Lixisenatide Associated With Sustained Gastric Emptying, Improved Glucose Metabolism

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Treatment with lixisenatide can significantly slow gastric emptying and reduce the rate of systemic appearance of orally ingested glucose.

Treatment with lixisenatide can significantly slow gastric emptying and reduce the rate of systemic appearance of orally ingested glucose, effects that persist with sustained use and are associated with substantial reduction in postprandial glycemia, according to study results published in Diabetes Care.

Glucagon-like peptide-1 (GLP-1) receptor agonists used to treat type 2 diabetes can lower glucose levels through several actions, including slowing of gastric emptying. However, previous studies have suggested a potential tachyphylaxis for this effect seen with continuous use of GLP-1 receptor agonists. The goal of the current study was to assess the effects of lixisenatide, a short-acting GLP-1 receptor agonist, on slowing of gastric emptying and reduction in postprandial glycemia.

The primary outcome was the change in gastric half emptying time from baseline to 56 days for lixisenatide vs placebo using a very accurate technique for scintigraphy. Gastric emptying was also evaluated by area under the curve (AUC) for retention over 0 to 240 and 0 to 120 minutes. The effects on postprandial glucose metabolism were assessed using a dual glucose tracer technique after consumption of a 75-g glucose drink. Assessments were completed twice, once at baseline and once at 56 days.

The double-blind randomized controlled trial enrolled 33 patients with type 2 diabetes, of whom 30 (21 men; mean age, 67.1 years) completed the study. Of these patients, 15 were randomly assigned to treatment with lixisenatide (20 µg subcutaneously daily) and 15 were treated with placebo.

As 4 of 15 patients treated with lixisenatide had significant retention of the glucose drink in the stomach at 240 minutes, measurement of gastric half emptying time could not be used. The ratio of adjusted geometric means for AUC over 0 to 240 minutes for lixisenatide and placebo at day 56 was 2.19 (95% CI, 1.82-2.64; P <.001), and for AUC over 0 to 120 minutes, this ratio was 1.55 (95% CI, 1.37-1.74; P <.001).

Treatment with lixisenatide was associated with marked reductions in postprandial glycemia (P <.001) over 120 and 240 minutes after oral glucose intake. Furthermore, lixisenatide treatment was associated with a substantial reduction in the rate of systemic appearance of orally ingested carbohydrates (P<.001).

There were no significant changes in endogenous glucose production or in fasting glucagon, insulin, or C-peptide levels after treatment with lixisenatide. However, treatment with lixisenatide suppressed glucagon secretion after consumption of the glucose drink and flattened the postprandial insulin and C-peptide curves.

There was a significant association between postprandial glucose lowering over 240 minutes after consumption of the glucose drink and the magnitude of slowing of gastric emptying by lixisenatide (r =-0.74; P =.002), as the reduction in postprandial glycemia was more significant among patients who achieved greater slowing of gastric empting with lixisenatide. In addition, postprandial glucose lowering over 240 minutes was strongly related to the baseline rate of gastric emptying (r =0.52; P =.048) and patients with more rapid gastric emptying at baseline had greater benefit in terms of postprandial glucose lowering.

The study had several limitations, including the relatively short duration, lack of power to assess the relationships between changes in gastric emptying and glycated hemoglobin, inclusion of patients with relatively good glycemic control and few complications, and the use of placebo rather than an active comparator.

Taken together, “[s]hort-acting GLP-1 receptor agonists therefore potentially represent an effective long-term therapy for specifically targeting postprandial glucose excursions,” concluded the researchers.

Disclosure: This clinical trial was supported by Sanofi. Please see the original reference for a full list of authors’ disclosures.

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Rayner CK, Watson LE, Phillips LK, et al. Effects of sustained treatment with lixisenatide on gastric emptying and postprandial glucose metabolism in type 2 diabetes: a randomized controlled trial [published online May 29, 2020]. Diabetes Care. doi:10.2337/dc20-0190