posted on 2020-10-01, 18:38authored byAda AdminAda Admin, Sofie Hædersdal, Asger Lund, Elisabeth Nielsen-Hannerup, Henrik Maagensen, Gerrit van Hall, Jens J. Holst, Filip K. Knop, Tina Vilsbøll
Sodium-glucose cotransporter 2 (SGLT2) inhibitors
(SGLT2i) effectively lower plasma glucose (PG) concentration in patients
with type 2 diabetes, but studies suggest that circulating glucagon
concentrations and endogenous glucose production (EGP) are increased by SGLT2i,
possibly compromising their glucose-lowering ability. To tease out whether and how
glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we
subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled,
double-blinded, crossover, double-dummy study comprising, on four separate
days, a liquid mixed meal test preceded by single-dose administration of either
1) placebo, 2) the SGLT2i empagliflozin (25 mg), 3) the glucagon receptor
antagonist LY2409021 (300 mg), and 4) the combination empagliflozin+LY2409021.
Empagliflozin and LY2409021 individually lowered fasting PG compared to placebo
and the combination further decreased fasting PG. Previous findings of
increased glucagon concentrations and EGP during acute administration of SGLT2i
were not replicated in this study. Empagliflozin reduced postprandial PG via increased
urinary glucose excretion. LY2409021 reduced EGP significantly, but gave rise
to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin
during their combination (empagliflozin+LY2409021). In conclusion, our findings
do not support that an SGLT2i-induced glucagonotropic effect is of importance
for the glucose-lowering property of SGLT2 inhibition.
Funding
The study was funded by the Danish Diabetes Academy supported by the Novo Nordisk Foundation and the A.P. Møller Foundation for the Advancement of Medical Sciences.