Impact of Dapagliflozin on MRI ‐Derived Epicardial Adipose Tissue: Secondary Imaging Analysis of a Randomized Trial

BACKGROUND: Epicardial adipose tissue (EAT) is a metabolically active fat depot associated with cardiovascular risk and represents a modifiable imaging biomarker. Studies have shown that sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce EAT thickness in patients with type 2 diabetes mellitus (T2DM). However, it is unclear whether this is a direct effect on EAT or is secondary to concomitant weight loss. PURPOSE: To evaluate whether the SGLT2 inhibitor dapagliflozin reduces EAT independently of weight change in patients with T2DM without overt cardiovascular disease. STUDY TYPE: Secondary longitudinal imaging analysis of a prospective, randomized, placebo-controlled trial. POPULATION: Fifty-six adults with T2DM without overt cardiovascular disease were randomized to dapagliflozin 10 mg daily (N = 27) or placebo (N = 29) for 12 months. FIELD STRENGTH/SEQUENCE: Balanced steady-state free precession cine at 3T. ASSESSMENT: EAT thickness was quantified at eight predefined anatomical locations on MR images acquired at baseline and 12 months. Body weight, body mass index (BMI), cardiovascular medication history, and C-reactive protein were also assessed. The primary endpoint was change in average EAT thickness. STATISTICAL TESTS: Between-group comparisons were performed using the Mann-Whitney U test. Mediation and multivariable regression analyses assessed whether EAT change was independent of weight change. A p value < 0.05 was considered significant. RESULTS: Dapagliflozin significantly reduced average EAT thickness compared with placebo (median change -0.8 mm [interquartile range (IQR): -1.3 to -0.4] vs. 0.1 mm [IQR: -0.1 to 0.3]). Mediation analysis demonstrated a significant direct treatment effect not mediated by weight change [direct effect coefficient 0.81, 95% confidence interval (CI), 0.61-1.04] and a non-significant indirect effect (indirect effect coefficient 0.15, 95% CI, -0.17 to 0.42, p = 0.29). The association remained significant after adjustment for baseline EAT, baseline and change in body weight or BMI, age, sex, baseline use of any cardiovascular medication, and C-reactive protein. DATA CONCLUSION: Dapagliflozin reduced EAT in patients with T2DM without overt cardiovascular disease, predominantly independent of weight change, supporting MRI-derived EAT as a treatment-responsive imaging biomarker. EVIDENCE LEVEL: 2. TECHNICAL EFFICACY: Stage 4. TRIAL REGISTRATION: https://clinicaltrials.gov; Unique identifier: NCT03782259. Epicardial adipose tissue is the fat surrounding the heart and is linked to cardiovascular disease. This study examined whether dapagliflozin reduces epicardial fat independently of weight loss in adults with type 2 diabetes without overt cardiovascular disease. Participants were randomly assigned to receive dapagliflozin or placebo for 12 months, and epicardial adipose tissue thickness was measured using cardiac magnetic resonance imaging before and after treatment. Dapagliflozin reduced epicardial adipose tissue more than placebo, even after accounting for changes in body weight. These findings suggest that measuring epicardial adipose tissue with cardiac magnetic resonance imaging may help assess treatment response.