Icosapent ethyl reduces CVD risk in cardiovascular-kidney-metabolic syndrome: REDUCE-IT CKM

Background/Introduction Cardiovascular-kidney-metabolic (CKM) syndrome is a recently defined disorder linking metabolic syndrome (MetS) risk factors to chronic kidney disease and cardiovascular disease (CVD). REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), an international multicenter, double-blind, placebo-controlled trial, randomized statin-treated patients with hypertriglyceridemia (150-499 mg/dL) to icosapent ethyl (IPE) or placebo (4 grams/day). IPE therapy yielded a 25% reduction in major adverse CVD outcomes compared with placebo. The present analysis examined the incremental CVD risk of CKM in secondary prevention patients with MetS but without diabetes at baseline (n=2860) and the associated benefit of IPE therapy. Purpose To examine CVD risk associated with CKM (beyond MetS) and the effect of IPE treatment. Methods Efficacy analyses of treatment with IPE versus placebo were performed using the eGFR cutoffs of 90 and 60 mL/min/1.73 m2 in secondary prevention patients with MetS without diabetes in REDUCE-IT. Groups were identified with normal eGFR (≥ 90 mL/min/1.73 m2; n=609), eGFR < 90 mL/min/1.73 m2 (n=2251), and eGFR < 60 mL/min/1.73 m2 (n=565). Results In the placebo arm, CKM was associated with increased risk of the primary composite endpoint at eGFR < 90 mL/min/1.73 m2 (Hazard Ratio [HR], 1.44 [95% CI, 1.05, 1.96]; P=0.02) and at eGFR < 60 mL/min/1.73 m2 (HR, 1.87 [95% CI, 1.31, 2.69]; P=0.0005) compared with patients with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). In patients with CKM (eGFR < 90 mL/min/1.73 m2), treatment with IPE compared with placebo was associated with significant reductions in the primary composite endpoint (HR, 0.72 [95% CI, 0.60, 0.87]; P=0.0005) and in total events (Rate Ratio [RR], 0.57 [95% CI, 0.46, 0.71]; P<0.0001). At eGFR < 60 mL/min/1.73 m2, the reduction in the primary composite endpoint and in total events was even more pronounced with IPE treatment (Figure); the numbers needed to treat to prevent an initial event in patients randomized to IPE with eGFR < 90 and < 60 mL/min/1.73 m2 were 18 and 9, respectively. Conclusions In REDUCE-IT secondary prevention patients, the CKM syndrome was associated with incremental CVD risk compared with MetS without diabetes and normal renal function. IPE treatment further reduced CVD risk in patients with CKM, thereby supporting a role for this therapy in affected patients. .