Response to Dahl et al.: Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes

Abstract

Dahl et al. 1 report the first evaluation of the effect of the oral glucagon-like peptide-1 (GLP-1) receptor agonist (RA), semaglutide, on gastric emptying in type 2 diabetes. We consider that their study is compromised by substantial methodological flaws and that interpretation of the outcomes is both incorrect and misleading.In brief, in a crossover design, Dahl et al. 1 studied 15 patients with well-controlled type 2 diabetes who received oral semaglutide, escalated to a dose of 14 mg over 12 weeks and 3 days, or placebo; the two treatment periods were separated by 5 to 9 weeks. Gastric emptying was assessed at 12 weeks and 3 days (i.e. at steady state

Response to the letter from Horowitz et al. to the Editor relating to the publication ‘Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes’ by Dahl et al.

“…believe that the study by Dahl et al strongly suggests that oral semaglutide has the capacity to delay gastric emptying markedly in at least some individuals with type 2 diabetes'. 1 In our article, we conclude that a 30% decrease of gastric emptying was evident in the first postprandial hour, and we were not able to detect any slowing of gastric emptying resulting from oral semaglutide in the period after the first hour. We, therefore, find it puzzling that Horowitz et al felt able to make such strong conclusions based on the reported data.…”

“…It is pointed out by Horowitz et al that it would be illogical that oral semaglutide, after repeated dosing and at steady state exposure level, would only influence the first hour of postprandial gastric emptying. 1 They seem to imply that an effect on the period 0-1 hours after a meal would be an acute effect comparable with that observed from administration of other shorter-acting glucagonlike peptide-1 (GLP-1) receptor analogues. However, we do not conclude that the duration of treatment or the steady state level of exposure is related to the timing of an effect on gastric emptying.…”

“…paracetamol in the period of 0-2 hours was not evaluated. 1 The prespecified endpoints for paracetamol were based on previous data from subcutaneous semaglutide showing that slowing of gastric emptying was only detectable in the 0-1 hour period postdose. 5 We have investigated the paracetamol data from the current study again and no significant difference arising from oral semaglutide treatment between the AUCs for paracetamol in the 0-2-hour period was observed (Table 1).…”

“…Horowitz et al mention that the optimal conditions for testing gastric emptying are in the morning after an overnight fast. 1 In this trial, the dosing of paracetamol with a standardized lunch meal instead of a breakfast was carried out because of the oral semaglutide formulation and dosing requirements. Like most other oral semaglutide trials, oral semaglutide tablets were dosed in the fasting state, and breakfast was served 30 minutes after dosing.…”

“…Response to the letter from Horowitz et al to the Editor relating to the publication 'Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes' by Dahl et al To the Editor: Horowitz et al have, in a Letter to the Editor, 1 raised a series of concerns related to the use of paracetamol for evaluation of gastric emptying as applied in our published work 'Oral semaglutide improves postprandial glucose and lipid metabolism, and delays gastric emptying, in subjects with type 2 diabetes'. 2 While the authors of the manuscript acknowledge that Horowitz et al have a genuine intent in promoting scintigraphy as a preferred method for assessment of gastric emptying, the authors assert that the data generated on the effects of semaglutide on gastric emptying are valid, relevant and consistent, and have been accepted by reviewers in peer-reviewed publications as well as by health authorities.…”