Abstract
Sodium-glucose transporter-2 inhibitors (SGLT2i), originally launched as glucose-lowering drugs, have been studied in large cardiovascular outcome trials to ascertain safety. Surprisingly, these compounds reduced the risk of cardiovascular events (cardiovascular death, non-fatal myocardial and non-fatal stroke) and total mortality. The mechanisms behind this benefit are only partly understood, but a major contributor is the reduction of heart failure hospitalisations, evident already within weeks after the initiation of the SGLT2i.SGLT2 inhibition increases urinary glucose excretion, thereby improving glycaemic control in an insulin-independent manner. Moreover, SGLT2i potentially impact the cardiovascular system both indirectly via weight loss and blood pressure lowering and directly through osmotic diuresis and increased sodium excretion and presumably by improving myocardial energetics.The aim of this review is to summarise evidence from all major outcome trials investigating SGLT2i in patients with diabetes, as well as recent evidence from trials in heart failure patients without glucose perturbations, which pave the way for novel treatment of large groups of patients.The results of these studies have been taken into account in recently issued guidelines for the management of diabetes and cardiovascular disease. An important task for diabetologists, cardiologists and general practitioners is to incorporate them into clinical practice to the benefit of many patients.
Highlights
The sodium-glucose transporter inhibitors (SGLT2i) have their origin in the phlorizin molecule detected in 1836 by de Koninck [1], who isolated this compound from the root bark of apple trees
The aim of this review is to summarise evidence from all major outcome trials investigating Sodium-glucose transporter-2 inhibitors (SGLT2i) in patients with diabetes, as well as recent evidence from trials in heart failure patients without glucose perturbations, which pave the way for novel treatment of large groups of patients
The landmark clinical trial indicating the beneficial effect of SGLT2i on heart failure (HF) was the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) trial, which randomized 7020 patients with T2DM and a history of a previous cardiovascular (CV) event to receive either empagliflozin (10 or 25 mg) or placebo on top of standard care [18]
Summary
The sodium-glucose transporter inhibitors (SGLT2i) have their origin in the phlorizin molecule detected in 1836 by de Koninck [1], who isolated this compound from the root bark of apple trees. The first orally absorbed phlorizin-like compound, T-1095, was synthesized by Japanese researchers in 1999 [9] It lowered glucose, increased insulin sensitivity and protected from development of neuropathy due to diabetes in the Goto-Kakizaki nonobese, nonhypertensive rat model of type 2 diabetes (T2DM) [10], it was never developed for clinical use since it was unselective, inhibiting the SGLT1 transporter. In experimental as well as human studies they cause a significant lowering of fasting plasma glucose and HbA1c without any risk for hypoglycaemia, at least in the absence of concomitant treatment with insulin or insulin-releasing drugs Since they cause a renal glucose excretion of approximately 60–80 g/day, corresponding to a daily calorie loss of 240–320 kcal, they induce a body weight reduction in the magnitude of 2–3 kg, of which a fair part is visceral fat. Experimental observations indicate that SGLT2 inhibition may improve pancreatic beta-cell function, myocardial fibrosis, left ventricular function and decrease oxidative stress and inflammatory activation [16,17]
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