SGLT-2 inhibitors as second-line therapy in type 2 diabetes.

Despite the development of several pharmacological agents over the past decade, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium glucose cotransporter 2 (SGLT2) inhibitors, the management of hyperglycaemia in patients with type 2 diabetes remains challenging. SGLT2 inhibitors are a new class of glucose-lowering agents that have a unique insulin-independent mechanism of action unlike sulfonylureas, GLP-1 receptor agonists, and DPP-4 inhibitors, which all have insulin-dependent action. SGLT2 inhibitors work primarily by increasing urinary glucose excretion, resulting in lowered of blood glucose concentrations and improvements in peripheral insulin sensitivity and β-cell function. Currently, two SGLT2 inhibitors—dapaglifl ozin and canaglifl ozin—have marketing authorisation, and empaglifl ozin is likely to be approved soon because of the Committee for Medicinal Products for Human Use’s positive opinion. The main advantages of SGLT2 inhibitors beyond glucose control include reduction in weight and blood pressure, and low risk of hypoglycaemia. Additionally, the insulin-independent mode of action suggests that these agents could be useful at any stage of the disease and in any combination with other antidiabetic agents. The main disadvantages of these agents are increased risk of genital infections and plasma volume depletion, and scarcity of long-term safety data. They are also less effi cacious in people with renal impairment. Although metformin is a well known fi rst-line pharma cotherapy for type 2 diabetes, there is little consensus about the best second-line agent. This lack in consensus was shown in the latest position statement from the American Diabetes Association and European Association for the Study of Diabetes that suggested that either sulfonylureas, thiazolidines, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin can be used in combination with metformin when glycaemic targets are not met. To properly ascertain the place of SGLT2 inhibitors in the treatment algorithm of patients with type 2 diabetes, head-to-head trials of other glucoselowering treatments are essential. SGLT2 inhibitors have a similar glucose lowering effi cacy to metformin and DPP-4 inhibitors when used as monotherapy, and are licensed for use as fi rst-line treatment when metformin cannot be used. Martin Ridderstråle and colleagues report in The Lancet Diabetes & Endocrinology a large (n=1549), 2–year, randomised, active-controlled trial of SGLT2 inhibitors as a second-line treatment. They compared the effi cacy and safety of empaglifl ozin 25 mg once daily with glimepiride 1–4 mg once daily as an add-on to metformin monotherapy. Empaglifl ozin was noninferior to glimepiride at 52 weeks (HbA1c diff erence vs glimepiride –0·07, 95% CI –0·15 to 0·01), whereas it was superior at 104 weeks (–0·11, –0·19 to –0·02). Although most of the patients did not attain the 4 mg dose in the glimiperide group, the non-inferiority of empaglifl ozin to glimiperide persisted irrespective of the glimiperide dose achieved during titration. The percentages of adverse events were similar between groups but empaglifl ozin was associated with more genital infections and glimepiride with more hypoglycaemia. As expected, empaglifl ozin was associated with reductions in weight and blood pressure, whereas glimepiride resulted in weight gain. In a substudy, the weight reduction in the empaglifl ozin group was mostly due to reductions in fat mass (assessed with dual energy X-ray absorptiometry) and abdominal visceral and subcutaneous adipose tissue (assessed with MRI); these results are consistent with those noted with other SGLT2 inhibitors. The results of previous similar studies showed that dapaglifl ozin and canaglifl ozin at 100 mg/day were non-inferior to glipizide and glimepiride, respectively, as add-ons to metformin monotherapy at 52 weeks, whereas canaglifl ozin 300 mg/day was superior to glimepiride (least squares mean diff erence –0·12%, 95% CI –0·22 to –0·02). Although the diff erence in HbA1c in favour of the SGLT2 inhibitors is small in Ridderstråle and colleagues’ study, it occurred in the context of less hypoglycaemia and weight loss than in the glimepiride group. Additionally, this study is fairly long, suggesting that the glycaemic benefi ts of empaglifl ozin are more long-lasting compared with glimiperide. Empaglifl ozin and canaglifl ozin have also been compared with sitagliptin as an add-on to metformin monotherapy. HbA1c reductions were similar between Ru ss el l K ig ht le y/ Sc ie nc e Ph ot o Li br ar y