Differing effect of statins on insulin sensitivity in non-diabetics: A systematic review and meta-analysis

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Abstract

Background

To determine whether individual statins had differing effects on insulin sensitivity (IS) in patients without pre-existing diabetes mellitus.

Methods

A systematic literature search of MEDLINE, EMBASE and Cochrane CENTRAL was conducted through December 2008. Trials were included if they compared pravastatin, atorvastatin, rosuvastatin or simvastatin to placebo/control, excluded patients with diabetes, and reported data on insulin sensitivity/resistance. IS data was pooled and evaluated as standardized mean differences (SMDs) and 95% confidence interval (CI) using a random-effects model.

Results

16 studies (n = 1146) were included, with patients receiving pravastatin in three trials (n = 164), atorvastatin in five trials (n = 315), rosuvastatin in five trials (n = 419), and simvastatin in five trials (n = 369). When pooled as a class, statins had no significant impact on IS as compared with placebo/control [SMD −0.084 (95% CI −0.210 to 0.042); p = 0.19]. Pravastatin was found to significantly improved IS [SMD 0.342 (95% CI 0.032–0.621); p = 0.03], whereas simvastatin significantly worsened IS [SMD −0.321 (95% CI −0.526 to −0.117); p = 0.03].

Conclusions

Statins do not appear to demonstrate a ‘class effect’ on IS in patients without diabetes. Differences between individual statins likely exist that may partially explain the findings of previously conducted meta-analyses examining the impact of statins on the development of diabetes.

Introduction

HMG-CoA reductase inhibitors (statins) reduce cardiovascular risk in both primary and secondary prevention populations [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12] but may increase the risk for myopathy and elevate liver function tests [13]. Concerns regarding longer term complications of statin therapy, including cancer risk, have largely been refuted [14], [15]. However, more recently, the potential of extended statin use to impact patients’ risk of developing new-onset diabetes mellitus has been suggested [16]. A recent meta-analysis of five prospective, randomized controlled trials (n = 39,791) suggested that, as a class, statins did not significantly alter a patients’ risk of developing type-2 diabetes versus placebo [relative risk (RR) 1.03; 95% confidence interval (CI) 0.89–1.03] [17]. However, subgroup analysis suggested potential differences between individual statins, with pravastatin showing a trend towards a reduction in risk (RR 0.84; 95% CI 0.86–1.49) and atorvastatin, rosuvastatin and simvastatin together demonstrating a significant increase in risk (RR 1.14; 95% CI 1.02–1.28) versus placebo [17]. The association between statin use and subsequent development of diabetes was further strengthened by the results of the recently reported Justification for the Use of statins in Prevention: an International Trial Evaluating Rosuvastatin (JUPITER) trial which demonstrated a significant increase in newly diagnosed diabetes with rosuvastatin as compared with placebo (3.0% vs. 2.4%; p = 0.01) [18]. However, a plausible pharmacologic mechanism underlying the potential effects of statins on incident diabetes (such as alterations in glucose production or storage or changes in insulin sensitivity) has not been presented. While several studies have evaluated the impact of statins on insulin sensitivity, the results are rarely conclusive and sometimes conflicting [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34].

In cases where a robust literature set comprised of mostly underpowered studies exists, meta-analysis can be particularly useful. Thus we conducted a meta-analysis of randomized, controlled trials to better characterize the impact of commonly prescribed statins (pravastatin, atorvastatin, rosuvastatin, or simvastatin) on insulin sensitivity, both collectively and individually. We then sought to determine if differences in insulin sensitivity might help explain the qualitative differences in developing new-onset of diabetes between these statins seen in the previous meta-analysis [17].

Section snippets

Search strategy and study selection

For primary studies, a systematic literature search was performed of MEDLINE (1966 to December 2008) using the Cochrane Highly Sensitive and Specific Search Strategy (Sensitivity and Precision Maximizing Version 2008) [35], Embase (1974 to December 2008) using the McMaster Health Information Research Unit (HiRU) strategy for minimizing differences between sensitivity and specificity [36], and the Cochrane Central Register of Controlled Trials (1966 to December 2008). The following Medical

Study characteristics

The initial search yielded 108 potential literature citations (Fig. 1). Of those, 36 were excluded through review of the abstracts, leaving 72 articles for full publication review. We found 16 studies (n = 1146 subjects; Table 1) that conformed to our inclusion criteria [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. We excluded studies for not comparing statin alone to placebo, not including insulin sensitivity endpoint data, not reporting data in

Discussion

Our meta-analysis suggests that statins do not demonstrate a ‘class effect’ on insulin sensitivity in non-diabetic patients, and thus should not be simply pooled together in future meta-analyses evaluating insulin sensitivity or the development of diabetes. Whereas pravastatin showed significant improvements in insulin sensitivity, other statins showed a trend towards a reduction (atorvastatin and rosuvastatin) or significant worsening in insulin sensitivity (simvastatin). Furthermore, when

Conclusions

In summary, use of statins as a class was not associated with a significant impact on insulin sensitivity in patients without diabetes. Whereas pravastatin alone improved insulin sensitivity, a worsening was seen with the combination of atorvastatin, rosuvastatin, and simvastatin or with simvastatin alone. These results provide a pharmacologic rationale for the potential reduction in incident diabetes seen with pravastatin, and the increase seen with other statins as previously reported. Future

Conflicts of interest

There are no conflicts of interest.

Acknowledgments

None.

References (55)

  • S. Huptas et al.

    Effect of atorvastatin (10 mg/day) on glucose metabolism in patients with the metabolic syndrome

    Am J Cardiol

    (2006)
  • R. Dersimonian et al.

    Meta-analysis in clinical trials

    Control Clin Trials

    (1986)
  • M. Hanefeld et al.

    Anti-inflammatory effects of pioglitazone and/or simvastatin in high cardiovascular risk patients with elevated high sensitivity c-reactive protein. The PIOSTAT study

    J Am Coll Cardiol

    (2007)
  • B.A. Masters et al.

    In vitro myotoxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductast inhibitors, pravastatin, lovastatin, and simvastatin, using neonatal rat skeletal myocytes

    Toxicol Appl Pharmacol

    (1995)
  • H.M. Colhoun et al.

    Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS)

    Lancet

    (2004)
  • Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations

    Lancet

    (2002)
  • MCR/BHF heart protection study of cholesterol lowering with simvastatin in 20536 high-risk individuals

    Lancet

    (2002)
  • Major outcomes in moderately hypercholesterolemic hypertensive patients randomized to pravastatin vs usual care

    JAMA

    (2002)
  • P.W. Serruys et al.

    Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial

    JAMA

    (2002)
  • F.M. Sacks et al.

    The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels

    N Engl J Med

    (1996)
  • J. Shepherd et al.

    Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia

    N Engl J Med

    (1995)
  • J. Kjekshus et al.

    Rosuvastatin in older patients with systolic heart failure

    N Engl J Med

    (2007)
  • C.P. Cannon et al.

    Intensive versus moderate lipid lowering with statins after acute coronary syndromes

    N Engl J Med

    (2004)
  • K.M. Dale et al.

    Statins and cancer risk: a meta-analysis

    JAMA

    (2006)
  • D.J. Freeman et al.

    Pravastatin in the development of diabetes mellitus. Evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study

    Circulation

    (2001)
  • C.I. Coleman et al.

    The effect of statins on the development of new-onset type 2 diabetes: a meta-analysis of randomized controlled trials

    Curr Med Res Opin

    (2008)
  • P.M. Ridker et al.

    Rosuvastatin to prevent vascular events in men and women with elevated c-reactive protein

    N Engl J Med

    (2008)
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