Multisystem effects of sacubitril/valsartan: clinical evidence, proposed mechanisms and limits of interpretation

Sacubitril/valsartan has established efficacy in heart failure with reduced ejection fraction, while its peptide pharmacology has prompted interest in additional therapeutic uses. This structured narrative review evaluates metabolic, renal, inflammatory, fibrotic, vascular, cognitive and cardio-oncology evidence, distinguishing overall treatment effects from proposed mechanisms and evidence for a separate indication. A descriptive framework considers the population, comparator, endpoint, replication and limits of causal attribution. Secondary analyses of randomized heart failure trials show modest glycated haemoglobin reductions and slower estimated glomerular filtration rate decline, but do not establish direct tissue mediation or independent diabetes and kidney indications. UK HARP-III did not demonstrate superior measured filtration compared with irbesartan. Lipid effects are mixed, and most systemic antifibrotic and anti-inflammatory mechanisms remain experimental. Randomized cognitive assessments are reassuring within follow-up, without demonstrating neuroprotection. In cardio-oncology, favourable strain-based prevention outcomes coexist with the neutral primary ejection-fraction result in PRADA II. Vascular studies and PARADISE-MI further limit broad extrapolation from biological plausibility. The review contributes a consistent assessment of what each endpoint can establish, retaining neutral results and distinguishing repeated analyses from independent replication. Future applications require appropriate active comparators, prospective investigation of mediation, and clinically meaningful benefit assessed alongside treatment-related harm.