Differing effect of statins on insulin sensitivity in non-diabetics: A systematic review and meta-analysis
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)
- et al.
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)
Lancet
(2003) - et al.
Pravastatin in Elderly individuals at Risk of Vascular Disease (PROSPER)
Lancet
(2002) - et al.
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): additional perspectives on tolerability of long-term treatment with lovastatin
Am J Cardiol
(2001) - et al.
Impact of statin dosing intensity on transaminase and creatine kinase
Am J Med
(2007) - et al.
Statins, low-density lipoprotein cholesterol, and risk of cancer
J Am Coll Cardiol
(2008) - et al.
Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients
Atherosclerosis
(2009) - et al.
Baseline triglyceride levels in insulin sensitivity are major determinants of the increase of LDL particle size and buoyancy induced by rosuvastatin treatment in patients with primary hyperlipidemia
Eur J Pharmacol
(2008) - et al.
Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin
Atherosclerosis
(2008) - et al.
Dose-dependent effect of rosuvastatin on apolipoprotein B-100 kinetics in the metabolic syndrome
Atherosclerosis
(2008) - et al.
Pravastatin improved glucose metabolism associated with increasing plasma adiponectin in patients with impaired glucose tolerance and coronary artery disease
Atherosclerosis
(2007)