Comparison of the Effects of Metformin and Empagliflozin on Cardiac Function in Heart Failure with Preserved Ejection Fraction Mice Short Title：Metformin vs Empagliflozin in HFpEF

Liu Xiehong^1*zhao huiqi¹liu sisi¹Siao Wen¹fan wenjuan¹xie qiong¹cui bo¹Lin Zhou²peng jianqiang¹pan hongwei¹zheng zhaofen¹zhang qihai¹

• ¹Hunan Provincial People's Hospital, Changsha, China
• ²Changsha Medical University, Changsha, Hunan Province, China

Recent evidence suggests that empagliflozin (EMPA) and metformin (MET) may improve prognosis in heart failure with preserved ejection fraction (HFpEF) patients. This study aims to compare their effects on cardiac structure and function in HFpEF. Methods Male C57BL/6J mice were fed a high-fat diet with L-NAME for 8 weeks to induce HFpEF, followed by 4 weeks of MET or EMPA treatment. Cardiac structure and function were assessed. Network pharmacology and bioinformatics identified key targets, validated by RT-qPCR and WB. Results EMPA-treated mice lost weight, unlike MET-treated ones. MET reduced systolic blood pressure significantly. Both treatments improved glucose tolerance; MET enhanced insulin sensitivity. EMPA increased exercise tolerance by extending exhaustion distance. Both treatments improved diastolic function, reduced heart weight, and attenuated myocardial fibrosis and hypertrophy. Plasma NT-proBNP levels were slightly elevated but not significant. EMPA downregulated HSP90 mRNA and protein expression; both drugs downregulated TGFβ. Conclusion MET and EMPA improve cardiac fibrosis, diastolic function, and pulmonary congestion in HFpEF mice. MET acts by downregulating TGFβ, while EMPA affects collagen metabolism and downregulates HSP90 and TGFβ. These findings offer insights into HFpEF treatment.