Abstract
Despite effective lipid reduction and corresponding benefits for cardiovascular disease prevention and treatment, statins have pleiotropic effects potentially increasing the risk of ischemic heart disease (IHD), particularly by increasing body mass index (BMI). We assessed whether the effects of genetically mimicked statins on IHD were strengthened by adjusting for BMI in men and women. We also assessed if increasing BMI was specific to statins in comparison to other major lipid-lowering treatments in current use, i.e., proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe. Using univariable and multivariable Mendelian randomization (MR) we found genetically mimicked effects of statins increased BMI (0.33, 95% confidence interval (CI) 0.28 to 0.38), but genetically mimicked PCSK9 inhibitors and ezetimibe did not. Genetically mimicked effects of statins on IHD reduction in both sexes (odds ratio (OR) 0.55 per unit decrease in effect size of low-density lipoprotein cholesterol (LDL-c), 95% confidence interval (CI) 0.40 to 0.76), was largely similar after adjusting for BMI, in both men (OR 0.48, 95% CI 0.38 to 0.61) and women (OR 0.66, 95% CI 0.53 to 0.82). Compared with variations in PCSK9 and NPC1L1, only variation in HMGCR was associated with higher BMI. The effects on IHD of mimicking statins were similar after adjusting for BMI in both men and women. The BMI increase due to statins does not seem to be a concern as regards the protective effects of statins on IHD, however other factors driving BMI and the protective effects of statins could be.
Highlights
Despite effective lipid reduction and corresponding benefits for cardiovascular disease prevention and treatment, statins have pleiotropic effects potentially increasing the risk of ischemic heart disease (IHD), by increasing body mass index (BMI)
Predicted proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, ezetimibe and statins reduce the risk of cardiovascular events per unit reduction in LDL-c5, but only statins are thought to increase BMI
Of the 5 correlated single nucleotide polymorphisms (SNP) mimicking effects of ezetimibe from NPC1L1 (Supplementary Table S1 and Supplementary Table S4, r2 > 0.05), rs10260606 was used in the main analysis given it had the strongest association with low-density lipoprotein cholesterol (LDL-c) (Fig. 1)
Summary
Despite effective lipid reduction and corresponding benefits for cardiovascular disease prevention and treatment, statins have pleiotropic effects potentially increasing the risk of ischemic heart disease (IHD), by increasing body mass index (BMI). Mimicked effects of statins on IHD reduction in both sexes (odds ratio (OR) 0.55 per unit decrease in effect size of low-density lipoprotein cholesterol (LDL-c), 95% confidence interval (CI) 0.40 to 0.76), was largely similar after adjusting for BMI, in both men (OR 0.48, 95% CI 0.38 to 0.61) and women (OR 0.66, 95% CI 0.53 to 0.82). Abbreviations BMI Body mass index CARDIoGRAMplusC4D Coronary artery disease genome wide replication and meta-analysis plus the coronary artery disease genetics CVD Cardiovascular disease GIANT Genetic investigation of anthropometric traits GLGC Global lipids genetics consortium GWAS Genome-wide association studies HbA1c Glycated haemoglobin IHD Ischaemic heart disease IVW Inverse-variance weighting LD Linkage disequilibrium LDL Low-density lipoprotein MR Mendelian randomization OR Odds ratio PCSK9 Proprotein convertase subtilisin/kexin type 9 SD Standard deviation SNP Single nucleotide polymorphisms. Sex-specific information may contribute to understanding the pleiotropic effects of statins and inform their use, for prevention where the risks and benefits can be finely balanced, and differ by s ex[10]
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