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

Literature - Leiter LA, Cariou B, Müller-Wieland D, et al. - Diabetes Obes Metab. 2017; published online ahead of print

Background

LDL-C-lowering with statins, and in combination with ezetimibe, leads to significant reductions in CV events in diabetic patients [1]. 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 [5].

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.

Main results

• 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.

Conclusion

References

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