Glucagon Levels During Short-Term SGLT2 Inhibition Are Largely Regulated by Glucose Changes in Patients With Type 2 Diabetes

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 1; pp. 193 - 201
• Main Authors: Lundkvist, Per, Pereira, Maria J, Kamble, Prasad G, Katsogiannos, Petros, Langkilde, Anna Maria, Esterline, Russell, Johnsson, Eva, Eriksson, Jan W
• Format: Journal Article
• Language: English
• Published: United States Copyright Oxford University Press 01.01.2019; Oxford University Press
• Subjects: Analysis; Care and treatment; Complications and side effects; Dextrose; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes therapy; Dipeptidyl-peptidase IV; Energy resources; Experiments; Fatty acids; Glucagon; Glucose; Glucose tolerance; Glucose tolerance tests; Glycerin; Glycerol; Hypoglycemic agents; Insulin; Insulin secretion; Medical research; Medicine, Experimental; Metformin; Multivariate analysis; Peptidase; Pharmaceutical industry; Short term; Sodium-glucose cotransporter; Type 2 diabetes; United Kingdom; Sweden
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2018-00969

The mechanism mediating sodium glucose cotransporter-2 (SGLT2) inhibitor-associated increase in glucagon levels is unknown. To assess short-term effects on glucagon, other hormones, and energy substrates after SGLT2 inhibition and whether such effects are secondary to glucose lowering. The impact of adding a dipeptidyl peptidase-4 inhibitor was addressed. A phase 4, single-center, randomized, three-treatment crossover, open-label study including 15 patients with type 2 diabetes treated with metformin. Patients received a single-dose of dapagliflozin 10 mg accompanied by the following in randomized order: isoglycemic clamp (experiment DG); saline infusion (experiment D); or saxagliptin 5 mg plus saline infusion (experiment DS). Directly after 5-hour infusions, a 2-hour oral glucose tolerance test (OGTT) was performed. Glucose and insulin levels were stable in experiment DG and decreased in experiment D [P for difference (Pdiff) < 0.001]. Glucagon-to-insulin ratio (Pdiff < 0.001), and levels of glucagon (Pdiff < 0.01), nonesterified fatty acids (Pdiff < 0.01), glycerol (Pdiff < 0.01), and β-OH-butyrate (Pdiff < 0.05) were lower in DG vs D. In multivariate analysis, change in glucose level was the main predictor of change in glucagon level. In DS, glucagon and active GLP-1 levels were higher than in D, but glucose and insulin levels did not differ. During OGTT, glucose levels rose less and glucagon levels fell more in DS vs D. The degree of glucose lowering markedly contributed to regulation of glucagon and insulin secretion and to lipid mobilization during short-term SGLT2 inhibition.