PCSK9 inhibitor effective and safe in patients with metabolic syndrome
Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy - Secondary Analysis From the FOURIER Randomized Clinical Trial
Introduction and methods
Patients with metabolic syndrome (MetS) are at increased risk of developing diabetes and major adverse CV events (MACE). High-dose statins in patients with MetS and atherosclerotic CVD (ASCVD) have demonstrated to significantly reduce risk of MACE . However, despite high-intensity statins, residual risk persists in these patients and risk of developing MACE remains high. In addition, use of statins could further increase their risk of developing diabetes [2-5].
The effect of PCSK9 inhibition on reducing MACE in patients with MetS is unknown. Therefore, efficacy and safety of treatment with evolocumab in patients with MetS was evaluated in a subanalysis of the FOURIER trial.
In the FOURIER trial, therapy with evolocumab reduced risk of MACE when added to moderate to high intensity statin therapy in patients with clinically evident ASCVD (defined as prior MI, prior nonhemorrhagic stroke or symptomatic peripheral arterial disease), including diabetes patients [6-9]. Patients were randomized 1:1 to receive evolumab or matching placebo. Patients were followed for a median of 2.2 year (IQR: 1.8-2.5 years). Primary endpoint in the FOURIER was the composite of CV death, MI, stroke, coronary revascularization, or hospitalization for unstable angina. Key secondary endpoint was the composite of CV death, MI or stroke.
For this analysis, patients were stratified into those with MetS or not; 16361 of 27342 patients (59.8%) had MetS. Patients with MetS were identified based on meeting 3 of 5 criteria: 1) waist circumference >102 cm for men or >88 cm for women, 2) triglyceride levels ≥150 mg/dL, 3) HDL-c <40 mg/dL for men of <50 mg/dL for women, 4) BP ≥130/85 mmHg, 5) fasting glucose levels ≥ 110 mg/dL. Patients were also stratified for presence or absence of diabetes at baseline.
- Patients with MetS were more likely to be women, younger, had peripheral artery disease and lower eGFR than those without MetS.
- After adjusting for baseline parameters, patients with MetS had greater risk for the primary and key secondary endpoints (adjusted HR 1.31, 95%CI: 1.18-1.46, P<0.001 and adjusted HR 1.39, 95%CI: 1.20-1.57, P<0.001, respectively).
- Evolocumab reduced the primary endpoint compared to placebo in patients with MetS (HR 0.83, 95%CI: 0.76-0.91) and in patients without MetS (HR 0.89, 95%CI: 0.79-1.01) to a similar degree (P for interaction =0.39). Key secondary endpoint was reduced by evolocumab in patient with MetS (HR 0.76, 95%CI: 0.68-0.86) and without MetS (HR 0.86, 95%CI: 0.74-1.01, P for interaction=0.23).
- Efficacy of evolocumab in 4 groups based on presence or absence of diabetes and/or MetS was as follows: for those with diabetes and MetS HR was 0.85 (95%CI: 0.76-0.96), those with diabetes without MetS HR was 0.78 (95%CI: 0.60-1.01), MetS without diabetes HR was 0.80 (95%CI: 0.70-0.92) and without diabetes and MetS HR was 0.91 (95%CI:0.76-1.09) (P interaction=0.47). The absolute risk reduction (ARR) in the primary endpoint over 3 years with evolocumab in patients with diabetes and MetS was 2.1%; in patients with diabetes without MetS 4.9%; in patients with MetS without diabetes 2.5%; and in patients with neither 0.9%.
- HRs for secondary endpoint were 0.84 (95%CI: 0.73-0.97) for those with diabetes and MetS, 0.74 (95%CI: 0.54-1.01) for those with diabetes without MetS, 0.65 (95%CI: 0.54-0.79) for those with MetS without diabetes and 0.91 (95%CI: 0.76-1.09) for those without diabetes and MetS (Pinteraction=0.07).
- Rates of adverse events and serious adverse events were similar in patients with vs. without MetS, except incidence of new-onset diabetes (more common in patients with MetS). But no difference was observed in new-onset diabetes or other measures of worsening glycemic control with evolocumab vs. placebo in patients with or without MetS.
Patients with ASCVD and MetS have an increased risk of MACE compared to patients with ASCVD without MetS, despite moderate-to-high intensity statin therapy. Treatment with evolocumab is associated with reduction in MACE in patients with ASCVD and MetS, regardless or presence of absence of diabetes. These results suggest that treatment with evolocumab in patients with ASCVD and MetS is efficacious and safe.