Pleiotropic effects of statins on ischemic heart disease: a Mendelian Randomization study in the UK Biobank

ObjectivesStatins appear to have pleiotropic effects. We examined whether specifically statins, of the major lipid modifiers, operate on ischemic heart disease (IHD) via testosterone. As a validation, we assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. DesignA sex-specific univariable and multivariable Mendelian randomization study SettingA large, population-based cohort study recruited in the UK from 2006-10, the UK Biobank Participants179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases Main Outcome measuresTestosterone and IHD ResultsOf the three lipid modulations considered, statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe, only genetically predicted statin use in men affected testosterone (-0.15 effect size testosterone per effect size lower (of low-density lipoprotein cholesterol), 95% confidence interval (CI) -0.23 to -0.06). The genetically predicted effect of statin use on IHD in specifically men was partially mediated by testosterone (odds ratio (OR) 0.55 per effect size lower (low-density lipoprotein cholesterol), 95% CI 0.38 to 0.79, compared to OR 0.73, 95% CI 0.46 to 1.11 after allowing for testosterone). The estimate for the effect of genetically predicted statin use, independent of testosterone, was very similar in women, giving overall meta-analyzed OR 0.72, 95% CI 0.57 to 0.90 per effect size lower of low-density lipoprotein cholesterol. The genetically predicted effect of anakinra use also affected testosterone (0.022 per effect size (of IL-1Ra), 95% CI 0.01 to 0.04), and increased IHD in men. ConclusionsStatins may partially operate via testosterone in men, which may contribute to sex-specific pleiotropic effects. Anakinra operating by testosterone may also explain its unexpected effects. Our findings could facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific investigations and possibly treatments. Section 1: What is already known on this topicStatins appear to have pleiotropic effects on cardiovascular disease. Whether such effects exist and why they should occur is unclear, but could be highly relevant to the prevention and treatment of the leading cause of death. Section 2: What this study addsOur study shows that statins have similar protective effects on ischemic heart disease via low-density lipoprotein cholesterol in men and women, but unlike other major lipid modifiers statins have an additional effect specific to men via testosterone, while any harms of anakinra in men may operate by a similar mechanism. Our findings highlighting the possibility of sex-specific causes of cardiovascular disease and the need for sex-specific investigations, prevention and treatment.