Emerging Pharmacological Therapies in the Management of Hyperlipidemia

Hyperlipidemia remains a major contributor to cardiovascular diseases, with statins and fibrates being the most prescribed treatments. However, these therapies are associated with significant adverse effects. Statin-associated muscle symptoms affect 5-20% of patients, ranging from mild myalgia to severe rhabdomyolysis, and some patients do not achieve optimal lipid control even at high doses. Fibrates, while used as adjuncts to statins, have limited cardiovascular benefits when used as monotherapy and carry risks of myopathy, liver/kidney dysfunction, limiting their clinical utility and signifying the unmet clinical needs. The review aims to provide an update on the clinical efficacy, safety profiles, and mechanistic foundations of emerging lipidlowering therapies as adjuncts for patients who exhibit statin intolerance or an ineffective response to conventional pharmacotherapeutics.

A comprehensive literature review was conducted using various databases to search relevant preclinical and clinical studies published up to 2025 on novel lipid-lowering drugs, including PCK9 inhibitors, bempedoic acid, siRNA-based therapies, and phototherapeutics.

PCSK9 inhibitors have demonstrated significant efficacy through the enhancement of LDL receptor activity and subsequent cholesterol clearance. Bempedoic acid offers an alternative mechanism via ATP citrate lyase inhibition, accomplishing prominent lipid reduction without musclerelated adverse events. Concurrently, siRNA technologies targeting apolipoprotein C3 (apoC-III) and PCSK9 demonstrate promising efficacy in addressing both hypertriglyceridemia and hypercholesterolemia with prolonged dosing intervals. Phytotherapeutic agents, including Ruta chalepensis, wheat β-glucan, quercetin, and Liubao tea extract, exert multifaceted effects through antiinflammatory mechanisms, regulation of lipid metabolic pathways, and modulation of gut microbiota composition, representing an integrative approach to dyslipidemia management.

These new treatments provide mechanistically distinct alternatives to statins and fibrates that improve lipid control in patients with intolerance or suboptimal response. Nevertheless, robust long-term outcome trials are required to validate cardiovascular benefits and to guide individualized treatment strategies.

These therapeutic innovations represent a paradigm shift in hyperlipidemia management, providing mechanistically diverse and efficacious alternatives for patients with statin intolerance or suboptimal response to conventional therapies, ultimately enhancing lipid control and cardiovascular outcomes.