Canagliflozin attenuates CMR-quantified myocardial fibrosis in individuals with type 2 diabetes mellitus at high cardiovascular risk: a randomised open-label controlled trial

Aims/hypothesis: We aimed to investigate canagliflozin's effects on myocardial fibrosis, cardiac structure and function, and microcirculation in high-cardiovascular-risk type 2 diabetes mellitus through cardiac magnetic resonance (CMR) quantification, while investigating the cardiovascular protective mechanisms of sodium-glucose cotransporter 2 (SGLT2) inhibitors. Methods: This open-label parallel RCT recruited 45 high-risk participants (18-75 years) with type 2 diabetes (HbA1c 53.0-91.3 mmol/mol [7.0-10.5%]) and left ventricular ejection fraction (LVEF) >50% from the Endocrinology Outpatient Clinic of Zhongshan Hospital, Fudan University (August 2022 to November 2024). Participants were 1:1 randomised via a computer-generated sequence through the centralised iClinicalStation system (allocation concealed, performed by independent personnel not involved in outcome assessment). They received canagliflozin 100 mg/day (n=23) or sitagliptin 100 mg/day (n=22) for 26 weeks. Consistent with the open-label design, participants and care providers were aware of treatment assignments; however, outcome assessors (radiologists, sonographers) and data analysts remained blinded to group allocation to minimise bias. The primary endpoint was CMR-quantified extracellular volume (ECV) change. Secondary outcomes included ventricular structure and function parameters, for example, left ventricular end-diastolic volume, left ventricular end-diastolic diameter, LVEF, etc. RESULTS: Among 67 individuals screened, 45 completed the intention-to-treat analysis (age 60.4 ± 9.7 years, BMI 26.4 ± 2.6 kg/m2, HbA1c 63.0 ± 8.7 mmol/mol [7.9 ± 0.8%]). At 26 weeks, compared with sitagliptin, canagliflozin significantly reduced the primary outcome of ECV (adjusted mean difference [AMD]: -3.67%; 95% CI -5.33, -2.01; p<0.001). Significant improvements were also observed in cardiac structure, including left ventricular end-diastolic volume (AMD: -20.72 ml; 95% CI -36.30, -5.14; p=0.010) and echocardiography-derived end-diastolic diameter (AMD: -2.82 mm; 95% CI -4.95, -0.70; p=0.010). Both groups showed comparable reductions in HbA1c (both Δ 0.7%, inter-group p=0.972). Conclusions/interpretation: This study demonstrates that 26 weeks of canagliflozin significantly reduces myocardial fibrosis, as assessed by CMR-derived ECV, in individuals with type 2 diabetes at high cardiovascular risk, providing imaging evidence for SGLT2 inhibitor cardiovascular protection mechanisms. Trial registration: ClinicalTrials.gov NCT05367063 FUNDING: This study was financially supported by the National Key Research and Development programme (2023YFA1802000), the National Natural Science Foundation of China (Youth Fund 82200909), the Young and Middle-aged Diabetes project from the Bethune Foundation (Z04JKM2022E002), the Joint Research Development project between Shenkang and United Imaging on Clinical Research and Translation (SKLY2022CRT201), the Shanghai Municipal 'Explorer plan' (the second batch) project in 2024 (24TS1411000) and the Shanghai pujiang programme (21PJD012).