Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies in Regard to Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Abstract

Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes. Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints. Twenty-three studies including 65,957 participants were identified. Compared with controls, PCSK9-mAb treatment was not associated with the adverse event of diabetes (RR 0.97, 95% CI 0.91-1.02; p = 0.22). When we analysed the trials in terms of PCSK9-mAb type, alirocumab was associated with a significant reduction in the risk of diabetes (RR 0.91, 95% CI 0.85-0.98; p = 0.01), whereas no significant reduction was observed in participants receiving evolocumab or bococizumab. Interestingly, compared with ezetimibe, which was actively used as lipid-modifying therapy in the control group, PCSK9-mAbs seem to have a lower risk of incident diabetes (RR 0.60, 95% CI 0.37-0.99; p = 0.04). This meta-analysis also revealed a noticeable increase in the risk of incident diabetes in the evolocumab and alirocumab pool (RR 2.14, 95% CI 1.12-4.07; p = 0.02) when the use of statins was equivalent between the experimental and active comparator arms. Compared with placebo or any other comparator, PCSK9-mAb treatment was not associated with the adverse event of diabetes. However, evolocumab and alirocumab show high risk of incident diabetes when there is no interference from unbalanced use of statins. The imbalance in background lipid modifying therapy or different comparators used in the control arms of the studies might have masked the effect of PCSK9-mAb therapy on diabetes.