Type 2 diabetes, heart failure and chronic kidney disease are interconnected conditions that amplify one another through shared metabolic and inflammatory pathways, collectively referred to as the cardiovascular-kidney-metabolic (CKM) syndrome. Their coexistence drives high morbidity, mortality and healthcare costs, highlighting the need for integrated therapeutic strategies rather than isolated disease management.

Recent new pharmacological treatments, such as SGLT2 inhibitors, have benefits beyond glucose lowering effect and provide cardiovascular and renal protection. These agents appear to mildly increase circulating ketone bodies levels, highlighting interest in the role of ketone bodies metabolism as a unifying mechanism behind their benefits.

Ketone bodies have been shown to be efficient energy substrates and powerful signalling molecules. In the failing heart, they improve energy efficiency and contractility, In the kidney, it could attenuate inflammation, oxidative stress and fibrosis. These effects suggest the existence of some adaptive mechanisms that could be explored and then use for therapeutic purposes. The ketogenic diet, by inducing prolonged nutritional ketosis, mimics this metabolic state. Glucometabolic effects are demonstrated in adults with type 2 diabetes, while potentially having cardiorenal protective effects.

This work provides the conceptual basis and rationale for an upcoming clinical study designed to specifically investigate the effects of ketone bodies in case of type 2 diabetes and heart failure. It aims to generate new insights into whether therapeutic modulation of ketone bodies metabolism could represent a novel strategy in the treatment of patients with these medical conditions.