Metformin versus placebo in patients with heart failure with preserved ejection fraction and obesity or insulin resistance (MET-HFpEF)
Heart failure with preserved ejection fraction (HFpEF), New York Heart Association (NYHA) Class II-III, insulin resistance, pre-diabetes, obesity
Eligible participants will be randomised in a 1:1 ratio to either metformin modified-release or matched placebo. Randomisation will be stratified by the presence of atrial fibrillation and use of SGLT2 inhibitors, and the proportion of participants in atrial fibrillation will be limited to 40% of the total cohort. The randomisation sequence will be generated by an independent statistician using a validated computer-based randomisation system. Metformin (modified-release) is titrated from 500 mg twice daily to 1000 mg twice daily (2000 mg/day) for 12 months; the comparator is a matching placebo (lactose).
1. Willing/able to consent 2. Aged ≥18 years 3. Symptomatic HFpEF (NYHA II–III) 4. Elevated indexed left ventricular (LV) mass on screening echo (males >81 g/h¹·⁷, females >60 g/h¹·⁷) 5. Insulin resistance (Fasting Insulin Resistance Index [FIRI] ≥2.7) or pre-diabetes (HbA1c 39–47 mmol/mol) or body mass index (BMI) ≥30 kg/m² 6. NT-proBNP >300 pg/mL (sinus rhythm) or >600 pg/mL (AF) 7. Left ventricular ejection fraction (LVEF) ≥45% 8. On loop diuretics 9. Able/willing to comply
1. Type 1 or 2 diabetes 2. HbA1c >47 mmol/mol 3. SBP >180 mmHg 4. eGFR <30 ml/min/1.73 m² 5. Contraindications to CMR 6. Previous LVEF <40% 7. Metformin hypersensitivity 8. Severe cognitive impairment 9. Active malignancy or other life-threatening disease 10. Hepatic insufficiency or history of alcoholism 11. Acute conditions affecting renal function 12. Pregnancy/lactation 13. Participation in another trial within 30 days 14. Investigator discretion