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

Abstract

Objectives: Statins 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. Design: A sex-specific univariable and multivariable Mendelian randomization study Setting: A large, population-based cohort study recruited in the UK from 2006-10, the UK Biobank Participants: 179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases Main Outcome measures: Testosterone and IHD Results: Of 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. Conclusions: Statins 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.

Genetic validation of the use of tocilizumab, statins and dexamethasone in COVID-19

“…Statins have pleiotropic effects, including on the immune and hemostatic systems. 12 13 37-39 Statins and anakinra also have opposite effects on testosterone, 40 when testosterone raises risk of VTE. 41 Dexamethasone may also have pleiotropic effects on testosterone.…”