Editorial. SGLT-2 receptor inhibitors: An opportunity to revise our therapeutic strategy for type 2 diabetes?

Type 2 diabetes is among the most important and prevalent chronic diseases, and any novel therapy that is able to address chronic hyperglycaemia is welcome as another tool for clinicians to help prevent the development of diabetic complications [1]. It is widely recommended that, if lifestyle interventions are inadequate, the first line of drug treatment is metformin, followed by a sulphonylurea, a glitazone, a dipeptidyl peptidase (DPP)-4 inhibitor or even a glucagonlike peptide (GLP)-1 analogue, before starting insulin [2]. However, every antidiabetic drug class has its own side-effects and limitations, including metformin [3]. Sulphonylureas, glitazones and insulin all cause weight gain, which can worsen insulin resistance. Sulphonylureas and insulin can also cause hypoglycaemia, while pioglitazone can induce oedema, heart failure and bone fractures [2]. These limitations of the classical glucose-lowering therapies have paved the way towards the development and success of incretin-based therapies for the management of hyperglycaemia in type 2 diabetes. However, beyond the potential safety issues, a major drawback of DPP-4 inhibitors (and, to a lesser extent, of GLP-1 analogues) is that a substantial proportion of diabetic patients will not respond sufficiently to these drugs and, thus, will fail to achieve glycated haemoglobin (HbA 1c ) targets. Therefore, diabetologists clearly need novel therapies with higher rates of clinical response, while the complexity of type 2 diabetes probably also requires combined therapies in most cases. The issue of an appropriate combination of antidiabetic drugs for type 2 diabetes is not so easily solved, as has already been emphasized by the American Diabetes Association/ European Association for the Study of Diabetes position statement [2]. Also, the choices offered to clinicians may become even more complicated, as health authorities and the European Medicines Agency (EMA) have approved the use of SGLT2 inhibitors for a wide range of indications, from a simple association with metformin to a triple oral therapy after failure of a metformin-sulphonylurea combination and even in association with insulin. Sodium-glucose cotransporter type 2 (SGLT2) inhibitors are glucose-lowering agents with a particular glucoretic mechanism of action, which allows significant reductions of both hyperglycaemia and body weight, a unique dual effect among oral glucose-lowering agents. In addition, even though SGLT2 inhibitors do not directly target insulin secretion or insulin sensitivity (as do other classical glucose-lowering agents), they can indirectly improve both beta-cell function and insulin action because of their potential to reduce glucotoxicity [4]. The arrival of the SGLT2 inhibitors may be viewed as an exciting opportunity to review our concept of how best to treat type 2 diabetes. Indeed, because of their specific and insulin-independent mechanisms of action, SGLT2 inhibitors may be combined with any other type of antidiabetic therapy. This means that physicians will have the opportunity to test novel combinations of antidiabetic drugs targeting persistent hyperglycaemia, particularly in patients who do not respond adequately to the conventional first and second lines of treatment [5]. Even after failure of metformin monotherapy, it may be of benefit to add an SGLT2 inhibitor instead of a sulphonylurea to avoid hypoglycaemia, weight gain and subsequent deterioration of glucose control. At such a stage of the disease, an SGLT2 inhibitor (canagliflozin) has been shown to be more effective than a DPP-4 inhibitor (sitagliptin), while producing significant weight loss and blood pressure reduction. Also, after the failure of dual therapy with metformin and sulphonylurea, it may be tempting to introduce an SGLT2 inhibitor either in combination with those same two drugs or after substituting the sulphonylurea with the SGLT2 inhibitor. Such a combination might be proposed as a priority in overweight or obese patients without renal failure to avoid hypoglycaemia and postpone the introduction of insulin therapy. SGLT2 inhibitors represent a valuable opportunity to shed new light on the association of antidiabetic drugs with sulphonylureas (with or without metformin). Beyond pioglitazone, which is not indicated for all patients and not available in all countries, the association of a sulphonylurea with a DPP-4 inhibitor is often of modest cumulative value. The additional decrease in HbA 1c conferred by such an association of two different insulin secretagogues, both targeting beta cells, is limited and less than 0.7% in most randomized clinical interventional studies, and the effect on glycaemia control SGLT2 receptor inhibitors: An opportunity to revise our therapeutic strategy for type 2 diabetes? Editorial