PCSK9i reduces MACE regardless of number of metabolic risk factors

Introduction and methods

Background

Although it has been demonstrated that high-intensity statin therapy decreases the risk of MACE in patients with metabolic syndrome and chronic coronary artery disease (CAD) or acute coronary syndrome (ACS), the residual risk in individuals with metabolic syndrome remains high [1,2].

Aim of the study

The aim of the study was to describe the association of metabolic risk factors with the risk of MACE in patients with ACS on high-intensity or maximum-tolerated statin therapy as well as assessing the effect of the PCSK9 inhibitor alirocumab according to the number of metabolic risk factors present.

Methods

This was a post-hoc analysis of the ODYSSEY OUTCOMES trial. ODYSSEY OUTCOMES was a randomized, double-blind trial comparing the efficacy and safety of alirocumab versus placebo in patients with recent ACS (in the past 1-12 months) who were treated with high-intensity or maximum tolerated statins [2]. Patients (≥40 years) with elevated levels of atherogenic lipoproteins were randomized to 75 mg alirocumab every 2 weeks (n=9462) or placebo (n=9462). Follow-up was 2.8 (IQR 2.3-3.4) years.

Metabolic risk factors were defined as blood pressure ≥130/85 mmHg or treatment with antihypertensive medication, triglyceride concentration ≥150 mg/dL, HDL-c <40 mg/dL for men and 50 mg/dL for women, fasting plasma glucose concentration ≥100 mg/dL or treatment with glucose-lowering medication and BMI ≥30 kg/m².

Outcomes

The primary outcome for this post-hoc analysis was composite of death from CAD, non-fatal MI, fatal or non-fatal ischemic stroke, or unstable angina requiring hospital admission.

The effect of alirocumab was compared across subgroups by number of metabolic risk factors and between groups ≥3 vs. < 3 metabolic risk factors (≥3 risk factors corresponds with the definition of metabolic syndrome). Also, an analysis excluding patients with diabetes was performed as diabetes is a strong independent risk factor for CV events.

Main results

• 41% of patients in the alirocumab group and 41% of patients in the placebo group had ≥3 metabolic risk factors.
• In the placebo group, with each metabolic risk factor (except low HDL-c), risk of MACE increased (7.8% in patients without risk factors to 19.6% in patients with 5 risk factors (HR 1.18, 95%CI:1.13−1.24 per metabolic risk factor).

Subgroups by number of metabolic risk factors

• Alirocumab decreased the relative risk of MACE regardless of number of metabolic risk factors (Pinteraction=0.77), but absolute risk reduction (aRR) increased with increasing number of metabolic risk factors from aRR 0.74%(95%CI: -1.81 to 3.29) with 0 risk factors to aRR 3.90%, (95%CI:-1.45 to 9.25) with 5 risk factors (Pinteraction<0.001).
• When comparing patients with ≥3 vs. <3 metabolic risk factors, relative reduction by alirocumab in MACE was consistent (HR 0.80, 95%CI:0.71-0.91 vs HR 0.90, 95%CI:0.79-1.02) and aRR was greater in patients with ≥3 metabolic risk factors than in those <3 (2.60%, 95%CI:1.15-4.06 vs aRR 0.87, 95%CI:-0.19 to 1.94, Pinteraction=0.08).

Analysis excluding patients with diabetes

• In an analysis without patients with DM, incidence of MACE in the placebo group increased with increasing number of risk factors (7.7% in patients with no metabolic risk factors to 14.6% in patients with 5 metabolic risk factors).
• Alirocumab consistently decreased relative risk of MACE regardless of number of metabolic risk factors, but aRR increased with increasing number of metabolic risk factors (aRR: 0.91% [95%CI:-1.65 to 3.47} for patients with no metabolic risk factors to 3.82% [95%CI: -4.14 to 11.79] for patients with 5 factors, Pinteraction<0.001).
• Benefit with treatment of alirocumab appeared more pronounced in patients ≥3 metabolic risk factors (HR 0.73, 95%CI: 0.59-0.90) than in patients <3 metabolic risk factors (HR 0.93, 95%CI: 0.81-1.07) (Pinteraction=0.05). Also, aRR with alirocumab was higher in patients ≥3 metabolic risk factors (aRR 2.76, 95%CI: 1.04-4.49) than in those <3 metabolic risk factors (aRR 0.54%,95%CI: -0.57 to 1.64) (Pinteraction=0.04).

Conclusion

References

Find this article online at Lancet Diabetes Endocrinol.