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

Cardiovascular-kidney-metabolic (CKM) syndrome was recently identified as a cardiometabolic disorder that incorporates chronic kidney disease with the metabolic syndrome (MetS). REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was an international, double-blind, placebo-controlled trial that randomized hypertriglyceridemic (TG, 150-499 mg/dL) statin-treated patients with established cardiovascular disease (CVD) or diabetes and multiple CVD risk factors to icosapent ethyl (IPE) or placebo (4 grams/day). It is unknown if renal insufficiency added to MetS confers incremental CVD risk in secondary prevention patients without diabetes and if IPE lowers that risk.

The current study evaluated the secondary prevention patient subgroup with a history of MetSyn, but without diabetes at baseline (n=2860). In the subset of patients with CVD and MetS without diabetes, subjects were divided into the following groups: eGFR < 60 mL/min/1.73 m² (n=565), eGFR ≥ 60 to < 90 mL/min/1.73 m² (n=1686), and eGFR ≥ 90 mL/min/1.73 m² (n=609). Event rates of the primary and secondary trial endpoints were compared in placebo subjects with higher vs lower baseline eGFR, and the effect of IPE on these endpoints was also compared within each of the three subgroups.

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 MetS patients with normal kidney function (eGFR ≥ 90 mL/min/1.73 m²). A similar trend but without statistical significance was observed for eGFR ≥ 60 to < 90 mL/min/1.73 m² (HR, 1.30 [95% CI, 0.94, 1.79]; P=0.11) compared with MetS patients with normal kidney function. In patients with CKM (eGFR < 60 mL/min/1.73 m²) adjusted for age and sex, treatment with IPE compared with placebo was associated with significant reductions in the primary composite endpoint (HR, 0.55 [95% CI, 0.38, 0.78]; P=0.0009) and in the key secondary composite endpoint (HR, 0.52 [95% CI, 0.35,0.79], P= 0.002). Treatment with IPE was associated with an absolute risk reduction of 11.2% and number needed to treat of 9 patients to prevent an initial primary composite endpoint event over the study period.

In this REDUCE-IT analysis of secondary prevention patients without diabetes at baseline, the recently defined CKM syndrome was associated with incremental CVD risk compared with MetS and normal renal function. Treatment with IPE substantially reduced CVD risk in MetS patients with renal insufficiency (i.e., CKM) and CVD.