Metyrapone is effective therapy for short- and long-term control of hypercortisolemia in CS.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are the latest addition to the class of oral glucose-lowering drugs. They have been rapidly adopted into clinical practice because of therapeutic advantages, including weight loss and reduction in blood pressure, in addition to glycaemic benefits and a low intrinsic risk of hypoglycaemia. Although there are extensive data on the clinical effects of SGLT2 inhibition, the metabolic effects of inhibiting renal glucose reabsorption have not been fully described. Recent studies have identified compensatory metabolic effects, such as an increase in endogenous glucose production, and have also shown an increase in glucagon secretion during SGLT2 inhibition. In addition, there is a discrepancy between the expected and observed weight loss found in clinical studies on SGLT2 inhibitors, probably as a result of changes in energy balance with this treatment approach. SGLT2 inhibition is likely to have intriguing effects on whole body metabolism which have not been fully elucidated, and which, if explained, might help optimize the use of this new class of medicines.

Inhibition of glucose transport in the kidney, to produce glucosuria and thus directly lower blood glucose seems a remarkably simple way to treat diabetes (type 1 or type 2). The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their subsequent clinical development has on one hand shown this to be true, but at another level has helped reveal a complex web of interacting effects starting in the kidney and modulating multiple metabolic pathways in a variety of other organs. These underlie the now clear benefits of this class of drugs in the management of type 2 diabetes from glucose lowering, weight loss and blood pressure reduction through to the reductions in cardiovascular and renal complications observed in long-term outcomes trials. They also explain some of the adverse effects that have emerged, including the risk of diabetic ketoacidosis. This review describes the effects of SGLT2 inhibition in relation to this complex physiology, and shows how this can favourably alter the pathophysiology of type 2 diabetes.anti-diabetic drug, clinical physiology, type 2 diabetes, SGLT2 inhibitor 1 | INTRODUCTION Sodium glucose transporter 2 inhibitors (SGLT2i) are one of the newest classes of drugs available to lower glucose in people with type 2 diabetes, but their origins go back to the 19th century, when phlorizin, extracted from the bark of apple trees was shown to induce glucosuria. Phlorizin was later used experimentally as a tool to help understand renal glucose transport and the effects of glucose toxicity, as it could be used to lower blood glucose without directly affecting insulin secretion or sensitivity. 1 However its therapeutic potential was limited, due to poor oral bioavailability, and effects on gut glucose absorption that resulted in diarrhoea; phlorizin also has an active metabolite (phloretin) that inhibits the GLUT1 glucose transporter that is important for normal glucose transport in many tissues. 2 Research conducted in the last 20 years has now identified the specific mechanisms by which phlorizin is able to induce glucosuria and lower blood glucose, and led to the development of drugs that are highly selective inhibitors of renal (and/or gut) glucose transport. These drugs work by inhibiting the facilitative sodium glucose co-transporters (SGLTs) that are responsible for renal glucose reabsorption (predominantly SGLT2 with some contribution from SGLT1, which also has a major role in gut glucose absorption). 3 Despite early concerns about some adverse effects that occur as a result of glucosuria, the development of SGLTi (and potentially dual inhibitors of SGLT1 and SGLT2) has led to greater understanding of the fundamental physiological processes involved in glucose transport in the kidney and gastrointestinal (GI) tract. These medications have both predictable and surprising effects that underpin some of their observed therapeutic benefits and adverse effects. This review will focus on the underlying physiology and show how this is modified by pharmacological inhibition of SG...

S154Diabetes Care Volume 39, Supplement 2, August 2016 SGLT2 THERAPYsensitizer (6,7). GLP-1 is part of the physiological system signaling satiety (8,9), reduces food intake and promotes weight loss in humans (10), and delays gastric emptying (11). Early studies showed that continuous subcutaneous GLP-1 infusion effectively lowered fasting and postprandial glucose levels and promoted weight loss in patients with T2DM (12). However, endogenous human GLP-1 has a short half-life (2-3 min) due to breakdown in the circulation by protease enzymes, notably, dipeptidyl peptidase (DPP)-4, which cleaves the molecule to leave the inactive GLP-1 (9-36). Hence, native GLP-1 has limited therapeutic efficacy. Pharmaceutical development took two routes: inhibition of the DPP-4-degrading enzyme and prolongation of the biological half-life by developing DPP-4-resistant GLP-1 receptor agonists (GLP-1 RAs). DPP-4 InhibitorsFour oral DPP-4 inhibitors (DPP-4i) are approved for use in both the U.S. and the European Union (sitagliptin, saxagliptin, alogliptin, and linagliptin) ( Table 1). Vildagliptin is approved in the European Union but not the U.S. Several other agents of this class are marketed worldwide (for example, omaragliptin and trelagliptin are available only in Japan). All five DPP-4i appear to have similar efficacy in terms of glucose lowering. An 18-week, phase 3b, multicenter, double-blind trial of saxagliptin versus sitagliptin has demonstrated noninferiority as add-on therapy to metformin (13). Trelagliptin, a once-weekly DPP-4i, was studied against alogliptin once daily and has demonstrated noninferiority in the Japanese population studied (14). Meta-analysis of DPP-4i has shown an average HbA 1c reduction (20.74%) (15) that is slightly less efficacious than sulfonylureas when used as monotherapy and similar to metformin and pioglitazone (16) but inferior to GLP-1 RAs. DPP-4i can be used in combination with other oral agents or with basal insulin (17), although the reduction of HbA 1c with insulin is modest (18,19). The DPP-4i are weight neutral and have a low risk of hypoglycemia. DPP-4i: Adverse EffectsIn general, the adverse effect profile of the DPP-4i is quite favorable. With the exception of linagliptin, the DPP-4i require dose reduction in patients with renal impairment. Some concern has been raised about the risk of pancreatitis and pancreatic cancer, based on preclinical studies and reports from postmarketing surveillance studies. However, the current data do not support a likely association (20). The U.S. Food and Drug Administration (FDA) has recently issued a warning about the possibility of joint pain developing during DPP-4i treatment after review of 33 cases reported over the past 8 years. However, the potential mechanism(s) are uncertain and a causal link is unproven, although symptoms appear to resolve after treatment withdrawal (21). Several large cardiovascular (CV) outcome trials have been completed, comparing these agents with placebo on the background of standard diabetes care (Table 2), and have ...