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

<i>Objective</i> <p>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. </p> <p> </p> <p><i>Research design and methods</i></p> <p>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.</p> <p> </p> <p><i>Results</i></p> <p>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).</p> <p> </p> <p><i>Conclusions</i></p> <p>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.</p>