Targeting Cardiometabolic Risk Beyond Statins: A Systematic Review of Evolocumab in Statin-Intolerant Patients with Metabolic Syndrome

Abstract

Statin intolerance presents a significant challenge in managing patients with metabolic syndrome, a high-risk group with elevated cardiovascular and metabolic burden. Evolocumab, a PCSK9 inhibitor, has emerged as a promising non-statin lipid-lowering therapy, yet its broader real-world impact on glycemic and inflammatory outcomes remains underexplored. This systematic review evaluated real-world evidence from observational and registry-based studies on the efficacy of evolocumab in statin-intolerant adults with metabolic syndrome. Databases including PubMed, Embase, Scopus, and Cochrane were searched for relevant studies from 2005 to 2024. Seventeen studies encompassing over 5,900 patients were included. Evolocumab consistently reduced LDL-C by 58%, increased HDL-C by 9%, and lowered triglycerides by 18%. Glycemic control remained stable or modestly improved, with an average HbA1c reduction of 0.2% and no evidence of increased diabetes risk. Inflammatory marker hsCRP decreased by 23%, suggesting potential anti-inflammatory effects. Adherence rates exceeded 85%, and muscle-related adverse events were rare (<2%), indicating high tolerability. When compared with emerging alternatives, such as inclisiran and bempedoic acid, evolocumab demonstrated superior real-world evidence for comprehensive cardiometabolic benefit, aligning with current ESC and AHA/ACC guideline recommendations. While heterogeneity in study design and populations limits definitive causal conclusions, the findings affirm evolocumab’s role as a safe and effective option for statin-intolerant patients with complex metabolic profiles. These results bridge a critical knowledge gap by providing consolidated real-world data on lipid, glycemic, and inflammatory outcomes, reinforcing the utility of PCSK9 inhibition in patients who are often excluded from clinical trials. Future comparative studies are warranted to evaluate long-term outcomes, cost-effectiveness, and optimal positioning of evolocumab within evolving lipidlowering treatment paradigms.