PCSK9 Inhibitor Therapy. A systematic review and meta-analysis of metabolic and cardiovascular outcomes in patients with diabetes

Aims: Pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors bring about a wide reduction in low-density lipoprotein (LDL) cholesterol, greater than that of other lipid-lowering agents. The aim of this metanalysis was assessment of the effects of PCSK9 inhibitors on glucose metabolism, LDL cholesterol, cardiovascular morbidity and mortality in individuals with and without diabetes. Materials and methods: A Medline and Clinicaltrials.gov search for eligible studies published before 1 December 2017 was performed. All randomized trials comparing PCSK-9 inhibitors with placebo or active drugs were included. Primary endpoints included (a) incident diabetes, fasting glucose and HbA1c, (b) LDL cholesterol at endpoint in patients with diabetes and in the total sample, and (c) major cardiovascular events (MACE) and mortality in individuals with and without diabetes. Results: A total of 38 trials was identified. The risk of incident diabetes was not increased by PCSK-9 inhibitors, vs placebo or any comparator. The reduction in LDL cholesterol vs placebo in patients with diabetes was 52.6 [41.3;63.8] mg/dL; the corresponding figure for all patients was 66.9 [62.4;71.3] mg/dL. Meta-regression analysis showed an inverse correlation between proportion of patients with diabetes and drug effect on LDL cholesterol in trials vs ezetimibe, but not in those vs placebo. In studies reporting data on MACE and mortality separately for individuals with and without diabetes, the effect of PCSK-9 did not appear to be affected by diabetes. Conclusion: PCSK-9 inhibitors do not affect glucose metabolism. Their efficacy on LDL cholesterol and MACE in patients with diabetes does not seem to be very dissimilar to that observed in non-diabetic participants.