Statins, Type 2 Diabetes, and Body Mass Index: A Univariable and Multivariable Mendelian Randomization Study

Abstract

Abstract Context Statins and possibly other lipid modifiers increase type 2 diabetes risk and body mass index (BMI). However, to what extent BMI mediates the diabetogenic effects of lipid modifiers remains unclear. Objective We used Mendelian randomization (MR) to investigate the effects of commonly used lipid modifiers on type 2 diabetes risk and glycemic traits, and any mediation by BMI. Methods Using established genetic variants to mimic commonly used lipid modifiers (ie, statins, PCSK9 inhibitors, and ezetimibe), we assessed their associations with type 2 diabetes risk, glycated hemoglobin (HbA1c), fasting insulin, fasting glucose, and BMI in the largest relevant genome-wide association studies (GWAS) in people of European ancestry, and where possible, in East Asians. We used multivariable MR to examine the role of lipid modifiers independent of BMI. Results Genetically mimicked effects of statins and ezetimibe, but not PCSK9 inhibitors were associated with higher risk of type 2 diabetes (odds ratio [OR] 1.74 [95% CI, 1.49 to 2.03]; 1.92 [1.22 to 3.02]; 1.06 [0.87 to 1.29] per SD reduction in low-density lipoprotein (LDL)-cholesterol). Of these lipid modifiers, only genetic mimics of statins were associated with higher BMI (0.33 SD [0.29 to 0.38] per SD reduction in LDL-cholesterol), which explained 54% of the total effect of statins on type 2 diabetes risk. Conclusion Higher BMI mediated more than half of the diabetogenic effects of statins, which did not extend to other commonly used lipid modifiers. Further investigations are needed to clarify drug-specific mechanisms underlying the effects of lipid modifiers on type 2 diabetes.