Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy: A Meta-analysis | Cardiology | JAMA | JAMA Network
[Skip to Navigation]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address Please contact the publisher to request reinstatement.
Baigent C, Blackwell L, Emberson J,  et al; Cholesterol Treatment Trialists' (CTT) Collaboration.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.  Lancet. 2010;376(9753):1670-168121067804PubMedGoogle ScholarCrossref
Kearney PM, Blackwell L, Collins R,  et al; Cholesterol Treatment Trialists' (CTT) Collaborators.  Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis.  Lancet. 2008;371(9607):117-12518191683PubMedGoogle ScholarCrossref
Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy.  J Am Coll Cardiol. 2006;48(3):438-44516875966PubMedGoogle ScholarCrossref
Sattar N, Preiss D, Murray HM,  et al.  Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials.  Lancet. 2010;375(9716):735-74220167359PubMedGoogle ScholarCrossref
Armitage J, Bowman L, Wallendszus K,  et al; Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group.  Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial.  Lancet. 2010;376(9753):1658-166921067805PubMedGoogle ScholarCrossref
Waters DD, Ho JE, DeMicco DA,  et al.  Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials.  J Am Coll Cardiol. 2011;57(14):1535-154521453832PubMedGoogle ScholarCrossref
Freeman DJ, Norrie J, Sattar N,  et al.  Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study.  Circulation. 2001;103(3):357-36211157685PubMedGoogle ScholarCrossref
Sabatine MS, Wiviott SD, Morrow DA, McCabe CH, Cannon CP. High-dose atorvastatin associated with worse glycemic control: a PROVE-IT TIMI 22 substudy.  Circulation. 2004;110:(suppl III)  834Google Scholar
Koh KK, Quon MJ, Han SH, Lee Y, Kim SJ, Shin EK. Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients.  J Am Coll Cardiol. 2010;55(12):1209-121620298928PubMedGoogle ScholarCrossref
Koren MJ, Hunninghake DB.ALLIANCE Investigators.  Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study.  J Am Coll Cardiol. 2004;44(9):1772-177915519006PubMedGoogle Scholar
Deedwania P, Stone PH, Bairey Merz CN,  et al.  Effects of intensive versus moderate lipid-lowering therapy on myocardial ischemia in older patients with coronary heart disease: results of the Study Assessing Goals in the Elderly (SAGE).  Circulation. 2007;115(6):700-70717283260PubMedGoogle ScholarCrossref
Nissen SE, Tuzcu EM, Schoenhagen P,  et al;  REVERSAL Investigators.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial.  JAMA. 2004;291(9):1071-108014996776PubMedGoogle ScholarCrossref
Post Coronary Artery Bypass Graft Trial Investigators.  The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary artery bypass grafts.  N Engl J Med. 1997;336(3):153-1628992351PubMedGoogle ScholarCrossref
Crouse JR III, Raichlen JS, Riley WA,  et al;  METEOR Study Group.  Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial.  JAMA. 2007;297(12):1344-135317384434PubMedGoogle ScholarCrossref
LaRosa JC, Grundy SM, Waters DD,  et al; Treating to New Targets (TNT) Investigators.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease.  N Engl J Med. 2005;352(14):1425-143515755765PubMedGoogle ScholarCrossref
Pedersen TR, Faergeman O, Kastelein JJ,  et al; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group.  High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.  JAMA. 2005;294(19):2437-244516287954PubMedGoogle ScholarCrossref
de Lemos JA, Blazing MA, Wiviott SD,  et al; A to Z Investigators.  Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.  JAMA. 2004;292(11):1307-131615337732PubMedGoogle ScholarCrossref
Cannon CP, Braunwald E, McCabe CH,  et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 Investigators.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes.  N Engl J Med. 2004;350(15):1495-150415007110PubMedGoogle ScholarCrossref
Moher D, Liberati A, Tetzlaff J, Altman DG.PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  BMJ. 2009;339:b253519622551PubMedGoogle ScholarCrossref
Verhagen AP, de Vet HCW, de Bie RA,  et al.  The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus.  J Clin Epidemiol. 1998;51(12):1235-124110086815PubMedGoogle ScholarCrossref
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-56012958120PubMedGoogle ScholarCrossref
Murphy SA, Cannon CP, Wiviott SD, McCabe CH, Braunwald E. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22) trial.  J Am Coll Cardiol. 2009;54(25):2358-236220082923PubMedGoogle ScholarCrossref
LaRosa JC, Deedwania PC, Shepherd J,  et al; TNT Investigators.  Comparison of 80 versus 10 mg of atorvastatin on occurrence of cardiovascular events after the first event (from the Treating to New Targets [TNT] trial).  Am J Cardiol. 2010;105(3):283-28720102935PubMedGoogle ScholarCrossref
Tikkanen MJ, Szarek M, Fayyad R,  et al; IDEAL Investigators.  Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial.  J Am Coll Cardiol. 2009;54(25):2353-235720082922PubMedGoogle ScholarCrossref
Jones PH, Davidson MH, Stein EA,  et al; STELLAR Study Group.  Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial).  Am J Cardiol. 2003;92(2):152-16012860216PubMedGoogle ScholarCrossref
Mallinson JE, Constantin-Teodosiu D, Sidaway J, Westwood FR, Greenhaff PL. Blunted Akt/FOXO signalling and activation of genes controlling atrophy and fuel use in statin myopathy.  J Physiol. 2009;587(pt 1):219-23019001041PubMedGoogle ScholarCrossref
Chew EY, Ambrosius WT, Davis MD,  et al;  ACCORD Study Group; ACCORD Eye Study Group.  Effects of medical therapies on retinopathy progression in type 2 diabetes.  N Engl J Med. 2010;363(3):233-24420587587PubMedGoogle ScholarCrossref
Keech AC, Mitchell P, Summanen PA,  et al; FIELD Study Investigators.  Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.  Lancet. 2007;370(9600):1687-169717988728PubMedGoogle ScholarCrossref
Wannamethee SG, Shaper AG, Whincup PH, Lennon L, Sattar N. Impact of diabetes on cardiovascular disease risk and all-cause mortality in older men: influence of age at onset, diabetes duration, and established and novel risk factors.  Arch Intern Med. 2011;171(5):404-41021403036PubMedGoogle ScholarCrossref
Baigent C, Keech A, Kearney PM,  et al; 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;366(9493):1267-127816214597PubMedGoogle ScholarCrossref
Cowie CC, Rust KF, Ford ES,  et al.  Full accounting of diabetes and pre-diabetes in the US population in 1988-1994 and 2005-2006.  Diabetes Care. 2009;32(2):287-29419017771PubMedGoogle ScholarCrossref
Clinical Review
June 22 2011

Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy: A Meta-analysis

Author Affiliations

Author Affiliations: BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom (Drs Preiss, Welsh, and Sattar); Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom (Dr Seshasai); TIMI Study Group, Cardiovascular Division, Harvard Medical School, Boston, Massachusetts (Ms Murphy and Drs Cannon, Sabatine, and Braunwald); Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston (Dr Ho); Department of Medicine, University of California, San Francisco (Dr Waters); Global Pharmaceuticals, Pfizer, New York, New York (Dr DeMicco); Heart Research Institute, Sydney, Australia (Dr Barter); Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands (Dr Kastelein); Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (Dr de Lemos); Duke Clinical Research Institute, Durham, North Carolina (Dr Blazing); University of Oslo and Centre for Preventative Medicine, Oslo University Hospital, Ullevål, Oslo, Norway (Dr Pedersen); University of Helsinki and Division of Cardiology, Helsinki University Hospital, and Folkhälsan Research Center, Helsinki, Finland (Dr Tikkanen); and Division of Cardiac and Vascular Sciences, St George's University of London, London, United Kingdom (Dr Ray).

JAMA. 2011;305(24):2556-2564. doi:10.1001/jama.2011.860

Context A recent meta-analysis demonstrated that statin therapy is associated with excess risk of developing diabetes mellitus.

Objective To investigate whether intensive-dose statin therapy is associated with increased risk of new-onset diabetes compared with moderate-dose statin therapy.

Data Sources We identified relevant trials in a literature search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (January 1, 1996, through March 31, 2011). Unpublished data were obtained from investigators.

Study Selection We included randomized controlled end-point trials that compared intensive-dose statin therapy with moderate-dose statin therapy and included more than 1000 participants who were followed up for more than 1 year.

Data Extraction Tabular data provided for each trial described baseline characteristics and numbers of participants developing diabetes and experiencing major cardiovascular events (cardiovascular death, nonfatal myocardial infarction or stroke, coronary revascularization). We calculated trial-specific odds ratios (ORs) for new-onset diabetes and major cardiovascular events and combined these using random-effects model meta-analysis. Between-study heterogeneity was assessed using the I2 statistic.

Results In 5 statin trials with 32 752 participants without diabetes at baseline, 2749 developed diabetes (1449 assigned intensive-dose therapy, 1300 assigned moderate-dose therapy, representing 2.0 additional cases in the intensive-dose group per 1000 patient-years) and 6684 experienced cardiovascular events (3134 and 3550, respectively, representing 6.5 fewer cases in the intensive-dose group per 1000 patient-years) over a weighted mean (SD) follow-up of 4.9 (1.9) years. Odds ratios were 1.12 (95% confidence interval [CI], 1.04-1.22; I2 = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I2 = 74%) for cardiovascular events for participants receiving intensive therapy compared with moderate-dose therapy. As compared with moderate-dose statin therapy, the number needed to harm per year for intensive-dose statin therapy was 498 for new-onset diabetes while the number needed to treat per year for intensive-dose statin therapy was 155 for cardiovascular events.

Conclusion In a pooled analysis of data from 5 statin trials, intensive-dose statin therapy was associated with an increased risk of new-onset diabetes compared with moderate-dose statin therapy.