. Only HbA(1c) was significantly associated with CVD. The demonstrated interrelationships among different measures of glycemia will need to be considered in future analyses of their roles in the development of long-term complications of type 1 diabetes.
.
Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial.
Arch Ophthalmol. 1998 Jul;116(7):874-86. doi: 10.1001/archopht.116.7.874.
Abstract/Text
OBJECTIVES: To document the frequency, importance of, and risk factors for "early worsening" of diabetic retinopathy in the Diabetes Control and Complications Trial (DCCT).
METHODS: The DCCT was a multicenter, randomized clinical trial comparing intensive vs conventional treatment in insulin-dependent diabetic patients who had no to moderate nonproliferative retinopathy. Retinopathy severity was assessed in 7-field stereoscopic fundus photographs taken at baseline and every 6 months. For this study, worsening was defined as progression of 3 steps or more on the Early Treatment Diabetic Retinopathy Study final scale, as the development of soft exudates and/or intraretinal microvascular abnormalities, as the development of clinically important retinopathy, or as any of the above, and was considered "early" if it occurred between baseline and 12-month follow-up visits.
RESULTS: Early worsening was observed at the 6- and/or 12-month visit in 13.1% of 711 patients assigned to intensive treatment and in 7.6% of 728 patients assigned to conventional treatment (odds ratio, 2.06; P < .001); recovery had occurred at the 18-month visit in 51% and 55% of these groups, respectively (P = .39). The risk of 3-step or greater progression from the retinopathy level present 18 months after entry into the trial was greater in patients who previously had had early worsening than in those who had not. However, the large long-term risk reduction with intensive treatment was such that outcomes in intensively treated patients who had early worsening were similar to or more favorable than outcomes in conventionally treated patients who had not. The most important risk factors for early worsening were higher hemoglobin A1c level at screening and reduction of this level during the first 6 months after randomization. We found no evidence to suggest that more gradual reduction of glycemia might be associated with less risk of early worsening. Early worsening led to high-risk proliferative retinopathy in 2 patients and to clinically significant macular edema in 3; all responded well to treatment.
CONCLUSIONS: In the DCCT, the long-term benefits of intensive insulin treatment greatly outweighed the risks of early worsening. Although no case of early worsening was associated with serious visual loss, our results are consistent with previous reports of sight-threatening worsening when intensive treatment is initiated in patients with long-standing poor glycemic control, particularly if retinopathy is at or past the moderate nonproliferative stage. Ophthalmologic monitoring before initiation of intensive treatment and at 3-month intervals for 6 to 12 months thereafter seems appropriate for such patients. In patients whose retinopathy is already approaching the high-risk stage, it may be prudent to delay the initiation of intensive treatment until photocoagulation can be completed, particularly if hemoglobin A1c is high.
American Geriatrics Society Expert Panel on Care of Older Adults with Diabetes Mellitus; Moreno G, Mangione CM, Kimbro L, Vaisberg E.
Guidelines abstracted from the American Geriatrics Society Guidelines for Improving the Care of Older Adults with Diabetes Mellitus: 2013 update.
J Am Geriatr Soc. 2013 Nov;61(11):2020-6. doi: 10.1111/jgs.12514.
Abstract/Text
Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB, Schaefer EJ, Faas FH, Anderson JW.
Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT).
Arch Intern Med. 2002 Dec 9-23;162(22):2597-604. doi: 10.1001/archinte.162.22.2597.
Abstract/Text
BACKGROUND: Diabetes mellitus, impaired fasting glucose level, or insulin resistance are associated with increased risk of cardiovascular disease.
OBJECTIVES: To determine the efficacy of gemfibrozil in subjects with varying levels of glucose tolerance or hyperinsulinemia and to examine the association between diabetes status and glucose and insulin levels and risk of cardiovascular outcomes.
METHODS: Subgroup analyses from the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized controlled trial that enrolled 2531 men with coronary heart disease (CHD), a high-density lipoprotein cholesterol level of 40 mg/dL or less (RESULTS: Compared with those with a normal fasting glucose level, risk was increased in subjects with known diabetes (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.44-2.43; P =.001) and those with newly diagnosed diabetes (HR, 1.72; 95% CI, 1.10-2.68; P =.02). In persons without diabetes, a fasting plasma insulin level of 39 micro U/mL or greater (>/=271 pmol/L) was associated with a 31% increased risk of events (P =.03). Gemfibrozil was effective in persons with diabetes (risk reduction for composite end point, 32%; P =.004). The reduction in CHD death was 41% (HR, 0.59; 95% CI, 0.39-0.91; P =.02). Among individuals without diabetes, gemfibrozil was most efficacious for those in the highest fasting plasma insulin level quartile (risk reduction, 35%; P =.04).
CONCLUSION: In men with CHD and a low high-density lipoprotein cholesterol level, gemfibrozil use was associated with a reduction in major cardiovascular events in persons with diabetes and in nondiabetic subjects with a high fasting plasma insulin level.
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M, Ehnholm C, Laakso M; FIELD study investigators.
Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
Lancet. 2005 Nov 26;366(9500):1849-61. doi: 10.1016/S0140-6736(05)67667-2.
Abstract/Text
BACKGROUND: Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.
METHODS: We did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481).
FINDINGS: Vital status was confirmed on all but 22 patients. Averaged over the 5 years' study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects.
INTERPRETATION: Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.
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Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study.
Lancet. 2001 Mar 24;357(9260):905-10.
Abstract/Text
BACKGROUND: Atherosclerosis is the most common complication of diabetes. Correction of hyperglycaemia helps to prevent microvascular complications but has little effect on macrovascular disease. Post-hoc analyses of diabetic subpopulations in lipid intervention trials suggest that correction of lipoprotein abnormalities will lead to a decrease in coronary-artery disease. The Diabetes Atherosclerosis Intervention Study (DAIS) was specifically designed to assess the effects of correcting lipoprotein abnormalities on coronary atherosclerosis in type 2 diabetes.
METHODS: 731 men and women with type 2 diabetes were screened by metabolic and angiographic criteria. 418 were randomly assigned micronised fenofibrate (200 mg/day) or placebo for at least 3 years. They were in good glycaemic control (mean haemoglobin A1c 7.5%), had mild lipoprotein abnormalities, typical of type 2 diabetes, and at least one visible coronary lesion. Half had no previous clinical coronary disease. Initial and final angiograms followed a standard protocol and were analysed by a computer-assisted quantitative approach. Missing data for the primary endpoints (minimum lumen diameter, mean segment diameter, and mean percentage stenosis) were imputed. Analyses were by intention to treat.
FINDINGS: Total plasma cholesterol, HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations all changed significantly more from baseline in the fenofibrate group (n=207) than in the placebo group (n=211). The fenofibrate group showed a significantly smaller increase in percentage diameter stenosis than the placebo group (mean 2.11 [SE 0.594] vs 3.65 [0.608]%, p=0.02), a significantly smaller decrease in minimum lumen diameter (-0.06 [0.016] vs -0.10 [0.016] mm, p=0.029), and a non-significantly smaller decrease in mean segment diameter (-0.06 [0.017] vs -0.08 [0.018] mm, p=0.171). The trial was not powered to examine clinical endpoints, but there were fewer in the fenofibrate group than the placebo group (38 vs 50).
INTERPRETATION: DAIS suggests that treatment with fenofibrate reduces the angiographic progression of coronary-artery disease in type 2 diabetes. This effect is related, at least partly, to the correction of lipoprotein abnormalities, even those previously judged not to need treatment.
日本糖尿病学会 編・著：糖尿病診療ガイドライン2024．南江堂、2024.
糖尿病標準診療マニュアル作成委員会編：糖尿病標準診療マニュアル2024 一般診療所・クリニック向け. 日本糖尿病・生活習慣病ヒューマンデータ学会、2024.
Pastors JG, Warshaw H, Daly A, Franz M, Kulkarni K.
The evidence for the effectiveness of medical nutrition therapy in diabetes management.
Diabetes Care. 2002 Mar;25(3):608-13. doi: 10.2337/diacare.25.3.608.
Abstract/Text
Kasiske BL, Lakatua JD, Ma JZ, Louis TA.
A meta-analysis of the effects of dietary protein restriction on the rate of decline in renal function.
Am J Kidney Dis. 1998 Jun;31(6):954-61. doi: 10.1053/ajkd.1998.v31.pm9631839.
Abstract/Text
Dietary protein restriction has been reported to delay the need for renal replacement therapy in clinical trials and meta-analyses. However, less clear is what effect dietary protein has on the rate of decline in renal function. We pooled the results of 13 randomized controlled trials (n = 1,919 patients) and found that dietary protein restriction reduced the rate of decline in estimated glomerular filtration rate by only 0.53 mL/min/yr (95% confidence interval [CI], 0.08 to 0.98 mL/min/yr). We also used weighted regression analysis to determine the reasons for the differences in the results of these 13 randomized trials along with 11 other nonrandomized controlled trials (n = 2,248 patients). The effect of dietary protein restriction (glomerular filtration rate decline in treatment minus control) was substantially less in randomized versus nonrandomized trials (regression coefficient, -5.2 mL/min/yr; 95% CI, -7.8 to -2.5 mL/min/yr; P < 0.05) and relatively greater among diabetic versus nondiabetic patients (5.4 mL/min/yr; 95% CI, 0.3 to 10.5 mL/min/yr; P < 0.05), while there was a trend toward a greater effect with each additional year of follow-up (2.1 mL/min/yr; 95% CI, -0.05 to 4.2 mL/min/yr; P = NS). However, the number of diabetic patients studied was small and the duration of follow-up was short in most trials. No other patient or study characteristics altered the effect of dietary protein restriction on the rate of decline in renal function. Thus, although dietary protein restriction retards the rate of renal function decline, the relatively weak magnitude of this effect suggests that better therapies are needed to slow the rate of renal disease progression.
Pijls LT, de Vries H, Donker AJ, van Eijk JT.
The effect of protein restriction on albuminuria in patients with type 2 diabetes mellitus: a randomized trial.
Nephrol Dial Transplant. 1999 Jun;14(6):1445-53. doi: 10.1093/ndt/14.6.1445.
Abstract/Text
BACKGROUND: A randomized trial was conducted to assess whether protein restriction helps to delay the onset of renal disorders in type 2 diabetic patients.
METHODS: Included in the trial were 121 type 2 diabetic patients with microalbuminuria or at least detectable albuminuria, or diabetes of duration > or =5 years. The experimental (39 male/19 female) and control group (35 male/28 female) received counselling on protein restriction and the usual dietary advice, respectively. The outcome measure was albuminuria (mg/24 h). Results. After 6 months in experimental and control groups the change in protein intake was -0.05+/-0.21 and +0.03+/-0.19 g/kg (P = 0.02), and in albuminuria -14% and +11% (P = 0.01), respectively. After 12 months, the differences between the experimental and the control group with respect to both protein intake and albuminuria had decreased. At 6 and 12 months, respectively, albuminuria was 28% (P<0.001) and 18% (P = 0.08) lower in the experimental than the control group. The effect in normoalbuminuric patients did not differ from that in microalbuminuric patients. In the experimental group, blood pressure, HbA1c and body weight decreased; in the control group, such decreases were less or absent. Dose-response analysis showed that a 0.10 g/kg change at 6 months in the intake of protein, of animal protein in particular, was related to an 11.1% change in albuminuria (P<0.005). Combining the intakes at 6 and 12 months suggested a percentage change of 9.1%.
CONCLUSIONS: Substantial protein restriction in primary care, type 2 diabetic patients with no nephropathy is barely feasible. However, even a small reduction has a substantial and potentially beneficial effect on albuminuria.
Balducci S, Leonetti F, Di Mario U, Fallucca F.
Is a long-term aerobic plus resistance training program feasible for and effective on metabolic profiles in type 2 diabetic patients?
Diabetes Care. 2004 Mar;27(3):841-2. doi: 10.2337/diacare.27.3.841.
Abstract/Text
Boulé NG, Haddad E, Kenny GP, Wells GA, Sigal RJ.
Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials.
JAMA. 2001 Sep 12;286(10):1218-27. doi: 10.1001/jama.286.10.1218.
Abstract/Text
CONTEXT: Exercise is widely perceived to be beneficial for glycemic control and weight loss in patients with type 2 diabetes. However, clinical trials on the effects of exercise in patients with type 2 diabetes have had small sample sizes and conflicting results.
OBJECTIVE: To systematically review and quantify the effect of exercise on glycosylated hemoglobin (HbA(1c)) and body mass in patients with type 2 diabetes.
DATA SOURCES: Database searches of MEDLINE, EMBASE, Sport Discuss, Health Star, Dissertation Abstracts, and the Cochrane Controlled Trials Register for the period up to and including December 2000. Additional data sources included bibliographies of textbooks and articles identified by the database searches.
STUDY SELECTION: We selected studies that evaluated the effects of exercise interventions (duration >/=8 weeks) in adults with type 2 diabetes. Fourteen (11 randomized and 3 nonrandomized) controlled trials were included. Studies that included drug cointerventions were excluded.
DATA EXTRACTION: Two reviewers independently extracted baseline and postintervention means and SDs for the intervention and control groups. The characteristics of the exercise interventions and the methodological quality of the trials were also extracted.
DATA SYNTHESIS: Twelve aerobic training studies (mean [SD], 3.4 [0.9] times/week for 18 [15] weeks) and 2 resistance training studies (mean [SD], 10 [0.7] exercises, 2.5 [0.7] sets, 13 [0.7] repetitions, 2.5 [0.4] times/week for 15 [10] weeks) were included in the analyses. The weighted mean postintervention HbA(1c) was lower in the exercise groups compared with the control groups (7.65% vs 8.31%; weighted mean difference, -0.66%; P<.001). The difference in postintervention body mass between exercise groups and control groups was not significant (83.02 kg vs 82.48 kg; weighted mean difference, 0.54; P =.76).
CONCLUSION: Exercise training reduces HbA(1c) by an amount that should decrease the risk of diabetic complications, but no significantly greater change in body mass was found when exercise groups were compared with control groups.
Thomas DE, Elliott EJ, Naughton GA.
Exercise for type 2 diabetes mellitus.
Cochrane Database Syst Rev. 2006 Jul 19;2006(3):CD002968. doi: 10.1002/14651858.CD002968.pub2. Epub 2006 Jul 19.
Abstract/Text
BACKGROUND: Exercise is generally recommended for people with type 2 diabetes mellitus. However, some studies evaluate an exercise intervention including diet or behaviour modification or both, and the effects of diet and exercise are not differentiated. Some exercise studies involve low participant numbers, lacking power to show significant differences which may appear in larger trials.
OBJECTIVES: To assess the effects of exercise in type 2 diabetes mellitus.
SEARCH STRATEGY: Trials were identified through the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and manual searches of bibliographies. Date of last search was March 3, 2005.
SELECTION CRITERIA: All randomised controlled trials comparing any type of well-documented aerobic, fitness or progressive resistance training exercise with no exercise in people with type 2 diabetes mellitus.
DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, assessed trial quality and extracted data. Study authors were contacted for additional information. Any information on adverse effects was collected from the trials.
MAIN RESULTS: Fourteen randomised controlled trials comparing exercise against no exercise in type 2 diabetes were identified involving 377 participants. Trials ranged from eight weeks to twelve months duration. Compared with the control, the exercise intervention significantly improved glycaemic control as indicated by a decrease in glycated haemoglobin levels of 0.6% (-0.6 % HbA(1c), 95% confidence interval (CI) -0.9 to -0.3; P < 0.05). This result is both statistically and clinically significant. There was no significant difference between groups in whole body mass, probably due to an increase in fat free mass (muscle) with exercise, as reported in one trial (6.3 kg, 95% CI 0.0 to 12.6). There was a reduction in visceral adipose tissue with exercise (-45.5 cm(2), 95% CI -63.8 to -27.3), and subcutaneous adipose tissue also decreased. No study reported adverse effects in the exercise group or diabetic complications. The exercise intervention significantly increased insulin response (131 AUC, 95% CI 20 to 242) (one trial), and decreased plasma triglycerides (-0.25 mmol/L, 95% CI -0.48 to -0.02). No significant difference was found between groups in quality of life (one trial), plasma cholesterol or blood pressure.
AUTHORS' CONCLUSIONS: The meta-analysis shows that exercise significantly improves glycaemic control and reduces visceral adipose tissue and plasma triglycerides, but not plasma cholesterol, in people with type 2 diabetes, even without weight loss.
Sigal RJ, Kenny GP.
Combined aerobic and resistance exercise for patients with type 2 diabetes.
JAMA. 2010 Nov 24;304(20):2298-9. doi: 10.1001/jama.2010.1719.
Abstract/Text
Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K, Mikus CR, Myers V, Nauta M, Rodarte RQ, Sparks L, Thompson A, Earnest CP.
Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial.
JAMA. 2010 Nov 24;304(20):2253-62. doi: 10.1001/jama.2010.1710.
Abstract/Text
CONTEXT: Exercise guidelines for individuals with diabetes include both aerobic and resistance training although few studies have directly examined this exercise combination.
OBJECTIVE: To examine the benefits of aerobic training alone, resistance training alone, and a combination of both on hemoglobin A(1c) (HbA(1c)) in individuals with type 2 diabetes.
DESIGN, SETTING, AND PARTICIPANTS: A randomized controlled trial in which 262 sedentary men and women in Louisiana with type 2 diabetes and HbA(1c) levels of 6.5% or higher were enrolled in the 9-month exercise program between April 2007 and August 2009.
INTERVENTION: Forty-one participants were assigned to the nonexercise control group, 73 to resistance training 3 days a week, 72 to aerobic exercise in which they expended 12 kcal/kg per week; and 76 to combined aerobic and resistance training in which they expended 10 kcal/kg per week and engaged in resistance training twice a week. Main Outcome Change in HbA(1c) level. Secondary outcomes included measures of anthropometry and fitness.
RESULTS: The study included 63.0% women and 47.3% nonwhite participants who were a mean (SD) age of 55.8 years (8.7 years) with a baseline HbA(1c) level of 7.7% (1.0%). Compared with the control group, the absolute mean change in HbA(1c) in the combination training exercise group was -0.34% (95% confidence interval [CI], -0.64% to -0.03%; P = .03). The mean changes in HbA(1c) were not statistically significant in either the resistance training (-0.16%; 95% CI, -0.46% to 0.15%; P = .32) or the aerobic (-0.24%; 95% CI, -0.55% to 0.07%; P = .14) groups compared with the control group. Only the combination exercise group improved maximum oxygen consumption (mean, 1.0 mL/kg per min; 95% CI, 0.5-1.5, P < .05) compared with the control group. All exercise groups reduced waist circumference from -1.9 to -2.8 cm compared with the control group. The resistance training group lost a mean of -1.4 kg fat mass (95% CI, -2.0 to -0.7 kg; P < .05) and combination training group lost a mean of -1.7 (-2.3 to -1.1 kg; P < .05) compared with the control group.
CONCLUSIONS: Among patients with type 2 diabetes mellitus, a combination of aerobic and resistance training compared with the nonexercise control group improved HbA(1c) levels. This was not achieved by aerobic or resistance training alone.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00458133.
Sone H, Tanaka S, Tanaka S, Suzuki S, Seino H, Hanyu O, Sato A, Toyonaga T, Okita K, Ishibashi S, Kodama S, Akanuma Y, Yamada N; Japan Diabetes Complications Study Group.
Leisure-time physical activity is a significant predictor of stroke and total mortality in Japanese patients with type 2 diabetes: analysis from the Japan Diabetes Complications Study (JDCS).
Diabetologia. 2013 May;56(5):1021-30. doi: 10.1007/s00125-012-2810-z. Epub 2013 Feb 27.
Abstract/Text
AIMS/HYPOTHESIS: Our aim was to clarify the association between leisure-time physical activity (LTPA) and cardiovascular events and total mortality in a nationwide cohort of Japanese diabetic patients.
METHODS: Eligible patients (1,702) with type 2 diabetes (mean age, 58.5 years; 47% women) from 59 institutes were followed for a median of 8.05 years. A comprehensive lifestyle survey including LTPA and occupation was performed using standardised questionnaires. Outcome was occurrence of coronary heart disease (CHD), stroke and total mortality. The adjusted HR and 95% CI were calculated by Cox regression analysis.
RESULTS: A significant reduction in HR in patients in the top (≥ 15.4 metabolic equivalents [MET] h/week) vs the bottom tertile (≤ 3.7 MET h/week) of LTPA, adjusted by age, sex and diabetes duration, was observed in stroke (HR 0.55, 95% CI 0.32, 0.94) and total mortality (HR 0.49, 95% CI 0.26, 0.91) but not in CHD (HR 0.77, 95% CI 0.48, 1.25). The HR for stroke became borderline significant or nonsignificant after adjustment for lifestyle or clinical variables including diet or serum lipids. The significantly reduced total mortality by LTPA was independent of these variables and seemed not to be, at least mainly, attributed to reduced cardiovascular disease.
CONCLUSIONS/INTERPRETATION: In Japanese persons with type 2 diabetes, LTPA of 15.4 MET h/week or more was associated with a significantly lower risk of stroke partly through ameliorating combinations of cardiovascular risk factors. It was also associated with significantly reduced total mortality but independently of cardiovascular risk factors or events. These findings, implying differences from Western diabetic populations, should be considered in the clinical management of East Asians with diabetes.
Schwingshackl L, Missbach B, Dias S, König J, Hoffmann G.
Impact of different training modalities on glycaemic control and blood lipids in patients with type 2 diabetes: a systematic review and network meta-analysis.
Diabetologia. 2014 Sep;57(9):1789-97. doi: 10.1007/s00125-014-3303-z. Epub 2014 Jul 5.
Abstract/Text
AIMS/HYPOTHESIS: This study aimed to systematically review randomised controlled trials comparing the effects of aerobic exercise training (AET), resistance training (RT) and combined training (CT) on glycaemic control and blood lipids in patients with type 2 diabetes mellitus.
METHODS: Searches were performed in MEDLINE, EMBASE and the Cochrane Library. Inclusion criteria were: type 2 diabetes mellitus, adult, supervised training and a minimum intervention period of 8 weeks. Pooled effects were calculated by fixed/random effect pairwise and Bayesian fixed/random effects network meta-analyses.
RESULTS: A total of 14 trials enrolling 915 participants were included. AET was more effective than RT in improving HbA1c levels (mean difference [MD] -0.20% [-2.2 mmol/mol]; 95% CI -0.32, -0.08; p = 0.0007, 10 trials/515 participants) and fasting glucose (MD -0.9 mmol/l; 95% CI -1.71, -0.09; p = 0.03, 8 trials/245 participants). Compared with AET, CT resulted in a significantly more pronounced reduction in HbA1c (MD -0.17% [-1.87 mmol/mol]; 95% CI -0.31, -0.03; p = 0.02, 9 trials/493 participants). Compared with RT, the MD of the change in HbA1c (MD -0.62%, [-6.82 mmol/mol]; 95% CI -0.95, -0.30; p = 0.0002, 5 trials/362 participants], fasting glucose (MD -1.99 mmol/l; 95% CI -3.07, -0.90; p = 0.0003, 3 trials/99 participants) and triacylglycerols (MD -0.28 mmol/l; 95% CI -0.46, -0.10; p = 0.003, 4 trials/213 participants) were all in favour of CT. The exclusion of trials with a high risk of bias yielded only non-significant results.
CONCLUSIONS/INTERPRETATION: The present data suggest that CT might be the most efficacious exercise modality to improve glycaemic control and blood lipids. Interpretation with respect to clinical relevance is limited by the low quality of the studies included and the limited information on the clinically important outcomes or adverse effects of exercise.
Haire-Joshu D, Glasgow RE, Tibbs TL.
Smoking and diabetes.
Diabetes Care. 1999 Nov;22(11):1887-98. doi: 10.2337/diacare.22.11.1887.
Abstract/Text
The objective of this review is to summarize the literature on diabetes and smoking related to epidemiological risks, efficacy and cost-effectiveness of different cessation approaches, and implications for clinical practice. Over 200 studies were reviewed, with special emphasis placed on publications within the past 10 years. Intervention studies that included patients with diabetes but did not report results separately by disease are included. Diabetes-specific studies are highlighted. There are consistent results from both cross-sectional and prospective studies showing enhanced risk for micro- and macrovascular disease, as well as premature mortality from the combination of smoking and diabetes. The general cessation literature is extensive, generally well-designed, and encouraging regarding the impact of cost-effective practical office-based interventions. In particular, system-based approaches that make smoking a routine part of office contacts and provide multiple prompts, advice, assistance, and follow-up support are effective. Although there is minimal information on the effectiveness of cessation interventions specifically for people with diabetes, there is no reason to assume that cessation intervention would be more or less effective in this population. There is a clear need to increase the frequency of smoking cessation advice and counseling for patients with diabetes given the strong and consistent data on smoking prevalence; combined risks of smoking and diabetes for morbidity, mortality, and several complications; and the proven efficacy and cost-effectiveness of cessation strategies.
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UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, UKPDS Group.
Metabolism. 1990 Sep;39(9):905-12.
Abstract/Text
The response to diet of 3,044 newly diagnosed diabetic patients with a fasting plasma glucose (mean +/- 1 SD) of 12.1 +/- 3.7 mmol/L, age 52 +/- 8 years, and body weight 130% +/- 26% ideal body weight has been studied. The reduction in the fasting plasma glucose was greater in those presenting with a high initial fasting plasma glucose and in those who lost more weight, but was not related to the degree of obesity. There was considerable variation in the response to dieting, but on average, patients presenting with a fasting plasma glucose of 10 to 12 mmol/L needed to lose 28% ideal body weight (18 kg) to attain a fasting plasma glucose less than 6.0 mmol/L. Sixteen percent of all patients achieved a near-normal (less than 6 mmol/L) fasting plasma glucose after 3 months' dieting, ranging from 50% of those presenting with fasting plasma glucose of 6 to 8 mmol/L to 10% of those with fasting plasma glucose of 16 to 22 mmol/L. In those who achieved less than 6.0 mmol/L, in the second 3 months the fasting plasma glucose increased by a mean of 0.4 mmol/L even though there was a further mean weight reduction of 2.1% ideal body weight (1.4 kg) in addition to their loss of 11.6% ideal body weight (8 kg) in the initial 3 months. This confirms that the decrease in fasting plasma glucose is determined more by the restriction of energy intake than by the body weight. Those who maintained their fasting plasma glucose at less than 6.0 mmol/L in the year following the initial 3-month dietary period lost a further 3% (2 kg) ideal body weight. The data confirm the value of dieting, but in view of the large weight loss and equivalent large reduction in energy intake required in most patients, it is not surprising that few patients achieve near-normal fasting plasma glucose concentrations by diet alone.
Look AHEAD Research Group; Pi-Sunyer X, Blackburn G, Brancati FL, Bray GA, Bright R, Clark JM, Curtis JM, Espeland MA, Foreyt JP, Graves K, Haffner SM, Harrison B, Hill JO, Horton ES, Jakicic J, Jeffery RW, Johnson KC, Kahn S, Kelley DE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montgomery B, Nathan DM, Patricio J, Peters A, Redmon JB, Reeves RS, Ryan DH, Safford M, Van Dorsten B, Wadden TA, Wagenknecht L, Wesche-Thobaben J, Wing RR, Yanovski SZ.
Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial.
Diabetes Care. 2007 Jun;30(6):1374-83. doi: 10.2337/dc07-0048. Epub 2007 Mar 15.
Abstract/Text
OBJECTIVE: The effectiveness of intentional weight loss in reducing cardiovascular disease (CVD) events in type 2 diabetes is unknown. This report describes 1-year changes in CVD risk factors in a trial designed to examine the long-term effects of an intensive lifestyle intervention on the incidence of major CVD events.
RESEARCH DESIGN AND METHODS: This study consisted of a multicentered, randomized, controlled trial of 5,145 individuals with type 2 diabetes, aged 45-74 years, with BMI >25 kg/m2 (>27 kg/m2 if taking insulin). An intensive lifestyle intervention (ILI) involving group and individual meetings to achieve and maintain weight loss through decreased caloric intake and increased physical activity was compared with a diabetes support and education (DSE) condition.
RESULTS: Participants assigned to ILI lost an average 8.6% of their initial weight vs. 0.7% in DSE group (P < 0.001). Mean fitness increased in ILI by 20.9 vs. 5.8% in DSE (P < 0.001). A greater proportion of ILI participants had reductions in diabetes, hypertension, and lipid-lowering medicines. Mean A1C dropped from 7.3 to 6.6% in ILI (P < 0.001) vs. from 7.3 to 7.2% in DSE. Systolic and diastolic pressure, triglycerides, HDL cholesterol, and urine albumin-to-creatinine ratio improved significantly more in ILI than DSE participants (all P < 0.01).
CONCLUSIONS: At 1 year, ILI resulted in clinically significant weight loss in people with type 2 diabetes. This was associated with improved diabetes control and CVD risk factors and reduced medicine use in ILI versus DSE. Continued intervention and follow-up will determine whether these changes are maintained and will reduce CVD risk.
Rejeski WJ, Ip EH, Bertoni AG, Bray GA, Evans G, Gregg EW, Zhang Q; Look AHEAD Research Group.
Lifestyle change and mobility in obese adults with type 2 diabetes.
N Engl J Med. 2012 Mar 29;366(13):1209-17. doi: 10.1056/NEJMoa1110294.
Abstract/Text
BACKGROUND: Adults with type 2 diabetes mellitus often have limitations in mobility that increase with age. An intensive lifestyle intervention that produces weight loss and improves fitness could slow the loss of mobility in such patients.
METHODS: We randomly assigned 5145 overweight or obese adults between the ages of 45 and 74 years with type 2 diabetes to either an intensive lifestyle intervention or a diabetes support-and-education program; 5016 participants contributed data. We used hidden Markov models to characterize disability states and mixed-effects ordinal logistic regression to estimate the probability of functional decline. The primary outcome was self-reported limitation in mobility, with annual assessments for 4 years.
RESULTS: At year 4, among 2514 adults in the lifestyle-intervention group, 517 (20.6%) had severe disability and 969 (38.5%) had good mobility; the numbers among 2502 participants in the support group were 656 (26.2%) and 798 (31.9%), respectively. The lifestyle-intervention group had a relative reduction of 48% in the risk of loss of mobility, as compared with the support group (odds ratio, 0.52; 95% confidence interval, 0.44 to 0.63; P<0.001). Both weight loss and improved fitness (as assessed on treadmill testing) were significant mediators of this effect (P<0.001 for both variables). Adverse events that were related to the lifestyle intervention included a slightly higher frequency of musculoskeletal symptoms at year 1.
CONCLUSIONS: Weight loss and improved fitness slowed the decline in mobility in overweight adults with type 2 diabetes. (Funded by the Department of Health and Human Services and others; ClinicalTrials.gov number, NCT00017953.).
Malone JM, Snyder M, Anderson G, Bernhard VM, Holloway GA Jr, Bunt TJ.
Prevention of amputation by diabetic education.
Am J Surg. 1989 Dec;158(6):520-3; discussion 523-4. doi: 10.1016/0002-9610(89)90183-9.
Abstract/Text
This prospective randomized study evaluated the influence of a simple education program on the incidence of lower extremity amputation in diabetic patients. Two hundred three patients were randomized into two groups: Group 1, education (103 patients, 203 limbs) and Group 2, no education (100 patients, 193 limbs). There were no significant differences in medical management or clinical risk factors between the two groups. The amputation rate was three times higher in Group 2 (21 of 177 limbs versus 7 of 177 limbs; p less than or equal to 0.025), the ulceration rate was three times higher in Group 2 (26 of 177 limbs versus 8 of 177 limbs; p less than or equal to 0.005), and there was no difference in the overall incidence of infection (2 of 177 limbs). Overall success in Group 1 was highly significantly different from Group 2 (160 of 177 limbs versus 128 of 177 limbs; p less than or equal to 0.0005). This study demonstrated that a simple education program significantly reduced the incidence of ulcer or foot and limb amputation in diabetic patients.
Darré L, Vergnes JN, Gourdy P, Sixou M.
Efficacy of periodontal treatment on glycaemic control in diabetic patients: A meta-analysis of interventional studies.
Diabetes Metab. 2008 Nov;34(5):497-506. doi: 10.1016/j.diabet.2008.03.006. Epub 2008 Oct 22.
Abstract/Text
AIM: There is growing evidence that periodontal disease may favour the incidence or aggravation of diabetes and its complications. To investigate the issue, we conducted a meta-analysis of the effect of periodontal therapy on glycaemic control in diabetic patients.
METHODS: A literature search was carried out using seven databases (Medline, EMBASE, LILACS, The Cochrane Library, Pascal, IADR Abstracts and Current Contents), with no language restrictions. We followed the QUOROM-recommended standards for improving the quality of reporting meta-analyses of interventional studies.
RESULTS: Twenty-five studies, involving 976 subjects altogether, were included in the present systematic review. Of these, nine studies, involving a total of 485 patients, were controlled trials and were included in the meta-analysis. The standardized mean difference in HbA(1c) with the treatment of periodontal disease was 0.46 (95% CI: 0.11, 0.82). These findings suggest that periodontal treatment could lead to a significant 0.79% (95% CI: 0.19, 1.40) reduction in HbA(1c) level.
CONCLUSION: The present meta-analysis represents the best information available to date that addresses this issue, and suggests that periodontal treatment could improve glycaemic control. Nevertheless, these results need to be viewed with caution because of a lack of robustness, and deficiencies in the design of some of the studies included. A randomized controlled trial with sufficient statistical power would help to confirm the results of this meta-analysis.
Rachmani R, Levi Z, Slavachevski I, Avin M, Ravid M.
Teaching patients to monitor their risk factors retards the progression of vascular complications in high-risk patients with Type 2 diabetes mellitus--a randomized prospective study.
Diabet Med. 2002 May;19(5):385-92. doi: 10.1046/j.1464-5491.2002.00701.x.
Abstract/Text
AIMS: Intensive management of risk parameters in diabetic patients may retard the progression of both micro- and macrovascular complications. Intensified care requires expert staff and is expensive. The aim of the present study was to examine whether sharing the therapeutic responsibility with the patients will improve the outcome.
METHODS: A randomized prospective study of 165 patients with diabetes mellitus Type 2, hypertension (> 140/90 mmHg) and hyperlipidaemia (LDL-C > 120 mg/dl). Patients were randomly allocated to standard annual consultation (SC) or to a patient participation programme (PP). The medical care for both groups was administered by primary care physicians, who were unaware of the nature of the intervention.
RESULTS: At 4 years the mean blood pressure was 148/88 (+/- 6.1/1.7) mmHg in the SC patients vs. 142/84 (+/- 5.8/1.8) mmHg in the PP group (P = 0.02). The mean LDL-C was 124 +/- 8 and 114 +/- 6 mg/dl (P = 0.01) and the mean HbA1c was 8.9 +/- 1.2% and 8.2 +/- 1.5% (P = 0.04) in the SC and PP groups, respectively. The average annual fall in estimated glomerular filtration rate was 3.5 ml/min per year in the SC group vs. 2.25 in the PP group (P < 0.05). Albumin/creatinine ratio > 300 mg/g developed in four SC patients vs. none of the PP patients. There was a total of 36 cardiovascular events in the SC group vs. 23 in the PP group (P = 0.04). All patients in the PP group received ACE inhibitors (or AII blockers) and statins vs. 52% and 43%, respectively, in the SC group. Glucose-lowering regimens were similar.
CONCLUSIONS: Well-informed and motivated patients were more insistent to reach and maintain target values of the main risk factors of diabetic complications. The differences between the PP and SC groups were of the same order of magnitude as those between intensive and standard care groups in other studies albeit with, comparatively, a very modest cost.
Gary TL, Genkinger JM, Guallar E, Peyrot M, Brancati FL.
Meta-analysis of randomized educational and behavioral interventions in type 2 diabetes.
Diabetes Educ. 2003 May-Jun;29(3):488-501. doi: 10.1177/014572170302900313.
Abstract/Text
PURPOSE: This meta-analysis was conducted to assess the effect of educational and behavioral interventions on body weight and glycemic control in type 2 diabetes.
METHODS: Studies selected for analysis were published randomized controlled trials that evaluated educational and behavioral interventions (no drug interventions) in type 2 diabetes (sample size > or = 10). These criteria were applied to searches of electronic databases and relevant bibliographies. Data were independently abstracted by 2 reviewers and adjudicated by consensus.
RESULTS: Of the 63 articles that met the inclusion criteria, 18 provided enough information for pooled estimates of glycohemoglobin (total Ghb, HbA1, or HbA1C). These 18 studies yielded 2720 participants (sample sizes of 18 to 749). Interventions ranged from 1 to 19 months; follow-up ranged from 1 to 26 months. Glycohemoglobin was reduced by a mean of 0.43%. When results were stratified by quality score, glycohemoglobin was -0.50% and -0.38% for studies with high and low quality scores, respectively. When weighting studies by sample size, fasting blood glucose was reduced by 24 mg/dL and weight by 3 lbs.
CONCLUSIONS: Previous educational and behavioral interventions in type 2 diabetes have produced modest improvements in glycemic control. Future research should refine such interventions and improve methodology.
Warsi A, Wang PS, LaValley MP, Avorn J, Solomon DH.
Self-management education programs in chronic disease: a systematic review and methodological critique of the literature.
Arch Intern Med. 2004 Aug 9-23;164(15):1641-9. doi: 10.1001/archinte.164.15.1641.
Abstract/Text
BACKGROUND: Self-management programs have been widely reported to help patients manage symptoms and contain utilization of health care resources for several chronic conditions, but to date no systematic review across multiple chronic diseases has been reported. We evaluated the efficacy of patient self-management educational programs for chronic diseases and critically reviewed their methodology.
METHODS: We searched MEDLINE and HealthSTAR for the period January 1, 1964, through January 31, 1999, then hand searched the reference section of each article for other relevant publications. We included studies if a self-management education intervention for a chronic disease was reported, a concurrent control group was included, and clinical outcomes were evaluated. Two authors reviewed each study and extracted the data on clinical outcomes.
RESULTS: We included 71 trials of self-management education. Trial methods varied substantially and were suboptimal. Diabetic patients involved with self-management education programs demonstrated reductions in glycosylated hemoglobin levels (summary effect size, 0.45; 95% confidence interval [CI], 0.17-0.74); diabetic patients had improvement in systolic blood pressure (summary effect size, 0.20; 95% CI, 0.01-0.39); and asthmatic patients experienced fewer attacks (log rate ratio, 0.59; 95% CI, 0.35-0.83). Although we found a trend toward a small benefit, arthritis self-management education programs were not associated with statistically significant effects. Evidence of publication bias existed.
CONCLUSIONS: Self-management education programs resulted in small to moderate effects for selected chronic diseases. In light of evidence of publication bias, further trials that adhere to a standard methodology would help clarify whether self-management education is worthwhile.
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Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 1997 Apr 4;46(RR-8):1-24.
Abstract/Text
This report updates the last recommendations by the Advisory Committee on Immunization Practices (ACIP) concerning pneumococcal polysaccharide vaccine (MMWR 1989;38:64-8, 73-6). ACIP recommends that the vaccine be used more extensively and administered to all persons in the following groups: a) persons aged > or = 65 years, b) immunocompetent persons aged > or = to 2 years who are at increased risk for illness and death associated with pneumococcal disease because of chronic illness, c) persons aged > or = 2 years with functional or anatomic asplenia, d) persons aged > or = 2 years living in environments in which the risk for disease is high, and e) immunocompromised persons aged > or = 2 years who are at high risk for infection. This report contains updated information regarding a) antimicrobial resistance among pneumococci, b) vaccine effectiveness and cost-effectiveness, c) indications for vaccination, d) guidelines for revaccination, e) strategies for improving delivery of vaccine, and f) development of pneumococcal conjugate vaccine.
Boxem KV, Zundert JV, van Kleef M.
Re: Staal JB, de Bie R, de Vet HC, et al. Injection therapy for subacute and chronic low-back pain. Cochrane Database Syst Rev 2008:CD001824.
Spine (Phila Pa 1976). 2009 Jul 1;34(15):1628-9; author reply 1629. doi: 10.1097/BRS.0b013e3181aa1ffa.
Abstract/Text
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Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
Lancet. 1998 Sep 12;352(9131):854-65.
Abstract/Text
BACKGROUND: In patients with type 2 diabetes, intensive blood-glucose control with insulin or sulphonylurea therapy decreases progression of microvascular disease and may also reduce the risk of heart attacks. This study investigated whether intensive glucose control with metformin has any specific advantage or disadvantage.
METHODS: Of 4075 patients recruited to UKPDS in 15 centres, 1704 overweight (>120% ideal bodyweight) patients with newly diagnosed type 2 diabetes, mean age 53 years, had raised fasting plasma glucose (FPG; 6.1-15.0 mmol/L) without hyperglycaemic symptoms after 3 months' initial diet. 753 were included in a randomised controlled trial, median duration 10.7 years, of conventional policy, primarily with diet alone (n=411) versus intensive blood-glucose control policy with metformin, aiming for FPG below 6 mmol/L (n=342). A secondary analysis compared the 342 patients allocated metformin with 951 overweight patients allocated intensive blood-glucose control with chlorpropamide (n=265), glibenclamide (n=277), or insulin (n=409). The primary outcome measures were aggregates of any diabetes-related clinical endpoint, diabetes-related death, and all-cause mortality. In a supplementary randomised controlled trial, 537 non-overweight and overweight patients, mean age 59 years, who were already on maximum sulphonylurea therapy but had raised FPG (6.1-15.0 mmol/L) were allocated continuing sulphonylurea therapy alone (n=269) or addition of metformin (n=268).
FINDINGS: Median glycated haemoglobin (HbA1c) was 7.4% in the metformin group compared with 8.0% in the conventional group. Patients allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47, p=0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63, p=0.017), and 36% for all-cause mortality (9-55, p=0.011). Among patients allocated intensive blood-glucose control, metformin showed a greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint (p=0.0034), all-cause mortality (p=0.021), and stroke (p=0.032). Early addition of metformin in sulphonylurea-treated patients was associated with an increased risk of diabetes-related death (96% increased risk [95% CI 2-275], p=0.039) compared with continued sulphonylurea alone. A combined analysis of the main and supplementary studies showed fewer metformin-allocated patients having diabetes-related endpoints (risk reduction 19% [2-33], p=0.033). Epidemiological assessment of the possible association of death from diabetes-related causes with the concurrent therapy of diabetes in 4416 patients did not show an increased risk in diabetes-related death in patients treated with a combination of sulphonylurea and metformin (risk reduction 5% [-33 to 32], p=0.78).
INTERPRETATION: Since intensive glucose control with metformin appears to decrease the risk of diabetes-related endpoints in overweight diabetic patients, and is associated with less weight gain and fewer hypoglycaemic attacks than are insulin and sulphonylureas, it may be the first-line pharmacological therapy of choice in these patients.
Lazarus B, Wu A, Shin JI, Sang Y, Alexander GC, Secora A, Inker LA, Coresh J, Chang AR, Grams ME.
Association of Metformin Use With Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study.
JAMA Intern Med. 2018 Jul 1;178(7):903-910. doi: 10.1001/jamainternmed.2018.0292.
Abstract/Text
IMPORTANCE: Approximately 1 million patients in the United States with type 2 diabetes mellitus and mild-to-moderate kidney disease do not receive guideline-directed therapy with metformin. This may reflect uncertainty regarding the risk of acidosis in patients with chronic kidney disease.
OBJECTIVE: To quantify the association between metformin use and hospitalization with acidosis across the range of estimated glomerular filtration rate (eGFR), accounting for change in eGFR stage over time.
DESIGN, SETTING, AND PARTICIPANTS: Community-based cohort of 75 413 patients with diabetes in Geisinger Health System, with time-dependent assessment of eGFR stage from January 2004 until January 2017. Results were replicated in 67 578 new metformin users and 14 439 new sulfonylurea users from 2010 to 2015, sourced from 350 private US health systems.
EXPOSURES: Metformin use.
MAIN OUTCOMES AND MEASURES: Hospitalization with acidosis (International Classification of Diseases, Ninth Revision, Clinical Modification code of 276.2).
RESULTS: In the primary cohort (n = 75 413), mean (SD) patient age was 60.4 (15.5) years, and 51% (n = 38 480) of the participants were female. There were 2335 hospitalizations with acidosis over a median follow-up of 5.7 years (interquartile range, 2.5-9.9 years). Compared with alternative diabetes management, time-dependent metformin use was not associated with incident acidosis overall (adjusted hazard ratio [HR], 0.98; 95% CI, 0.89-1.08) or in patients with eGFR 45 to 59 mL/min/1.73 m2 (adjusted HR, 1.16; 95% CI, 0.95-1.41) and eGFR 30 to 44 mL/min/1.73 m2 (adjusted HR, 1.09; 95% CI, 0.83-1.44). On the other hand, metformin use was associated with an increased risk of acidosis at eGFR less than 30 mL/min/1.73 m2 (adjusted HR, 2.07; 95% CI, 1.33-3.22). Results were consistent when new metformin users were compared with new sulfonylurea users (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.77; 95% CI, 0.29-2.05), in a propensity-matched cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.71; 95% CI, 0.45-1.12), when baseline insulin users were excluded (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 1.16; 95% CI, 0.87-1.57), and in the replication cohort (adjusted HR for eGFR 30-44 mL/min/1.73 m2, 0.86; 95% CI, 0.37-2.01).
CONCLUSIONS AND RELEVANCE: In 2 real-world clinical settings, metformin use was associated with acidosis only at eGFR less than 30 mL/min/1.73 m2. Our results support cautious use of metformin in patients with type 2 diabetes and eGFR of at least 30 mL/min/1.73 m2.
Tanabe M, Nomiyama T, Motonaga R, Murase K, Yanase T.
Reduced vascular events in type 2 diabetes by biguanide relative to sulfonylurea: study in a Japanese Hospital Database.
BMC Endocr Disord. 2015 Sep 17;15:49. doi: 10.1186/s12902-015-0045-y. Epub 2015 Sep 17.
Abstract/Text
BACKGROUND: Some oral hypoglycemic agents (OHAs) have been suggested to reduce the risk of cardiovascular disease (CVD) in type-2 diabetes mellitus (T2DM). We ascertained if OHAs affect CVD risk in a cohort analysis of a multicenter medical-cost accounting database in Japan.
METHODS: Data of 4095 and 1273 T2DM patients in study 1 and study 2, respectively, were extracted from the database based on the following conditions: (i) began treatment with a single OHA (sulfonylurea, biguanide, thiazolidinedione, α-glucosidase inhibitor, glinide, or dipeptidyl peptidase-4 inhibitor) and continued the medication for ~1-1.4 years; (ii) hemoglobin (Hb)A1c level at baseline was available; (iii) age at baseline was 40-70 years; (iv) presence or absence of CVD history was not considered in study 1, but presence of CVD history was considered in study 2. Effects of OHAs relative to sulfonylurea on CVD risk according to ICD-10 were analysed using Kaplan-Meier curves during 104 weeks.
RESULTS: In study 1 targeting T2DM patients with and without a history of CVD, initial and baseline treatment with a biguanide significantly lowered the risk of CVD compared with that with a sulfonylurea, and was independent of HbA1c control. In study 2, a similar significant preventive effect of a biguanide on CVD risk relative to a sulfonylurea was observed in T2DM patients with history of CVD.
CONCLUSIONS: Initial treatment and baseline treatment with a biguanide can reduce CVD risk relative to a sulfonylurea independent of the blood glucose-lowering effect of the biguanide in Japanese T2DM patients.
Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, Zhou Z, Tang W, Zhao J, Cui L, Zou D, Wang D, Li H, Liu C, Wu G, Shen J, Zhu D, Wang W, Shen W, Ning G; SPREAD-DIMCAD Investigators.
Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease.
Diabetes Care. 2013 May;36(5):1304-11. doi: 10.2337/dc12-0719. Epub 2012 Dec 10.
Abstract/Text
OBJECTIVE: The two major classes of antidiabetic drugs, sulfonylureas and metformin, may differentially affect macrovascular complications and mortality in diabetic patients. We compared the long-term effects of glipizide and metformin on the major cardiovascular events in type 2 diabetic patients who had a history of coronary artery disease (CAD).
RESEARCH DESIGN AND METHODS: This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 304 type 2 diabetic patients with CAD, mean age = 63.3 years (range, 36-80 years), were enrolled. Participants were randomly assigned to receive either glipizide (30 mg daily) or metformin (1.5 g daily) for 3 years. The primary end points were times to the composite of recurrent cardiovascular events, including death from a cardiovascular cause, death from any cause, nonfatal myocardial infarction, nonfatal stroke, or arterial revascularization.
RESULTS: At the end of study drug administration, both groups achieved a significant decrease in the level of glycated hemoglobin (7.1% in the glipizide group and 7.0% in the metformin group). At a median follow-up of 5.0 years, 91 participants had developed 103 primary end points. Intention-to-treat analysis showed an adjusted hazard ratio (HR) of 0.54 (95% CI 0.30-0.90; P = 0.026) for the composites of cardiovascular events among the patients that received metformin, compared with glipizide. The secondary end points and adverse events were not significantly different between the two groups.
CONCLUSIONS: Treatment with metformin for 3 years substantially reduced major cardiovascular events in a median follow-up of 5.0 years compared with glipizide. Our results indicated a potential benefit of metformin therapy on cardiovascular outcomes in high-risk patients.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA.
10-year follow-up of intensive glucose control in type 2 diabetes.
N Engl J Med. 2008 Oct 9;359(15):1577-89. doi: 10.1056/NEJMoa0806470. Epub 2008 Sep 10.
Abstract/Text
BACKGROUND: During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes.
METHODS: Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories.
RESULTS: Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002).
CONCLUSIONS: Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.)
2008 Massachusetts Medical Society
Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D.
Metformin monotherapy for type 2 diabetes mellitus.
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002966. doi: 10.1002/14651858.CD002966.pub3. Epub 2005 Jul 20.
Abstract/Text
BACKGROUND: Metformin is an anti-hyperglycaemic agent used for the treatment of type 2 diabetes mellitus. Type 2 diabetes may present long-term complications: micro- (retinopathy, nephropathy and neuropathy) and macrovascular (stroke, myocardial infarction and peripheral vascular disease). Two meta-analyses have been published before, although only secondary outcomes were assessed.
OBJECTIVES: To assess the effects of metformin monotherapy on mortality, morbidity, quality of life, glycaemic control, body weight, lipid levels, blood pressure, insulinaemia, and albuminuria in patients with type 2 diabetes mellitus.
SEARCH STRATEGY: Studies were obtained from computerised searches of multiple electronic databases and hand searches of reference lists of relevant trials identified. Date of last search: September 2003.
SELECTION CRITERIA: Trials fulfilling the following inclusion criteria: Diabetes mellitus type 2, metformin versus any other oral intervention, assessment of relevant clinical outcome measures, use of random allocation.
DATA COLLECTION AND ANALYSIS: Two reviewers extracted data, using a standard data extraction form. Data were summarised under a random effects model. Dichotomous data were expressed as relative risk. We calculated the risk difference (RD), and the Number Needed to Treat, when it was possible. We collected data of mean and standard deviation from changes to baseline. However many trials reported end point data. This limitation lead to the expression of the results as standardised mean differences (SMD) and an overall SMD was calculated. Heterogeneity was tested for using the Z score and the I-squared statistic. Subgroup, sensitivity analysis and meta-regression were used to explore heterogeneity.
MAIN RESULTS: We included for analysis 29 trials with 37 arms (5259 participants), comparing metformin (37 arms and 2007 participants) with sulphonylureas (13 and 1167), placebo (12 and 702), diet (three and 493), thiazolidinediones (three and 132), insulin (two and 439), meglitinides (two and 208), and glucosidase inhibitors (two and 111). Nine studies reported data on primary outcomes. Obese patients allocated to intensive blood glucose control with metformin showed a greater benefit than chlorpropamide, glibenclamide, or insulin for any diabetes-related outcomes (P = 0.009), and for all-cause mortality (P = 0.03). Obese participants assigned to intensive blood glucose control with metformin showed a greater benefit than overweight patients on conventional treatment for any diabetes-related outcomes (P = 0.004), diabetes-related death (P = 0.03), all-cause mortality (P = 0.01), and myocardial infarction (P = 0.02). Patients assigned to metformin monotherapy showed a significant benefit for glycaemia control, weight, dyslipidaemia, and diastolic blood pressure. Metformin presents a strong benefit for HbA1c when compared with placebo and diet; and a moderated benefit for: glycaemia control, LDL cholesterol, and BMI or weight when compared with sulphonylureas.
AUTHORS' CONCLUSIONS: Metformin may be the first therapeutic option in the diabetes mellitus type 2 with overweight or obesity, as it may prevent some vascular complications, and mortality. Metformin produces beneficial changes in glycaemia control, and moderated in weight, lipids, insulinaemia and diastolic blood pressure. Sulphonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycaemia control, body weight, or lipids, than metformin.
Selvin E, Bolen S, Yeh HC, Wiley C, Wilson LM, Marinopoulos SS, Feldman L, Vassy J, Wilson R, Bass EB, Brancati FL.
Cardiovascular outcomes in trials of oral diabetes medications: a systematic review.
Arch Intern Med. 2008 Oct 27;168(19):2070-80. doi: 10.1001/archinte.168.19.2070.
Abstract/Text
BACKGROUND: A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus, but it is unclear how these agents compare with respect to long-term cardiovascular risk. Our objective was to systematically examine the peer-reviewed literature on the cardiovascular risk associated with oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides) for treating adults with type 2 diabetes.
METHODS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception through January 19, 2006. Forty publications of controlled trials that reported information on cardiovascular events (primarily myocardial infarction and stroke) met our inclusion criteria. Using standardized protocols, 2 reviewers serially abstracted data from each article. Trials were first described qualitatively. For comparisons with 4 or more independent trials, results were pooled quantitatively using the Mantel-Haenszel method. Results are presented as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).
RESULTS: Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular mortality (pooled OR, 0.74; 95% CI, 0.62-0.89) compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity and all-cause mortality were similar but not statistically significant. No other significant associations of oral diabetes agents with fatal or nonfatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity or mortality, but this result was not statistically significant (OR, 1.68; 95% CI, 0.92-3.06).
CONCLUSIONS: Meta-analysis suggested that, compared with other oral diabetes agents and placebo, metformin was moderately protective and rosiglitazone possibly harmful, but lack of power prohibited firmer conclusions. Larger, long-term studies taken to hard end points and better reporting of cardiovascular events in short-term studies will be required to draw firm conclusions about major clinical benefits and risks related to oral diabetes agents.
Roussel R, Travert F, Pasquet B, Wilson PW, Smith SC Jr, Goto S, Ravaud P, Marre M, Porath A, Bhatt DL, Steg PG; Reduction of Atherothrombosis for Continued Health (REACH) Registry Investigators.
Metformin use and mortality among patients with diabetes and atherothrombosis.
Arch Intern Med. 2010 Nov 22;170(21):1892-9. doi: 10.1001/archinternmed.2010.409.
Abstract/Text
BACKGROUND: Metformin is recommended in type 2 diabetes mellitus because it reduced mortality among overweight participants in the United Kingdom Prospective Diabetes Study when used mainly as a means of primary prevention. However, metformin is often not considered in patients with cardiovascular conditions because of concerns about its safety.
METHODS: We assessed whether metformin use was associated with a difference in mortality among patients with atherothrombosis. The study sample comprised 19 691 patients having diabetes with established atherothrombosis participating in the Reduction of Atherothrombosis for Continued Health (REACH) Registry between December 1, 2003, and December 31, 2004, treated with or without metformin. Multivariable adjustment and propensity score were used to account for baseline differences. The main outcome measure was 2-year mortality.
RESULTS: The mortality rates were 6.3% (95% confidence interval [CI], 5.2%-7.4%) with metformin and 9.8% 8.4%-11.2%) without metformin; the adjusted hazard ratio (HR) was 0.76 (0.65-0.89; P < .001). Association with lower mortality was consistent among subgroups, noticeably in patients with a history of congestive heart failure (HR, 0.69; 95% CI, 0.54-0.90; P = .006), patients older than 65 years (0.77; 0.62-0.95; P = .02), and patients with an estimated creatinine clearance of 30 to 60 mL/min/1.73 m(2) (0.64; 95% CI, 0.48-0.86; P = .003) (to convert creatinine clearance to mL/s/m(2), multiply by 0.0167).
CONCLUSIONS: Metformin use may decrease mortality among patients with diabetes when used as a means of secondary prevention, including subsets of patients in whom metformin use is not now recommended. Metformin use should be tested prospectively in this population to confirm its effect on survival.
Strowig SM, Avilés-Santa ML, Raskin P.
Improved glycemic control without weight gain using triple therapy in type 2 diabetes.
Diabetes Care. 2004 Jul;27(7):1577-83. doi: 10.2337/diacare.27.7.1577.
Abstract/Text
OBJECTIVE: To evaluate the safety and effectiveness of triple therapy using insulin, metformin, and a thiazolidinedione following a course of dual therapy using insulin and metformin or insulin and a thiazolidinedione in type 2 diabetes.
RESEARCH DESIGN AND METHODS: Twenty-eight type 2 diabetic subjects using insulin monotherapy (baseline HbA(lc) level 8.5%) who had been randomly assigned to insulin (INS) and metformin (MET) (INS + MET, n = 14) or INS and the thiazolidinedione troglitazone (TGZ) (INS + TGZ, n = 14) (dual therapy) for 4 months were given INS, MET, and TGZ (triple therapy: INS + MET, add TGZ; or INS + TGZ, add MET) for another 4 months. The INS dose was not increased.
RESULTS: HbA(1c) levels decreased in both groups during dual therapy and improved further during triple therapy (INS + MET 7.0 +/- 0.8, INS + TGZ 6.2 +/- 0.8, P < 0.0001; INS + MET, add TGZ 6.1 +/- 0.4%, P < 0.001; INS + TGZ, add MET 5.8 +/- 0.6%, P < 0.05; and INS + TGZ vs. INS + MET, P = 0.02). Significant reductions in total daily insulin dose occurred in the INS + TGZ (-14.1 units, P < 0.0001), INS + TGZ add MET (-13.7 units, P < 0.01), and the INS + MET add TGZ groups (-17.3 units, P < 0.003), but not in the INS + MET group (-3.2 units) (INS + TGZ vs. INS + MET P < 0.05). Subjects in the INS + TGZ group experienced significant weight gain (4.4 +/- 2.7 kg, P < 0.0005). No weight gain occurred in the INS + MET, INS + MET add TGZ, and INS + TGZ add MET groups.
CONCLUSIONS: Triple therapy using INS, MET, and TGZ resulted in lower HbA(lc) levels and total daily insulin dose than during dual therapy. The use of triple therapy resulted in 100% of subjects achieving an HbA(lc) <7.0%, while decreasing the dose of INS. Weight gain was avoided when MET therapy preceded the addition of TGZ therapy. The addition of TGZ resulted in the greatest reductions in HbA(lc) levels and insulin dose. Triple therapy using INS, MET, and a thiazolidinedione (such as TGZ) can be a safe and effective treatment in type 2 diabetes.
Rosenstock J, Brown A, Fischer J, Jain A, Littlejohn T, Nadeau D, Sussman A, Taylor T, Krol A, Magner J.
Efficacy and safety of acarbose in metformin-treated patients with type 2 diabetes.
Diabetes Care. 1998 Dec;21(12):2050-5. doi: 10.2337/diacare.21.12.2050.
Abstract/Text
OBJECTIVE: To demonstrate the efficacy, tolerability, and safety of acarbose compared with placebo in patients with type 2 diabetes inadequately controlled with diet and metformin (2,000 or 2,500 mg/day in divided doses).
RESEARCH DESIGN AND METHODS: This study had a multicenter randomized double-blind placebo-controlled parallel-group comparison design. The trial lasted 31 weeks and consisted of a 1-week screening period, a 6-week placebo pretreatment period, and a 24-week period of acarbose or placebo, with a forced titration from 25-50 mg t.i.d. and a titration of 50-100 mg tid that was based on glucose control. The primary efficacy variable was the mean change from baseline in HbA1c. Secondary efficacy variables included mean changes from baseline in fasting and postprandial plasma glucose, serum insulin, and triglyceride levels.
RESULTS: The addition of acarbose to patients on background metformin and diet therapy showed a statistically significant reduction in mean HbA1c of 0.65%. There were statistically significant reductions in fasting and postprandial plasma glucose and serum insulin levels compared with placebo. Gastrointestinal side effects were more frequently reported in the acarbose-treated patients. No significant differences in liver transaminase elevations were observed between patients treated with acarbose and those treated with placebo.
CONCLUSIONS: The results of this study demonstrate that the addition of acarbose to patients with type 2 diabetes who are inadequately controlled with metformin and diet is safe and generally well tolerated and that it significantly lowers HbA1c and fasting and postprandial glucose and insulin levels.
Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI.
Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus.
N Engl J Med. 1998 Mar 26;338(13):867-72. doi: 10.1056/NEJM199803263381303.
Abstract/Text
BACKGROUND: Combination therapy is logical for patients with non-insulin-dependent (type 2) diabetes mellitus, because they often have poor responses to single-drug therapy. We studied the efficacy and physiologic effects of metformin and troglitazone alone and in combination in patients with type 2 diabetes.
METHODS: We randomly assigned 29 patients to receive either metformin or troglitazone for three months, after which they were given both drugs for another three months. Plasma glucose concentrations during fasting and postprandially and glycosylated hemoglobin values were measured periodically during both treatments. Endogenous glucose production and peripheral glucose disposal were measured at base line and after three and six months.
RESULTS: During metformin therapy, fasting and postprandial plasma glucose concentrations decreased by 20 percent (58 mg per deciliter [3.2 mmol per liter], P<0.001) and 25 percent (87 mg per deciliter [4.8 mmol per liter], P<0.001), respectively. The corresponding decreases during troglitazone therapy were 20 percent (54 mg per deciliter [2.9 mmol per liter], P=0.01) and 25 percent (83 mg per deciliter [4.6 mmol per liter], P<0.001). Endogenous glucose production decreased during metformin therapy by a mean of 19 percent (P=0.001), whereas it was unchanged by troglitazone therapy (P=0.04 for the comparison between groups). The mean rate of glucose disposal increased by 54 percent during troglitazone therapy (P=0.006) and 13 percent during metformin therapy (P= 0.03 for the comparison within the group and between groups). In combination, metformin and troglitazone further lowered fasting and postprandial plasma glucose concentrations by 18 percent (41 mg per deciliter [2.3 mmol per liter], P=0.001) and 21 percent (54 mg per deciliter [3.0 mmol per liter], P<0.001), respectively, and the mean glycosylated hemoglobin value decreased 1.2 percentage points.
CONCLUSIONS: Metformin and troglitazone have equal and additive beneficial effects on glycemic control in patients with type 2 diabetes. Metformin acts primarily by decreasing endogenous glucose production, and troglitazone by increasing the rate of peripheral glucose disposal.
Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S.
Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes.
Diabetes Care. 2000 Nov;23(11):1660-5. doi: 10.2337/diacare.23.11.1660.
Abstract/Text
OBJECTIVE: To evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients inadequately controlled by diet, focusing on changes in HbA1c, fasting plasma glucose (FPG), and mealtime glucose excursions.
RESEARCH DESIGN AND METHODS: In this randomized double-blind study, patients with an HbA1c level between 6.8 and 11.0% during a 4-week placebo run-in received 24 weeks' treatment with 120 mg nateglinide before meals (n = 179), 500 mg metformin three times a day (n = 178), combination therapy (n = 172), or placebo (n = 172). HbA1c and FPG were evaluated regularly, and plasma glucose levels were determined after Sustacal challenge at weeks 0, 12, and 24. Hypoglycemia and other adverse events were recorded.
RESULTS: At study end point, HbA1c was reduced from baseline with nateglinide and metformin but was increased with placebo (-0.5, -0.8, and +0.5%, respectively; P < or = 0.0001). Changes in FPG followed the same pattern (-0.7, -1.6, and +0.4 mmol/l; P < or = 0.0001). Combination therapy was additive (HbA1c -1.4% and FPG -2.4 mmol/l; P < or = 0.01 vs. monotherapy). After Sustacal challenge, there was a greater reduction in mealtime glucose with nateglinide monotherapy compared with metformin monotherapy or placebo (adjusted area under the curve [AUC]0-130 min -2.1, -1.1, and -0.6 mmol x h(-1) x l(-1); p < or = 0.0001). An even greater effect was observed with combination therapy (AUC0-130 min -2.5 mmol x h(-1) x l(-1); P < or = 0.0001 vs. metformin and placebo). All regimens were well tolerated.
CONCLUSIONS: Nateglinide and metformin monotherapy each improved overall glycemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected FPG. In combination, nateglinide and metformin had complementary effects, improving HbA1c, FPG, and postprandial hyperglycemia.
Rao AD, Kuhadiya N, Reynolds K, Fonseca VA.
Is the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies.
Diabetes Care. 2008 Aug;31(8):1672-8. doi: 10.2337/dc08-0167. Epub 2008 May 5.
Abstract/Text
OBJECTIVE: Observational studies assessing the association of combination therapy of metformin and sulfonylurea on all-cause and/or cardiovascular mortality in type 2 diabetes have shown conflicting results. We therefore evaluated the effects of combination therapy of sulfonylureas and metformin on the risk of all-cause mortality and cardiovascular disease (CVD) among people with type 2 diabetes.
RESEARCH DESIGN AND METHODS: A MEDLINE search (January 1966-July 2007) was conducted to identify observational studies that examined the association between combination therapy of sulfonylureas and metformin on risk of CVD or all-cause mortality. From 299 relevant reports, 9 were included in the meta-analysis. In these studies, combination therapy of metformin and sulfonylurea was assessed, the risk of CVD and/or mortality was reported, and adjusted relative risk (RR) or equivalent (hazard ratio and odds ratio) and corresponding variance or equivalent was reported.
RESULTS: The pooled RRs (95% CIs) of outcomes for individuals with type 2 diabetes prescribed combination therapy of sulfonylureas and metformin were 1.19 (0.88-1.62) for all-cause mortality, 1.29 (0.73-2.27) for CVD mortality, and 1.43 (1.10-1.85) for a composite end point of CVD hospitalizations or mortality (fatal or nonfatal events).
CONCLUSIONS: The combination therapy of metformin and sulfonylurea significantly increased the RR of the composite end point of cardiovascular hospitalization or mortality (fatal and nonfatal events) irrespective of the reference group (diet therapy, metformin monotherapy, or sulfonylurea monotherapy); however, there were no significant effects of this combination therapy on either CVD mortality or all-cause mortality alone.
Roumie CL, Hung AM, Greevy RA, Grijalva CG, Liu X, Murff HJ, Elasy TA, Griffin MR.
Comparative effectiveness of sulfonylurea and metformin monotherapy on cardiovascular events in type 2 diabetes mellitus: a cohort study.
Ann Intern Med. 2012 Nov 6;157(9):601-10. doi: 10.7326/0003-4819-157-9-201211060-00003.
Abstract/Text
BACKGROUND: The effects of sulfonylureas and metformin on outcomes of cardiovascular disease (CVD) in type 2 diabetes are not well-characterized.
OBJECTIVE: To compare the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death.
DESIGN: Retrospective cohort study.
SETTING: National Veterans Health Administration databases linked to Medicare files.
PATIENTS: Veterans who initiated metformin or sulfonylurea therapy for diabetes. Patients with chronic kidney disease or serious medical illness were excluded.
MEASUREMENTS: Composite outcome of hospitalization for acute myocardial infarction or stroke, or death, adjusted for baseline demographic characteristics; medications; cholesterol, hemoglobin A1c, and serum creatinine levels; blood pressure; body mass index; health care utilization; and comorbid conditions.
RESULTS: Among 253 690 patients initiating treatment (98 665 with sulfonylurea therapy and 155 025 with metformin therapy), crude rates of the composite outcome were 18.2 per 1000 person-years in sulfonylurea users and 10.4 per 1000 person-years in metformin users (adjusted incidence rate difference, 2.2 [95% CI, 1.4 to 3.0] more CVD events with sulfonylureas per 1000 person-years; adjusted hazard ratio [aHR], 1.21 [CI, 1.13 to 1.30]). Results were consistent for both glyburide (aHR, 1.26 [CI, 1.16 to 1.37]) and glipizide (aHR, 1.15 [CI, 1.06 to 1.26]) in subgroups by CVD history, age, body mass index, and albuminuria; in a propensity score-matched cohort analysis; and in sensitivity analyses.
LIMITATION: Most of the veterans in the study population were white men; data on women and minority groups were limited but reflective of the Veterans Health Administration population.
CONCLUSION: Use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality and the U.S. Department of Health and Human Services.
ビグアナイド薬の適正使用に関する委員会：メトホルミンの適正使用に関するRecommendation. 2020. Available from: http://www.jds.or.jp/modules/important/index.php?content_id=20
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators.
Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
N Engl J Med. 2013 Oct 3;369(14):1327-35. doi: 10.1056/NEJMoa1305889. Epub 2013 Sep 2.
Abstract/Text
BACKGROUND: To assess potentially elevated cardiovascular risk related to new antihyperglycemic drugs in patients with type 2 diabetes, regulatory agencies require a comprehensive evaluation of the cardiovascular safety profile of new antidiabetic therapies. We assessed cardiovascular outcomes with alogliptin, a new inhibitor of dipeptidyl peptidase 4 (DPP-4), as compared with placebo in patients with type 2 diabetes who had had a recent acute coronary syndrome.
METHODS: We randomly assigned patients with type 2 diabetes and either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days to receive alogliptin or placebo in addition to existing antihyperglycemic and cardiovascular drug therapy. The study design was a double-blind, noninferiority trial with a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point of a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
RESULTS: A total of 5380 patients underwent randomization and were followed for up to 40 months (median, 18 months). A primary end-point event occurred in 305 patients assigned to alogliptin (11.3%) and in 316 patients assigned to placebo (11.8%) (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P<0.001 for noninferiority). Glycated hemoglobin levels were significantly lower with alogliptin than with placebo (mean difference, -0.36 percentage points; P<0.001). Incidences of hypoglycemia, cancer, pancreatitis, and initiation of dialysis were similar with alogliptin and placebo.
CONCLUSIONS: Among patients with type 2 diabetes who had had a recent acute coronary syndrome, the rates of major adverse cardiovascular events were not increased with the DPP-4 inhibitor alogliptin as compared with placebo. (Funded by Takeda Development Center Americas; EXAMINE ClinicalTrials.gov number, NCT00968708.).
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators.
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
N Engl J Med. 2013 Oct 3;369(14):1317-26. doi: 10.1056/NEJMoa1307684. Epub 2013 Sep 2.
Abstract/Text
BACKGROUND: The cardiovascular safety and efficacy of many current antihyperglycemic agents, including saxagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, are unclear.
METHODS: We randomly assigned 16,492 patients with type 2 diabetes who had a history of, or were at risk for, cardiovascular events to receive saxagliptin or placebo and followed them for a median of 2.1 years. Physicians were permitted to adjust other medications, including antihyperglycemic agents. The primary end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke.
RESULTS: A primary end-point event occurred in 613 patients in the saxagliptin group and in 609 patients in the placebo group (7.3% and 7.2%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio with saxagliptin, 1.00; 95% confidence interval [CI], 0.89 to 1.12; P=0.99 for superiority; P<0.001 for noninferiority); the results were similar in the "on-treatment" analysis (hazard ratio, 1.03; 95% CI, 0.91 to 1.17). The major secondary end point of a composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, coronary revascularization, or heart failure occurred in 1059 patients in the saxagliptin group and in 1034 patients in the placebo group (12.8% and 12.4%, respectively, according to 2-year Kaplan-Meier estimates; hazard ratio, 1.02; 95% CI, 0.94 to 1.11; P=0.66). More patients in the saxagliptin group than in the placebo group were hospitalized for heart failure (3.5% vs. 2.8%; hazard ratio, 1.27; 95% CI, 1.07 to 1.51; P=0.007). Rates of adjudicated cases of acute and chronic pancreatitis were similar in the two groups (acute pancreatitis, 0.3% in the saxagliptin group and 0.2% in the placebo group; chronic pancreatitis, <0.1% and 0.1% in the two groups, respectively).
CONCLUSIONS: DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. (Funded by AstraZeneca and Bristol-Myers Squibb; SAVOR-TIMI 53 ClinicalTrials.gov number, NCT01107886.).
Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS.
SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials.
Lancet. 2019 Jan 5;393(10166):31-39. doi: 10.1016/S0140-6736(18)32590-X. Epub 2018 Nov 10.
Abstract/Text
BACKGROUND: The magnitude of effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics remains undefined.
METHODS: We did a systematic review and meta-analysis of randomised, placebo-controlled, cardiovascular outcome trials of SGLT2i in patients with type 2 diabetes. We searched PubMed and Embase for trials published up to Sept 24, 2018. Data search and extraction were completed with a standardised data form and any discrepancies were resolved by consensus. Efficacy outcomes included major adverse cardiovascular events (myocardial infarction, stroke, or cardiovascular death), the composite of cardiovascular death or hospitalisation for heart failure, and progression of renal disease. Hazard ratios (HRs) with 95% CIs were pooled across trials, and efficacy outcomes were stratified by baseline presence of atherosclerotic cardiovascular disease, heart failure, and degree of renal function.
FINDINGS: We included data from three identified trials and 34 322 patients (60·2% with established atherosclerotic cardiovascular disease), with 3342 major adverse cardiovascular events, 2028 cardiovascular deaths or hospitalisation sfor heart failure events, and 766 renal composite outcomes. SGLT2i reduced major adverse cardiovascular events by 11% (HR 0·89 [95% CI 0·83-0·96], p=0·0014), with benefit only seen in patients with atherosclerotic cardiovascular disease (0·86 [0·80-0·93]) and not in those without (1·00 [0·87-1·16], p for interaction=0·0501). SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (0·77 [0·71-0·84], p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure. SGLT2i reduced the risk of progression of renal disease by 45% (0·55 [0·48-0·64], p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease. The magnitude of benefit of SGLT2i varied with baseline renal function, with greater reductions in hospitalisations for heart failure (p for interaction=0·0073) and lesser reductions in progression of renal disease (p for interaction=0·0258) in patients with more severe kidney disease at baseline.
INTERPRETATION: SGLT2i have moderate benefits on atherosclerotic major adverse cardiovascular events that seem confined to patients with established atherosclerotic cardiovascular disease. However, they have robust benefits on reducing hospitalisation for heart failure and progression of renal disease regardless of existing atherosclerotic cardiovascular disease or a history of heart failure.
FUNDING: None.
Copyright © 2019 Elsevier Ltd. All rights reserved.
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators.
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
N Engl J Med. 2019 Nov 21;381(21):1995-2008. doi: 10.1056/NEJMoa1911303. Epub 2019 Sep 19.
Abstract/Text
BACKGROUND: In patients with type 2 diabetes, inhibitors of sodium-glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
METHODS: In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
RESULTS: Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.
CONCLUSIONS: Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. (Funded by AstraZeneca; DAPA-HF ClinicalTrials.gov number, NCT03036124.).
Copyright © 2019 Massachusetts Medical Society.
Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators.
Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure.
N Engl J Med. 2020 Oct 8;383(15):1413-1424. doi: 10.1056/NEJMoa2022190. Epub 2020 Aug 28.
Abstract/Text
BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure in patients regardless of the presence or absence of diabetes. More evidence is needed regarding the effects of these drugs in patients across the broad spectrum of heart failure, including those with a markedly reduced ejection fraction.
METHODS: In this double-blind trial, we randomly assigned 3730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive empagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure.
RESULTS: During a median of 16 months, a primary outcome event occurred in 361 of 1863 patients (19.4%) in the empagliflozin group and in 462 of 1867 patients (24.7%) in the placebo group (hazard ratio for cardiovascular death or hospitalization for heart failure, 0.75; 95% confidence interval [CI], 0.65 to 0.86; P<0.001). The effect of empagliflozin on the primary outcome was consistent in patients regardless of the presence or absence of diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.70; 95% CI, 0.58 to 0.85; P<0.001). The annual rate of decline in the estimated glomerular filtration rate was slower in the empagliflozin group than in the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001), and empagliflozin-treated patients had a lower risk of serious renal outcomes. Uncomplicated genital tract infection was reported more frequently with empagliflozin.
CONCLUSIONS: Among patients receiving recommended therapy for heart failure, those in the empagliflozin group had a lower risk of cardiovascular death or hospitalization for heart failure than those in the placebo group, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Reduced ClinicalTrials.gov number, NCT03057977.).
Copyright © 2020 Massachusetts Medical Society.
Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, Brunner-La Rocca HP, Choi DJ, Chopra V, Chuquiure-Valenzuela E, Giannetti N, Gomez-Mesa JE, Janssens S, Januzzi JL, Gonzalez-Juanatey JR, Merkely B, Nicholls SJ, Perrone SV, Piña IL, Ponikowski P, Senni M, Sim D, Spinar J, Squire I, Taddei S, Tsutsui H, Verma S, Vinereanu D, Zhang J, Carson P, Lam CSP, Marx N, Zeller C, Sattar N, Jamal W, Schnaidt S, Schnee JM, Brueckmann M, Pocock SJ, Zannad F, Packer M; EMPEROR-Preserved Trial Investigators.
Empagliflozin in Heart Failure with a Preserved Ejection Fraction.
N Engl J Med. 2021 Oct 14;385(16):1451-1461. doi: 10.1056/NEJMoa2107038. Epub 2021 Aug 27.
Abstract/Text
BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain.
METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure.
RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin.
CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951).
Copyright © 2021 Massachusetts Medical Society.
Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW; CREDENCE Trial Investigators.
Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy.
N Engl J Med. 2019 Jun 13;380(24):2295-2306. doi: 10.1056/NEJMoa1811744. Epub 2019 Apr 14.
Abstract/Text
BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.
RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P = 0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P = 0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.
CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).
Copyright © 2019 Massachusetts Medical Society.
Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators.
Dapagliflozin in Patients with Chronic Kidney Disease.
N Engl J Med. 2020 Oct 8;383(15):1436-1446. doi: 10.1056/NEJMoa2024816. Epub 2020 Sep 24.
Abstract/Text
BACKGROUND: Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.
METHODS: We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.
RESULTS: The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.
CONCLUSIONS: Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.).
Copyright © 2020 Massachusetts Medical Society.
American Diabetes Association: Standards of Medical Care in Diabetes-2023. Diabetes Care. 2023; 46: S1-S291.
SGLT2阻害薬薬の適正使用に関する委員会. 糖尿病治療におけるSGLT2阻害薬の適正使用に関するRecommendation. 2022. Available from: http://www.jds.or.jp/uploads/files/recommendation/SGLT2.pdf
Hanefeld M, Cagatay M, Petrowitsch T, Neuser D, Petzinna D, Rupp M.
Acarbose reduces the risk for myocardial infarction in type 2 diabetic patients: meta-analysis of seven long-term studies.
Eur Heart J. 2004 Jan;25(1):10-6. doi: 10.1016/s0195-668x(03)00468-8.
Abstract/Text
AIMS: To assess if treatment with the alpha-glucosidase inhibitor acarbose can reduce cardiovascular events in type 2 diabetic patients.
METHODS AND RESULTS: This meta-analysis included seven randomized, double-blind, placebo-controlled acarbose studies with a minimum treatment duration of 52 weeks. Type 2 diabetic patients valid for safety were randomized to either acarbose (n=1248) or placebo (n=932). The primary outcome measure was the time to develop a cardiovascular event. Primary analysis was conducted using Cox regression analysis. The effect of acarbose on metabolic parameters was also investigated. Acarbose therapy showed favourable trends towards risk reduction for all selected cardiovascular event categories. The treatment significantly reduced the risk for "myocardial infarction" (hazards ratio=0.36 [95% Cl 0.16-0.80], P=0.0120) and "any cardiovascular event" (0.65 [95% Cl 0.48-0.88], P=0.0061). Glycaemic control, triglyceride levels, body weight and systolic blood pressure also improved significantly during acarbose treatment.
CONCLUSION: Intervention with acarbose can prevent myocardial infarction and cardiovascular disease in type 2 diabetic patients while most of them are already on intensive concomitant cardiovascular medication.
Van de Laar FA, Lucassen PL, Akkermans RP, Van de Lisdonk EH, Rutten GE, Van Weel C.
Alpha-glucosidase inhibitors for type 2 diabetes mellitus.
Cochrane Database Syst Rev. 2005 Apr 18;2005(2):CD003639. doi: 10.1002/14651858.CD003639.pub2. Epub 2005 Apr 18.
Abstract/Text
BACKGROUND: Alpha-glucosidase inhibitors such as acarbose or miglitol, have the potential to improve glycemic control in type 2 diabetes mellitus. The true value of these agents, especially in relation to diabetes related mortality and morbidity, has never been investigated in a systematic literature review and meta-analysis.
OBJECTIVES: To assess the effects of alpha-glucosidase inhibitors s in patients with type 2 diabetes mellitus.
SEARCH STRATEGY: We searched The Cochrane Library, MEDLINE, EMBASE, Current Contents, LILACS, databases of ongoing trials, reference lists of reviews on the topic of alpha-glucosidase inhibitors and we contacted experts and manufacturers for additional trials. Date of most recent search: December 2003 (Current Contents) and April 2003 (other databases).
SELECTION CRITERIA: Randomised controlled trials of at least 12 weeks duration comparing alpha-glucosidase inhibitor monotherapy in patients with type 2 diabetes with any other intervention and that included at least one of the following outcomes: mortality, morbidity, quality of life, glycemic control, lipids, insulin levels, body weight, adverse events.
DATA COLLECTION AND ANALYSIS: Two reviewers read all abstracts, assessed quality and extracted data independently. Discrepancies were resolved by consensus or by the judgement of a third reviewer. A statistician checked all extracted data entrance in the database. We attempted to contact all authors for data clarification.
MAIN RESULTS: We included 41 trials (8130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life. Acarbose had a clear effect on glycemic control compared to placebo: glycated haemoglobin -0.8% (95% confidence interval -0.9 to -0.7), fasting blood glucose -1.1 mmol/L (95% confidence interval -1.4 to -0.9), post-load blood glucose -2.3 mmol/L (95% confidence interval -2.7 to -1.9). The effect on glycated haemoglobin by acarbose was not dose-dependent. We found a decreasing effect on post-load insulin and no clinically relevant effects on lipids or body weight. Adverse effects were mostly of gastro-intestinal origin and dose dependent. Compared to sulphonylurea, acarbose decreased fasting and post-load insulin levels by -24.8 pmol/L (95% confidence interval -43.3 to -6.3) and -133.2 pmol/L (95% confidence interval -184.5 to -81.8) respectively and acarbose caused more adverse effects.
AUTHORS' CONCLUSIONS: It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated hemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators.
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes.
N Engl J Med. 2016 Jul 28;375(4):311-22. doi: 10.1056/NEJMoa1603827. Epub 2016 Jun 13.
Abstract/Text
BACKGROUND: The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown.
METHODS: In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes.
RESULTS: A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group.
CONCLUSIONS: In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048.).
Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T; REWIND Investigators.
Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial.
Lancet. 2019 Jul 13;394(10193):121-130. doi: 10.1016/S0140-6736(19)31149-3. Epub 2019 Jun 9.
Abstract/Text
BACKGROUND: Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.
METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.
FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years [SD 6·5], median HbA1c 7·2% [IQR 6·6-8·1], 4589 [46·3%] women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1-5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio [HR] 0·88, 95% CI 0·79-0·99; p=0·026). All-cause mortality did not differ between groups (536 [10·8%] in the dulaglutide group vs 592 [12·0%] in the placebo group; HR 0·90, 95% CI 0·80-1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).
INTERPRETATION: Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
FUNDING: Eli Lilly and Company.
Copyright © 2019 Elsevier Ltd. All rights reserved.
Kosiborod MN, Petrie MC, Borlaug BA, Butler J, Davies MJ, Hovingh GK, Kitzman DW, Møller DV, Treppendahl MB, Verma S, Jensen TJ, Liisberg K, Lindegaard ML, Abhayaratna W, Ahmed FZ, Ben-Gal T, Chopra V, Ezekowitz JA, Fu M, Ito H, Lelonek M, Melenovský V, Merkely B, Núñez J, Perna E, Schou M, Senni M, Sharma K, van der Meer P, Von Lewinski D, Wolf D, Shah SJ; STEP-HFpEF DM Trial Committees and Investigators.
Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.
N Engl J Med. 2024 Apr 18;390(15):1394-1407. doi: 10.1056/NEJMoa2313917. Epub 2024 Apr 6.
Abstract/Text
BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes.
METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level.
RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group.
CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).
Copyright © 2024 Massachusetts Medical Society.
Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R; FLOW Trial Committees and Investigators.
Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes.
N Engl J Med. 2024 Jul 11;391(2):109-121. doi: 10.1056/NEJMoa2403347. Epub 2024 May 24.
Abstract/Text
BACKGROUND: Patients with type 2 diabetes and chronic kidney disease are at high risk for kidney failure, cardiovascular events, and death. Whether treatment with semaglutide would mitigate these risks is unknown.
METHODS: We randomly assigned patients with type 2 diabetes and chronic kidney disease (defined by an estimated glomerular filtration rate [eGFR] of 50 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio [with albumin measured in milligrams and creatinine measured in grams] of >300 and <5000 or an eGFR of 25 to <50 ml per minute per 1.73 m2 and a urinary albumin-to-creatinine ratio of >100 and <5000) to receive subcutaneous semaglutide at a dose of 1.0 mg weekly or placebo. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml per minute per 1.73 m2), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes. Prespecified confirmatory secondary outcomes were tested hierarchically.
RESULTS: Among the 3533 participants who underwent randomization (1767 in the semaglutide group and 1766 in the placebo group), median follow-up was 3.4 years, after early trial cessation was recommended at a prespecified interim analysis. The risk of a primary-outcome event was 24% lower in the semaglutide group than in the placebo group (331 vs. 410 first events; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.88; P = 0.0003). Results were similar for a composite of the kidney-specific components of the primary outcome (hazard ratio, 0.79; 95% CI, 0.66 to 0.94) and for death from cardiovascular causes (hazard ratio, 0.71; 95% CI, 0.56 to 0.89). The results for all confirmatory secondary outcomes favored semaglutide: the mean annual eGFR slope was less steep (indicating a slower decrease) by 1.16 ml per minute per 1.73 m2 in the semaglutide group (P<0.001), the risk of major cardiovascular events 18% lower (hazard ratio, 0.82; 95% CI, 0.68 to 0.98; P = 0.029), and the risk of death from any cause 20% lower (hazard ratio, 0.80; 95% CI, 0.67 to 0.95, P = 0.01). Serious adverse events were reported in a lower percentage of participants in the semaglutide group than in the placebo group (49.6% vs. 53.8%).
CONCLUSIONS: Semaglutide reduced the risk of clinically important kidney outcomes and death from cardiovascular causes in patients with type 2 diabetes and chronic kidney disease. (Funded by Novo Nordisk; FLOW ClinicalTrials.gov number, NCT03819153.).
Copyright © 2024 Massachusetts Medical Society.
Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, Fosbøl EL, Køber L, Norgaard ML, Madsen M, Hansen PR, Torp-Pedersen C.
Mortality and cardiovascular risk associated with different insulin secretagogues compared with metformin in type 2 diabetes, with or without a previous myocardial infarction: a nationwide study.
Eur Heart J. 2011 Aug;32(15):1900-8. doi: 10.1093/eurheartj/ehr077. Epub 2011 Apr 6.
Abstract/Text
AIMS: The impact of insulin secretagogues (ISs) on long-term major clinical outcomes in type 2 diabetes remains unclear. We examined mortality and cardiovascular risk associated with all available ISs compared with metformin in a nationwide study.
METHODS AND RESULTS: All Danish residents >20 years, initiating single-agent ISs or metformin between 1997 and 2006 were followed for up to 9 years (median 3.3 years) by individual-level linkage of nationwide registers. All-cause mortality, cardiovascular mortality, and the composite of myocardial infarction (MI), stroke, and cardiovascular mortality associated with individual ISs were investigated in patients with or without previous MI by multivariable Cox proportional-hazard analyses including propensity analyses. A total of 107 806 subjects were included, of whom 9607 had previous MI. Compared with metformin, glimepiride (hazard ratios and 95% confidence intervals): 1.32 (1.24-1.40), glibenclamide: 1.19 (1.11-1.28), glipizide: 1.27 (1.17-1.38), and tolbutamide: 1.28 (1.17-1.39) were associated with increased all-cause mortality in patients without previous MI. The corresponding results for patients with previous MI were as follows: glimepiride: 1.30 (1.11-1.44), glibenclamide: 1.47 (1.22-1.76), glipizide: 1.53 (1.23-1.89), and tolbutamide: 1.47 (1.17-1.84). Results for gliclazide [1.05 (0.94-1.16) and 0.90 (0.68-1.20)] and repaglinide and [0.97 (0.81-1.15) and 1.29 (0.86-1.94)] were not statistically different from metformin in both patients without and with previous MI, respectively. Results were similar for cardiovascular mortality and for the composite endpoint.
CONCLUSION: Monotherapy with the most used ISs, including glimepiride, glibenclamide, glipizide, and tolbutamide, seems to be associated with increased mortality and cardiovascular risk compared with metformin. Gliclazide and repaglinide appear to be associated with a lower risk than other ISs.
Holstein A, Plaschke A, Egberts EH.
Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.
Diabetes Metab Res Rev. 2001 Nov-Dec;17(6):467-73. doi: 10.1002/dmrr.235.
Abstract/Text
BACKGROUND: Severe hypoglycaemia is a potentially life-threatening condition. The aim of the present study was to compare the frequency of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.
METHODS: This prospective, population-based, 4-year study examined the incidence of severe hypoglycaemia in a region of Germany with 200 000 inhabitants. The blood glucose of all 30 768 patients who attended the emergency department of the region's central hospital was determined to detect severe hypoglycaemia, which was defined by the requirement for intravenous glucose or glucagon injection and blood glucose value of <2.8 mmol/l. Additionally, 6631/7804 patients (85%) attended to by the emergency medical services received a blood glucose test at the emergency site. The regional prescribing frequency of both sulphonylureas was determined by an independent external institute.
RESULTS: Despite glimepiride being prescribed more frequently than glibenclamide (6976 vs 6789 person-years), glimepiride induced fewer episodes of hypoglycaemia (6 vs 38 episodes); one episode occurred with a combination of the two preparations. The incidence of severe hypoglycaemia was 0.86/1000 person-years for glimepiride and 5.6/1000 person-years for glibenclamide. The characteristics of the 45 patients who presented with sulphonylurea-associated hypoglycaemia were as follows: mean age 79 years (95% CI 75.2; 82.6); glycosylated haemoglobin 5.4% (95% CI 5.1; 5.7); impaired renal function in 62%.
CONCLUSIONS: In people with type 2 diabetes, glimepiride was associated with fewer episodes of severe hypoglycaemia than glibenclamide in routine clinical use. However, severe hypoglycaemia did occur with glimepiride and may be minimised if treatment targets are determined on an individual basis.
Copyright 2001 John Wiley & Sons, Ltd.
Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM.
A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin.
Diabetes Care. 2007 Feb;30(2):389-94. doi: 10.2337/dc06-1789.
Abstract/Text
OBJECTIVE: Glyburide is the most widely used sulfonylurea but has unique pharmacodynamic properties that may increase harm. We hypothesized that glyburide causes more hypoglycemia and cardiovascular events than other secretagogues or insulin.
RESEARCH DESIGN AND METHODS: Data sources were Medline, Embase, Cochrane, and three other web-based clinical trial registers (1966-2005). Parallel, randomized, controlled trials in people with type 2 diabetes comparing glyburide monotherapy with monotherapy using secretagogues or insulin were selected. Outcomes were hypoglycemia, glycemic control, cardiovascular events, body weight, and death. Titles and abstracts of 1,806 publications were reviewed in duplicate and 21 relevant articles identified. Data on patient characteristics, interventions, outcomes, and validity were extracted in duplicate using predefined criteria.
RESULTS: Glyburide was associated with a 52% greater risk of experiencing at least one episode of hypoglycemia compared with other secretagogues (relative risk 1.52 [95% CI 1.21-1.92]) and with 83% greater risk compared with other sulfonylureas (1.83 [1.35-2.49]). Glyburide was not associated with an increased risk of cardiovascular events (0.84 [0.56-1.26]), death (0.87 [0.70-1.07]), or end-of-trial weight (weighted mean difference 1.69 kg [95% CI -0.41 to 3.80]) compared with other secretagogues. Limitations included suboptimal reporting of original trials. Loss to follow-up exceeded 20% in some studies, and major hypoglycemia was infrequently reported.
CONCLUSIONS: Glyburide caused more hypoglycemia than other secretagogues and other sulfonylureas. Glyburide was not associated with an increased risk of cardiovascular events, death, or weight gain.
Zeller M, Danchin N, Simon D, Vahanian A, Lorgis L, Cottin Y, Berland J, Gueret P, Wyart P, Deturck R, Tabone X, Machecourt J, Leclercq F, Drouet E, Mulak G, Bataille V, Cambou JP, Ferrieres J, Simon T; French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction investigators.
Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction.
J Clin Endocrinol Metab. 2010 Nov;95(11):4993-5002. doi: 10.1210/jc.2010-0449. Epub 2010 Aug 11.
Abstract/Text
BACKGROUND: The impact of antidiabetic medications on clinical outcomes in patients developing acute myocardial infarction (MI) is controversial. We sought to determine whether in-hospital outcomes in patients who were on sulfonylureas (SUs) when they developed their MIs differed from that of diabetic patients not receiving SUs and whether clinical outcomes were related to the pancreatic cells specificity of SUs.
METHODS AND RESULTS: We analyzed the outcomes of the 1310 diabetic patients included in the nationwide French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction in 2005. Medications used before the acute episode were recorded. In-hospital complications were analyzed according to prior antidiabetic treatment. Mortality was lower in patients previously treated with SUs (3.9%) vs. those on other oral medications (6.4%), insulin (9.4%), or no medication (8.4%) (P = 0.014). Among SU-treated patients, in-hospital mortality was lower in patients receiving pancreatic cells-specific SUs (gliclazide or glimepiride) (2.7%), compared with glibenclamide (7.5%) (P = 0.019). Arrhythmias and ischemic complications were also less frequent in patients receiving gliclazide/glimepiride. The lower risk in patients receiving gliclazide/glimepiride vs. glibenclamide persisted after multivariate adjustment (odds ratio 0.15; 95% confidence interval 0.04-0.56) and in propensity score-matched cohorts.
CONCLUSION: In this nationwide registry of patients hospitalized for acute MI, no hazard was associated with the use of SUs before the acute episode. In addition, patients previously receiving gliclazide/glimepiride had improved in-hospital outcomes, compared with those on glibenclamide.
Monami M, Balzi D, Lamanna C, Barchielli A, Masotti G, Buiatti E, Marchionni N, Mannucci E.
Are sulphonylureas all the same? A cohort study on cardiovascular and cancer-related mortality.
Diabetes Metab Res Rev. 2007 Sep;23(6):479-84. doi: 10.1002/dmrr.736.
Abstract/Text
BACKGROUND: Aim of the present study is the comparison of all-cause, cardiovascular and non-cardiovascular mortality, and cardiac morbidity, between patients treated with glibenclamide and gliclazide.
METHODS: A retrospective observational cohort study was performed on a consecutive series of 568 outpatients (282 women, 286 men) with type 2 diabetes treated with either glibenclamide (n = 378) or gliclazide (n = 190). Information on all-cause mortality and on causes of death up to 31 December 2004 was obtained by the City of Florence Registry Office. Non-fatal cases requiring hospitalization were identified through the regional hospital discharge system using International Classification of Diseases.
RESULTS: Mean follow-up was 5.0 +/- 1.6 and 4.4 +/- 2.0 years for death and cardiac events, respectively; during follow-up, 33 and 11 deaths were observed in the glibenclamide and gliclazide groups, with a yearly mortality rate of 4.3 and 2.2%, respectively (p < 0.05). At Cox regression, after adjustment for potential confounders, including comorbidity, glibenclamide treatment was associated with a significant increase in all-cause mortality [OR 2.1(1.2;2.7), p < 0.05], while the difference in cardiovascular mortality was not statistically significant after adjustment for age and sex. Mortality for malignancies was significantly higher in patients treated with glibenclamide after adjustment for age, sex, BMI, and insulin and metformin treatment, [OR 3.6(1.1;11.9); p < 0.05]. A higher incidence of cardiac events was associated with glibenclamide treatment only in patients with previously known ischaemic heart disease.
CONCLUSIONS: Treatment with glibenclamide could be associated with higher mortality for cardiovascular diseases and malignancies, in comparison with gliclazide.
Vaccaro O, Masulli M, Nicolucci A, Bonora E, Del Prato S, Maggioni AP, Rivellese AA, Squatrito S, Giorda CB, Sesti G, Mocarelli P, Lucisano G, Sacco M, Signorini S, Cappellini F, Perriello G, Babini AC, Lapolla A, Gregori G, Giordano C, Corsi L, Buzzetti R, Clemente G, Di Cianni G, Iannarelli R, Cordera R, La Macchia O, Zamboni C, Scaranna C, Boemi M, Iovine C, Lauro D, Leotta S, Dall'Aglio E, Cannarsa E, Tonutti L, Pugliese G, Bossi AC, Anichini R, Dotta F, Di Benedetto A, Citro G, Antenucci D, Ricci L, Giorgino F, Santini C, Gnasso A, De Cosmo S, Zavaroni D, Vedovato M, Consoli A, Calabrese M, di Bartolo P, Fornengo P, Riccardi G; Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA.IT) study group; Italian Diabetes Society.
Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial.
Lancet Diabetes Endocrinol. 2017 Nov;5(11):887-897. doi: 10.1016/S2213-8587(17)30317-0. Epub 2017 Sep 13.
Abstract/Text
BACKGROUND: The best treatment option for patients with type 2 diabetes in whom treatment with metformin alone fails to achieve adequate glycaemic control is debated. We aimed to compare the long-term effects of pioglitazone versus sulfonylureas, given in addition to metformin, on cardiovascular events in patients with type 2 diabetes.
METHODS: TOSCA.IT was a multicentre, randomised, pragmatic clinical trial, in which patients aged 50-75 years with type 2 diabetes inadequately controlled with metformin monotherapy (2-3 g per day) were recruited from 57 diabetes clinics in Italy. Patients were randomly assigned (1:1), by permuted blocks randomisation (block size 10), stratified by site and previous cardiovascular events, to add-on pioglitazone (15-45 mg) or a sulfonylurea (5-15 mg glibenclamide, 2-6 mg glimepiride, or 30-120 mg gliclazide, in accordance with local practice). The trial was unblinded, but event adjudicators were unaware of treatment assignment. The primary outcome, assessed with a Cox proportional-hazards model, was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularisation, assessed in the modified intention-to-treat population (all randomly assigned participants with baseline data available and without any protocol violations in relation to inclusion or exclusion criteria). This study is registered with ClinicalTrials.gov, number NCT00700856.
FINDINGS: Between Sept 18, 2008, and Jan 15, 2014, 3028 patients were randomly assigned and included in the analyses. 1535 were assigned to pioglitazone and 1493 to sulfonylureas (glibenclamide 24 [2%], glimepiride 723 [48%], gliclazide 745 [50%]). At baseline, 335 (11%) participants had a previous cardiovascular event. The study was stopped early on the basis of a futility analysis after a median follow-up of 57·3 months. The primary outcome occurred in 105 patients (1·5 per 100 person-years) who were given pioglitazone and 108 (1·5 per 100 person-years) who were given sulfonylureas (hazard ratio 0·96, 95% CI 0·74-1·26, p=0·79). Fewer patients had hypoglycaemias in the pioglitazone group than in the sulfonylureas group (148 [10%] vs 508 [34%], p<0·0001). Moderate weight gain (less than 2 kg, on average) occurred in both groups. Rates of heart failure, bladder cancer, and fractures were not significantly different between treatment groups.
INTERPRETATION: In this long-term, pragmatic trial, incidence of cardiovascular events was similar with sulfonylureas (mostly glimepiride and gliclazide) and pioglitazone as add-on treatments to metformin. Both of these widely available and affordable treatments are suitable options with respect to efficacy and adverse events, although pioglitazone was associated with fewer hypoglycaemia events.
FUNDING: Italian Medicines Agency, Diabete Ricerca, and Italian Diabetes Society.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M, Baanstra D, Meinicke T, George JT, von Eynatten M, McGuire DK, Marx N; CAROLINA Investigators.
Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial.
JAMA. 2019 Sep 24;322(12):1155-1166. doi: 10.1001/jama.2019.13772.
Abstract/Text
IMPORTANCE: Type 2 diabetes is associated with increased cardiovascular risk. In placebo-controlled cardiovascular safety trials, the dipeptidyl peptidase-4 inhibitor linagliptin demonstrated noninferiority, but it has not been tested against an active comparator.
OBJECTIVE: This trial assessed cardiovascular outcomes of linagliptin vs glimepiride (sulfonylurea) in patients with relatively early type 2 diabetes and risk factors for or established atherosclerotic cardiovascular disease.
DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, active-controlled, noninferiority trial, with participant screening from November 2010 to December 2012, conducted at 607 hospital and primary care sites in 43 countries involving 6042 participants. Adults with type 2 diabetes, glycated hemoglobin of 6.5% to 8.5%, and elevated cardiovascular risk were eligible for inclusion. Elevated cardiovascular risk was defined as documented atherosclerotic cardiovascular disease, multiple cardiovascular risk factors, aged at least 70 years, and evidence of microvascular complications. Follow-up ended in August 2018.
INTERVENTIONS: Patients were randomized to receive 5 mg of linagliptin once daily (n = 3023) or 1 to 4 mg of glimepiride once daily (n = 3010) in addition to usual care. Investigators were encouraged to intensify glycemic treatment, primarily by adding or adjusting metformin, α-glucosidase inhibitors, thiazolidinediones, or insulin, according to clinical need.
MAIN OUTCOMES AND MEASURES: The primary outcome was time to first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke with the aim to establish noninferiority of linagliptin vs glimepiride, defined by the upper limit of the 2-sided 95.47% CI for the hazard ratio (HR) of linagliptin relative to glimepiride of less than 1.3.
RESULTS: Of 6042 participants randomized, 6033 (mean age, 64.0 years; 2414 [39.9%] women; mean glycated hemoglobin, 7.2%; median duration of diabetes, 6.3 years; 42% with macrovascular disease; 59% had undergone metformin monotherapy) were treated and analyzed. The median duration of follow-up was 6.3 years. The primary outcome occurred in 356 of 3023 participants (11.8%) in the linagliptin group and 362 of 3010 (12.0%) in the glimepiride group (HR, 0.98 [95.47% CI, 0.84-1.14]; P < .001 for noninferiority), meeting the noninferiority criterion but not superiority (P = .76). Adverse events occurred in 2822 participants (93.4%) in the linagliptin group and 2856 (94.9%) in the glimepiride group, with 15 participants (0.5%) in the linagliptin group vs 16 (0.5%) in the glimepiride group with adjudicated-confirmed acute pancreatitis. At least 1 episode of hypoglycemic adverse events occurred in 320 (10.6%) participants in the linagliptin group and 1132 (37.7%) in the glimepiride group (HR, 0.23 [95% CI, 0.21-0.26]).
CONCLUSIONS AND RELEVANCE: Among adults with relatively early type 2 diabetes and elevated cardiovascular risk, the use of linagliptin compared with glimepiride over a median 6.3 years resulted in a noninferior risk of a composite cardiovascular outcome.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01243424.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefèbvre PJ, Murray GD, Standl E, Wilcox RG, Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Korányi L, Laakso M, Mokán M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W, Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive Investigators.
Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.
Lancet. 2005 Oct 8;366(9493):1279-89. doi: 10.1016/S0140-6736(05)67528-9.
Abstract/Text
BACKGROUND: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor gamma (PPAR gamma) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.
METHODS: We did a prospective, randomised controlled trial in 5238 patients with type 2 diabetes who had evidence of macrovascular disease. We recruited patients from primary-care practices and hospitals. We assigned patients to oral pioglitazone titrated from 15 mg to 45 mg (n=2605) or matching placebo (n=2633), to be taken in addition to their glucose-lowering drugs and other medications. Our primary endpoint was the composite of all-cause mortality, non fatal myocardial infarction (including silent myocardial infarction), stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN NCT00174993.
FINDINGS: Two patients were lost to follow-up, but were included in analyses. The average time of observation was 34.5 months. 514 of 2605 patients in the pioglitazone group and 572 of 2633 patients in the placebo group had at least one event in the primary composite endpoint (HR 0.90, 95% CI 0.80-1.02, p=0.095). The main secondary endpoint was the composite of all-cause mortality, non-fatal myocardial infarction, and stroke. 301 patients in the pioglitazone group and 358 in the placebo group reached this endpoint (0.84, 0.72-0.98, p=0.027). Overall safety and tolerability was good with no change in the safety profile of pioglitazone identified. 6% (149 of 2065) and 4% (108 of 2633) of those in the pioglitazone and placebo groups, respectively, were admitted to hospital with heart failure; mortality rates from heart failure did not differ between groups.
INTERPRETATION: Pioglitazone reduces the composite of all-cause mortality, non-fatal myocardial infarction, and stroke in patients with type 2 diabetes who have a high risk of macrovascular events.
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE.
Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials.
JAMA. 2007 Sep 12;298(10):1180-8. doi: 10.1001/jama.298.10.1180.
Abstract/Text
CONTEXT: Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes.
OBJECTIVE: To systematically evaluate the effect of pioglitazone on ischemic cardiovascular events.
DATA SOURCES AND STUDY SELECTION: A database containing individual patient-level time-to-event data collected during pioglitazone clinical trials was transferred from the drug's manufacturer for independent analysis. Trials were included if they were randomized, double-blinded, and controlled with placebo or active comparator.
DATA EXTRACTION: The primary outcome was a composite of death, myocardial infarction, or stroke. Secondary outcome measures included the incidence of serious heart failure. A fixed-effects approach was used to combine the estimates across the duration strata and statistical heterogeneity across all the trials was tested with the I2 statistic.
DATA SYNTHESIS: A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005). Progressive separation of time-to-event curves became apparent after approximately 1 year of therapy. Individual components of the primary end point were all reduced by a similar magnitude with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (HR, 1.41; 95% CI, 1.14-1.76; P = .002). The magnitude and direction of the favorable effect of pioglitazone on ischemic events and unfavorable effect on heart failure was homogeneous across trials of different durations, for different comparators, and for patients with or without established vascular disease. There was no evidence of heterogeneity across the trials for either end point (I2 = 0%; P = .87 for the composite end point and I2 = 0%; P = .97 for heart failure).
CONCLUSIONS: Pioglitazone is associated with a significantly lower risk of death, myocardial infarction, or stroke among a diverse population of patients with diabetes. Serious heart failure is increased by pioglitazone, although without an associated increase in mortality.
Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH.
Pioglitazone for type 2 diabetes mellitus.
Cochrane Database Syst Rev. 2006 Oct 18;2006(4):CD006060. doi: 10.1002/14651858.CD006060.pub2. Epub 2006 Oct 18.
Abstract/Text
BACKGROUND: Diabetes has long been recognised as a strong, independent risk factor for cardiovascular disease, a problem which accounts for approximately 70% of all mortality in people with diabetes. Prospective studies show that compared to their non-diabetic counterparts, the relative risk of cardiovascular mortality for men with diabetes is two to three and for women with diabetes is three to four. The two biggest trials in type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study did not reveal a reduction of cardiovascular endpoints through improved metabolic control. Theoretical benefits of the newer peroxisome proliferator activated receptor gamma (PPAR-gamma) activators like pioglitazone on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in people with type 2 diabetes mellitus.
OBJECTIVES: To assess the effects of pioglitazone in the treatment of type 2 diabetes.
SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library. The last search was conducted in August 2006.
SELECTION CRITERIA: Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 24 weeks.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analysis could be performed for adverse events only.
MAIN RESULTS: Twenty-two trials which randomised approximately 6200 people to pioglitazone treatment were identified. Longest duration of therapy was 34.5 months. Published studies of at least 24 weeks pioglitazone treatment in people with type 2 diabetes mellitus did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects, costs and health-related quality of life are positively influenced by this compound. Metabolic control measured by glycosylated haemoglobin A1c (HbA1c) as a surrogate endpoint did not demonstrate clinically relevant differences to other oral antidiabetic drugs. Occurrence of oedema was significantly raised. The results of the single trial with relevant clinical endpoints (Prospective Pioglitazone Clinical Trial In Macrovascular Events--PROactive study) have to be regarded as hypothesis-generating and need confirmation.
AUTHORS' CONCLUSIONS: Until new evidence becomes available, the benefit-risk ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone of the two big U.S. and European drug agencies should be clarified to reduce uncertainties amongst patients and physicians.
Kaku K, Daida H, Kashiwagi A, Yamashina A, Yamazaki T, Momomura S, Iwase T, Yamasaki Y, Nagatsuka K, Kitagawa K, Kawamori R.
Long-term effects of pioglitazone in Japanese patients with type 2 diabetes without a recent history of macrovascular morbidity.
Curr Med Res Opin. 2009 Dec;25(12):2925-32. doi: 10.1185/03007990903328124.
Abstract/Text
OBJECTIVE: To evaluate the efficacy of pioglitazone for the prevention of macrovascular outcomes in Japanese patients with type 2 diabetes, without a recent history of macrovascular morbidity.
RESEARCH DESIGN AND METHODS: This 2.5-4 year, prospective, randomized, open-label, blinded-endpoint study was conducted in 20 Japanese centers. Patients received pioglitazone +/- other oral glucose-lowering drugs (excluding another thiazolidinedione) [n = 293] or oral glucose-lowering drugs excluding thiazolidinediones (n = 294). Treatment was adjusted to achieve HbA(1c) < 6.5%. The primary endpoint was the time to onset of a macrovascular event.
RESULTS: Pioglitazone delayed the time to onset of macrovascular events and was associated with a lower cumulative incidence of such events (3.56% vs. 4.49% for controls). Neither finding achieved statistical significance. This was likely because of the type of patient included in the study (i.e. no recent history of cardiovascular events) and the high use of concomitant anti-diabetic agents. Reductions in HbA(1c), fasting blood glucose and fasting blood insulin levels, and an increase in HDL-C were significantly greater with pioglitazone throughout most of the study (p < 0.05). Fewer patients in the pioglitazone group commenced permanent treatment with insulin (3.3% vs. 13.7% in the control group). Adverse events were reported by 97.6% of the pioglitazone group and 96.9% of the control group (serious adverse events, including deaths, were 20.1 vs. 22.2%, respectively). The only notable difference between the two groups was a higher incidence of edema in the pioglitazone group. The main limitation of this study was that too few patients were included to identify statistically significant differences in the primary endpoint.
CONCLUSIONS: Pioglitazone produced good glycemic control in Japanese patients with type 2 diabetes, and significantly fewer patients treated with pioglitazone needed long-term insulin therapy. These changes were associated with a trend towards delayed onset of macrovascular events.
CLINICAL TRIAL REGISTRATION: UMIN000001363.
Yoshii H, Onuma T, Yamazaki T, Watada H, Matsuhisa M, Matsumoto M, Kitagawa K, Kitakaze M, Yamasaki Y, Kawamori R; PROFIT-J Study Group.
Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study.
J Atheroscler Thromb. 2014;21(6):563-73. Epub 2014 Jan 29.
Abstract/Text
AIM: The present study evaluated the effects of pioglitazone treatment on the incidence of primary cardiovascular events in Japanese subjects with type 2 diabetes mellitus at high risk of stroke.
METHODS: A prospective, multicenter, randomized, open label, comparative study was conducted among diabetic patients recruited from 50 medical institutions nationwide. A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n=254) or without pioglitazone (n=268) and observed for a medium of 672 days. The hypertension and dyslipidemia were concurrently treated according to the respective treatment guidelines. The primary outcome was the time to the first occurrence of a composite of all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction.
RESULTS: Treatment with pioglitazone resulted in significant reductions in the levels of HbA1c, diastolic blood pressure and LDL-cholesterol and a significant increase in the levels of HDL-cholesterol. The pioglitazone non-users exhibited a significant reduction in the LDL-cholesterol levels alone. Primary events were registered during the study period in nine patients in the pioglitazone group and 10 patients in the non-pioglitazone group. The difference in the cumulative incidence of the primary outcome was not significant between the two groups(1.8% per year).
CONCLUSIONS: Pioglitazone therapy produces immediate and effective improvements in glycemic control, diastolic blood pressure and lipid profiles. While this study was too underpowered to determine the effects of pioglitazone on the incidence of cardiovascular events, the results indicated that two years of pioglitazone treatment did not produce any statistically significant reductions in the rate of primary cardiovascular events.
WHO. Pioglitazone.Long-term treatment associated with increased incidence of fractures in women. WHO Pharmaceuticals Newsletter 2007; 3: 5.
