LAUSR

Following on from the success of last year’s special edition of Diabetologia, celebrating 60 years’ clinical use of metformin, for this year’s special edition we have chosen to focus on the newest class of glucose-lowering agents, the sodium–glucose cotransporter (SGLT) inhibitors. The 2015 update to the 2012 joint position statement from the EASD and the ADA suggested that metformin was in general the optimal first-line glucose-lowering agent, and, based on their beneficial effects on glucose, weight and blood pressure, placed the SGLT inhibitors as secondor third-line agents, together with all the other classes [1]. The statement pointed out that data on microvascular and macrovascular outcomes were lacking for almost all agents. Since then, new evidence has accumulated, particularly for the SGLT2 inhibitors, which has delighted us and challenged us to rethink our approach to glucose lowering in type 2 diabetes. In a previous editorial, I suggested that an ideal glucoselowering agent would ‘address the underlying pathophysiology of type 2 diabetes and have added value in terms of reducing non-glycaemic risk factors for, and the incidence of, microand macrovascular complications of diabetes’ [2]. In 2015, to commemorate 50 years of Diabetologia, several authors gave personal views on how glucose-lowering agents would develop over the next 50 years. Kahn and Buse endorsed the demands of regulators for cardiovascular outcome trials and highlighted forthcoming trial results, including those using the SGLT2 inhibitors [3]. In addition, Ahrén suggested the need for glucose-lowering agents with physiological targets other than beta cells and insulin resistant tissues, with few side effects [4]. At that time, short-term studies had already confirmed that SGLT2 inhibitors were effective glucoselowering agents that also reduced weight and blood pressure. Estimates suggested that the reductions in HbA1c and blood pressure were, to a large extent, independent of weight loss [5]. Thus, the beneficial reductions in weight, HbA1c and blood pressure with the SGLT2 inhibitor empagliflozin compared with placebo in the Empagliflozin, Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study were not surprising [6]. However, few people anticipated the cardiovascular endpoint results. For the first time, a randomised controlled trial of a glucose-lowering agent had demonstrated significant cardiovascular benefit in individuals with type 2 diabetes and preexisting cardiovascular disease (CVD). Broadly similar results using another agent from the same drug class, canagliflozin [7], and from a non-randomised, ‘real world’ registry study [8] have suggested that these cardiovascular benefits are a class effect. In addition, these and other trials have demonstrated consistent reductions in albuminuria and possible slowing of decline in renal function [6, 7, 9, 10]. The wealth of knowledge with regard to the benefits (and risks) of SGLT inhibitor use continues to build. Hence, to bring us all up to date, this year we devote our special issue to this important group of drugs. It was in the 1930s that several critical pieces of information came together to lay the foundations that eventually led to the development of SGLT inhibitors. First, Himsworth demonstrated a parallel relationship between blood and urine glucose concentrations [11]: below a certain blood glucose concentration, glucose filtered by the glomerulus was reabsorbed by the renal tubule and no glucose appeared in the urine; however, as blood glucose rose above this level, glucose appeared in the urine and increased with blood glucose concentration. Second, in a literature review, Hjarne * Sally M. Marshall [email protected]