Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years.

Abstract

Like mutations with loss of function in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, inhibitors of PCSK9 (PCSK9i) may potentially favor the manifestation of diabetes. A meta-analysis of phase 2/3 randomized clinical trials (RCTs) assessed PCSK9i versus placebo in the primary hypercholesterolemia setting. Statins and ezetimibe were used in 98.4% of these studies and balanced between PCSK9i and placebo. We calculated relative risks (RRs) and 95% CIs using random- and fixed-effect models. We included 68,123 participants (20 RCTs) with median follow-up of 78 weeks. PCSK9i increased fasting blood glucose (weighted mean difference 1.88 mg/dL [95% CI 0.91-2.68]; <i>I</i>² = 0%; <i>P</i> < 0.001) and HbA_1c (0.032% [0.011-0.050]; <i>I</i>² = 15.5%; <i>P</i> < 0.001) when compared with placebo. This effect was not sufficient to increase incidence of diabetes (RR 1.04 [0.96-1.13]; <i>I</i>² = 0%; <i>P</i> = 0.427). Exploratory meta-regression analyses indicated an association between the increased risk of diabetes and the potency (<i>P</i> = 0.029) and duration (<i>P</i> = 0.026) of PCSK9i treatment. In the short term, PCSK9i therapy favors a small but significant increase in plasma glycemia and HbA_1c.