Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.

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 Unpublished data were obtained from investigators.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 I(2) 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; I(2) = 0%) for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; I(2) = 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.

[1]  P. Barter,et al.  Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. , 2011, Journal of the American College of Cardiology.

[2]  Peter H Whincup,et al.  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. , 2011, Archives of internal medicine.

[3]  R. Collins,et al.  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. , 2010, Lancet.

[4]  R. Collins,et al.  Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials , 2010, The Lancet.

[5]  R. Collins,et al.  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 , 2010, The Lancet.

[6]  Walter T Ambrosius,et al.  Effects of medical therapies on retinopathy progression in type 2 diabetes. , 2010, The New England journal of medicine.

[7]  J. McEvoy.  Statins and risk of incident diabetes , 2010, The Lancet.

[8]  M. Quon,et al.  Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. , 2010, Journal of the American College of Cardiology.

[9]  Heiner Greten,et al.  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). , 2010, The American journal of cardiology.

[10]  Christina Lindahl,et al.  Total cardiovascular disease burden: comparing intensive with moderate statin therapy insights from the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial. , 2009, Journal of the American College of Cardiology.

[11]  E. Braunwald,et al.  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 , 2009, Journal of the American College of Cardiology.

[12]  D. Moher,et al.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement , 2009, BMJ.

[13]  Desmond E. Williams,et al.  Full Accounting of Diabetes and Pre-Diabetes in the U.S. Population in 1988–1994 and 2005–2006 , 2009, Diabetes Care.

[14]  F. Westwood,et al.  Blunted Akt/FOXO signalling and activation of genes controlling atrophy and fuel use in statin myopathy , 2009, The Journal of physiology.

[15]  Cholesterol Treatment Trialists' Collaborators.  Efficacy of cholesterol-lowering therapy in 18 686 people with diabetes in 14 randomised trials of statins: a meta-analysis , 2008, The Lancet.

[16]  R Peto,et al.  Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. , 2008, Lancet.

[17]  P. Mitchell,et al.  Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial , 2007, The Lancet.

[18]  Diederick E Grobbee,et al.  Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. , 2007, JAMA.

[19]  Prakash Deedwania,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) , 2007, Circulation.

[20]  Christopher P Cannon,et al.  Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. , 2006, Journal of the American College of Cardiology.

[21]  O. Faergeman,et al.  High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. , 2005, JAMA.

[22]  R. Collins,et al.  Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins , 2005, The Lancet.

[23]  Philip J. Barter,et al.  Intensive lipid lowering with atorvastatin in patients with stable coronary disease. , 2005, The New England journal of medicine.

[24]  D. Hunninghake,et al.  Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the alliance study. , 2004, Journal of the American College of Cardiology.

[25]  M. Pfeffer,et al.  Early Intensive vs a Delayed Conservative Simvastatin Strategy in Patients With Acute Coronary Syndromes , 2004 .

[26]  Christopher P Cannon,et al.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes. , 2004, The New England journal of medicine.

[27]  Paul Schoenhagen,et al.  Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. , 2004, JAMA.

[28]  J. LeLorier,et al.  Intensive versus moderate lipid lowering with statins after acute coronary syndromes. , 2004, The New England journal of medicine.

[29]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[30]  Elinor Miller,et al.  Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). , 2003, The American journal of cardiology.

[31]  P W Macfarlane,et al.  Pravastatin and the Development of Diabetes Mellitus: Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study , 2001, Circulation.

[32]  H. Vet,et al.  The Delphi list: a criteria list for quality assessment of randomized clinical trials for conducting systematic reviews developed by Delphi consensus. , 1998, Journal of clinical epidemiology.

[33]  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. , 1997, The New England journal of medicine.