PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

Abstract

SummaryBackgroundStatin 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 offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.MethodsIn 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.FindingsData 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).InterpretationPCSK9 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 benefits of PCSK9 inhibitor treatment, as was previously done for statins.FundingBritish Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials

“…Recent evidence suggested a link between PCSK9 genetic loss‐of‐function variants that reduce LDL cholesterol levels and increases in FPG levels and diabetes risk 15, 16. However, one prospective study found no association between the PCSK9 loss‐of‐function variant R46L and the risk of new‐onset Type 2 diabetes during a 9‐year follow‐up 27.…”

“…Recent evidence suggests that PCSK9 genetic variants associated with LDL cholesterol reductions are also associated with a small increase in risk of developing new‐onset diabetes in people with impaired FPG 15, or with an increased risk of Type 2 diabetes and higher FPG concentrations, but not HbA 1c 16. The GLAGOV study of evolocumab, another PCSK9 inhibitor, found a small but statistically significant increase in FPG, but no change in HbA 1c levels, at 78 weeks of treatment 17, although no effect of evolocumab on glycaemia was observed in a pooled analysis of phase III trials 18.…”

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…Analyses of PROFICIO trials of 48 to 52 weeks of follow‐up and the diabetes mellitus subanalysis of the FOURIER trial of 168 weeks of follow‐up also did not show changes in fasting plasma glucose or hemoglobin A1c levels with evolocumab in patients with and without diabetes mellitus,71 high risk of diabetes mellitus,70 impaired fasting glucose, metabolic syndrome, or normoglycemia,73 although a small but statistically significant increase in fasting plasma glucose with evolocumab (but no change in hemoglobin A1c) at 78 weeks of treatment was found in the GLAGOV study 64. Furthermore, in contrast to the results seen in the statin and PCSK9 genetic variant studies mentioned above,4, 81, 82, 83, 84 no evidence of increased transition from normoglycemia to new‐onset diabetes mellitus following alirocumab or evolocumab treatment was found in pooled analyses 70, 73, 85. Findings from the FOURIER trial showed no significant differences in rates of adjudicated new‐onset diabetes mellitus cases between evolocumab and placebo over a median follow‐up of 2.2 years 63, 71.…”

“…Statin therapy and recent genetic epidemiology studies of PCSK9 loss‐of‐function genetic variants associated with LDL‐C reductions have suggested a small but statistically significant increased risk of the development of new‐onset diabetes mellitus 4, 81, 82, 83, 84. However, current clinical trial data for alirocumab and evolocumab do not suggest an association between PCSK9 inhibitors and loss of glycemic control.…”

“…The lack of increased risk of developing new‐onset diabetes mellitus on a PCSK9 inhibitor was further confirmed in the longest‐running PCSK9 inhibitor trial to date (the 4‐year assessment of the ongoing open‐label extension of the phase 2 OSLER‐1 trial), which indicated an annualized incidence of new‐onset diabetes mellitus of 2.8% for the evolocumab group over up to 4 years of continued exposure (versus 4.0% for the control group) 65. The lack of effect of PCSK9 inhibitors on new‐onset diabetes mellitus in contrast to the increased risk of new‐onset diabetes mellitus in those with PCSK9 loss‐of‐function genetic variants could be attributed to differences in biological effects of LDL‐C lowering associated with treatment with a PCSK9 inhibitor (ie, inhibiting circulating, extracellular PCSK9) versus the lifelong exposure to decreased LDL‐C levels because of PCSK9 loss‐of‐function genetic variants 81, 83. Indeed, PCSK9 monoclonal antibodies have been shown to affect the PCSK9 extracellular pathway without altering the PCSK9 intracellular pathway, which remains poorly characterized, especially in beta cells 86…”