Acute Effects of Lixisenatide on Energy Intake in Healthy Subjects and Patients with Type 2 Diabetes: Relationship to Gastric Emptying and Intragastric Distribution

Abstract

<jats:p>Glucagon-like peptide-1 receptor agonists induce weight loss, which has been suggested to relate to the slowing of gastric emptying (GE). In health, energy intake (EI) is more strongly related to the content of the distal, than the total, stomach. We evaluated the effects of lixisenatide on GE, intragastric distribution, and subsequent EI in 15 healthy participants and 15 patients with type 2 diabetes (T2D). Participants ingested a 75-g glucose drink on two separate occasions, 30 min after lixisenatide (10 mcg) or placebo subcutaneously, in a randomised, double-blind, crossover design. GE and intragastric distribution were measured for 180 min followed by a buffet-style meal, where EI was quantified. Relationships of EI with total, proximal, and distal stomach content were assessed. In both groups, lixisenatide slowed GE markedly, with increased retention in both the proximal (p &lt; 0.001) and distal (p &lt; 0.001) stomach and decreased EI (p &lt; 0.001). EI was not related to the content of the total or proximal stomach but inversely related to the distal stomach at 180 min in health on placebo (r = −0.58, p = 0.03) but not in T2D nor after lixisenatide in either group. In healthy and T2D participants, the reduction in EI by lixisenatide is unrelated to changes in GE/intragastric distribution, consistent with a centrally mediated effect.</jats:p>

Macronutrient intake, appetite, food preferences and exocrine pancreas function after treatment with short‐ and long‐acting glucagon‐like peptide‐1 receptor agonists in type 2 diabetes

“…Individual patterns of gastrointestinal symptoms were found and are probably attributable to the pharmacological differences of liraglutide and lixisenatide. We find an association between prolonged gastric emptying and the reduction in energy intake after GLP‐1 RA treatment, in contrast to a previous publication 48 . This may just be an association, indicating GLP‐1 receptor target engagement leading to diverse biological responses.…”

Gastrointestinal adverse events with insulin glargine/lixisenatide fixed‐ratio combination versus glucagon‐like peptide‐1 receptor agonists in people with type 2 diabetes mellitus: A network meta‐analysis

“…It is possible that a reduced effect of long‐ versus short‐acting GLP‐1 RAs to slow gastric emptying may contribute to the lower incidence of GI AEs with long‐acting GLP‐1 RAs; however, it has recently been demonstrated that exenatide once weekly slows gastric emptying significantly even at steady‐state concentrations 38 . Moreover, the suppression of energy intake by lixisenatide is not related to slowing of gastric emptying or changes in intragastric meal distribution 39 . It is notable that recent updates to titration schemas for weekly GLP‐1 RA therapies have incorporated extended titration steps for up to 4 weeks to help minimize GI AEs 40–42 …”

“…38 Moreover, the suppression of energy intake by lixisenatide is not related to slowing of gastric emptying or changes in intragastric meal distribution. 39 It is notable that recent updates to titration schemas for weekly GLP-1 RA therapies have incorporated extended titration steps for up to 4 weeks to help minimize GI AEs. [40][41][42] The strengths of our analysis include a comprehensive literature search based on standardized prespecified search criteria, with confounding reduced by using only studies with the recommended titrated dose of each GLP-1 RA.…”

Gastric Sensory and Motor Functions and Energy Intake in Health and Obesity—Therapeutic Implications

“…The weight loss achieved with subcutaneous semaglutide is independent of gastrointestinal adverse events though other studies confirm that both weekly and oral semaglutide retard gastric emptying [ 154 , 189 , 190 ]. Nevertheless, weight loss associated with GLP-1 receptor agonists may be independent of gastric motor changes and related to central appetite regulation [ 191 , 192 , 193 ].…”