今日の臨床サポート

高LDLコレステロール血症

著者: 井上郁夫 埼玉医科大学 内分泌・糖尿病内科

監修: 野田光彦 国際医療福祉大学市川病院 糖尿病・代謝・内分泌内科

著者校正/監修レビュー済:2022/02/02
参考ガイドライン:
  1. 日本動脈硬化学会:動脈硬化性疾患予防ガイドライン2017年版
患者向け説明資料

概要・推奨   

  1. 0.6%/年以上の冠動脈疾患のリスクがある患者が高LDLコレステロール(LDL-C)血症を呈している場合には、スタチン系薬剤を投与することが強く勧められる。リスクがそれ未満の患者では、LDL-C値と患者のリスクを併せて検討した上で治療の適応を決定することが勧められる(推奨度1)
  1. スタチン系薬剤の間の効果を比較した研究の結果、スタチン系薬剤間に心疾患による死亡率低下効果の差があるとのエビデンスは得られていない。このことより、動脈硬化症予防としてスタチン系薬剤にてLDL-Cを低下させる場合には、どのスタチン系薬剤を選んでもよい(推奨度1)
  1. 妊娠・出産を考えている女性にスタチン系薬剤を投与すべきではない(推奨度4)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
井上郁夫 : 特に申告事項無し[2022年]
監修:野田光彦 : 特に申告事項無し[2022年]

改訂のポイント:
  1. 動脈硬化性疾患予防ガイドライン2017年版に基づき改訂した。 

病態、疫学、診察

疾患情報(疫学・病態)  
  1. 高LDLコレステロール(LDL-C)血症とは、血清中のLDL-Cが高値を示す病態であり、動脈硬化症の最も重要な危険因子の1つである。
  1. 高LDL-C血症の診断には、まず二次性の高LDL-C血症を除外する必要がある。
  1. 日本人で総コレステロール(TC)値が220mg/dL(LDL-C:140mg/dL相当)を超えている頻度は男性で24%、女性で34%以上である(平成26年国民健康・栄養調査報告)。
  1. 「動脈硬化性疾患予防ガイドライン2017」では、LDL-C値140mg/dL以上を高LDL-C血症と規定している。ただし治療基準はこれとは別に定められている。
  1. 高LDL-C血症の治療目標値は、各患者が持つ動脈硬化性疾患の危険因子数により異なる。
  1. 動脈硬化性疾患予防ガイドライン2017では、患者の今後10年間の冠動脈疾患による発症率により低リスク群から高リスク群に分類している。冠動脈疾患による発症率は吹田スコアを用いて算定する。低リスク群はLDL-C 160mg/dL、中リスク群は140mg/dL、高リスク群は120mg/dL、冠動脈疾患の既往は100mg/dL未満を目標に治療を行う。
  1. LDL-C値は、空腹時血清でTC値、HDL-C値、トリグリセライド(TG)値を測定し、Friedewaldの式(TC-HDL-C-TG/5)で計算する。ただしTG値が400mg/dL以上の場合には、この式は使用できない。空腹時採血ができない場合やTGが高値の場合には、nonHDL-C(TC-HDL-C)を用いる。nonHDL-CはLDL-Cより約30mg/dL高値を示す。直接測定法でLDL-Cを求めることも可能だが、TGが1,000以上の際の直接法のLDL-C、600以上の際のnonHDL-Cは正確性に欠けるので、他の方法での評価を考慮する。
  1. LDL-C値を低下させることで動脈硬化性疾患は有意に減少する。
  1. ACC/AHAガイドラインは、スタチン系薬剤のみがエビデンスのある薬剤であるとの見解から、LDL-C低下率に基づいた治療指針である。しかしながら、患者のアドヒアランスを考慮すると、絶対的なLDL-Cの管理目標値を設定する方が実際的である。
病歴・診察のポイント  
  1. 他の動脈硬化危険因子の有無を確認する。主たる危険因子は、年齢、高血圧症、糖尿病、耐糖能異常、性別、喫煙、早発性冠動脈疾患の家族歴、低HDL-C血症である。

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文献 

Abstract/Text
PMID 11368702
Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS), Alberico L Catapano, Zeljko Reiner, Guy De Backer, Ian Graham, Marja-Riitta Taskinen, Olov Wiklund, Stefan Agewall, Eduardo Alegria, M John Chapman, Paul Durrington, Serap Erdine, Julian Halcox, Richard Hobbs, John Kjekshus, Pasquale Perrone Filardi, Gabriele Riccardi, Robert F Storey, David Wood, ESC Committee for Practice Guidelines 2008-2010 and 2010-2012 Committees
ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Atherosclerosis. 2011 Jul;217 Suppl 1:S1-44. doi: 10.1016/j.atherosclerosis.2011.06.012.
Abstract/Text
PMID 21723445
P R Jackson, E J Wallis, I U Haq, L E Ramsay
Statins for primary prevention: at what coronary risk is safety assured?
Br J Clin Pharmacol. 2001 Oct;52(4):439-46.
Abstract/Text AIMS: Increasingly HMG CoA reductase inhibitors (statins) are being used for primary prevention of vascular disease in patients with a raised cholesterol but at low absolute risk of coronary heart disease (CHD). This study uses clinical trial results to explore the limits of absolute safety for statin use in such patients.
METHODS: The major placebo controlled statin outcome trials were identified by automated and manual literature searches. Principal results including all cause mortality in placebo and intervention groups and baseline values of standard coronary risk factors were abstracted for each trial. For the trials identified the reduction in overall mortality with statin treatment for each study was regressed against the underlying CHD risk of the population recruited into that trial using a statistically robust method.
RESULTS: The regression line describing the relationship between mortality benefit and risk suggests that statin use could be associated with an increase in mortality of 1% in 10 years. This would be sufficiently large to negate statin's beneficial effect on CHD mortality in patients with a CHD event risk less than 13% over 10 years.
CONCLUSIONS: Absolute safety of statins has not been demonstrated for patients at low risk of CHD. Patients absolute risk of CHD should be calculated before starting statin treatment for primary prevention. Extensions of such treatment to low risk patients should await further evidence of safety.

PMID 11678788
Kunihiro Nishimura, Tomonori Okamura, Makoto Watanabe, Michikazu Nakai, Misa Takegami, Aya Higashiyama, Yoshihiro Kokubo, Akira Okayama, Yoshihiro Miyamoto
Predicting coronary heart disease using risk factor categories for a Japanese urban population, and comparison with the framingham risk score: the suita study.
J Atheroscler Thromb. 2014;21(8):784-98. Epub 2014 Mar 25.
Abstract/Text AIM: The Framingham risk score (FRS) is one of the standard tools used to predict the incidence of coronary heart disease (CHD). No previous study has investigated its efficacy for a Japanese population cohort. The purpose of this study was to develop new coronary prediction algorithms for the Japanese population in the manner of the FRS, and to compare them with the original FRS.
METHODS: Our coronary prediction algorithms for Japanese were based on a large population-based cohort study (Suita study). The study population comprised 5,521 healthy Japanese. They were followed-up for 11.8 years on average, and 213 cases of CHD were observed. Multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model.
RESULTS: Our coronary prediction algorithms for Japanese patients were based on a large populationbased cohort study (the Suita study). A multiple Cox proportional hazard model by stepwise selection was used to construct the prediction model. The C-statistics showed that the new model had better accuracy than the original and recalibrated Framingham scores. The net reclassification improvement (NRI) by the Suita score with the inclusion of CKD was 41.2% (P<0.001) compared with the original FRS. The recalibration of the FRS slightly improved the efficiency of the prediction, but it was still worse than the Suita score with the CKD model. The calibration analysis suggested that the original FRS and the recalibrated FRS overestimated the risk of CHD in the Japanese population. The Suita score with CKD more accurately predicted the risk of CHD.
CONCLUSION: The FRS and recalibrated FRS overestimated the 10-year risk of CHD for the Japanese population. A predictive score including CKD as a coronary risk factor for the Japanese population was more accurate for predicting CHD than the original Framingham risk scores in terms of the C-statics and NRI.

PMID 24671110
John C LaRosa, Scott M Grundy, David D Waters, Charles Shear, Philip Barter, Jean-Charles Fruchart, Antonio M Gotto, Heiner Greten, John J P Kastelein, James Shepherd, Nanette K Wenger, Treating to New Targets (TNT) Investigators
Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
N Engl J Med. 2005 Apr 7;352(14):1425-35. doi: 10.1056/NEJMoa050461. Epub 2005 Mar 8.
Abstract/Text BACKGROUND: Previous trials have demonstrated that lowering low-density lipoprotein (LDL) cholesterol levels below currently recommended levels is beneficial in patients with acute coronary syndromes. We prospectively assessed the efficacy and safety of lowering LDL cholesterol levels below 100 mg per deciliter (2.6 mmol per liter) in patients with stable coronary heart disease (CHD).
METHODS: A total of 10,001 patients with clinically evident CHD and LDL cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) were randomly assigned to double-blind therapy and received either 10 mg or 80 mg of atorvastatin per day. Patients were followed for a median of 4.9 years. The primary end point was the occurrence of a first major cardiovascular event, defined as death from CHD, nonfatal non-procedure-related myocardial infarction, resuscitation after cardiac arrest, or fatal or nonfatal stroke.
RESULTS: The mean LDL cholesterol levels were 77 mg per deciliter (2.0 mmol per liter) during treatment with 80 mg of atorvastatin and 101 mg per deciliter (2.6 mmol per liter) during treatment with 10 mg of atorvastatin. The incidence of persistent elevations in liver aminotransferase levels was 0.2 percent in the group given 10 mg of atorvastatin and 1.2 percent in the group given 80 mg of atorvastatin (P<0.001). A primary event occurred in 434 patients (8.7 percent) receiving 80 mg of atorvastatin, as compared with 548 patients (10.9 percent) receiving 10 mg of atorvastatin, representing an absolute reduction in the rate of major cardiovascular events of 2.2 percent and a 22 percent relative reduction in risk (hazard ratio, 0.78; 95 percent confidence interval, 0.69 to 0.89; P<0.001). There was no difference between the two treatment groups in overall mortality.
CONCLUSIONS: Intensive lipid-lowering therapy with 80 mg of atorvastatin per day in patients with stable CHD provides significant clinical benefit beyond that afforded by treatment with 10 mg of atorvastatin per day. This occurred with a greater incidence of elevated aminotransferase levels.

Copyright 2005 Massachusetts Medical Society.
PMID 15755765
G G Schwartz, A G Olsson, M D Ezekowitz, P Ganz, M F Oliver, D Waters, A Zeiher, B R Chaitman, S Leslie, T Stern, Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators
Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.
JAMA. 2001 Apr 4;285(13):1711-8.
Abstract/Text CONTEXT: Patients experience the highest rate of death and recurrent ischemic events during the early period after an acute coronary syndrome, but it is not known whether early initiation of treatment with a statin can reduce the occurrence of these early events.
OBJECTIVE: To determine whether treatment with atorvastatin, 80 mg/d, initiated 24 to 96 hours after an acute coronary syndrome, reduces death and nonfatal ischemic events.
DESIGN AND SETTING: A randomized, double-blind trial conducted from May 1997 to September 1999, with follow-up through 16 weeks at 122 clinical centers in Europe, North America, South Africa, and Australasia.
PATIENTS: A total of 3086 adults aged 18 years or older with unstable angina or non-Q-wave acute myocardial infarction.
INTERVENTIONS: Patients were stratified by center and randomly assigned to receive treatment with atorvastatin (80 mg/d) or matching placebo between 24 and 96 hours after hospital admission.
MAIN OUTCOME MEASURES: Primary end point event defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia with objective evidence and requiring emergency rehospitalization.
RESULTS: A primary end point event occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group (relative risk [RR], 0.84; 95% confidence interval [CI], 0.70-1.00; P =.048). There were no significant differences in risk of death, nonfatal myocardial infarction, or cardiac arrest between the atorvastatin group and the placebo group, although the atorvastatin group had a lower risk of symptomatic ischemia with objective evidence and requiring emergency rehospitalization (6.2% vs 8.4%; RR, 0.74; 95% CI, 0.57-0.95; P =.02). Likewise, there were no significant differences between the atorvastatin group and the placebo group in the incidence of secondary outcomes of coronary revascularization procedures, worsening heart failure, or worsening angina, although there were fewer strokes in the atorvastatin group than in the placebo group (12 vs 24 events; P =.045). In the atorvastatin group, mean low-density lipoprotein cholesterol level declined from 124 mg/dL (3.2 mmol/L) to 72 mg/dL (1.9 mmol/L). Abnormal liver transaminases (>3 times upper limit of normal) were more common in the atorvastatin group than in the placebo group (2.5% vs 0.6%; P<.001).
CONCLUSION: For patients with acute coronary syndrome, lipid-lowering therapy with atorvastatin, 80 mg/d, reduces recurrent ischemic events in the first 16 weeks, mostly recurrent symptomatic ischemia requiring rehospitalization.

PMID 11277825
Christopher P Cannon, Michael A Blazing, Robert P Giugliano, Amy McCagg, Jennifer A White, Pierre Theroux, Harald Darius, Basil S Lewis, Ton Oude Ophuis, J Wouter Jukema, Gaetano M De Ferrari, Witold Ruzyllo, Paul De Lucca, KyungAh Im, Erin A Bohula, Craig Reist, Stephen D Wiviott, Andrew M Tershakovec, Thomas A Musliner, Eugene Braunwald, Robert M Califf, IMPROVE-IT Investigators
Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.
N Engl J Med. 2015 Jun 18;372(25):2387-97. doi: 10.1056/NEJMoa1410489. Epub 2015 Jun 3.
Abstract/Text BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known.
METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years.
RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups.
CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

PMID 26039521
Robert P Giugliano, Terje R Pedersen, Jeong-Gun Park, Gaetano M De Ferrari, Zbigniew A Gaciong, Richard Ceska, Kalman Toth, Ioanna Gouni-Berthold, Jose Lopez-Miranda, François Schiele, François Mach, Brian R Ott, Estella Kanevsky, Armando Lira Pineda, Ransi Somaratne, Scott M Wasserman, Anthony C Keech, Peter S Sever, Marc S Sabatine, FOURIER Investigators
Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial.
Lancet. 2017 Oct 28;390(10106):1962-1971. doi: 10.1016/S0140-6736(17)32290-0. Epub 2017 Aug 28.
Abstract/Text BACKGROUND: LDL cholesterol is a well established risk factor for atherosclerotic cardiovascular disease. How much one should or safely can lower this risk factor remains debated. We aimed to explore the relationship between progressively lower LDL-cholesterol concentrations achieved at 4 weeks and clinical efficacy and safety in the FOURIER trial of evolocumab, a monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9).
METHODS: In this prespecified secondary analysis of 25 982 patients from the randomised FOURIER trial, the relationship between achieved LDL-cholesterol concentration at 4 weeks and subsequent cardiovascular outcomes (primary endpoint was the composite of cardiovascular death, myocardial infarction, stroke, coronary revascularisation, or unstable angina; key secondary endpoint was the composite of cardiovascular death, myocardial infarction, or stroke) and ten prespecified safety events of interest was examined over a median of 2·2 years of follow-up. We used multivariable modelling to adjust for baseline factors associated with achieved LDL cholesterol. This trial is registered with ClinicalTrials.gov, number NCT01764633.
FINDINGS: Between Feb 8, 2013, and June 5, 2015, 27 564 patients were randomly assigned a treatment in the FOURIER study. 1025 (4%) patients did not have an LDL cholesterol measured at 4 weeks and 557 (2%) had already had a primary endpoint event or one of the ten prespecified safety events before the week-4 visit. From the remaining 25 982 patients (94% of those randomly assigned) 13 013 were assigned evolocumab and 12 969 were assigned placebo. 2669 (10%) of 25 982 patients achieved LDL-cholesterol concentrations of less than 0·5 mmol/L, 8003 (31%) patients achieved concentrations between 0·5 and less than 1·3 mmol/L, 3444 (13%) patients achieved concentrations between 1·3 and less than 1·8 mmol/L, 7471 (29%) patients achieved concentrations between 1·8 to less than 2·6 mmol/L, and 4395 (17%) patients achieved concentrations of 2·6 mmol/L or higher. There was a highly significant monotonic relationship between low LDL-cholesterol concentrations and lower risk of the primary and secondary efficacy composite endpoints extending to the bottom first percentile (LDL-cholesterol concentrations of less than 0·2 mmol/L; p=0·0012 for the primary endpoint, p=0·0001 for the secondary endpoint). Conversely, no significant association was observed between achieved LDL cholesterol and safety outcomes, either for all serious adverse events or any of the other nine prespecified safety events.
INTERPRETATION: There was a monotonic relationship between achieved LDL cholesterol and major cardiovascular outcomes down to LDL-cholesterol concentrations of less than 0·2 mmol/L. Conversely, there were no safety concerns with very low LDL-cholesterol concentrations over a median of 2·2 years. These data support further LDL-cholesterol lowering in patients with cardiovascular disease to well below current recommendations.
FUNDING: Amgen.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28859947
George A Kelley, Kristi S Kelley, Zung Vu Tran
Walking, lipids, and lipoproteins: a meta-analysis of randomized controlled trials.
Prev Med. 2004 May;38(5):651-61. doi: 10.1016/j.ypmed.2003.12.012.
Abstract/Text BACKGROUND: The purpose of this study was to use the meta-analytic approach to examine the effects of walking on lipids and lipoproteins in adults.
METHODS: Randomized controlled trials that examined the effects of walking on total cholesterol (TC), high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), the ratio of TC/HDL, and triglycerides (TG) in adults ages 18 years and older were retrieved via computerized literature searches, cross-referencing, hand-searching, and expert review of our reference list.
RESULTS: Twenty-five studies that included 1,176 subjects (692 walkers, 484 controls) and up to 33 outcomes were available for pooling. Using random-effects modeling, statistically significant, walking-induced decreases of 5% and 6% were observed for LDL-C and TC/HDL-C (LDL-C, mean +/- SE, -5.5 +/- 2.2 mg/dL, 95% CI, -9.9 to -1.2 mg/dL; TC/HDL-C, mean +/- SE, -0.3 +/- 0.1, 95% CI, -0.6 to -0.1). No statistically significant changes were observed for TC, HDL, or TG (P > 0.05), although changes were in the direction of benefit. No statistically significant changes occurred in body composition (P > 0.05).
CONCLUSIONS: Walking reduces LDL-C and TC/HDL-C in adults independent of changes in body composition.

PMID 15066369
George A Kelley, Kristi S Kelley
Impact of progressive resistance training on lipids and lipoproteins in adults: another look at a meta-analysis using prediction intervals.
Prev Med. 2009 Dec;49(6):473-5. doi: 10.1016/j.ypmed.2009.09.018. Epub 2009 Oct 3.
Abstract/Text OBJECTIVE: Given recently developed prediction intervals (PIs) in which a random mean effect for a new study is estimated from meta-analytic data, we used the results from our previously published meta-analysis to calculate PIs for changes in lipids and lipoproteins as a result of progressive resistance training (PRT) in adults.
METHODS: Twenty-nine studies representing 1329 men and women (676 exercise, 653 control) were included. The primary outcomes included total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C), non-high-density lipoprotein cholesterol (non-HDL-C,) low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Separate PIs (95%) were calculated for all lipids and lipoproteins.
RESULTS: The expected outcomes of a new study on this topic were as follows: TC, -5.5 (-24.0, 13.0) mg/dl; HDL-C, 0.7 (-8.9, 10.4) mg/dl; TC/HDL-C, -0.5 (-1.8, 0.8); non-HDL-C, -8.7 (-35.7, 18.3) mg/dl; LDL-C, -6.1 (-28.9, 16.4) mg/dl; TG, -8.1 (-34.5, 18.3) mg/dl.
CONCLUSIONS: Caution may be warranted in recommending that PRT improves TC, HDL-C, TC/HDL-C, non-HDL-C, LDL-C, and TG in adults. Future research should continue to examine the effects of PRT on lipids and lipoproteins in adults so as to determine optimal programs and populations in which PRT may have a positive effect.

PMID 19804794
Shinji Koba, Hiroaki Tanaka, Chizuko Maruyama, Norio Tada, Sadatoshi Birou, Tamio Teramoto, Jun Sasaki
Physical activity in the Japan population: association with blood lipid levels and effects in reducing cardiovascular and all-cause mortality.
J Atheroscler Thromb. 2011;18(10):833-45. Epub 2011 Sep 24.
Abstract/Text According to many prospective cohort studies and meta-analyses of those studies, physical inactivity and/or low levels of physical fitness are associated with an elevated risk for the development of metabolic syndrome, type 2 diabetes, hypertension, coronary artery disease (CAD), and stroke, and with an increased risk of cardiovascular disease (CVD) mortality and all-cause mortality. Most of these analyses, however, were conducted on non-Japanese populations in the West. This report summarizes prospective observational and clinical studies in Japan. The annual national nutrition survey has shown a gradual decline in the number of walking steps in both genders and in all age groups over the last 10 years. While exercise habits have been gradually increasing in the elderly, only one-fifth of young and middle-aged people undertake leisure-time physical activity. Prospective cohort studies have shown that increased physical fitness and greater physical activity in either daily life or leisure time are of benefit in preventing all-cause mortality and CVD mortality. The daily number of walking steps is positively associated with HDL cholesterol levels and negatively associated with triglyceride levels. According to a random-effects model meta-analysis of 4 randomized controlled trials comparing supervised aerobic exercise training with non-exercise control in subjects without CAD, exercise resulted in a significant increase in HDL-cholesterol (10.01 mg/dL, 95% CI 5.38 to 14.65, p< 0.0001). While this confirms the importance of physical activity in preventing CVD mortality and all-cause mortality, the levels of physical activity are on a declining trend in Japan, particularly among the young.

PMID 21946534
Kohji Shirai, Atsuhito Saiki, Shinichi Oikawa, Tamio Teramoto, Nobuhiro Yamada, Shun Ishibashi, Norio Tada, Shigeru Miyazaki, Ikuo Inoue, Shunichi Murano, Naoki Sakane, Noriko Satoh-Asahara, Hideaki Bujo, Yoh Miyashita, Yasushi Saito
The effects of partial use of formula diet on weight reduction and metabolic variables in obese type 2 diabetic patients--multicenter trial.
Obes Res Clin Pract. 2013 Jan-Feb;7(1):e43-54. doi: 10.1016/j.orcp.2012.03.002.
Abstract/Text AIMS: To clarify the usefulness of protein-sparing modified formula diet in obese type 2 diabetic patients, the effects of partial use of formula diet on weight reduction and changes in related metabolic variables, and the improving rates of risk factors per 1% body weight reduction, were compared with those of conventional subcaloric diet.
SUBJECTS AND METHODS: Obese patients [BMI >25 kg/m²] with diabetic mellitus were randomly assigned to a low-caloric diet with partial use of formula diet group (FD, n = 119) and a conventional low-caloric diet group (CD, n = 110). Subjects in FD took one pack of formula diet (MicroDiet®, 240 kcal/pack) in place of one of three daily low-caloric meals for 24 weeks. Total daily calorie prescribed was same.
RESULT: Weight reduction was greater in FD than in CD (week 24: -3.5 vs -1.4 kg; all p < 0.001). Systolic blood pressure decreased significantly only in FD. HbA1c reduction was greater in FD than in CD. HDL-cholesterol increased significantly more in FD than in CD (week 24: +2.8 vs. +0.6 mg/dl, p < 0.001). Among several improving rates (%) of risk factors/1% body weight reduction, those of HbA1c at weeks 16 and 24, triglyceride at week 8 and HDL-cholesterol at week 24, were significantly higher in FD than CD. Doses of sulfonylurea and thiazolidinedione were significantly decreased in FD than in CD.
CONCLUSION: Partial use of formula diet was much more effective in reducing body weight, and also in improving coronary risk factors than conventional diet in part due to reduced body weight through decreased energy diet intake and due to dietary composition of the formula diet.

© 2013 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.
PMID 24331681
C Baigent, A Keech, P M Kearney, L Blackwell, G Buck, C Pollicino, A Kirby, T Sourjina, R Peto, R Collins, R Simes, Cholesterol Treatment Trialists' (CTT) Collaborators
Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
Lancet. 2005 Oct 8;366(9493):1267-78. doi: 10.1016/S0140-6736(05)67394-1. Epub 2005 Sep 27.
Abstract/Text BACKGROUND: Results of previous randomised trials have shown that interventions that lower LDL cholesterol concentrations can significantly reduce the incidence of coronary heart disease (CHD) and other major vascular events in a wide range of individuals. But each separate trial has limited power to assess particular outcomes or particular categories of participant.
METHODS: A prospective meta-analysis of data from 90,056 individuals in 14 randomised trials of statins was done. Weighted estimates were obtained of effects on different clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol.
FINDINGS: During a mean of 5 years, there were 8186 deaths, 14,348 individuals had major vascular events, and 5103 developed cancer. Mean LDL cholesterol differences at 1 year ranged from 0.35 mmol/L to 1.77 mmol/L (mean 1.09) in these trials. There was a 12% proportional reduction in all-cause mortality per mmol/L reduction in LDL cholesterol (rate ratio [RR] 0.88, 95% CI 0.84-0.91; p<0.0001). This reflected a 19% reduction in coronary mortality (0.81, 0.76-0.85; p<0.0001), and non-significant reductions in non-coronary vascular mortality (0.93, 0.83-1.03; p=0.2) and non-vascular mortality (0.95, 0.90-1.01; p=0.1). There were corresponding reductions in myocardial infarction or coronary death (0.77, 0.74-0.80; p<0.0001), in the need for coronary revascularisation (0.76, 0.73-0.80; p<0.0001), in fatal or non-fatal stroke (0.83, 0.78-0.88; p<0.0001), and, combining these, of 21% in any such major vascular event (0.79, 0.77-0.81; p<0.0001). The proportional reduction in major vascular events differed significantly (p<0.0001) according to the absolute reduction in LDL cholesterol achieved, but not otherwise. These benefits were significant within the first year, but were greater in subsequent years. Taking all years together, the overall reduction of about one fifth per mmol/L LDL cholesterol reduction translated into 48 (95% CI 39-57) fewer participants having major vascular events per 1000 among those with pre-existing CHD at baseline, compared with 25 (19-31) per 1000 among participants with no such history. There was no evidence that statins increased the incidence of cancer overall (1.00, 0.95-1.06; p=0.9) or at any particular site.
INTERPRETATION: Statin therapy can safely reduce the 5-year incidence of major coronary events, coronary revascularisation, and stroke by about one fifth per mmol/L reduction in LDL cholesterol, largely irrespective of the initial lipid profile or other presenting characteristics. The absolute benefit relates chiefly to an individual's absolute risk of such events and to the absolute reduction in LDL cholesterol achieved. These findings reinforce the need to consider prolonged statin treatment with substantial LDL cholesterol reductions in all patients at high risk of any type of major vascular event.

PMID 16214597
Robin J Edison, Maximilian Muenke
Central nervous system and limb anomalies in case reports of first-trimester statin exposure.
N Engl J Med. 2004 Apr 8;350(15):1579-82. doi: 10.1056/NEJM200404083501524.
Abstract/Text
PMID 15071140
Christopher O'Regan, Ping Wu, Paul Arora, Dan Perri, Edward J Mills
Statin therapy in stroke prevention: a meta-analysis involving 121,000 patients.
Am J Med. 2008 Jan;121(1):24-33. doi: 10.1016/j.amjmed.2007.06.033.
Abstract/Text PURPOSE: More than 120,000 patients now have taken part in randomized trials evaluating statin therapy for stroke prevention. We aimed to conduct a comprehensive review of all randomized trials and determine the therapeutic potential of statins for all strokes.
METHODS: We searched 10 electronic databases (from inception to December 2006). We additionally contacted study authors and authors of previous reviews. We extracted data on study characteristics and outcomes related to all-cause mortality, all-stroke incidence, specific type of strokes, and cholesterol changes. We pooled data using a random-effects model and conducted meta-regression.
RESULTS: We included 42 trials assessing statin therapy for all-stroke prevention (n=121,285), resulting in a pooled relative risk (RR) of 0.84 (95% confidence interval [CI], 0.79-0.91). The pooled RR of statin therapy for all-cause mortality (n=116,080) was 0.88 (95% CI, 0.83-0.93). Each unit increase in low-density lipoprotein (LDL) resulted in a 0.3% increased RR of death (P=.02). Seventeen trials evaluated statins on cardiovascular death (n=57,599, RR 0.81, 95% CI, 0.74-0.90), and 11 evaluated nonhemorrhagic cerebrovascular events (n=58,604, RR 0.81, 95% CI, 0.69-0.94). Eleven trials reported hemorrhagic stroke incidence (total n=54,334, RR 0.94, 95% CI, 0.68-1.30) and 21 trials reported on fatal strokes (total n=82,278, RR 0.99, 95% CI, 0.80-1.21). Only one trial reported on statin therapy for secondary prevention.
CONCLUSIONS: Statin therapy provides high levels of protection for all-cause mortality and nonhemorrhagic strokes. This overview reinforces the need to consider prolonged statin treatment in patients at high risk of major vascular events, but caution remains for patients at risk of bleeds.

PMID 18187070
M Thomas, J Mann
Increased thrombotic vascular events after change of statin.
Lancet. 1998 Dec 5;352(9143):1830-1. doi: 10.1016/S0140-6736(05)79893-7.
Abstract/Text
PMID 9851392
Abstract/Text The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a multicenter, randomized, double-blind study, tested the efficacy of cholesterol lowering in reducing risk of coronary heart disease (CHD) in 3,806 asymptomatic middle-aged men with primary hypercholesterolemia (type II hyperlipoproteinemia). The treatment group received the bile acid sequestrant cholestyramine resin and the control group received a placebo for an average of 7.4 years. Both groups followed a moderate cholesterol-lowering diet. The cholestyramine group experienced average plasma total and low-density lipoprotein cholesterol (LDL-C) reductions of 13.4% and 20.3%, respectively, which were 8.5% and 12.6% greater reductions than those obtained in the placebo group. The cholestyramine group experienced a 19% reduction in risk (p less than .05) of the primary end point--definite CHD death and/or definite nonfatal myocardial infarction--reflecting a 24% reduction in definite CHD death and a 19% reduction in nonfatal myocardial infarction. The cumulative seven-year incidence of the primary end point was 7% in the cholestyramine group v 8.6% in the placebo group. In addition, the incidence rates for new positive exercise tests, angina, and coronary bypass surgery were reduced by 25%, 20%, and 21%, respectively, in the cholestyramine group. The risk of death from all causes was only slightly and not significantly reduced in the cholestyramine group. The magnitude of this decrease (7%) was less than for CHD end points because of a greater number of violent and accidental deaths in the cholestyramine group. The LRC-CPPT findings show that reducing total cholesterol by lowering LDL-C levels can diminish the incidence of CHD morbidity and mortality in men at high risk for CHD because of raised LDL-C levels. This clinical trial provides strong evidence for a causal role for these lipids in the pathogenesis of CHD.

PMID 6361299
Abstract/Text In the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT), a 19% lower incidence of coronary heart disease (CHD) in cholestyramine-treated men was accompanied by mean falls of 8% and 12% in plasma total (TOTAL-C) and low-density lipoprotein (LDL-C) cholesterol levels relative to levels in placebo-treated men. When the cholestyramine treatment group was analyzed separately, a 19% reduction in CHD risk was also associated with each decrement of 8% in TOTAL-C or 11% in LDL-C levels (P less than .001). Moreover, CHD incidence in men sustaining a fall of 25% in TOTAL-C or 35% in LDL-C levels, typical responses to the prescribed dosage (24 g/day) of cholestyramine resin, was half that of men who remained at pretreatment levels. Adherence to medication was associated with reduced incidence of CHD only when accompanied by falls in TOTAL-C and LDL-C levels. Small increases in high-density lipoprotein cholesterol levels, which accompanied cholestyramine treatment, independently accounted for a 2% reduction in CHD risk. Thus, the reduction of CHD incidence in the cholestyramine group seems to have been mediated chiefly by reduction of TOTAL-C and LDL-C levels.

PMID 6361300
J D Alderman, R C Pasternak, F M Sacks, H S Smith, E S Monrad, W Grossman
Effect of a modified, well-tolerated niacin regimen on serum total cholesterol, high density lipoprotein cholesterol and the cholesterol to high density lipoprotein ratio.
Am J Cardiol. 1989 Oct 1;64(12):725-9.
Abstract/Text One hundred one patients with coronary artery disease and pretreatment ratios of total cholesterol to high density lipoprotein (HDL) cholesterol greater than 4.0 were treated with niacin, commencing at low dosages (100 to 250 mg twice daily) and gradually increasing the dosage over 4 to 8 weeks to 1,000 mg twice daily. Dosage adjustments were made to minimize side effects. At a mean follow-up duration of 11 +/- 7 months, and a mean dosage of 1,415 +/- 698 mg/day, the group had a 13% reduction in total cholesterol, 31% increase in HDL and 32% decrease in the cholesterol to HDL ratio. A subgroup of 62 patients taking greater than 1,000 mg/day of niacin had an 18% reduction in total cholesterol, 32% increase in HDL and 36% improvement in the cholesterol to HDL ratio. A subgroup of 39 patients taking less than or equal to 1,000 mg/day of niacin had only a 5% reduction in total cholesterol, although a 29% increase in HDL and a 24% decrease in the cholesterol to HDL ratio were recorded. Side effects of niacin were reported in 38% of the patients, but led to discontinuation of therapy in only 4. Niacin can be administered in a fashion that is well tolerated, inexpensive and very effective in improving the cholesterol to HDL ratio.

PMID 2801522
Mitsuhiro Yokoyama, Hideki Origasa, Masunori Matsuzaki, Yuji Matsuzawa, Yasushi Saito, Yuichi Ishikawa, Shinichi Oikawa, Jun Sasaki, Hitoshi Hishida, Hiroshige Itakura, Toru Kita, Akira Kitabatake, Noriaki Nakaya, Toshiie Sakata, Kazuyuki Shimada, Kunio Shirato, 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.

PMID 17398308
Isabelle Demonty, Rouyanne T Ras, Henk C M van der Knaap, Guus S M J E Duchateau, Linsie Meijer, Peter L Zock, Johanna M Geleijnse, Elke A Trautwein
Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake.
J Nutr. 2009 Feb;139(2):271-84. doi: 10.3945/jn.108.095125. Epub 2008 Dec 17.
Abstract/Text Phytosterols (plant sterols and stanols) are well known for their LDL-cholesterol (LDL-C)-lowering effect. A meta-analysis of randomized controlled trials in adults was performed to establish a continuous dose-response relationship that would allow predicting the LDL-C-lowering efficacy of different phytosterol doses. Eighty-four trials including 141 trial arms were included. A nonlinear equation comprising 2 parameters (the maximal LDL-C lowering and an incremental dose step) was used to describe the dose-response curve. The overall pooled absolute (mmol/L) and relative (%) LDL-C-lowering effects of phytosterols were also assessed with a random effects model. The pooled LDL-C reduction was 0.34 mmol/L (95% CI: -0.36, -0.31) or 8.8% (95% CI: -9.4, -8.3) for a mean daily dose of 2.15 g phytosterols. The impacts of subject baseline characteristics, food formats, type of phytosterols, and study quality on the continuous dose-response curve were determined by regression or subgroup analyses. Higher baseline LDL-C concentrations resulted in greater absolute LDL-C reductions. No significant differences were found between dose-response curves established for plant sterols vs. stanols, fat-based vs. non fat-based food formats and dairy vs. nondairy foods. A larger effect was observed with solid foods than with liquid foods only at high phytosterol doses (>2 g/d). There was a strong tendency (P = 0.054) towards a slightly lower efficacy of single vs. multiple daily intakes of phytosterols. In conclusion, the dose-dependent LDL-C-lowering efficacy of phytosterols incorporated in various food formats was confirmed and equations of the continuous relationship were established to predict the effect of a given phytosterol dose. Further investigations are warranted to investigate the impact of solid vs. liquid food formats and frequency of intake on phytosterol efficacy.

PMID 19091798
Peter Sever, Björn Dahlöf, Neil Poulter, Hans Wedel, Gareth Beevers, Mark Caulfield, Rory Collins, Sverre Kjeldsen, Arni Kristinsson, Gordon McInnes, Jesper Mehlsen, Markku Nieminem, Eoin O'Brien, Jan Ostergren, ASCOT Steering Committee Members
Potential synergy between lipid-lowering and blood-pressure-lowering in the Anglo-Scandinavian Cardiac Outcomes Trial.
Eur Heart J. 2006 Dec;27(24):2982-8. doi: 10.1093/eurheartj/ehl403. Epub 2006 Dec 4.
Abstract/Text AIMS: A prespecified objective of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) was to assess whether any synergistic effects were apparent between the lipid-lowering and blood-pressure-lowering regimens in preventing cardiovascular events.
METHODS AND RESULTS: A total of 19 257 hypertensive subjects were randomized to an amlodipine-based regimen or an atenolol-based regimen. Of these, 10 305 subjects with total cholesterol < or =6.5 mmol/L were further randomized to atorvastatin 10 mg daily or placebo. In this analysis, the effects of atorvastatin were compared with placebo on coronary heart disease (CHD), cardiovascular and stroke events in those assigned amlodipine-based and atenolol-based regimens. In the ASCOT lipid-lowering arm (LLA), overall, atorvastatin reduced the relative risk of the primary endpoint of non-fatal myocardial infarction and fatal CHD events by 36% (HR 0.64, CI 0.50-0.83, P=0.0005), total cardiovascular events by 21% (HR 0.79, CI 0.69-0.90, P=0.0005), and stroke by 27% (HR 0.73, CI 0.56-0.96, P=0.024). However, atorvastatin reduced the relative risk of CHD events by 53% (HR 0.47, CI 0.32-0.69, P<0.0001) among those allocated the amlodipine-based regimen, and by 16% (HR 0.84, CI 0.60-1.17, p: n.s.) among those allocated the atenolol-based regimen (P=0.025 for heterogeneity). There were no significant differences between the effects of atorvastatin on total cardiovascular events or strokes among those assigned amlodipine (HR 0.73, CI 0.60-0.88, P<0.005 and HR 0.69, CI 0.45-1.06, P: n.s., respectively) or atenolol (HR 0.85, CI 0.71-1.02, P: n.s and HR 0.76, CI 0.53-1.08, P: n.s, respectively). Differences in blood pressure and lipid parameters (placebo corrected) between the two antihypertensive treatment limbs could not account for the differences observed in CHD outcome.
CONCLUSION: These findings of an apparent interaction between atorvastatin and an amlodipine-based regimen in the prevention of CHD events are of borderline significance, and hence generate an hypothesis that merits independent evaluation in other trials.

PMID 17145722

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