Shedding light on the effects of sodium-glucose cotransporter 2 inhibitors in the early stages of heart failure.

Heart failure (HF), which falls outside of the historical macrovascular or microvascular categorizations of diabetes complications, has been overlooked for long time in diabetic patients, despite its increasing prevalence and mortality. As originally stated in the Framingham studies, diabetes is associated with an increased risk of HF. Subsequent studies not only corroborated these findings but also identified HF as the most frequent first onset of cardiovascular involvement. The paramount role of proper management of common modifiable risk factors such as hypertension, obesity, dyslipidemia and smoking, became rapidly clear. Conversely, the impact of intensive glycemic control was more contentious. A large meta-analysis of randomized controlled trials reported a lack of effect of strict glycemic control as compared to standard care on HF-related outcomes. The considerable heterogeneity of the effect estimate and the higher risk conferred by thiazolidinediones suggested that mechanism of action of antidiabetic drugs played a key role. Furthermore, the safety concerns of pioglitazone led Food and Drug Administration to release a guidance for drug manufacturers stating that cardiovascular risk should be comprehensively evaluated during drug development. Surprisingly, in just a few years, large cardiovascular outcome trials established the beneficial cardiovascular effects of sodium-glucose cotransporter 2 inhibitors. These effects were consistent regardless diabetes and ejection fraction. Therefore, scientific community started to question the glucose-lowering and diuretic properties of sodium-glucose cotransporter 2 inhibitors as the unique mechanisms for improved outcomes. A plenty of preclinical and clinical studies identified several mechanisms besides glucose-lowering effects. However, these mechanistic studies focused on animal models and patients with established HF. If the same mechanisms account for beneficial effects in patients at risk for or with pre-HF is unknown. Grubić Rotkvić published an interesting work adding data in early stages HF.