The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition

Abstract

Sodium–glucose cotransporter 2 inhibitors (SGLT2i) effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies have suggested 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 4 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), or 4 ) the combination empagliflozin + LY2409021. Empagliflozin and LY2409021 individually lowered fasting PG compared with 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 through 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.

Do sodium‐glucose co‐transporter‐2 inhibitors increase plasma glucagon by direct actions on the alpha cell? And does the increase matter for the associated increase in endogenous glucose production?

“…In this study, drug‐naïve subjects, who all had type 2 diabetes, did not, during fasting, show reduced SGLT2i‐mediated EGP on the day of LY2409021 co‐administration. On the contrary, EGP was larger when the drugs were co‐administered compared with LY2409021 alone, suggesting that glucagon did not mediate SGLT2i‐induced increase in EGP, at least not acutely 20 . With the limitation of a lack of large‐scale studies with subchronic treatments, it appears that the available balance of evidence does not favour that SGLT2i‐induced increase in circulating glucagon levels should play a quantitative important role in the increase in EGP associated with SGLT2i therapy.…”

“…With the limitation of a lack of large‐scale studies with subchronic treatments, it appears that the available balance of evidence does not favour that SGLT2i‐induced increase in circulating glucagon levels should play a quantitative important role in the increase in EGP associated with SGLT2i therapy. The strongest data to support this viewpoint are that (a) the increased EGP associated with SGLT2i therapy occurs during hyperglycaemic conditions 8–10 where the window for glucagon to increase EGP generally is low because of the low glucagon/insulin ratio, (b) the rise in plasma glucagon concentrations is modest, 14,16,18,19 (c) the onset of EGP after SGLT2i ingestion is rapid (30‐60 minutes) and occurs well before the increase in plasma glucagon levels, 8 (d) preventing SGLT2i lowering of blood glucose by clamping abolishes the increase in circulating glucagon but does not prevent increased EGP, 20,21,67 and (e) glucagon receptor blockade does not acutely lower SGLT2i‐induced EGP 20 . Alternative mechanisms must therefore explain the causal link between SGLT2i therapy and increased EGP.…”

“…[85][86][87] In support of this reasoning, addition of incretins was reported to prevent the rise in glucagon associated with SGLT2i treatment. 51 [8][9][10] where the window for glucagon to increase EGP generally is low because of the low glucagon/insulin ratio, (b) the rise in plasma glucagon concentrations is modest, 14,16,18,19 (c) the onset of EGP after SGLT2i ingestion is rapid (30-60 minutes) and occurs well before the increase in plasma glucagon levels, 8 (d) preventing SGLT2i lowering of blood glucose by clamping abolishes the increase in circulating glucagon but does not prevent increased EGP, 20,21,67 and (e) glucagon receptor blockade does not acutely lower SGLT2i-induced EGP. 20 Alternative mechanisms must therefore explain the causal link between SGLT2i therapy and increased EGP.…”

“…The underlying mechanisms coupling SGLT2i therapy to increased EGP remains debated, and one prevailing hypothesis is that it results, at least partially, from SGLT2i‐induced increases in plasma glucagon concentrations, which in some studies have been reported to be increased both when treatment is initiated and after prolonged use 14,16,18,19 . In other studies, however, an association between SGLT2i intake (at therapeutic dosing) in drug‐naïve individuals and increased plasma glucagon levels was not found 20–22 . Because glucagon acts to increase blood glucose levels by stimulating hepatic glucose output, 23 SGLT2i‐induced increases in plasma glucagon could potentially explain the increased EGP.…”

“…14,16,18,19 In other studies, however, an association between SGLT2i intake (at therapeutic dosing) in drug-naïve individuals and increased plasma glucagon levels was not found. [20][21][22] Because glucagon acts to increase blood glucose levels by stimulating hepatic glucose output, 23 SGLT2i-induced increases in plasma glucagon could potentially explain the increased EGP. However, as the stimulatory effect of glucagon on hepatic glucose production is tightly coupled to blood glucose levels 24 and the insulin/glucagon ratio, 25 it could be argued that an SGLT2i-mediated rise in glucagon, although potentially reducing maximal efficacy on blood glucose lowering, could be beneficial in individuals with wellcontrolled fasting glycaemia, as it would minimize the risk of hypoglycaemia.…”