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Effects of sustained treatment with lixisenatide on gastric emptying and postprandial glucose metabolism in type 2 diabetes: a randomized controlled trial

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posted on 29.05.2020 by Christopher K. Rayner, Linda E. Watson, Liza K. Phillips, Kylie Lange, Michelle J. Bound, Jacqueline Grivell, Tongzhi Wu, Karen L. Jones, Michael Horowitz, Ele Ferrannini, Domenico Tricò, Silvia Frascerra, Andrea Mari, Andrea Natali
Objective

Slowing of gastric emptying by GLP-1 exhibits tachyphylaxis with continuous exposure. We therefore aimed to establish whether prolonged use of a “short-acting” GLP-1 receptor agonist (GLP-1RA), lixisenatide, achieves sustained slowing of gastric emptying and reduction in postprandial glycemia.

Research design and methods

30 patients with metformin-treated type 2 diabetes underwent assessment of gastric emptying (scintigraphy) and glucose metabolism (dual tracer technique) after a 75g glucose drink, before and after 8 weeks’ treatment with lixisenatide (20µg subcutaneously daily) or placebo, in a double-blind randomized parallel design.

Results

Gastric retention of the glucose drink was markedly increased after lixisenatide versus placebo (ratio of adjusted geometric means for area under curve (AUC) over 240 min of 2.19 (95% CI 1.82, 2.64; P<0.001), associated with substantial reductions in the rate of systemic appearance of oral glucose (P<0.001) and incremental AUC for blood glucose (P<0.001). Lixisenatide suppressed both glucagon (P=0.003) and insulin (P=0.032), but not endogenous glucose production, over 120 min after oral glucose. Postprandial glucose-lowering over 240 min was strongly related to the magnitude of slowing of gastric emptying by lixisenatide (r = -0.74, P = 0.002) and to the baseline rate of emptying (r = 0.52, P = 0.048), but unrelated to ß-cell function (assessed by ß-cell glucose sensitivity).

Conclusions

8 weeks’ treatment with lixisenatide is associated with sustained slowing of gastric emptying and marked reductions in postprandial glycemia and appearance of ingested glucose. Short-acting GLP-1RAs therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions.

Funding

This investigator-initiated study was supported financially by Sanofi. Sanofi also supplied lixisenatide and matching placebo, but had no involvement in the design or development of the study, nor any role in the collection, analysis, or interpretation of data. T. W. is supported by a Royal Adelaide Hospital Florey Fellowship. K.L.J. is supported by a University of Adelaide William T Southcott Research Fellowship.

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