Karol E. Watson, MD, PhD, FACC reviewing Ference BA et al. N Engl J Med 2016 Dec 1.

The reduction in cardiovascular risk and increase in diabetes risk were similar for genetic variants that mimic the effect of PCSK9 inhibitors and those that mimic statin effects.

Inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9) dramatically lower LDL cholesterol (LDL-c) levels, but how much these decreases affect cardiovascular or diabetes risks remains unknown. To gain insight, investigators examined data on 112,772 previously genotyped participants from 14 studies. The authors created an algorithm scoring the number of PCSK9 and HMGCR genetic variants (mimicking the effect of PCSK9 inhibitors and statins, respectively) and grouped the participants by these scores. They compared the effects of lower LDL-c levels, mediated by these variants, on the risks for cardiovascular events (a composite of myocardial infarction and death from coronary heart disease) and diabetes.

The PCSK9 and HMGCR variants were associated with about a 20% reduction in the risk for cardiovascular events per 10 mg/dL decrease in LDL-c level. Variants of both genes were also associated with an increase in diabetes risk: by 11% for PCSK9 polymorphisms and 13% for HMGCR polymorphisms per 10 mg/dL decrease in LDL-c level. The increased diabetes risk was limited to people with impaired fasting glucose. The presence of both types of variants had additive effects on risks for both cardiovascular events and diabetes.

CITATION(S):

Ference BA et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med 2016 Dec 1; 375:2144. 

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