Discussion
In this study of over 136 936 patients hospitalised for a major cardiovascular event or procedure, a group in which statin treatment is strongly indicated for secondary prevention, we observed a moderately increased risk of new onset diabetes in patients prescribed higher potency statins compared with lower potency statins. Although the increased risk of diabetes is small and somewhat imprecise, the risk warrants careful consideration given that randomised controlled trials making head to head comparisons of higher potency and lower potency statins in patients with stable coronary heart disease showed no difference in all cause mortality (odds ratios between 0.98 and 1.01)19 20 or serious adverse events (which includes cardiovascular events; relative risk 1.00).21 Multiple trials have shown that the risk of all cause mortality is reduced in patients treated with a statin for secondary prevention of cardiovascular events instead of placebo, but the risk of all cause mortality was equally likely in trials that directly compared higher potency and lower potency statins in patients with stable coronary heart disease.19 20 21 22 Serious adverse events were also equally likely, and withdrawals from treatment due to adverse events were more likely in patients prescribed higher potency statins.22
We conducted both fixed and random effects analyses. On an empirical basis, the results of some χ2 tests for heterogeneity would suggest that some of the exposure categories could be analysed assuming random effects. Random effects analysis assumes that the studies were drawn from populations that differ from each other in ways that could affect the treatment effect. Fixed effect analysis assumes that all studies in the meta-analysis share a common true effect size. Our site-specific estimates were adjusted for age, sex, and several other potential confounders using high dimensional propensity scores. We believe that the fixed effect analysis is more valid given our statistical adjustments and the fact that we used a common analytical protocol at all sites.
Comparison with existing evidence
The overall rate ratio for current treatment that we observed in our analysis of statins and diabetes (rate ratio 1.15) was similar to the relative risks reported in the meta-analyses by Rajpathak et al (relative risk 1.13),2 by Sattar et al (odds ratio 1.09),3 and by Preiss et al in a meta-analysis of trials comparing higher potency and lower potency statins (odds ratio 1.12).4 Our rate ratios are also close to hazard ratios reported in another Canadian observational study.23Our results differ from other observational studies that have reported either no significant association24 or multi-fold increases in relative risk.25 26 The proximity of our results with our a priori hypothesis, and their agreement with the maximum likelihood estimates observed in most other studies, together lend meaningful support for an increased risk of diabetes associated with higher potency statins compared with lower potency statins.
Some researchers have argued that a potential absolute increase in new onset diabetes with high dose statins compared with low dose statins is outweighed by a larger reduction in cardiovascular events.27 28 A meta-analysis of randomised controlled trials lends support to this argument,4 the basis for which comes from trials specifically designed to measure cardiovascular events but where diabetes events were not recorded in a consistent or required way. In fact, most diabetes events in the trials in question relied on physicians’ adverse event reports, which are often underreported. Our study was partially motivated by these aspects of the trials of higher potency versus lower potency statins.
Our study was specifically designed to examine a hypothesis that the risk of new onset diabetes was associated with statin potency. While there are several plausible mechanisms consistent with a potency hypothesis,29 other distinct hypotheses have also been advanced, such as an effect related to the hydrophylic/lipophylic status of each statin, or a statin-specific effect. Our results do not lend support to a hydrophylic/lipophylic hypothesis because the two hydrophylic statins (pravastatin and rosuvastatin) are at near opposite ends of the potency spectrum in their effect on serum LDL cholesterol. Our results are somewhat compatible with other research that showed an increased diabetes risk with rosuvastatin, atorvastatin, and simvastatin.23 Although potency and statin-specific mechanisms are distinctly different hypothesis, the results might be expected to be compatible because the specific statins associated with an increased risk above are also the three most potent statins.