Clinical benefit of PCSK9 inhibition in diabetic patients on insulin at high CV risk
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
LDL-C-lowering with statins, and in combination with ezetimibe, leads to significant reductions in CV events in diabetic patients . Current guidelines recommend targeting an LDL-C goal of <70 mg/dL (1.8 mmol/L), or even <50 mg/dL (1.3 mmol/L), and/or a reduction of ≥50% from baseline, in subjects with T2DM or T1DM at high or very high CV risk [2-4]. However, a significant proportion of diabetic individuals do not reach target LDL-C levels in real-life studies, and are therefore exposed to a significant residual CV risk .
In the phase 3b randomized, double-blind, placebo-controlled, parallel-group, multicenter ODYSSEY DM-INSULIN study, the efficacy and safety of alirocumab, a PCSK9 inhibitor, was evaluated, in insulin-treated individuals with T1DM or T2DM at high CV risk, not reaching LDL-C goals despite maximum tolerated statin therapy, with or without other lipid-lowering therapies (LLTs).
The study consisted of a screening period of up to 3 weeks and a double-blind treatment period of 24 weeks, followed by a safety observation period of 8 weeks. 441 patients with T2DM and 76 patients with T1DM were randomized to alirocumab or placebo (2:1). Alirocumab was administered at a starting dose of 75 mg Q2W, with a blinded dose increase to 150 mg Q2W at week 12, if week 8 LDL-C levels were ≥70 mg/dL. Other LLT remained stable throughout the entire study.
- In the overall population, the primary efficacy endpoint of least squares (LS) mean (SE) % change in calculated LDL-C levels from baseline to week 24 was –50.1% (1.9%) for alirocumab and -1.3% (2.4%) for placebo, with a difference between groups of –48.8% (2.5%; P < 0.0001). In participants with T2DM, the difference between groups was –49.0% (2.7%; P < 0.0001) and –47.8% (6.5%; P < 0.0001) in those with T1DM.
- Alirocumab resulted in significant reductions from baseline to week 24 (difference vs placebo) in levels of non-HDL-C (–38.7%; P < 0.0001), apolipoprotein B (ApoB) (–36.7%; P < 0.0001), total cholesterol (–27.6%; P < 0.0001), and Lp(a) (–18.4%; P < 0.0001), as well as a significant increase in HDL-C (difference vs placebo 4.4%; P < 0.01).
- At week 24, the proportion of individuals achieving LDL-C <70 mg/dL was 76.4% in the alirocumab group and 7.4% in the placebo group (P < .0001), and the proportion of individuals attaining LDL-C of <50 mg/dL were 50.7% and 2.7% respectively (P < 0.0001).
- The proportion of patients with at least one TEAE was similar between the treatment groups. Treatment discontinuation due to a TEAE occurred in 4.9% in the alirocumab group and in 2.4% in the placebo group. TEAEs leading to discontinuation were headache, cognitive disorder, allergic dermatitis, and myalgia.
- In the T2DM population, 3.2% of alirocumab had treatment-emergent persistent anti-drug antibodies with a low-titer. The respective percentage for T1DM participants was 2.1%.
- The proportion of participants in the alirocumab group at weeks 12 and 24 with neutralizing anti-drug antibodies was 2.1% and 0.7% for the T2DM population, and 0% and 2% for the T1DM population, respectively.
- The participant-reported acceptability of subcutaneous injection of study treatment was high and showed no significant difference between treatment arms in perceived efficacy, acceptance of side effects, injection self-efficacy (confidence in self-injection), injection convenience, or overall acceptance for both the T2DM and T1DM populations.
The PCSK9-antibody alirocumab produced significant LDL-C reductions in individuals with hypercholesterolemia with either T2DM or T1DM at high CV risk receiving insulin treatment, with no apparent effect on overall safety or measures of glycemic control. These data show that the concomitant therapy with alirocumab and insulin is feasible.