In the first study that evaluated the statin-diabetes association, Freeman et al. (1
) reported an inverse association between pravastatin use and diabetes incidence in the WOSCOPS (RR 0.7 [95% CI 0.55–0.99]) but used additional nonstandardized criteria for diabetes diagnosis. Subsequent statin trials did not confirm this protective effect, and in the recent JUPITER a small but significant increase in physician-reported diabetes was reported among statin users compared with those taking placebo, although in the absence of any effect on glucose levels (6
). As suggested here, and contrary to the hypothesis-generating data from WOSCOPS, in this meta-analysis of five hypothesis-testing trials a small but statistically significant increase in diabetes incidence may be associated with statin use, which does not appear to be drug or dose specific. This potential effect was attenuated and no longer significant in meta-analysis of all available data including WOSCOPS.
Our data suggest that continued efforts to understand relationships between statin therapy and diabetes are needed, both in future clinical trials and in terms of laboratory exploration. Understanding the potential mechanisms that may explain this effect will require direct experimental effort. One possible explanation is that in addition to CVD protective effects, statin therapy may interfere with normal glucose metabolism (11
). In this regard, both in vitro and in vivo data suggest that atorvastatin decreases adipocyte maturation and results in a decline in expression of GLUT4 and upregulation of GLUT1 in cultured preadipocytes and in mice (12
). This results in a marked reduction in insulin-mediated cellular glucose uptake caused by decreased insulin sensitivity, which may possibly result in exacerbation of glucose intolerance (13
). It is also possible that statin-induced insulin resistance may result from inhibition of isoprenoid biosynthesis, an intermediate product in cholesterol formation, becausee these effects can be reversed by the isoprenoid precursor mevalonate (12
). Furthermore, in addition to inducing insulin resistance, statin therapy may also directly affect insulin secretion. From this perspective, the most relevant experimental data in rats have demonstrated that when pancreatic β-cells are incubated with statins, insulin secretion is reduced due to inhibition of glucose-stimulated increase in free cytoplasmic Ca2+
). Similar findings were also reported in another study using a β-cell line, MIN6 cells, where investigators demonstrated that high doses of lipophilic but not hydrophilic statins decrease insulin secretion, either due to hydroxymethylglutaryl-CoA inhibition or cytotoxicity (16
). Another possibility is that statins may uncover diabetes in high-risk individuals, which on a population basis could result in modest hazard. For example, within the JUPITER, 77% of those in the intervention arm who developed diabetes in the follow-up had impaired fasting glucose at study entry; this is not surprising because JUPITER, unlike all prior statin trials, enrolled subjects on the basis of elevated high-sensitivity C-reactive protein, an inflammatory biomarker that is associated with increased diabetes risk. Balancing this modest risk to major macrovascular benefits is important because this JUPITER subgroup also was observed to have large and highly significant reductions in myocardial infarction, stroke, and cardiovascular death associated with rosuvastatin allocation.
A few studies have suggested that statin use may result in an increase in A1C levels (2
), although these effects have been quite small. Human data also raise the possibility that lipophilic and hydrophilic statins may have different effects on glucose (18
). In this regard, the Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI 22) trial reported that although treatment with both 80 mg atorvastatin and 40 mg pravastatin were both associated with a small increase in A1C (atorvastatin 0.37% and pravastatin 0.18%), atorvastatin significantly increased risk of developing an A1C >6% compared with pravastatin (RR 1.84 [95% CI 1.52–2.22]; P
< 0.0001) (19
). Similarly, in two Japanese studies among nondiabetic adults, atorvastatin but not pravastatin was associated with an increase in A1C levels (12
Certain limitations of our meta-analysis warrant consideration. First, our analysis was restricted to the few clinical trials that reported data on diabetes incidence in statin trials; other statin trials may have data on diabetes available that can augment these analyses. Second, none of these clinical trials were conducted with diabetes as the primary outcome and therefore were not statistically powered to evaluate this outcome. Our data are also limited in that the diagnostic criterion for diabetes varied among the trials and often was based on physician report rather than systematic surveillance. Finally, we cannot rule out the possibility that the increased risk of diabetes among statin users may be due to survival bias related to better survival in the intervention group. We conducted meta-analysis both with and without the initial hypothesis-generating WOSCOPS for two important reasons. First, as indicated earlier, WOSCOPS used additional nonstandardized criteria for diabetes diagnosis. Second, the practice of conducting summary analysis after excluding the chronologically first (hypothesis-generating) study is commonly used in meta-analysis. In fact, Fleming et al. (20
) recently suggested that this approach is important to avoid any regression-to-the-mean effect and to provide the most unbiased estimates of effect. Furthermore, when we additionally conducted a meta–regression analysis of the included trials, both age (P
= 0.029) and female sex (P
= 0.002) were significantly associated with an increased risk of statin-induced diabetes. When both age and sex were included together, only sex (elevated risk among women) remained significant (P
= 0.044). WOSCOPS was the only trial that included only men and hence may be considered as an outlier for this additional reason. Finally, unlike the analysis that excluded WOSCOPS, there was significant heterogeneity between trials when WOSCOPS was included in the analysis. Nonetheless, we believe the fully inclusive meta-analysis is also meaningful, underscoring the need for future statin trials to formally investigate this issue.
In conclusion, in the hypothesis-testing component of this meta-analysis, we found no evidence for a protective role of statin treatment on incident diabetes but rather observed a small but significant increase in risk. By contrast, this effect was attenuated and no longer significant in a meta-analysis that included all available evidence, including the original hypothesis-generating data. Given this uncertainty, ongoing efforts in clinical and experimental settings should continue to investigate these relationships. In the meantime, the clear benefits of statins on CVD likely outweigh any potential detrimental effects on glucose metabolism and diabetes risk.