SGLT2 inhibitors: a promising class of antidiabetic agents

The international guidelines for the management of type 2 diabetes mellitus have seen many changes over the last decade. They have moved from a strict glycemic control in all patients with diabetes to a more individualized approach of the diabetic patient. These changes are the result of some trials which have demonstrated, for example, that in patients with long-standing type 2 diabetes a strict glycemic control may increase the risk of complications, such as hypoglycemia and cardiovascular events1-3. While glucose lowering prevents the appearance of microvascular complications, its impact is less significant on the cardiovascular and renal complications. The most preferred oral antidiabetic drug is undoubtedly metformin. There are six antidiabetic drug classes currently recommended by the American and European international societies, in addition to metformin: sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, sulfonylureas, thiazolidinediones, and insulin. SGLT2 inhibitors are a promising new class of antidiabetic drugs, that have entered very recently in the diabetes therapeutic armamentarium. These drugs enhance the urinary glucose excretion and decrease hyperglycemia, acting independently from insulin and being effective in all diabetic patients with preserved renal function. They have a favorable efficacy-to adverse event profile in type 2 diabetes patients with moderate-to-high risk. Currently, there are four SGLT2 inhibitors approved by the US Food and Drug Administration (FDA) and the European Medicines Agency: canaglifozin, dapaglifozin, empaglifozin, and ertuglifozin3. These may be used as monotherapy or in combination with other antidiabetic agents.SGLT2 inhibitors have also pleiotropic effects, such as reducing body weight by 2-3 Kg, decreasing the blood pressure (both systolic and diastolic), decreasing plasma triglycerides, increasing HDL cholesterol, attenuating some factors associated with nonalcoholic steatohepatitis and nonalcoholic liver disease, improving the whole-body sodium balance and volume status by stimulating the natriuresis, which leads further to a better endothelial function by reducing the vascular stiffness1. Due to these effects, SGLT2 inhibitors are useful especially in obese patients with arterial hypertension. They may be indicated as single or combination therapy, with other antidiabetic agents, and are contraindicated in patients with kidney failure1 with a GFR < 45 mL/min/1.73 m2. Regarding the glucose control, in a meta-analysis, the HbA1c reduction at 24-weeks was higher in studies that included younger patients, with a shorter duration of diabetes and a higher body mass index, HbA1c and basal glucose4. The cardiovascular benefits of SGLT2 inhibitors have been demonstrated by some major trials, such as EMPA-REG OUTCOME trial (Empaglifozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients)5 and CANVAS (Canaglifozin Cardiovascular Assessment Study)6. EMPA-REG OUTCOME trial has found a reduced incidence of cardiovascular death in diabetic patients treated with Empaglifozin and also a decreased rate of hospitalization for heart failure5. CANVAS Program has showed also a decreased rate of hospitalization for heart failure in patients treated with Canaglifozin6. This is extremely important, especially for patients with type 2 diabetes and already established cardiovascular diseases, as they may benefit most from the treatment with SGLT2 inhibitors. The main side effects of SGLT2 inhibitors consist in the increased risk of genital infections (up to four-fold in clinical trials). Other side effects, more rarely, may be the risk of hypoglycemia, diabetic ketoacidosis, bone fractures (with Canaglifozin). Recently, the US Food and Drug Administration warned about the risk of necrotizing fasciitis of the perineum (Fournier’s gangrene) in patients treated with SGLT2 inhibitors7. This is an extremely rare, but life-threatening infection of the tissues around the perineal muscles, nerves, fat and blood vessels. In conclusion, SGLT2 inhibitors are the newest antidiabetic drugs class, with cardiovascular benefits in a selected population of type 2 diabetes patients. There are ongoing studies with these antidiabetic agents expected to report their data in the near futur