Metabolic alterations associated with sacubitril/valsartan treatment: a systematic review and meta-analysis

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, influences metabolic pathways, potentially altering glycemic indices and lipid profiles, but evidence remains scattered. Therefore, we aimed to quantify changes in glycemic indices, lipid profiles, and uric acid with sacubitril/valsartan.

This study followed PRISMA guidelines and was registered on PROSPERO. We searched PubMed, Scopus, and Web of Science for studies reporting within-group changes in metabolic parameters in adults receiving sacubitril/valsartan. Risk of bias was separately assessed for randomized clinical trials (RCTs) and non-RCTs. Whenever multiple populations from a single record were included in an outcome, a multilevel meta-analysis was used; otherwise, a conventional random-effects meta-analysis was applied.

Twenty-seven studies were included, involving a total of 11,093 participants. Meta-analysis showed significant reduction in hemoglobin A1c (MD -0.47%; 95% confidence interval [CI] -0.75 to - 0.20), fasting blood glucose (MD -11.94 mg/dL; 95% CI -23.63 to -0.25), lowdensity lipoprotein (MD -12.1 mg/dL; 95% CI - 20.37 to -3.82), triglycerides (MD -21.95 mg/dL; 95% CI -40.02 to -3.88), total cholesterol (MD -17.08 mg/dL; 95% CI -32.38 to -1.78), highdensity lipoprotein (MD 2.21 mg/dL; 95% CI 0.91 to 3.5), uric acid (MD -0.41 mg/dL; 95% CI -0.80 to -0.01), but non-significant changes were observed in homeostatic model assessment index (MD -2.34; 95% CI: -4.83 to 0.14), and fasting plasma insulin (MD -4.03 µU/mL; 95% CI: -8.88 to 0.82). No publication bias was detected.

Sacubitril/valsartan provides modest but significant improvements across multiple glycemic and lipid parameters, supporting a favorable metabolic action in clinical practice in patients with heart failure.

The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251057875).