Background: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions
in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest
hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way off sets their
substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2
diabetes and related biomarkers to gauge the likely eff ects of PCSK9 inhibitors on diabetes risk.
Methods: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials,
case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol,
fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using
a standardised analysis plan, meta-analyses, and weighted gene-centric scores.
Findings: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses
of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower
LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight
(1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50).
Based on the collected data, we did not identify associations with HbA1c (0·03%, –0·01 to 0·08), fasting insulin (0·00%,
–0·06 to 0·07), and BMI (0·11 kg/m², –0·09 to 0·30).
Interpretation: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher
fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of
PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefi ts
of PCSK9 inhibitor treatment, as was previously done for statins.
Funding: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National
Institute for Health Research (NIHR) Biomedical Research Centre