Empagliflozin in the Absence of Diabetes: A Systematic Review of Its Anthropometric and Metabolic Effects in Humans and Animals.

Purpose: Obesity raises metabolic and cardiovascular risk and represents a major public health challenge. The sodium-glucose cotransport-2 inhibitor empagliflozin (EMPA) may improve metabolic parameters beyond glycemic control. This systematic review critically evaluated the effects of EMPA on anthropometric and metabolic outcomes in overweight or obese subjects without diabetes and identified key areas for future research. Methods: This systematic review included studies identified through searches of five databases (Scopus, Web of Science, PubMed, Google Scholar, and the Cochrane Library) from January 2023 to May 2026. Following duplicate removal and PRISMA-guided screening, 27 studies were included (7 randomized controlled trials and 20 animal studies). Studies were excluded if they involved diabetic populations, lacked appropriate comparator groups, or did not meet predefined eligibility criteria. The Cochrane and SYRCLE tools were used to assess the quality of human and animal evidence, respectively. Results: Animal studies primarily used EMPA doses of 8-30 mg/kg/day, whereas human trials employed fixed clinical doses of 10-12.5 mg daily. In human investigations, EMPA significantly lowered body weight with notable improvements in fasting glucose. Preclinical studies largely supported these findings and additionally demonstrated improvements in hepatic steatosis, lipid metabolism, and inflammatory markers. Proposed mechanisms included modulation of FGF21 signaling, hepatic PDK4 expression, hypothalamic neuropeptides, NF-κB activity, mitochondrial function, and gut microbiome composition. Conclusion: Even in the absence of diabetes, EMPA shows potential for improving anthropometric and metabolic indices. However, clinical evidence remains limited and further human trials are needed to confirm its long-term safety, efficacy, and underlying molecular mechanisms.