title: Metabolic effects of SGLT-2 inhibitors beyond increased glucosuria: A review of the clinical evidence.
abstract: Sodium-glucose cotransporter type 2 (SGLT-2) inhibitors (canagliflozin, dapagliflozin, empagliflozin) are new glucose-lowering agents that exert their therapeutic activity independently of insulin by facilitating glucose excretion through the kidneys. However, this simple renal mechanism that results in sustained glucose urinary loss leads to more complex indirect metabolic effects. First, by reduction of chronic hyperglycaemia and attenuation of glucose toxicity, SGLT-2 inhibitors can improve both insulin secretion by beta cells and peripheraltissue insulin sensitivity. In the case of canagliflozin, because of low-potency SGLT1 inhibition, a non-renal (intestinal) effect may also be considered, which may contribute to better control of postprandial hyperglycaemia, although this contribution remains to be better analyzed in humans. Second, chronic glucose loss most probably leads to compensatory mechanisms. One of them, although not well evidenced in humans, might involve an increase in energy intake, an effect that may limit weight loss in the long run. Another could be an increase in endogenous glucose production, most probably driven by increased glucagon secretion, which may somewhat attenuate the glucoselowering effect. Nevertheless, despite these compensatory mechanisms and most probably because of the positive effects of the reduction in glucotoxicity, SGLT-2 inhibitors exert clinically relevant glucose-lowering activity while promoting weight loss, a unique dual effect among oral antidiabetic agents. Furthermore, the combination of SGLT-2 inhibitors with other drugs that either have anorectic effects (such as incretin-based therapies) or reduce hepatic glucose output (like metformin) and, thus, may dampen these two compensatory mechanisms appears appealing for the management of type 2 diabetes mellitus.
authors.affiliation: Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, University of Liège, Liège, Belgium; Clinical Pharmacology Unit, CHU Liège, Center for Interdisciplinary Research on Medicines (CIRM), University of Liège, Liège, Belgium. Electronic address: andre.scheen@chu.ulg.ac.be.
authors.forename: A J
authors.initials: AJ
authors.lastname: Scheen
authors.affiliation: Division of Diabetes, Nutrition and Metabolic Disorders, Department of Medicine, CHU Liège, University of Liège, Liège, Belgium; Diabetology and Nutrition, GIGA I3, University of Liège, Liège, Belgium.
authors.forename: N
authors.initials: N
authors.lastname: Paquot
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D019317:Evidence-Based Medicine; D006801:Humans; D006943:Hyperglycemia / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D049990:Membrane Transport Modulators / Q000009:adverse effects / Q000627:therapeutic use*; D050177:Overweight / Q000150:complications / Q000178:diet therapy / Q000517:prevention & control; D065667:Renal Elimination / Q000187:drug effects; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D015431:Weight Loss / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D049990:Membrane Transport Modulators; C089180:SLC5A2 protein, human; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors
keywords: Canagliflozin; Dapagliflozin; Empagliflozin; Energy balance; Glucotoxicity; Insulin secretion; Insulin sensitivity; Type 2 diabetes