Protective Effect of PCSK9 and HMGCR on CV Events, Diabetes Risk

PCKS9 and HMGCR variants were associated with similar protective effects on cardiovascular event risk and diabetes risk.

Variants in both proprotein convertase subtilisin-kexin type 9 (PCSK9) and 3-hydroxy-3-methylglutaryl–coenzyme A reductase (HMGCR) had similar effects on cardiovascular event risk and diabetes risk with additive effects with both were present, according to research published in the New England Journal of Medicine.

Brian A. Ference, MD, of the Division of Cardiovascular Medicine at Wayne State University School of Medicine in Detroit, and colleagues conducted the study.

Nearly 113,000 participants (14,120 cardiovascular events and 10,635 cases of diabetes) were pooled from 14 prospective cohort or case-control studies. Genetic scores were given to all participants, who were then divided based on whether their score was above or below the median. Four groups were then created to compare the separate and combined effects of variants in PCSK9 and HMGCR using a 2×2 factorial analysis. 

The study’s primary cardiovascular outcome was a composite of the first occurrence of myocardial infarction (MI) or death from coronary heart disease (CHD); primary safety outcome was diabetes or treatment with a glucose-lowering medication. Key secondary outcomes were major coronary events and major vascular events, fasting plasma glucose level, weight, and BMI.

Weighted mean age of the study cohort was 59.9 years. Weighted mean values of LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were 129.9 mg/dL, 52.3 mg/dL, and 155.3 mg/dL, respectively. No significant differences were found in nonlipid baseline characteristics.

Participants with higher PCSK9 genetic scores had lower mean LDL cholesterol levels (difference: -4.2 mg/dL; P =5.6×10-16), lower non-HDL cholesterol (difference: -4.5 mg/dL; P =1.8×10-16), lower median triglycerides (difference: -5.3 mg/dL; P =6.8×10-10), and a higher mean level of HDL cholesterol (difference: 0.5 mg/dL; P =5.4×10-5) vs those with lower PCSK9 scores. Those with higher PCSK9 genetic scores had an 8.4% lower risk of MI or death from CHD (odds ratio [OR]: 0.92; 95% confidence interval [CI], 0.88-0.95).

Similar analyses were conducted using HMGCR genetic scores. Participants with higher HMGCR scores were found to have a 3.2 mg/dL lower mean LDL cholesterol level than those with lower scores (P =2.9×10-15), as well as a 6.6% lower risk of MI or death from CHD (OR: 0.93; 95% CI, 0.90-0.97).

Those with higher PCSK9 scores had a 6.1% higher risk of diabetes than those with lower PCKS9 scores (OR: 1.06, 95% CI, 1.02-1.11); again, similar risks were associated with HMGCR variants (OR: 1.13; 95% CI, 1.06-1.20). Both PCSK9 and HMGCR were found to have additive effects on diabetes risk. In those with impaired fasting glucose levels at baseline, both scores were linked to an elevated risk of incident diabetes; comparatively, those with normal fasting glucose levels were not at an increased risk (PCSK9 OR: 0.99; 95% CI, 0.84-1.17; HMGCR OR: 1.04; 95% CI, 0.89-1.22).

“The genetic evidence suggests that PCSK9 and HMGCR inhibition … may cause mildly impaired glucose tolerance … without materially increasing fasting glucose levels, which may then lead to an increased likelihood of incident diabetes among persons who have impaired fasting glucose levels,” the researchers concluded. “Variants in PSCK9 and HMGCR were associated with approximately the same effects on the risk of cardiovascular events and very similar effects on the risk of diabetes.”

Study Limitations

  • Lifelong exposure to decreased LDL cholesterol levels mediated by genetic variants is linked to greater reductions in CVD risk.
  • The effect of PCSK9 variants on cardiovascular events is likely to be quantitatively much bigger than the effect observed in ongoing trials. 


Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375:2144-2153. doi:10.1056/NEJMoa1604304.