Ketones: the double-edged sword of SGLT2 inhibitors?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of medications used by individuals with type 2 diabetes that reduce hyperglycaemia by targeting glucose transport in the kidney, preventing its reabsorption, thereby inducing glucosuria. Besides improving HbA_1c and reducing body weight and blood pressure, the SGLT2 inhibitors have also been demonstrated to improve cardiovascular and kidney outcomes, an effect largely independent of their effect on blood glucose levels. Indeed, the mechanisms underlying these benefits remain elusive. Treatment with SGLT2 inhibitors has been found to modestly increase systemic ketone levels. Ketone bodies are an ancillary fuel source substituting for glucose in some tissues and may also possess intrinsic anti-oxidative and anti-inflammatory effects. Some have proposed that ketones may in fact mediate the cardio-renal benefits of this drug category. However, a rare complication of SGLT2 inhibition is ketoacidosis, sometimes with normal or near-normal blood glucose concentrations, albeit occurring more frequently in patients with type 1 diabetes who are treated (predominately off-label) with one of these agents. We herein explore the notion that an underpinning of one of the more serious adverse effects of SGLT2 inhibitors may, in fact, explain, at least in part, some of their benefits-a potential 'double-edged sword' of this novel drug category.