Alirocumab vs usual lipid‐lowering care as add‐on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: The ODYSSEY DM‐DYSLIPIDEMIA randomized trial

Abstract

AimTo compare alirocumab, a proprotein convertase subtilisin‐kexin type 9 inhibitor, with usual care (UC) in individuals with type 2 diabetes (T2DM) and mixed dyslipidaemia not optimally managed by maximally tolerated statins in the ODYSSEY DM‐DYSLIPIDEMIA trial (NCT02642159).Materials and MethodsThe UC options (no additional lipid‐lowering therapy; fenofibrate; ezetimibe; omega‐3 fatty acid; nicotinic acid) were selected prior to stratified randomization to open‐label alirocumab 75 mg every 2 weeks (with increase to 150 mg every 2 weeks at week 12 if week 8 non‐HDL cholesterol concentration was ≥2.59 mmol/L [100 mg/dL]) or UC for 24 weeks. The primary efficacy endpoint was percentage change in non‐HDL cholesterol from baseline to week 24.ResultsThe randomized population comprised 413 individuals (intention‐to‐treat population, n = 409; safety population, n = 412). At week 24, the mean non‐HDL cholesterol reductions were superior with alirocumab (−32.5% difference vs UC, 97.5% confidence interval −38.1 to −27.0; P < .0001). Overall, 63.6% of alirocumab‐treated individuals were maintained on 75 mg every 2 weeks. Alirocumab also reduced LDL cholesterol (−43.0%), apolipoprotein B (−32.3%), total cholesterol (−24.6%) and LDL particle number (−37.8%) at week 24 vs UC (all P < .0001). Consistent with the overall trial comparison, alirocumab reduced non‐HDL cholesterol to a greater degree within each UC stratum at week 24. The incidence of treatment‐emergent adverse events was 68.4% (alirocumab) and 66.4% (UC). No clinically meaningful effect on glycated haemoglobin, or change in number of glucose‐lowering agents, was seen.ConclusionsIn individuals with T2DM and mixed dyslipidaemia on maximally tolerated statin, alirocumab showed superiority to UC in non‐HDL cholesterol reduction and was generally well tolerated.

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.…”

“…The primary efficacy end point in this trial was non‐HDL‐C: at week 24, mean non‐HDL‐C changes were superior with alirocumab (−37.3%) vs usual care (−4.7%). The LDL‐C reduction (secondary end point) values shown for DM‐DYSLIPIDEMIA in this table are measured LDL‐C values, not calculated LDL‐C 76, 77…”

“…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).…”

“…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).…”

“…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.…”