Icosapent ethyl reduces CV event risk in patients with metabolic syndrome

In statin-treated patients with metabolic syndrome but with no diabetes at baseline, icosapent ethyl reduced the risks of first and total CV events compared with placebo.

This summary is based on the publication of Miller M, et al. - Effectiveness of icosapent ethyl on first and total cardiovascular events in patients with metabolic syndrome, but without diabetes: REDUCE-IT MetSyn. Eur Heart J Open. 2023 Nov 12;3(6):oead114. doi: 10.1093/ehjopen/oead114

Introduction and methods

Background

Patients with metabolic syndrome have at least a 2-fold increased risk of adverse CV outcomes compared with individuals with no metabolic syndrome, even in the absence of diabetes [1]. However, few studies have evaluated the effect of pharmacologic therapy and/or lifestyle interventions on CVD risk in this patient population. Recently, the REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl Trial) study showed that icosapent ethyl (IPE) reduced CV events compared with placebo in statin-treated patients with hypertriglyceridemia and established CVD or elevated CVD risk [2].

Aim of the study

In a prespecified subgroup analysis of the REDUCE-IT trial, the authors examined the efficacy of IPE in patients with metabolic syndrome but with no diabetes at baseline and whether IPE had any impact on the risk of new-onset diabetes.

Methods

The REDUCE-IT trial was an international, double-blind, placebo-controlled, phase 3b RCT in which 8179 statin-treated patients with high CVD risk, hypertriglyceridemia, and controlled LDL-c levels were randomized to IPE 4 g/day or placebo. Mean follow-up time was 4.9 years.

At baseline, 2866 patients of the intention-to-treat group (35%) had metabolic syndrome but no diabetes. Metabolic syndrome was defined as the presence of ≥3 of the following 5 risk factors: (1) waist circumference ≥40 inches (102 cm) in men and ≥35 inches (88 cm) in women, (2) blood pressure ≥130/85 mmHg, (3) glucose ≥100 mg/dL, (4) triglycerides ≥150 mg/dL, and (5) HDL-c <40 mg/dL in men and <50 mg/dL in women. Almost all patients included in this subgroup analysis (99.8%) were secondary prevention patients.

Outcomes

The primary endpoint was a composite outcome of CV death, nonfatal MI, nonfatal stroke, coronary revascularization, or unstable angina requiring hospitalization. The key secondary endpoint was a composite outcome of CV death, nonfatal MI, or nonfatal stroke.

Results

• Among patients with metabolic syndrome but with no diabetes, treatment with IPE was associated with a 29% relative risk reduction of the first occurrence of the primary composite endpoint compared with placebo (15.8% vs. 21.7%; HR: 0.71; 95%CI: 0.59–0.84; P<0.0001; absolute risk reduction (ARR): 5.9%; number needed to treat (NNT): 17) and a 41% reduction of total (i.e., first plus subsequent) events (rate ratio (RR): 0.59; 95%CI: 0.48–0.72; P<0.0001).
• For the key secondary composite endpoint, the relative risk of the first event was reduced by 20% (10.1% vs. 12.5%; HR: 0.80; 95%CI: 0.64–1.00; P=0.05; ARR: 2.4%; NNT: 42), whereas the risk of total events was decreased by 27% (RR: 0.73; 95%CI: 0.57–0.93; P=0.01).
• There was a 27% relative risk reduction in first fatal or nonfatal MI event (HR: 0.73; 95%CI: 0.56–0.97; P=0.03; ARR: 2.1%), a 47% relative risk reduction in first urgent/emergent revascularization (HR: 0.53; 95%CI: 0.40–0.72; P<0.0001; ARR: 3.9%), and a 58% relative risk reduction in first hospitalization for unstable angina (HR: 0.42; 95%CI: 0.27–0.64; P<0.0001; ARR: 2.8%).
• Non-statistically significant reductions for IPE versus placebo were observed in the first incidence of cardiac arrest (44%), sudden cardiac death (34%), fatal or nonfatal stroke (27%), the combination of total mortality, nonfatal MI, and nonfatal stroke (17%), and CV death or nonfatal MI (16%) (all P>0.05).
• Treatment with IPE versus placebo did not alter the risk of new-onset diabetes, irrespective of the metabolic syndrome status at baseline (HR for patients with metabolic syndrome at baseline: 1.06; 95%CI: 0.74–1.52; log-rank P=0.74; HR for patients with no metabolic syndrome at baseline: 0.55; 95%CI: 0.14–2.22; log-rank P=0.40; P for interaction=0.40).

Conclusion

In this prespecified analysis of the REDUCE-IT trial among statin-treated patients with metabolic syndrome but with no diabetes at baseline, IPE reduced the risk of first (by 29%) and total (by 41%) CV events compared with placebo. These findings compared favorably with the overall results of the REDUCE-IT trial (relative risk reductions of 25% and 30%, respectively [2,3]).

References

1. Mottillo S, Filion KB, Genest J, Joseph L, Pilote L, Poirier P, Rinfret S, Schiffrin EL, Eisenberg MJ. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2020;56:1113–1132.
2. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Ballantyne CM; REDUCE-IT Investigators. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11–22.
3. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, Doyle RT Jr, Juliano RA, Jiao L, Granowitz C, Tardif JC, Gregson J, Pocock SJ, Ballantyne CM; REDUCE-IT Investigators. Effects of icosapent ethyl on total ischemic events: from REDUCE-IT. J Am Coll Cardiol 2019;73:2791–2802.

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