Among REDUCE-IT participants with cardiovascular-kidney-metabolic (CKM) syndrome and baseline eGFR below 60 mL/min/1.73m2, icosapent ethyl cut time to first major adverse cardiovascular event by 44% versus placebo (HR 0.56; 95% CI 0.39–0.79; P=0.001), an absolute reduction of 11.2% and number needed to treat of 9. Across baseline ApoB quartiles, hazard ratios for MACE ranged from 0.72 to 0.80 (all P≤0.02), and across fasting TRL-C quartiles 2–4, hazard ratios were 0.74, 0.79, and 0.68 (all P≤0.02). Total hospitalizations fell 9% (HR 0.91; 95% CI 0.84–0.98; P=0.017), with higher odds of surviving to study end without hospitalization (OR 1.12; P=0.016) and fewer days lost to hospitalization or death (rate ratio 0.93; P<0.001). The core news is twofold: three post hoc analyses from REDUCE-IT presented at ESC 2025 extend the signal for icosapent ethyl across CKM risk, ApoB, and triglyceride-rich lipoprotein strata, and hospitalization burden; and the ESC/EAS 2025 Focused Update reaffirmed high-dose icosapent ethyl as a Class IIa recommendation for high- or very high-risk patients with triglycerides 135–499 mg/dL on statins. Together, the data and guideline language tighten the clinical positioning of icosapent ethyl as an add-on therapy for residual atherothrombotic risk in statin-treated patients. Strategically, this is a durability play. With U.S. generics eroding brand economics and uneven adoption across European markets, Amarin is leaning on secondary analyses to deepen the clinical narrative where payers and HTAs now demand subgroup clarity and health-economic relevance. Framing benefit through CKM—a cross-disciplinary construct resonating with cardiology, nephrology, and endocrinology—aligns the product with emerging care pathways and broadens the addressable high-risk pool without biomarker gatekeeping. Emphasizing consistency across ApoB and TRL-C quartiles positions icosapent ethyl as agnostic to finer lipid stratification, while hospitalization reductions speak directly to budget holders and national reimbursement bodies. The guideline’s comparative language distancing outcomes evidence from fibrates and omega-3 mixtures further differentiates a pure EPA product in a crowded residual-risk discussion. The operational impact lands across several fronts. For sites and sponsors, background therapy standards in cardiometabolic outcomes trials will continue to normalize icosapent ethyl use in high-risk, statin-treated populations, particularly those with CKD features, which may shift event rates and power calculations. CROs and HEOR teams can expect more demand for RWE syntheses focused on hospitalization and resource utilization endpoints to support country-level reimbursement dossiers. Regulators are unlikely to revisit the label on post hoc signals alone, but guideline reinforcement can accelerate inclusion in national formularies and care pathways, especially in Europe where country-by-country access remains patchy. For payers, the NNT of nine in CKD-adjacent patients is notable and could justify targeted coverage criteria tied to eGFR and triglyceride thresholds. The next test is prospective confirmation in CKM- or CKD-enriched cohorts and real-world replication of the hospitalization effect under contemporary practice. Country-level guideline adoption and HTA decisions will determine whether the ESC/EAS Class IIa stance translates into meaningful uptake beyond early-adopter markets. Watch for pragmatic trials, registry-based evidence quantifying days out of hospital, and updates to background-therapy requirements in cardiometabolic programs. The unresolved question is whether post hoc breadth can sustain commercial momentum against generic competition and alternative residual-risk strategies, or whether sponsors will need definitive, prospectively powered studies focused on CKM populations to lock in long-term policy and reimbursement gains.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
