Beneficial effects of sodium glucose co-transporter 2 inhibitors (SGLT2i) on heart failure and cardiovascular death in patients with type 2 diabetes might be due to their off-target effects on cardiac metabolism

Sodium/glucose co-transporter 2 inhibitors (SGLT2i) lower blood glucose by inhibiting the reabsorption of glucose in the proximal renal tubules.[1] There are several licensed SGLT2i. One of them, empagliflozin, was evaluated in the EMPA-REG OUTCOME trial.[2] This prospective, randomised, double-blind, placebo-controlled, survival study included 7020 patients with type 2 diabetes mellitus (T2DM) and followed them for a median period of 3.1 years.[2] The EMPAREG OUTCOME trial showed that the use of either 10 or 25 mg/d of empagliflozin (cumulative results presentation because there were no significant differences between the two doses) on top of standard therapy produced relative risk reductions in the primary endpoint [cumulative incidence of death from cardiovascular disease (CVD), nonfatal myocardial infarction (MI) or nonfatal stroke] by 14%, total mortality by 32%, of CVD mortality by 38% and hospitalisation for heart failure (HF) by 35% compared with placebo; all reductions were highly statistically significant.[2] The main side effect was an increased rate of genital infection.[2] Following a review of a few cases, the European Medical Agency recommended an update of all SGLT2i Summary of Product Characteristics to include diabetic ketoacidosis as a rare of (1/1000 patients) adverse reaction (http:// www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors/humanreferral_ prac000052.jsp&mid=WC0b01ac05805c516f ). The EMPA-REG OUTCOME trial results were a surprise; the Evaluation of Cardiovascular Outcome Results (LEADER) trial with liraglutide, a human glucagon like peptide 1 receptors agonist (GLP1 RA), that showed similar clinical benefits in terms of improved survival, except for the reduction in hospitalisation for HF, were presented a few months later.[3] The mechanisms driving the effects of empagliflozin on HF and CVD death are not clear.[4] Potential mechanisms include osmotic diuresis, modulation of the cardiorenal axis that reduced plasma volume and less sodium retention, reduction in arterial stiffness, reduced left ventricular afterload, fall in body weight and blood pressure (BP), without increases in sympathetic nervous activity, delay in renal function impairment, reduction in hyperglycaemia with linked reduction in insulin levels and reductions in serum uric acid (SUA) levels.[4,5] However, even all those collectively may not be enough to explain the substantial clinical benefits of empagliflozin manifested early (within the first 3 months of the study) in the EMPA-REG trial.[2] Recently, two papers tried to explain the possible mechanism of empagliflozin clinical benefits focusing on its effect on heart metabolism or “energetics”; this hypothesis, together with all the off-target effects mentioned above, might be an explanation for the beneficial outcomes of empagliflozin in the EMPA-REG trial.[6,7] Several years ago, it was suggested that people with T2DM or insulin resistance have an impaired myocardial metabolism with decreased utilisation of glucose and increased myocardial free fatty acid (FFA) uptake and oxidation, resulting in a mismatch between blood/metabolite supply and cardiac metabolic needs.[8] It has also been suggested that if myocardial dysfunction is no longer considered as the simple oxygen/metabolite demand/supply unbalance, but as an energetic disorder, this will motivate the development of drugs aiming at this specific metabolic disorder rather than just treating the risk factors and the symptoms of the ischaemic and/or failing diabetic heart. [9] It has been suggested that a therapeutic approach aiming at an improvement of cardiac metabolism, through