Ketone bodies are small lipid-derived molecules that serve as a circulating energy source for tissues in times of fasting or prolonged exercise. Produced in the liver from fatty acids mobilized from adipocytes, they are distributed via the circulation to metabolically active tissues, such as muscle or brain, where they are converted to acetyl-CoA. In humans, basal serum levels of beta-hydroxybutyrate (BHB) are in the low micromolar range, but can reach 1–2 mM after two days of fasting, and over 2 mM with a ketogenic diet that is almost devoid of carbohydrates. Ketone bodies are emerging as crucial regulators of metabolic health. More than just a metabolite, the ketone body BHB can regulate cellular processes directly via HDAC inhibition and binding to cell surface receptors, and indirectly by altering the levels of other regulatory metabolites including acetyl-CoA. Sodium–glucose transporter 2 (SGLT2) carries glucose across apical membranes of polarized epithelial cells against concentration gradients, driven by Na+ gradients. SGLT2 is mainly expressed in the kidney and responsible for most glucose reabsorption in the convoluted proximal tubules. Recent CV outcome trials reported that SGLT2 inhibitors significantly reduce renal events as well as CV events in humans with type 2 diabetes. As SGLT2 inhibitor treatment significantly elevates serum levels of BHB, ketone bodies may be involved in pleotropic effects of SGLT2 inhibitor, which will be covered in this lecture.