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Efficacy of Evolocumab to Reduce CV Events in MetS Patients on Statin Therapy
Quick Takes
- In this high-risk population, after adjustment for major risk predictors, the presence of the metabolic syndrome (MetS) increased the ASCVD event rates by over 30%.
- The absolute risk reduction in the primary endpoint over 3 years with evolocumab in patients with diabetes and MetS was 2.1%; in diabetes without MetS, 4.9%; in patients with MetS without diabetes, 2.5%; and in patients with neither, 0.9%.
Study Questions:
Does the effect of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab on lipids and cardiovascular (CV) outcomes differ between patients with and without the metabolic syndrome (MetS)?
Methods:
The FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) trial randomized patients worldwide with stable atherosclerotic CV disease (ASCVD) receiving statins to evolocumab versus placebo with follow-up for a median of 2.2 years. For this prespecified analysis by intention to treat, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria and further substratified by diabetes at baseline. The primary endpoint included CV death, myocardial infarction (MI), stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary endpoint was cardiovascular death, MI, or stroke.
Results:
Of 27,342 patients in FOURIER (mean age 64 years), 20,623 men (75.4%) were included. Compared to those without the MetS, the 16,361 (59.8%) with baseline MetS were at higher risk of CV events (adjusted hazard ratio [aHR], 1.31; 95% confidence interval [CI], 1.18-1.46; p < 0.001 for the primary and aHR, 1.38; 95% CI, 1.20-1.57; p < 0.001 for the key secondary endpoint). At 48 weeks, evolocumab reduced low-density lipoprotein cholesterol (LDL-C) similarly in patients with MetS (baseline median interquartile range [IQR], 92 [79-109] mg/dl to 30 [19-48] mg/dl; p < 0.001) and without MetS (baseline median IQR, 92 [81-108] mg/dl to 29 [18-44] mg/dl; p < 0.001). For the primary endpoint, the HRs with evolocumab versus placebo were 0.83 (0.76-0.91) and 0.89 (0.79-1.01) in patients with and without MetS (p for interaction = 0.39). For the key secondary endpoint, the corresponding HRs were 0.76 (0.68-0.86) and 0.86 (0.74-1.01) (p for interaction = 0.23), respectively. Evolocumab did not increase the risk of new-onset diabetes or other major safety outcomes including worsening glycemic control, compared with placebo in patients with MetS.
Conclusions:
Patients with ASCVD and MetS have substantial residual risk of CV events despite statin therapy. Evolocumab significantly reduced LDL-C and CV risk in patients with MetS without increasing new-onset diabetes, worsening glycemic control, or other major safety events. These data suggest the addition of evolocumab to statin therapy in patients with ASCVD and MetS is safe and efficacious to reduce residual CV risk.
Perspective:
While each of the statins is associated with an increase in diabetes primarily in persons with prediabetes, this does not appear to be the case with PCSK9 inhibitors. The findings of an increase in CV events in MetS despite a similar marked lowering of LDL-C with statins and evolocumab lends further support to early intervention in the MetS with lifestyle change and directed treatment of each of the five criteria, but for the low HDL-C.
Clinical Topics: Cardiac Surgery, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins
Keywords: Atherosclerosis, Angina, Unstable, Antibodies, Monoclonal, Cholesterol, LDL, Diabetes Mellitus, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Metabolic Syndrome, Myocardial Infarction, Myocardial Revascularization, PCSK9 protein, human, Prediabetic State, Primary Prevention, Proprotein Convertase 9, Risk Factors, Stroke, Vascular Diseases
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