Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials

Abstract

AimsIndividuals with both diabetes mellitus (DM) and atherosclerotic cardiovascular disease (ASCVD) are at very high risk of cardiovascular events. This post‐hoc analysis evaluated efficacy and safety of the PCSK9 inhibitor alirocumab among 984 individuals with DM and ASCVD pooled from 9 ODYSSEY Phase 3 trials.Materials and methodsChanges in low‐density lipoprotein cholesterol (LDL‐C) and other lipids from baseline to Week 24 were analysed (intention‐to‐treat) in four pools by alirocumab dosage (150 mg every 2 weeks [150] or 75 mg with possible increase to 150 mg every 2 weeks [75/150]), control (placebo/ezetimibe) and background statin usage (yes/no).ResultsAt Week 24, LDL‐C changes from baseline in pools with background statins were −61.5% with alirocumab 150 (vs −1.0% with placebo), −46.4% with alirocumab 75/150 (vs +6.3% with placebo) and −48.7% with alirocumab 75/150 (vs −20.6% with ezetimibe), and −54.9% with alirocumab 75/150 (vs +4.0% with ezetimibe) without background statins. A greater proportion of alirocumab recipients achieved LDL‐C < 70 and < 55 mg/dL at Week 24 vs controls. Alirocumab also resulted in significant reductions in non‐high‐density lipoprotein cholesterol, apolipoprotein B and lipoprotein(a) vs controls. Alirocumab did not appear to affect glycaemia over 78‐104 weeks. Overall safety was similar between treatment groups, with a higher injection‐site reaction frequency (mostly mild) with alirocumab.ConclusionAlirocumab significantly reduced LDL‐C and other atherogenic lipid parameters, and was generally well tolerated in individuals with DM and ASCVD.

Randomized study of evolocumab in patients with type 2 diabetes and dyslipidaemia on background statin: Pre‐specified analysis of the Chinese population from the BERSON clinical trial

“…Most serious AEs were not considered to be related to treatment with evolocumab. Results from prior studies with alirocumab showed no impact on glycaemic parameters or on the risk of newonset diabetes 39,[44][45][46]. However, there were no noteworthy differences between the global population41 and the Chinese population in terms of type or severity of the most frequently reported AEs and no noteworthy differences between the evolocumab and placebo treatment groups in either population, and the overall safety profile of evolocumab in Chinese patients was similar to that reported in previous global studies of evolocumab 23,25,37,42.…”

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

“…Several sub‐analyses of ODYSSEY and PROFICIO have specifically examined whether the inhibition of PCSK9 is effective in T2DM patients. As can be observed in Table , the reductions in plasma LDL‐C, non‐HDL‐C and APOB levels following treatment with alirocumab or evolocumab were highly similar between diabetic and non‐diabetic patients . A small sub‐analysis of ORION‐1 showed that inclisiran is similarly efficacious in non‐diabetic and diabetic patients .…”

“…In the PROFICIO and ODYSSEY programs, the treatment with evolocumab or alirocumab moderately reduced fasting plasma TG (−16.2% and –15.6%) compared to baseline, while HDL‐C slightly increased (+8.4% and +4.0%). When focusing on the diabetic population, post‐hoc analyses and dedicated clinical trials indicated that the reduction in plasma TG levels and the increase in plasma HDL‐C levels in diabetic patients were similar to those observed in non‐diabetic patients (see Table ) . A sub‐analysis of the ODYSSEY LONG‐TERM clinical study, conducted in patients at high risk for cardiovascular disease, also demonstrated that the changes in plasma TG and HDL‐C levels were similar in T2DM with or without mixed dyslipidaemia .…”

“…Patients with higher Lp(a) concentrations at baseline tended to have greater absolute Lp(a) reductions and a greater relative and absolute coronary risk reduction with evolocumab treatment, suggesting that these patients might derive more benefit from anti‐PCSK9 mAb treatment . Reductions in plasma Lp(a) levels were similar between diabetic patient and non‐diabetic patient populations, as determined by post‐hoc analyses and dedicated clinical trials (see Table ) . The mechanism underlying the reduction in plasma Lp(a) levels following PCSK9 inhibition remains highly controversial.…”

“…When looking specifically at the diabetic population, post‐hoc analyses and dedicated clinical trials have not revealed a deterioration of fasting plasma glucose concentrations or plasma HbA1c levels following alirocumab or evolocumab treatment, when compared to placebo (Table ) . Only in the ODYSSEY‐DM‐DYSLIPIDAEMIA trial fasting plasma glucose levels increased with 5.7 mg/dL in alirocumab‐treated T2DM patients compared to −0.10 mg/dL in patients treated with usual care, but this difference was not significant .…”