Cardiac Uptake REstoration of Glucose in diabetic Heart Failure

Objective

Heart failure (HF) affects over 64 million people worldwide and is a leading cause of hospitalization and premature death. About 40% of HF patients also have type 2 diabetes, doubling mortality risk. In HF, the stressed myocardium shifts toward glucose metabolism, but in diabetes cardiomyocytes fail to take up glucose and remain reliant on fatty acids, leaving the heart energy-starved. Current HF therapies target neurohormonal pathways to reduce workload and slow progression but do not address this root metabolic defect. Insulin and GLP-1 receptor agonists can influence glucose metabolism, but their use in HF is limited by side effects, lack of direct cardiac efficacy, or even potential harm. CURE-HF proposes a novel approach by developing small-molecule inhibitors of a newly identified gene. Patient data revealed that this gene was the most differentially expressed in patients with heart failure and diabetes compared to heart failure patients without diabetes. Knockdown of this gene in hiPSC-derived cardiomyocytes increased glucose uptake, while mice lacking this gene on a high-fat diet with induced HF had better glucose control and 20% higher myocardial glucose uptake by FDG-PET and a better cardiac function. These findings demonstrate that inhibition of this gene restores energy balance and protects against diabetic HF. Building on these insights, CURE-HF will design and optimise selective, safe, and synthetically accessible small molecules to inhibit the newly identified gene. Lead compounds will be validated in human iPSC-cardiomyocytes and in diabetic HF mouse models, with functional readouts including glucose uptake, echocardiography, and FDG-PET. In parallel, the project will secure IP, engage stakeholders, and assess market potential. By addressing the root energetic deficit of diabetic HF, CURE-HF has the potential to deliver a disease-modifying small-molecule therapy, reduce hospitalization and improve prognosis.