Design and rationale of the ODYSSEY DM-DYSLIPIDEMIA trial: lipid-lowering efficacy and safety of alirocumab in individuals with type 2 diabetes and mixed dyslipidaemia at high cardiovascular risk

Abstract

BackgroundType 2 diabetes mellitus (T2DM) is often associated with mixed dyslipidaemia, where non-high-density lipoprotein cholesterol (non-HDL-C) levels may more closely align with cardiovascular risk than low-density lipoprotein cholesterol (LDL-C). We describe the design and rationale of the ODYSSEY DM-DYSLIPIDEMIA study that assesses the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk with non-HDL-C inadequately controlled despite maximally tolerated statin therapy. For the first time, atherogenic cholesterol-lowering with a PCSK9 inhibitor will be assessed with non-HDL-C as the primary endpoint with usual care as the comparator.MethodsDM-DYSLIPIDEMIA is a Phase 3b/4, randomised, open-label, parallel group, multinational study that planned to enrol 420 individuals. Main inclusion criteria were T2DM and mixed dyslipidaemia (non-HDL-C ≥100 mg/dl [≥2.59 mmol/l], and triglycerides ≥150 and <500 mg/dl [≥1.70 and <5.65 mmol/l]) with documented atherosclerotic cardiovascular disease or ≥1 additional cardiovascular risk factor. Participants were randomised (2:1) to alirocumab 75 mg every 2 weeks (Q2W) or lipid-lowering usual care on top of maximally tolerated statin (or no statin if intolerant). If randomised to usual care, investigators were able to add their pre-specified choice of one of the following to the patient’s current statin regimen: ezetimibe, fenofibrate, omega-3 fatty acids or nicotinic acid, in accordance with local standard-of-care. Alirocumab-treated individuals with non-HDL-C ≥100 mg/dl at week 8 will undergo a blinded dose increase to 150 mg Q2W at week 12. The primary efficacy endpoint is non-HDL-C change from baseline to week 24 with alirocumab versus usual care; other lipid levels (including LDL-C), glycaemia-related measures, safety and tolerability will also be assessed. Alirocumab will be compared to fenofibrate in a secondary analysis.ResultsRecruitment completed with 413 individuals randomised in 14 countries worldwide. Results of this trial are expected in the second quarter of 2017.ConclusionsODYSSEY DM-DYSLIPIDEMIA will provide information on the efficacy and safety of alirocumab versus lipid-lowering usual care in individuals with T2DM and mixed dyslipidaemia at high cardiovascular risk using non-HDL-C as the primary efficacy endpoint. Trial registration NCT02642159 (registered December 24, 2015)Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-017-0552-4) contains supplementary material, which is available to authorized users.

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

“…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).…”

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease

“…Alirocumab's effects on lipids and lipoproteins will be specifically examined in high‐risk patients with diabetes who have non‐HDL cholesterol ≥2.59 mmol/L and triglycerides between 1.7 and 5.65 mmol/L, in the ODYSSEY DM‐DYSLIPIDAEMIA trial . Recently presented intention‐to‐treat data showed a reduction in LDL cholesterol of 70.8% for alirocumab compared with 16.3% for placebo, and in non‐HDL cholesterol of 66.9% vs 17.7% at 24 weeks…”

The ODYSSEY DM-DYSLIPIDEMIA trial: confirming the benefits of alirocumab in diabetic mixed dyslipidemia

“…The ODYSSEY DM-DYSLIPIDEMIA trial was designed to examine the effects of alirocumab in an important group of patients with type 2 diabetes mellitus (T2DM) with mixed dyslipidemia at high cardiovascular risk, a group that has not previously been studied prospectively in the development programs with the proprotein convertase subtilisin-kexin type 9 (PCSK9) monoclonal antibodies (mAbs) (9). Likewise, the other ODYSSEY trial in diabetic patients, the ODYSSEY DM-INSULIN trial, focused on another novel group of patients with either type 1 diabetes mellitus (T1DM) or T2DM who were treated with insulin, again a group that has not been studied prospectively before (10).…”