Abstract

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, prompting the exploration of novel therapies to improve patient outcomes beyond traditional pharmacological and interventional approaches. This systematic review evaluates the efficacy of emerging treatments, including PCSK9 inhibitors, SGLT2 inhibitors, gene therapies, stem cell therapies, and RNA-based therapeutics, in reducing major adverse cardiovascular events (MACE), heart failure hospitalizations, and other key endpoints in patients with established CVD. Through a comprehensive literature search and analysis of 10 high-quality randomized controlled trials and meta-analyses, the review synthesizes evidence demonstrating significant benefits across these modalities. PCSK9 inhibitors, such as alirocumab and evolocumab, achieved LDL-C reductions of up to 60% and lowered MACE by 15-20% in high-risk populations, with consistent safety profiles showing no increase in neurocognitive events or new-onset diabetes. SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, reduced heart failure hospitalizations by 23-30% and cardiovascular death by 12-16%, with benefits extending to patients with or without type 2 diabetes and preserved or reduced ejection fraction. Gene therapies targeting pathways like SERCA2a or protein phosphatase 1 inhibition showed promising improvements in cardiac function and ejection fraction in phase 1/2 trials, with early data indicating safety and potential reversal of heart failure progression. Stem cell therapies, particularly mesenchymal stem cells, enhanced myocardial regeneration and reduced infarct size by 10-20% in ischemic cardiomyopathy, though long-term efficacy requires further validation. RNA therapeutics, such as siRNA targeting ANGPTL3 or mRNA for revascularization, demonstrated LDL-C lowering and cardiac remodeling benefits in ongoing trials. Overall, these novel therapies collectively reduced composite endpoints of cardiovascular death, myocardial infarction, and stroke by 10-25%, with subgroup analyses revealing greater absolute risk reductions in patients with higher baseline risk, such as those with atherosclerotic CVD or chronic kidney disease. Adverse events were minimal, primarily injection-site reactions or mild hypoglycemia, underscoring the potential of these interventions to transform CVD management, though cost-effectiveness and accessibility remain barriers to widespread adoption.

DOI: doi.org/10.63721/26/JCVI0114

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