Efficacy and safety of alirocumab in insulin‐treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: The ODYSSEY DM‐INSULIN randomized trial

Abstract

AimsTo investigate the efficacy and safety of alirocumab in participants with type 2 (T2D) or type 1 diabetes (T1D) treated with insulin who have elevated LDL cholesterol levels despite maximally tolerated statin therapy.MethodsParticipants at high cardiovascular risk with T2D (n = 441) or T1D (n = 76) and LDL cholesterol levels ≥1.8 mmol/L (≥70 mg/dL) were randomized 2:1 to alirocumab:placebo administered subcutaneously every 2 weeks, for 24 weeks' double‐blind treatment. Alirocumab‐treated participants received 75 mg every 2 weeks, with blinded dose increase to 150 mg every 2 weeks at week 12 if week 8 LDL cholesterol levels were ≥1.8 mmol/L. Primary endpoints were percentage change in calculated LDL cholesterol from baseline to week 24, and safety assessments.ResultsAlirocumab reduced LDL cholesterol from baseline to week 24 by a mean ± standard error of 49.0% ± 2.7% and 47.8% ± 6.5% vs placebo (both P < .0001) in participants with T2D and T1D, respectively. Significant reductions were observed in non‐HDL cholesterol (P < .0001), apolipoprotein B (P < .0001) and lipoprotein (a) (P ≤ .0039). At week 24, 76.4% and 70.2% of the alirocumab group achieved LDL cholesterol <1.8 mmol/L in the T2D and T1D populations (P < .0001), respectively. Glycated haemoglobin and fasting plasma glucose levels remained stable for the study duration. Treatment‐emergent adverse events were observed in 64.5% of alirocumab‐ vs 64.1% of placebo‐treated individuals (overall population).ConclusionsAlirocumab produced significant LDL cholesterol reductions in participants with insulin‐treated diabetes regardless of diabetes type, and was generally well tolerated. Concomitant administration of alirocumab and insulin did not raise any safety concerns (NCT02585778).

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

“…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.…”

“…Further information on the impact of alirocumab in patients with diabetes mellitus is available from the ODYSSEY DM‐INSULIN74, 75 and DM‐DYSLIPIDEMIA76, 77 trials, which were dedicated phase 3b and phase 4 studies, respectively, investigating alirocumab in individuals with diabetes mellitus. The placebo‐controlled DM‐INSULIN trial assessed the efficacy and safety of concomitant administration of 2 injectable biological agents (alirocumab and insulin) in insulin‐treated individuals with hypercholesterolemia and T1D or T2D at high cardiovascular risk, on background stable maximally tolerated statin therapy with or without other lipid‐lowering therapy (Table).…”

“…The placebo‐controlled DM‐INSULIN trial assessed the efficacy and safety of concomitant administration of 2 injectable biological agents (alirocumab and insulin) in insulin‐treated individuals with hypercholesterolemia and T1D or T2D at high cardiovascular risk, on background stable maximally tolerated statin therapy with or without other lipid‐lowering therapy (Table). 74, 75 The DM‐DYSLIPIDEMIA trial assessed the efficacy and safety of alirocumab versus lipid‐lowering usual care (ezetimibe, fenofibrate, omega‐3 fatty acids, or nicotinic acid) in individuals with T2D and mixed dyslipidemia at high cardiovascular risk, on background stable maximally tolerated statin therapy without other lipid‐lowering therapies; this trial was the first trial of a PCSK9 inhibitor to evaluate non‐high‐density lipoprotein cholesterol as a primary efficacy end point (Table). 76, 77 Two evolocumab phase 3 trials study individuals with T2D and hypercholesterolemia or mixed dyslipidemia (NCT02739984, NCT02662569).…”

“…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, in those with diabetes mellitus, several analyses showed lower rates of local injection‐site reactions with alirocumab/evolocumab versus control 66, 67, 75. Furthermore, alirocumab/evolocumab‐treated individuals with diabetes mellitus showed a lower incidence of local injection‐site reactions compared with alirocumab/evolocumab‐treated individuals without diabetes mellitus 66, 67, 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.…”