Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Ezetimibe on Risk of New-Onset Diabetes: A Systematic Review and Meta-Analysis of Large, Double-Blinded Randomized Controlled Trials

Abstract

Background: Previous meta-analyses have shown that statins may cause incident diabetes. This article reviews randomized controlled trials using proprotein convertase subtilisin/kexin 9 inhibitors (PCSK9i) or ezetimibe on the risk of new-onset diabetes. Methods: Eight trials involving PCSK9i and 3 trials of ezetimibe were selected for review. PubMed, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov were thoroughly searched for relevant trials. Inclusion criteria included at least 100 patients per treatment arm, follow-up of at least 52 weeks, and at least double-blinded study design. Exclusion criteria included patients with previously diagnosed diabetes, nonrandomized, placebo-controlled, open-label, and crossover trials. The primary outcome was the number of incident diabetes cases. A random effects model was used. Heterogeneity in effect sizes was measured with I 2 parameter and the Q statistic was used to test for excessive between-study heterogeneity. Results: A total of 52 214 participants for the PCSK9i and a total of 20 084 for the ezetimibe meta-analyses were included. Participants randomized to PCSK9i did not differ from the control patients in diabetes incidence (risk ratio [RR] = 0.99, P = .87, 95% CI = 0.92-1.07). Participants randomized to ezetimibe did not differ from the control patients in diabetes incidence (RR = 1.05, P = .37, 95% CI = 0.95-1.15). Discussion: The use of PCSK9i and ezetimibe does not appear to impact the risk of incident diabetes mellitus when added to guideline-directed medical therapy.

Unraveling Potential Sex‐Specific Effects of Cardiovascular Medications on Longevity Using Mendelian Randomization

“…For positive control outcomes, our findings corroborate previous trials 8 , 11 , 45 , 46 and MR studies 47 , 48 , 49 , 50 that genetically mimicked cardiovascular medications were generally associated with IHD, diabetes, or both as expected.…”

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

“…Neither LDL-C lowering (38.7 mg/dL) nor the use of PCSK9 inhibitors was associated with the incidence of diabetes, respectively, risk ratio = 1.07 (95%CI 1.03-1.11) and risk ratio = 1.00 (95%CI 0.93-1.07) [58]. In line with this evidence, other meta-analyses failed to detect a raised risk of hyperglycaemia or diabetes [59][60][61]. To quantify the safety of PCSK9 inhibitors with a specific focus on type 2 diabetes was also the topic of a Cochrane analysis.…”

Real-world safety of PCSK9 inhibitors: A pharmacovigilance study based on spontaneous reports in FAERS

“…In this study, a positive diabetes signal was observed only with evolocumab (ROR = 2.5) and not with alirocumab. Although diabetes and worsening glycemic control were not found to be associated with PCSK9 inhibitors in clinical trials ( Carvalho et al, 2017 ; Chiu et al, 2020 ), it has been suggested that the FOURIER trial may not be robust enough to detect diabetes risk ( van Bruggen and Luijendijk, 2019 ). However, in the present study, the lower risk of metabolism and nutrition disorders of PCSK9 inhibitors compared to statins provide reassurance regarding their clinical benefit.…”