Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials

Abstract

AimTo assess the lipid‐lowering efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, in people with hypercholesterolaemia and prediabetes at baseline vs people with normoglycaemia at baseline in a pooled analysis of 10 ODYSSEY phase III trials.MethodsPeople classified as having prediabetes had baseline HbA1c ≥39 mmol/mol (5.7%) and <48 mmol/mol (6.5%), or two baseline fasting plasma glucose values ≥5.6 mmol/l (100 mg/dl) but no more than one fasting plasma glucose value ≥7.0 mmol/l (126 mg/dl), or had specific terms reported in their medical history; people diagnosed with diabetes at baseline were excluded, and the remainder were classified as having normoglycaemia. Participants received alirocumab or control (placebo/ezetimibe) for 24–104 weeks, with maximally tolerated statin in most cases. The primary efficacy endpoint was LDL cholesterol reductions from baseline to week 24 in the intention‐to‐treat population using the mixed‐effect model with a repeated measures approach.ResultsReductions in LDL cholesterol from baseline to week 24 with alirocumab were 44.0–61.8% (prediabetes group) and 45.8–59.5% (normoglycaemia group). In both subgroups, LDL cholesterol reductions were generally similar in those with and without baseline triglycerides ≥1.7 mmol/l (150 mg/dl). Alirocumab was not associated with changes in HbA1c or fasting plasma glucose over time in either subgroup (up to 24 months' follow‐up). Adverse event rates were generally similar in those with and without prediabetes.ConclusionsOver a mean follow‐up of 24–104 weeks, alirocumab treatment resulted in significant LDL cholesterol reductions from baseline that were similar in participants with prediabetes and those with normoglycaemia at baseline, with no effect on glycaemia and a safety profile similar to that of the control.

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

“…In this analysis of patients with existing DM, treatment with alirocumab had no effect on FPG or HbA1c levels compared with placebo over 78 weeks of treatment and compared with ezetimibe over 104 weeks of follow‐up, including comparison of individuals receiving insulin vs those not receiving insulin. These findings are consistent with those of the ODYSSEY DM‐INSULIN trial27 and previous sub‐analyses that revealed no effect of alirocumab on glycaemic parameters31, 33, 45 or no increase in new‐onset DM compared with controls 45. Furthermore, in a recent meta‐analysis of 15 randomized controlled trials with PCSK9 inhibitors, including alirocumab, there was no increase in glycaemic parameters in those without DM or pre‐existing DM (crude rate, 5.6% vs 5.9%; odds ratio, 1.05 [95% confidence interval, 0.95‐1.17], P = .32, I2 = 0%, heterogeneity P = .86) 46.…”

“…Alirocumab has also been demonstrated to reduce major adverse cardiovascular events vs placebo in patients with recent acute coronary syndrome in the ODYSSEY OUTCOMES trial 29. Subgroup analyses have suggested similar efficacy and tolerability of alirocumab in individuals with and without DM 26, 30, 31, 32, 33. However, it is important to examine the effects of alirocumab in the specific subgroup of individuals with both DM and ASCVD who are at particularly high risk and may benefit from additional lipid‐lowering therapy beyond a statin 7, 8, 9, 10, 15.…”

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…Findings were consistent in the prespecified diabetes mellitus subanalysis of FOURIER, which analyzed 11 031 patients with diabetes mellitus versus 16 533 patients without diabetes mellitus; compared with placebo, median LDL‐C levels were reduced by 57% in those with diabetes mellitus and by 60% in those without diabetes mellitus 71. Other subanalyses of ODYSSEY and PROFICIO phase 3 trials showed that LDL‐C reductions were also similar in those with and without prediabetes,72 impaired fasting glucose, and metabolic syndrome (Table). 73 Similarly, a recent post‐hoc subanalysis of 9 ODYSSEY phase 3 trials (24–104 weeks’ treatment duration) showed significant LDL‐C reductions with alirocumab in patients with both diabetes mellitus and ASCVD (Table).…”

“…Overall safety was also comparable versus control between patients with diabetes mellitus and ASCVD,68 insulin‐treated patients with diabetes mellitus in the DM‐INSULIN study,75 patients with T2D and mixed dyslipidemia in the DM‐DYSLIPIDEMIA study,77 individuals with prediabetes and normoglycemia,72 and those with and without dysglycemia or metabolic syndrome 73. As shown in prior studies in the overall patient population,63, 78 higher rates of local injection‐site reactions (also generally mild) were typically seen with alirocumab/evolocumab compared with control for patients both with and without diabetes mellitus 69, 71, 80.…”

“…However, current clinical trial data for alirocumab and evolocumab do not suggest an association between PCSK9 inhibitors and loss of glycemic control. Analyses of ODYSSEY phase 3 trials with alirocumab with duration of 78 to 104 weeks of follow‐up showed no changes in fasting plasma glucose or hemoglobin A1c levels over time with alirocumab or control in patients with and without diabetes mellitus 67, 68, 75, 77, 80, 85 or in individuals with prediabetes or normoglycemia at baseline 72. Analyses of PROFICIO trials of 48 to 52 weeks of follow‐up and the diabetes mellitus subanalysis of the FOURIER trial of 168 weeks of follow‐up also did not show changes in fasting plasma glucose or hemoglobin A1c levels with evolocumab in patients with and without diabetes mellitus,71 high risk of diabetes mellitus,70 impaired fasting glucose, metabolic syndrome, or normoglycemia,73 although a small but statistically significant increase in fasting plasma glucose with evolocumab (but no change in hemoglobin A1c) at 78 weeks of treatment was found in the GLAGOV study 64.…”