Research into the effect of sodium-glucose linked transporter inhibition in left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM Trial)

Introduction: Diabetes (DM) and heart failure (HF) are a lethal combination, with limited diabetic therapy options.^1,2 Sodium-glucose linked transporter 2 (SGLT2) inhibitors have been reported to have CV benefits in at risk DM patients.^3,4 We are the first to study the CV effects of SGLT2-inhibition in patients with DM and HF.5

Patients and Methods: In this randomized double-blind placebo-controlled trial, 56 patients (mean age: 67.1 years, males: 66%) with DM and echocardiographically confirmed HF with reduced ejection fraction (HFrEF) on regular diuretic therapy were assigned to dapagliflozin 10 mg once daily or placebo for one year. Primary endpoint was the difference in left ventricular (LV) volumes between both groups using cardiac MRI. Secondary endpoints include LV mass, LV ejection fraction (EF), weight, BP and diuretic use. Outcomes were analysed using linear regression controlling for baseline values, age, sex and renal function.

Results: There was no difference between dapagliflozin and placebo in the primary endpoints of LV end diastolic volume (LVEDV) or LV end systolic volume (LVESV); +4.71mls; 95%CI: −17.08 to 26.50 and + 1.52mls; 95%CI: −15.68 to 18.72 respectively. However, when an interaction term for starting LVEF was added to the model, dapagliflozin significantly lowered LVEDV, LVESV and LV mass in those with starting LVEF ≥ 45%; −15.59mls; p = 0.019, −15.20mls; p = 0.016 and −4.87 gm/m2; p = 0.026. Patients on dapagliflozin also had weight loss; −1.90 kg; 95%CI: −3.83 to + 0.04; p = 0.054, lower diastolic BP; −6.34 mmHg; 95%CI: −11.35 to −1.32; p = 0.014 and higher haemoglobin; +12.3 g/L; 95%CI: 6.5 to 18.2; p < 0.001. Loop diuretic requirements for patients in the dapagliflozin arm was reduced by more than half; −28.04 mg; 95%CI: −42.35 to −13.74; p < 0.001. They were also more likely to stop or reduce loop diuretics; 50.0% vs 8.7%; p = 0.005.

Conclusions: Dapagliflozin treatment resulted in reduction of weight, diastolic blood pressure and loop diuretic requirements among patients with DM and HFrEF. There was evidence to suggest that dapagliflozin may cause positive LV remodelling in DM patients with mild, but not with more severe HFrEF.