Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies

Abstract

Background: Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778).

Methods: In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies.

Results: This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls.

Conclusions: Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.

Keywords: Alirocumab; Atherosclerotic cardiovascular disease; Dyslipidemia; Low-density lipoprotein cholesterol; Type 2 diabetes mellitus.

Fig. 1

Percentage change from baseline to week 24 in non-HDL-C, LDL-C, ApoB, LDL-PN (ITT). Apo apolipoprotein, HDL-C high-density lipoprotein cholesterol, ITT intent-to-treat, LDL-C low-density lipoprotein cholesterol, LDL-PN low-density lipoprotein particle number, LS least-squares, SE standard error, UC usual care

Fig. 2

Percentage of individuals achieving non-HDL-C, LDL-C, and ApoB targets at week 24 (ITT). Non-HDL-C: 100 mg/dL = 2.59 mmol/L; LDL-C: 70 mg/dL = 1.81 mmol/L. Apo apolipoprotein, HDL-C high-density lipoprotein cholesterol, ITT intent-to-treat, LDL-C low-density lipoprotein cholesterol, UC usual care