Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Sodium-Glucose Cotransporter 2 Inhibition

Studies suggest that sodium-glucose cotransporter 2 inhibitors (SGLT2i) induce hyperglucagonemia, which might counteract its glucose-lowering ability in type 2 diabetes. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, 12 middle-aged patients with type 2 diabetes (BMI [mean (SD)]: 30.3 (5.8) kg/m 2 ; HbA1c: 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration: 1) Placebo, 2) SGLT2i (25 mg empagliflozin), 3) glucagon receptor antagonist (GRA) (300 mg LY2409021), and 4) GRA + SGLT2i. The SGLT2i and GRA individually lowered fasting plasma glucose (FPG) compared to placebo and the combination further decreased FPG. SGLT2i reduced postprandial glucose excursions as assessed by baseline-subtracted area under curve (bsAUC) whereas GRA increased bsAUC compared to placebo (Figure). The paradoxical GRA-induced increment in bsAUC was annulled by a potent SGLT2i-induced reduction of bsAUC during the combination of SGLT2i and GRA (Figure). In conclusion, SGLT2i and GRA combined reduce FPG beyond their individual capacity in patients with type 2 diabetes, and in the context of GRA, SGLT2i’s beneficial effect on postprandial glucose excursions seems to be potentiated. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. H. Maagensen: None. E. Nielsen-Hannerup: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker9s Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker9s Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker9s Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker9s Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker9s Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker9s Bureau; Self; Sanofi. T. Vilsboll: None.