Statin therapy and risk of developing type 2 diabetes: a meta-analysis

Swapnil N Rajpathak, Dharam J Kumbhani, Jill Crandall, Nir Barzilai, Michael Alderman, Paul M Ridker, Swapnil N Rajpathak, Dharam J Kumbhani, Jill Crandall, Nir Barzilai, Michael Alderman, Paul M Ridker

Abstract

Objective: Although statin therapy reduces cardiovascular risk, its relationship with the development of diabetes is controversial. The first study (West of Scotland Coronary Prevention Study [WOSCOPS]) that evaluated this association reported a small protective effect but used nonstandardized criteria for diabetes diagnosis. However, results from subsequent hypothesis-testing trials have been inconsistent. The aim of this meta-analysis is to evaluate the possible effect of statin therapy on incident diabetes.

Research design and methods: A systematic literature search for randomized statin trials that reported data on diabetes through February 2009 was conducted using specific search terms. In addition to the hypothesis-generating data from WOSCOPS, hypothesis-testing data were available from the Heart Protection Study (HPS), the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study, the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), and the Controlled Rosuvastatin Multinational Study in Heart Failure (CORONA), together including 57,593 patients with mean follow-up of 3.9 years during which 2,082 incident diabetes cases accrued. Weighted averages were reported as risk ratios (RRs) with 95% CIs using a random-effects model. Statistical heterogeneity scores were assessed with the Q and I(2) statistic.

Results: In the meta-analysis of the hypothesis-testing trials, we observed a small increase in diabetes risk (RR 1.13 [95% CI 1.03-1.23]) with no evidence of heterogeneity across trials. However, this estimate was attenuated and no longer significant when the hypothesis-generating trial WOSCOPS was included (1.06 [0.93-1.25]) and also resulted in significant heterogeneity (Q 11.8 [5 d.f.], P = 0.03, I(2) = 57.7%).

Conclusions: Although statin therapy greatly lowers vascular risk, including among those with and at risk for diabetes, the relationship of statin therapy to incident diabetes remains uncertain. Future statin trials should be designed to formally address this issue.

Figures

Figure 1
Figure 1
Flowchart of selection of studies for inclusion in the meta-analysis.
Figure 2
Figure 2
Meta-analysis of clinical trials evaluating the effects of statins on diabetes risk.

References

    1. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A: Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001;103:357–362
    1. Collins R, Armitage J, Parish S, Sleigh P, Peto R: MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003;361:2005–2016
    1. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J: Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Drugs 2004;64(Suppl. 2):43–60
    1. Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, Hague W, Beller E, Arulchelvam M, Baker J, Tonkin A: Secondary prevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care 2003;26:2713–2721
    1. Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Janosi A, Kamensky G, Komajda M, Korewicki J, Kuusi T, Mach F, Mareev V, McMurray JJ, Ranjith N, Schaufelberger M, Vanhaecke J, van Veldhuisen DJ, Waagstein F, Wedel H, Wikstrand J: Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248–2261
    1. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ: Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195–2207
    1. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ: Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12
    1. DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–188
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003;327:557–560
    1. Begg CB, Mazumdar M: Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50:1088–1101
    1. Sasaki J, Iwashita M, Kono S: Statins: beneficial or adverse for glucose metabolism. J Atheroscler Thromb 2006;13:123–129
    1. Nakata M, Nagasaka S, Kusaka I, Matsuoka H, Ishibashi S, Yada T: Effects of statins on the adipocyte maturation and expression of glucose transporter 4 (SLC2A4): implications in glycaemic control. Diabetologia 2006;49:1881–1892
    1. Kanda M, Satoh K, Ichihara K: Effects of atorvastatin and pravastatin on glucose tolerance in diabetic rats mildly induced by streptozotocin. Biol Pharm Bull 2003;26:1681–1684
    1. Chamberlain LH: Inhibition of isoprenoid biosynthesis causes insulin resistance in 3T3–L1 adipocytes. FEBS Lett 2001;507:357–361
    1. Yada T, Nakata M, Shiraishi T, Kakei M: Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet beta-cells. Br J Pharmacol 1999;126:1205–1213
    1. Ishikawa M, Okajima F, Inoue N, Motomura K, Kato T, Takahashi A, Oikawa S, Yamada N, Shimano H: Distinct effects of pravastatin, atorvastatin, and simvastatin on insulin secretion from a beta-cell line, MIN6 cells. J Atheroscler Thromb 2006;13:329–335
    1. Ridker PM: C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007;49:2129–2138
    1. Ishikawa M, Namiki A, Kubota T, Yajima S, Fukazawa M, Moroi M, Sugi K: Effect of pravastatin and atorvastatin on glucose metabolism in nondiabetic patients with hypercholesterolemia. Intern Med 2006;45:51–55
    1. Sabatine MS, Wiviott SD, Morrow DA, McCabe CH, Canon CP: High-dose atorvastatin asssociated with worse glycemic control: A PROVE-IT TIMI 22 substudy (Abstract). Circulation 2004;110:S834
    1. Fleming TR: Identifying and addressing safety signals in clinical trials. N Engl J Med 2008;359:1400–1402

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅