Dapagliflozin-Induced Cardioprotection in Diabetic Cardiomyopathy Correlates with HMGB1-RAGE Axis Suppression

Background: Diabetic Cardiomyopathy (DCM) is a clinically important cardiac complication of Type 2 Diabetes Mellitus (T2DM). Its progression is closely related not only to chronic hyperglycemia and metabolic overload, but also to sustained inflammatory activation. Among the candidate inflammatory pathways, the High Mobility Group Box 1 Protein (HMGB1)-Receptor for Advanced Glycation End products (RAGE) axis has attracted attention because it can connect tissue injury, innate immune signaling, and adverse myocardial remodeling. Objectives: To examine whether dapagliflozin can improve myocardial function in patients with T2DM complicated by DCM and to explore whether the benefits are associated with downregulation of circulating HMGB1 and RAGE. Materials and Methods: Eighty patients with T2DM-associated DCM who were admitted to the Department of Endocrinology of Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine between July 2023 and July 2024 were randomly assigned to a control group or an observation group, with 40 cases in each arm. All participants received conventional management. The control group was treated with metformin sustained-release tablets, whereas the observation group received dapagliflozin in addition to metformin. The intervention period was 6 months. Fasting Blood Glucose (FBG), 2-hr Postprandial Blood Glucose (2hPBG), Glycated Hemoglobin (HbA1C), serum HMGB1, serum RAGE, and the myocardial performance index (Tei index) were assessed before treatment and again at 3 and 6 months. Results: Baseline characteristics were comparable between the two groups. After treatment, both regimens were associated with lower FBG, 2hPBG, HbA1C, HMGB1, RAGE, and Tei index compared with pretreatment levels. However, the decreases in glycemic variables and inflammatory markers were greater in the dapagliflozin group than in the metformin-alone group at both follow-up points (all p<0.05). Tei index improved in both groups, and the between-group difference became significant by month 6, favoring combination therapy (p<0.05). Conclusion: For patients with T2DM complicated by DCM, dapagliflozin added to standard glucose-lowering therapy may confer additional cardiac benefit. Its favorable effect appears to occur together with better metabolic control and lower circulating HMGB1 and RAGE levels, suggesting that the improvement of myocardial function is possibly related to the suppression of HMGB1-RAGEmediated inflammation.