Individual and Combined Glucose-Lowering Effects of Glucagon Receptor Antagonism and Dipeptidyl Peptidase-4 Inhibition

Abstract

Type 2 diabetes is characterized by absolute or relative hypoinsulinemia and hyperglucagonemia. Dipeptidyl peptidase 4 inhibitors (DPP-4i) augment insulin secretion and decrease glucagon secretion, but if glucagon is removed from the metabolic equation, the effect of DPP-4i is unknown. In a randomized, placebo-controlled, double-dummy, double-blinded, cross-over study, patients with type 2 diabetes (n=12, age [mean (SD)]: 60.9 (7.8) years, BMI 34.6 (7.1) kg/m2; HbA1c 50.3 (10.5) mmol/mol) underwent four 4-hour liquid mixed meal tests preceded by single-dose administration of 1) placebo, 2) DPP-4i (5 mg linagliptin) 2 hours before the meal, 3) glucagon receptor antagonist (GRA) (300 mg LY2409021) 12 hours before the meal, and 4) GRA + DPP-4i. Compared to placebo, fasting plasma glucose (FPG) was lowered by GRA but not DPP-4i. Adding DPP-4i to GRA did not lower FPG further. Compared to placebo, DPP-4i increased insulin responses to the meal (C-peptide AUC) (P<0.01), but did not result in a difference in plasma glucose excursions (Figure). GRA alone lowered glucose AUC, and the combination of GRA and DPP-4i lowered glucose AUC further. In conclusion, the combination of DPP-4i and GRA has additive effects on postprandial glucose excursions. This seems to be driven by the efficient reduction in FPG by GRA combined with additional reduction in postprandial glucose excursions by DPP-4i. Disclosure S. Haedersdal: None. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. E. Nielsen-Hannerup: None. H. Maagensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's 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. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.