Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes

Background: Pharmacologic inhibitors of the proprotein convertase subtilisin-kexin type 9 (PCSK9) are in clinical trials for the treatment of coronary artery disease. The effect of lowering low-density lipoprotein cholesterol (LDL-C) by inhibiting PCSK9 on risk of cardiovascular events and risk of diabetes is unknown

Methods: We used genetic scores consisting of independently inherited variants in the PCSK9 and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) genes, respectively, as instruments to randomly allocate 112,772 persons (14,120 cardiovascular events; 10,635 cases of diabetes) from 14 studies to higher or lower LDL-C levels. (HMGCR is the target of statins.) We compared the effect of lower LDL-C mediated by variants in PCSK9, HMGCR or both on the risk of cardiovascular events and diabetes.
Results: Variants in PCSK9 (OR:0.811; 95%-CI:0.738-0.885) and HMGCR (OR:0.809; 95%-CI:0.722-0.903) were associated with nearly identical protective effects on the risk of cardiovascular events per 10 mg/dL lower LDL-C. Variants in PCSK9 (OR:1.112; 95%-CI:1.049-1.189) and HMGCR (OR:1.127; 95%-CI:1.060-1.198) also had very similar effects on the risk of diabetes per 10 mg/dL lower LDL-C. The increased risk of diabetes was limited to persons with impaired fasting glucose for both scores, and in magnitude, was less than (approximately 60% of) the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on both cardiovascular events and diabetes.
Conclusions: Variants in PCSK9 and HMGCR are associated with approximately the same effect on the risk of cardiovascular events and diabetes per unit lower LDL-C. These effects are independent and additive.