Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N, Bingham S, Boekholdt SM, Khaw KT, Gudnason V.
Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies.
Circulation. 2007 Jan 30;115(4):450-8. doi: 10.1161/CIRCULATIONAHA.106.637793. Epub 2006 Dec 26.
Abstract/Text
BACKGROUND: Many epidemiological studies have reported on associations between serum triglyceride concentrations and the risk of coronary heart disease, but this association has not been reliably quantified. In the present study, we report 2 separate nested case-control comparisons in 2 different prospective, population-based cohorts, plus an updated meta-analysis of 27 additional prospective studies in general Western populations.
METHODS AND RESULTS: Measurements were made in a total of 3582 incident cases of fatal and nonfatal coronary heart disease and 6175 controls selected from among the 44,237 men and women screened in the Reykjavik and the European Prospective Investigation of Cancer (EPIC)-Norfolk studies. Repeat measurements were obtained an average of 4 years apart in 1933 participants in the EPIC-Norfolk Study and an average of 12 years apart in 379 participants in the Reykjavik study. The long-term stability of log-triglyceride values (within-person correlation coefficients of 0.64 [95% CI, 0.60 to 0.68] over 4 years and 0.63 [95% CI, 0.57 to 0.70] over 12 years) was similar to those of blood pressure and total serum cholesterol. After adjustment for baseline values of several established risk factors, the strength of the association was substantially attenuated, and the adjusted odds ratio for coronary heart disease was 1.76 (95% CI, 1.39 to 2.21) in the Reykjavik study and 1.57 (95% CI, 1.10 to 2.24) in the EPIC-Norfolk study in a comparison of individuals in the top third with those in the bottom third of usual log-triglyceride values. Similar overall findings (adjusted odds ratio, 1.72; 95% CI, 1.56 to 1.90) were observed in an updated meta-analysis involving a total of 10,158 incident coronary heart disease cases from 262,525 participants in 29 studies.
CONCLUSIONS: Available prospective studies in Western populations consistently indicate moderate and highly significant associations between triglyceride values and coronary heart disease risk. Because these associations depend considerably on levels of established risk factors, however, further studies are needed to help assess the nature of any independent associations.
Iso H, Naito Y, Sato S, Kitamura A, Okamura T, Sankai T, Shimamoto T, Iida M, Komachi Y.
Serum triglycerides and risk of coronary heart disease among Japanese men and women.
Am J Epidemiol. 2001 Mar 1;153(5):490-9. doi: 10.1093/aje/153.5.490.
Abstract/Text
To examine the relation of triglycerides with coronary heart disease among populations with low mean total cholesterol, the authors conducted a 15.5-year prospective study ending in 1997 of 11,068 Japanese aged 40-69 years (4,452 men and 6,616 women with mean total cholesterol = 4.73 mmol/liter and 5.03 mmol/liter, respectively), initially free of coronary heart disease or stroke. There were 236 coronary heart disease events comprising 133 myocardial infarctions, 68 angina pectoris events, and 44 sudden cardiac deaths. The coronary heart disease incidence was greater in a dose-response manner across increasing quartiles of nonfasting triglycerides for both sexes. The multivariate relative risk of coronary heart disease adjusting for coronary risk factors and time since last meal associated with a 1-mmol/liter increase in triglycerides was 1.29 (95% confidence interval (CI): 1.09, 1.53; p = 0.004) for men and 1.42 (95% CI: 1.15, 1.75; p = 0.001) for women. The trend was similar for myocardial infarction, angina pectoris, and sudden cardiac death. The relation of triglycerides with coronary heart disease was not influenced materially by total cholesterol levels or, in a subsample analysis (51% of total sample), by high density lipoprotein cholesterol levels. Nonfasting serum triglycerides predict the incidence of coronary heart disease among Japanese men and women who possess low mean values of total cholesterol. Further adjustment for high density lipoprotein cholesterol suggests an independent role of triglycerides on the coronary heart disease risk.
Fukushima H, Kugiyama K, Sugiyama S, Honda O, Koide S, Nakamura S, Kawano H, Soejima H, Miyamoto S, Yoshimura M, Sakamoto T, Ogawa H.
Comparison of remnant-like lipoprotein particles in postmenopausal women with and without coronary artery disease and in men with coronary artery disease.
Am J Cardiol. 2001 Dec 15;88(12):1370-3. doi: 10.1016/s0002-9149(01)02115-4.
Abstract/Text
It is known that hypertriglyceridemia is a risk factor of coronary artery disease (CAD) in postmenopausal women. This study prospectively examined whether remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, may have a significant risk and prognostic values in postmenopausal women with angiographically verified CAD. Remnant-like lipoprotein particles cholesterol (RLP cholesterol) levels in fasting serum were measured in 134 consecutive postmenopausal women with (n = 56) or without (n = 78) CAD by an immunoseparation method. The women with CAD were followed for < or =24 months until occurrence of the following clinical coronary events: readmission or coronary revascularization due to recurrent or refractory angina pectoris, nonfatal myocardial infarction, and cardiac death. Multivariate logistic regression analysis showed that high RLP cholesterol levels (>5.7 mg/dl cholesterol; 90th percentile of the distribution of RLP cholesterol levels in controls) were a significant risk factor for the presence of CAD independent of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, and other traditional risk factors. Kaplan-Meier analysis demonstrated that women with CAD and higher RLP cholesterol levels had a significantly higher probability of developing coronary events (p <0.001). In multivariate Cox hazard analysis, high RLP cholesterol levels as well as diabetes and hypercholesterolemia were a significant predictor of future coronary events independent of other risk factors in women with CAD (odds ratio 9.7, 95% confidence intervals 1.3 to 20.3, p = 0.02). In conclusion, increased levels of RLP cholesterol are a significant and independent risk factor of CAD and predict future coronary events in postmenopausal women with CAD.
Miller BD, Alderman EL, Haskell WL, Fair JM, Krauss RM.
Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project.
Circulation. 1996 Nov 1;94(9):2146-53. doi: 10.1161/01.cir.94.9.2146.
Abstract/Text
BACKGROUND: LDL particles differ in size and density. Individuals with LDL profiles that peak in relatively small, dense particles have been reported to be at increased risk of coronary artery disease. We hypothesized that response to coronary disease therapy in such individuals might differ from response in individuals whose profiles peak in larger, more buoyant LDL. We examined this hypothesis in the Stanford Coronary Risk Intervention Project, an angiographic trial that compared multifactorial risk-reduction intervention with the usual care of physicians.
METHODS AND RESULTS: For 213 men, a bimodal frequency distribution of peak LDL density (g/mL) determined by analytical ultracentrifugation was used to classify baseline LDL profiles as "buoyant mode" (density < or = 1.0378) or "dense mode" (density > 1.0378). Coronary disease progression after 4 years was assessed by rates of change (mm/y, negative when arteries narrow) of minimum artery diameter. Rates for buoyant-mode subjects were -0.038 +/- 0.007 (mean +/- SEM) in usual care (n = 65) and -0.039 +/- 0.010 in intervention (n = 56; P = .6). Rates for dense-mode subjects were -0.054 +/- 0.012 in usual care (n = 51) and -0.008 +/- 0.009 in intervention (n = 41, P = .007). Lipid changes did not account for this difference in angiographic response.
CONCLUSIONS: Different types of LDL profile may predict different-responses to specific therapies, perhaps because metabolic processes determine both LDL profiles and responses to therapies.
Sprecher DL, Harris BV, Stein EA, Bellet PS, Keilson LM, Simbartl LA.
Higher triglycerides, lower high-density lipoprotein cholesterol, and higher systolic blood pressure in lipoprotein lipase-deficient heterozygotes. A preliminary report.
Circulation. 1996 Dec 15;94(12):3239-45. doi: 10.1161/01.cir.94.12.3239.
Abstract/Text
BACKGROUND: Heterozygous lipoprotein lipase (LPL) deficiency has been associated with familial hypertriglyceridemia and familial combined hyperlipidemia. Studies of heterozygotes with LPL gene defects at amino acid residues 188 and 207 showed higher triglycerides (TG) and lower HDL cholesterol (HDL-C), with no elevation in LDL cholesterol (LDL-C). Other LPL defects may reveal alternate clinical phenotypes.
METHODS AND RESULTS: We evaluated three families with defects at amino acid residues 64, 194, and 188. Thirty-eight heterozygotes (8 with defect 64, 14 with defect 194, and 16 with defect 188) and 95 family members without defects were studied. Plasma lipid, lipoprotein, and apolipoprotein (apo) values were measured, as well as blood pressure. Pooled carriers demonstrated higher systolic blood pressure (SBP) (127 versus 116 mm Hg, P < .0001) and TG (160 versus 125 mg/dL, P = .004) and lower HDL-C (44 versus 52 mg/dL, P = .001) than did noncarriers. A comparison of the 188 carriers and noncarriers revealed the most striking phenotypic characteristics, with lower HDL-C (36 versus 51 mg/dL, P < .0001) and HDL-C/(apo A-I + apo A-II) (0.21 versus 0.24, P = .002) and higher TG (206 versus 123 mg/dL, P = .0003), SBP (132 versus 116 mm Hg, P = .0004), and apo B/LDL-C (1.12 versus 0.93, P < .0001).
CONCLUSIONS: These data confirm past observations that LPL deficient heterozygotes trend toward lower HDL-C and higher TG levels while potentially expressing higher SBP. These data also implicate the specific LPL gene defect as a contributing factor to the variable expression of HDL-C, TG, and SBP.
McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G.
Use of metabolic markers to identify overweight individuals who are insulin resistant.
Ann Intern Med. 2003 Nov 18;139(10):802-9. doi: 10.7326/0003-4819-139-10-200311180-00007.
Abstract/Text
BACKGROUND: Insulin resistance is more common in overweight individuals and is associated with increased risk for type 2 diabetes mellitus and cardiovascular disease. Given the current epidemic of obesity and the fact that lifestyle interventions, such as weight loss and exercise, decrease insulin resistance, a relatively simple means to identify overweight individuals who are insulin resistant would be clinically useful.
OBJECTIVE: To evaluate the ability of metabolic markers associated with insulin resistance and increased risk for cardiovascular disease to identify the subset of overweight individuals who are insulin resistant.
DESIGN: Cross-sectional study.
SETTING: General clinical research center.
PATIENTS: 258 nondiabetic, overweight volunteers.
MEASUREMENTS: Body mass index; fasting glucose, insulin, lipid and lipoprotein concentrations; and insulin-mediated glucose disposal as quantified by the steady-state plasma glucose concentration during the insulin suppression test. Overweight was defined as body mass index of 25 kg/m2 or greater, and insulin resistance was defined as being in the top tertile of steady-state plasma glucose concentrations. Receiver-operating characteristic curve analysis was used to identify the best markers of insulin resistance; optimal cut-points were identified and analyzed for predictive power.
RESULTS: Plasma triglyceride concentration, ratio of triglyceride to high-density lipoprotein cholesterol concentrations, and insulin concentration were the most useful metabolic markers in identifying insulin-resistant individuals. The optimal cut-points were 1.47 mmol/L (130 mg/dL) for triglyceride, 1.8 in SI units (3.0 in traditional units) for the triglyceride-high-density lipoprotein cholesterol ratio, and 109 pmol/L for insulin. Respective sensitivity and specificity for these cut-points were 67%, 64%, and 57% and 71%, 68%, and 85%. Their ability to identify insulin-resistant individuals was similar to the ability of the criteria proposed by the Adult Treatment Panel III to diagnose the metabolic syndrome (sensitivity, 52%, and specificity, 85%).
CONCLUSIONS: Three relatively simple metabolic markers can help identify overweight individuals who are sufficiently insulin resistant to be at increased risk for various adverse outcomes. In the absence of a standardized insulin assay, we suggest that the most practical approach to identify overweight individuals who are insulin resistant is to use the cut-points for either triglyceride concentration or the triglyceride-high-density lipoprotein cholesterol concentration ratio.
Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM.
Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies.
J Am Coll Cardiol. 2007 Jan 30;49(4):403-14. doi: 10.1016/j.jacc.2006.09.032. Epub 2007 Jan 12.
Abstract/Text
OBJECTIVES: The purpose of this research was to assess the association between the metabolic syndrome (MetSyn) and cardiovascular events and mortality by meta-analyses of longitudinal studies.
BACKGROUND: Controversy exists regarding the cardiovascular risk associated with MetSyn.
METHODS: We searched electronic reference databases through March 2005, studies that referenced Reaven's seminal article, abstracts presented at meetings in 2003 to 2004, and queried experts. Two reviewers independently assessed eligibility. Longitudinal studies reporting associations between MetSyn and cardiovascular events or mortality were eligible. Two reviewers independently used a standardized form to collect data from published reports. Authors were contacted. Study quality was assessed by the control of selection, detection, and attrition biases.
RESULTS: We found 37 eligible studies that included 43 cohorts (inception 1971 to 1997) and 172,573 individuals. Random effects meta-analyses showed MetSyn had a relative risk (RR) of cardiovascular events and death of 1.78 (95% confidence interval [CI] 1.58 to 2.00). The association was stronger in women (RR 2.63 vs. 1.98, p = 0.09), in studies enrolling lower risk (<10%) individuals (RR 1.96 vs. 1.43, p = 0.04), and in studies using factor analysis or the World Health Organization definition (RR 2.68 and 2.06 vs. 1.67 for National Cholesterol Education Program definition and 1.35 for other definitions; p = 0.005). The association remained after adjusting for traditional cardiovascular risk factors (RR 1.54, 95% CI 1.32 to 1.79).
CONCLUSIONS: The best available evidence suggests that people with MetSyn are at increased risk of cardiovascular events. These results can help clinicians counsel patients to consider lifestyle interventions, and should fuel research of other preventive interventions.
Lloret Linares C, Pelletier AL, Czernichow S, Vergnaud AC, Bonnefont-Rousselot D, Levy P, Ruszniewski P, Bruckert E.
Acute pancreatitis in a cohort of 129 patients referred for severe hypertriglyceridemia.
Pancreas. 2008 Jul;37(1):13-2. doi: 10.1097/MPA.0b013e31816074a1.
Abstract/Text
OBJECTIVES: The aim of this study was to assess retrospectively the prevalence and the predictive factors of acute pancreatitis (AP) in a population of patients referred in our endocrinology department for evaluation of very high triglyceride (TG) levels.
METHODS: One hundred twenty-nine patients (119 with type IV phenotypes and 10 with type V phenotypes according to Fredrickson's classification) were referred to our hospital between 2000 and 2005.
RESULTS: Twenty-six subjects (20.2% of the population) presented with AP. This population was significantly younger at diagnosis of hyperlipidemia (32 vs 40 years, P < 0.001) and at age of investigation (43 vs 48 years, P = 0.05) and had maximum TG levels greater than the population without AP (44.7 vs 24.5, P < 0.001). Subjects of the third tertile of TG levels had a 4.0-fold increased risk (95% confidence interval, 1.3-12.3) of AP compared with the first tertile. Severe pancreatitis (need for intensive care, C-reactive protein >150 mg/L, or Balthazar score >C) was observed in 71.5% of the patients.
CONCLUSIONS: Twenty percent of patients with severe hypertriglyceridemia experience at least 1 attack of AP. Pancreatitis seems to occur in young patients at higher levels of TG than previously thought (85% of patients >30 g/L) and is associated with a severe clinical course.
Murad MH, Hazem A, Coto-Yglesias F, Dzyubak S, Gupta S, Bancos I, Lane MA, Erwin PJ, Berglund L, Elraiyah T, Montori VM.
The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis.
BMC Endocr Disord. 2012 Mar 31;12:2. doi: 10.1186/1472-6823-12-2. Epub 2012 Mar 31.
Abstract/Text
BACKGROUND: Hypertriglyceridemia may be associated with important complications. The aim of this study is to estimate the magnitude of association and quality of supporting evidence linking hypertriglyceridemia to cardiovascular events and pancreatitis.
METHODS: We conducted a systematic review of multiple electronic bibliographic databases and subsequent meta-analysis using a random effects model. Studies eligible for this review followed patients longitudinally and evaluated quantitatively the association of fasting hypertriglyceridemia with the outcomes of interest. Reviewers working independently and in duplicate reviewed studies and extracted data.
RESULTS: 35 studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate to low with fair level of multivariable adjustments and adequate exposure and outcome ascertainment. Fasting hypertriglyceridemia was significantly associated with cardiovascular death (odds ratios (OR) 1.80; 95% confidence interval (CI) 1.31-2.49), cardiovascular events (OR, 1.37; 95% CI, 1.23-1.53), myocardial infarction (OR, 1.31; 95% CI, 1.15-1.49), and pancreatitis (OR, 3.96; 95% CI, 1.27-12.34, in one study only). The association with all-cause mortality was not statistically significant.
CONCLUSIONS: The current evidence suggests that fasting hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis.Précis: hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis.
Hokanson JE, Austin MA.
Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.
J Cardiovasc Risk. 1996 Apr;3(2):213-9.
Abstract/Text
OBJECTIVES: Despite nearly 40 years of research, the role of plasma triglyceride as a risk factor for cardiovascular disease remains elusive. The objectives of the present study were to quantify the magnitude of the association between triglyceride and cardiovascular disease in the general population, and to determine whether this relationship is independent of high-density lipoprotein (HDL) cholesterol, using the semi-quantitative techniques of metaanalysis.
METHODS AND DESIGN: Seventeen studies were selected for the analysis based on published reports of population-based, prospective studies, including 46413 men and 10864 women. To insure comparability, only studies reporting the association between fasting triglyceride levels and incident cardiovascular endpoints were included. Using standard meta-analysis calculations, relative risks (RR) and 95% confidence intervals (CI) were calculated and standardized with respect to a 1 mmol/l increase in triglyceride. Multivariable-adjusted RRs were determined for the six studies in men and two studies in women that reported adjustments for HDL cholesterol.
RESULTS: For men and women, the univariate RRs for triglyceride were 1.32 (95% Cl 1.26-1.39) and 1.76 (95% Cl 1.50-2.07), respectively, indicating an approximately 30% increased risk in men and a 75% increase in women. Adjustment of HDL cholesterol and other risk factors attenuated these RRs to 1.14 (95% Cl 1.05-1.28) and 1.37 (95% Cl 1.13-1.66), respectively, which were still statistically significant values.
CONCLUSION: Based on combined data from prospective studies, triglyceride is a risk factor for cardiovascular disease for both men and women in the general population, independent of HDL cholesterol. These finding demonstrate the necessity for clinical trials to evaluate whether lowering plasma triglyceride decreases the risk of cardiovascular disease.
Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S; American Heart Association Clinical Lipidology, Thrombosis, and Prevention Committee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular Nursing; Council on the Kidney in Cardiovascular Disease.
Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association.
Circulation. 2011 May 24;123(20):2292-333. doi: 10.1161/CIR.0b013e3182160726. Epub 2011 Apr 18.
Abstract/Text
Fortson MR, Freedman SN, Webster PD 3rd.
Clinical assessment of hyperlipidemic pancreatitis.
Am J Gastroenterol. 1995 Dec;90(12):2134-9.
Abstract/Text
OBJECTIVE: This study addresses three questions: 1) What are the clinical presentations of pancreatitis secondary to hyperlipidemia? 2) What is the role of alcohol, diabetes, or known causes of hypertriglyceridemia? and 3) Does the course of pancreatitis secondary to hypertriglyceridemia differ from that of other etiologies?
METHODS: We reviewed patients between 1982 and 1994 with a diagnosis of pancreatitis (577.0) and hypertriglyceridemia (272.0). Four hospitals participated. Seventy patients had a clinical presentation consistent with pancreatitis, that is elevated amylase and lipase or evidence of pancreatitis by ultrasound or CT imaging and serum triglyceride levels greater than 500 mg/dl or lactescent serum. Clinical data were derived from hospital admissions.
RESULTS: Hypertriglyceridemia was the etiology in 1.3-3.8% of patients discharged with a diagnosis of pancreatitis. A history of diabetes mellitus was present in 72%, hypertriglyceridemia in 77%, alcohol use 23%, and gallstones in 7%. Lipemic serum was described on admission in 45%. Mean triglyceride levels were 4587 +/- 3616 ml/dl. Amylase was elevated two times normal in 54%, and lipase was elevated two times normal in 67%. CT scans were abnormal in 82%, with peripancreatic fluid in 34%, pseudocyst 37%, and necrosis in 15%. Abscess occurred in 13%, death in 6%.
CONCLUSION: Acute pancreatitis secondary to hyperlipidemia is characterized by three presentations. All patients present with abdominal pain, nausea, and vomiting of hours to days duration. The most common presentation is a poorly controlled diabetic with a history of hypertriglyceridemia. The second presentation is the alcoholic found to have hypertriglyceridemia or lactescent serum on admission. The third, about 15-20% of patients, is the nondiabetic, nonalcoholic, nonobese patient with drug- or diet-induced hypertriglyceridemia.
Toskes PP.
Hyperlipidemic pancreatitis.
Gastroenterol Clin North Am. 1990 Dec;19(4):783-91.
Abstract/Text
Marked elevation of triglyceride levels appears to be causally linked to acute pancreatitis and is found in 12% to 38% of patients presenting with acute pancreatitis. Elevated cholesterol levels are not associated with pancreatitis. The pathogenesis of pancreatitis associated with hypertriglyceridemia is not clear. Clinical recognition of this association is extremely important, because therapy with diet and lipid-lowering agents may prevent development of pancreatitis.
Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; Japan EPA lipid intervention study (JELIS) Investigators.
Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis.
Lancet. 2007 Mar 31;369(9567):1090-8. doi: 10.1016/S0140-6736(07)60527-3.
Abstract/Text
BACKGROUND: Epidemiological and clinical evidence suggests that an increased intake of long-chain n-3 fatty acids protects against mortality from coronary artery disease. We aimed to test the hypothesis that long-term use of eicosapentaenoic acid (EPA) is effective for prevention of major coronary events in hypercholesterolaemic patients in Japan who consume a large amount of fish.
METHODS: 18 645 patients with a total cholesterol of 6.5 mmol/L or greater were recruited from local physicians throughout Japan between 1996 and 1999. Patients were randomly assigned to receive either 1800 mg of EPA daily with statin (EPA group; n=9326) or statin only (controls; n=9319) with a 5-year follow-up. The primary endpoint was any major coronary event, including sudden cardiac death, fatal and non-fatal myocardial infarction, and other non-fatal events including unstable angina pectoris, angioplasty, stenting, or coronary artery bypass grafting. Analysis was by intention-to-treat. The study was registered at ClinicalTrials.gov, number NCT00231738.
FINDINGS: At mean follow-up of 4.6 years, we detected the primary endpoint in 262 (2.8%) patients in the EPA group and 324 (3.5%) in controls-a 19% relative reduction in major coronary events (p=0.011). Post-treatment LDL cholesterol concentrations decreased 25%, from 4.7 mmol/L in both groups. Serum LDL cholesterol was not a significant factor in a reduction of risk for major coronary events. Unstable angina and non-fatal coronary events were also significantly reduced in the EPA group. Sudden cardiac death and coronary death did not differ between groups. In patients with a history of coronary artery disease who were given EPA treatment, major coronary events were reduced by 19% (secondary prevention subgroup: 158 [8.7%] in the EPA group vs 197 [10.7%] in the control group; p=0.048). In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18%, but this finding was not significant (104 [1.4%] in the EPA group vs 127 [1.7%] in the control group; p=0.132).
INTERPRETATION: EPA is a promising treatment for prevention of major coronary events, and especially non-fatal coronary events, in Japanese hypercholesterolaemic patients.
Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M.
Extended-release niacin or ezetimibe and carotid intima-media thickness.
N Engl J Med. 2009 Nov 26;361(22):2113-22. doi: 10.1056/NEJMoa0907569. Epub 2009 Nov 15.
Abstract/Text
BACKGROUND: Treatment added to statin monotherapy to further modify the lipid profile may include combination therapy to either raise the high-density lipoprotein (HDL) cholesterol level or further lower the low-density lipoprotein (LDL) cholesterol level.
METHODS: We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol per liter, respectively) had been achieved. The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial.
RESULTS: The mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter (P < 0.001), and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per liter) (P < 0.001). Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima-media thickness over 14 months (P = 0.003), leading to significant reduction of both mean (P = 0.001) and maximal carotid intima-media thickness (P < or = 0.001 for all comparisons). Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness (R = -0.31, P < 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04 by the chi-square test).
CONCLUSIONS: This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima-media thickness when combined with a statin and that niacin is superior to ezetimibe. (ClinicalTrials.gov number, NCT00397657.)
2009 Massachusetts Medical Society
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
LaRosa JC, He J, Vupputuri S.
Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials.
JAMA. 1999 Dec 22-29;282(24):2340-6. doi: 10.1001/jama.282.24.2340.
Abstract/Text
CONTEXT: Lowering low-density lipoprotein cholesterol (LDL-C) is known to reduce risk of recurrent coronary heart disease in middle-aged men. However, this effect has been uncertain in elderly people and women.
OBJECTIVE: To estimate the risk reduction of coronary heart disease and total mortality associated with statin drug treatment, particularly in elderly individuals and women.
DATA SOURCES: Trials published in English-language journals were retrieved by searching MEDLINE (1966-December 1998), bibliographies, and authors' reference files.
STUDY SELECTION: Studies in which participants were randomized to statin or control treatment for at least 4 years and clinical disease or death was the primary outcome were included in the meta-analysis (5 of 182 initially identified).
DATA EXTRACTION: Information on sample size, study drug duration, type and dosage of statin drug, participant characteristics at baseline, reduction in lipids during intervention, and outcomes was abstracted independently by 2 authors (J.H. and S.V.) using a standardized protocol. Disagreements were resolved by consensus.
DATA SYNTHESIS: Data from the 5 trials, with 30 817 participants, were included in this meta-analysis. The mean duration of treatment was 5.4 years. Stati n drug treatment was associated with a20% reduction in total cholesterol, 28% reduction in LDL-C, 13% reduction in triglycerides, and 5% increase in high-density lipoprotein cholesterol. Overall, statin drug treatment reduced risk 31 % in major coronary events (95% confidence interval [CI], 26%-36%) and 21 % in all-cause mortality (95% CI, 14%-28%). The risk reduction in major coronary events was similar between women (29%; 95% Cl, 13 %-42 %) and men (31 %; 95% CI, 26%-35%), and between persons aged at least 65 years (32%; 95% CI, 23%-39%) and persons younger than 65 years (31 %; 95% CI, 24%-36%).
CONCLUSIONS: Our meta-analysis indicates that reduction in LDL-C associated with statin drug treatment decreases the risk of coronary heart disease and all-cause mortality. The risk reduction was similar for men and women and for elderly and middle-aged persons.
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.
Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, Campbell SE, Oshima R, Amarenco P, Blom DJ, Brinton EA, Eckel RH, Elam MB, Felicio JS, Ginsberg HN, Goudev A, Ishibashi S, Joseph J, Kodama T, Koenig W, Leiter LA, Lorenzatti AJ, Mankovsky B, Marx N, Nordestgaard BG, Páll D, Ray KK, Santos RD, Soran H, Susekov A, Tendera M, Yokote K, Paynter NP, Buring JE, Libby P, Ridker PM; PROMINENT Investigators.
Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.
N Engl J Med. 2022 Nov 24;387(21):1923-1934. doi: 10.1056/NEJMoa2210645. Epub 2022 Nov 5.
Abstract/Text
BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.
METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.
RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.
CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).
Copyright © 2022 Massachusetts Medical Society.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
Circulation. 2002 Dec 17;106(25):3143-421.
Abstract/Text
Saito Y, Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; JELIS Investigators, Japan.
Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS).
Atherosclerosis. 2008 Sep;200(1):135-40. doi: 10.1016/j.atherosclerosis.2008.06.003. Epub 2008 Jun 19.
Abstract/Text
BACKGROUND: Japan EPA Lipid Intervention Study (JELIS) was a large-scale clinical trial examining the effects of eicosapentaenoic acid (EPA) on coronary artery disease (CAD) in hypercholesterolemic patients. Herein, we focused on risk factors other than low-density lipoprotein cholesterol (LDL-C) to investigate the effects of EPA on CAD among JELIS primary prevention cases.
METHODS: Hypercholesterolemic patients on statin therapy but without evidence of CAD (n=14,981) were randomly assigned to an EPA group (n=7503) or a control group (n=7478). The relationships between incident CAD, the number of CAD risk factors (hypercholesterolemia; obesity; high triglyceride (TG) or low high-density lipoprotein cholesterol (HDL-C); diabetes; and hypertension) and EPA treatment were investigated.
RESULTS: For the control and EPA groups combined, a higher number of risk factors was directly associated with an increased incidence of CAD. Incidence was lower for the EPA group than for the control group regardless of the numbers of risk factors. Compared to patients with normal serum TG and HDL-C levels, those with abnormal levels (TG >or=150 mg/dL; HDL-C <40 mg/dL) had significantly higher CAD hazard ratio (HR: 1.71; 95% CI: 1.11-2.64; P=0.014). In this higher risk group, EPA treatment suppressed the risk of CAD by 53% (HR: 0.47; 95% CI: 0.23-0.98; P=0.043).
CONCLUSIONS: Multiple risk factors besides cholesterol are associated with markedly increased incidence of CAD. High TG with low HDL-C represents a particularly potent risk factor. EPA was effective in reducing the incidence of CAD events for patients with this dyslipidemic pattern, suggesting that EPA may be especially beneficial in patients who with abnormal TG and HDL-C levels.
