Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity

Abstract

Aim: To investigate the effects of semaglutide on fasting and postprandial glucose and lipid responses, and on gastric emptying.

Materials and methods: This was a randomized, double-blind, placebo-controlled, 2-period, crossover trial. Subjects with obesity (N = 30) received once-weekly subcutaneous semaglutide, dose-escalated to 1.0 mg, or placebo. After each 12-week treatment period, glucose and lipid metabolism were assessed before and after standardized meals. Gastric emptying (paracetamol absorption test) and peptide YY (PYY) response were also assessed.

Results: Semaglutide treatment significantly lowered fasting concentrations of glucose and glucagon, and increased insulin vs placebo (estimated treatment ratio: 0.95 [95% confidence interval: 0.91, 0.98]; 0.86 [0.75, 0.98]; 1.45 [1.20, 1.75], respectively). Postprandial glucose metabolism significantly improved with semaglutide vs placebo (incremental area under the curve 0 to 5 hours [iAUC_0-5h ]; estimated treatment difference: glucose -1.34 mmol h/L [-2.42, -0.27]; insulin -921 pmol h/L [-1461, -381]; C-peptide -1.42 nmol h/L [-2.33, -0.51]). Fasting and postprandial lipid metabolism improved with semaglutide vs placebo. First-hour gastric emptying after the meal was delayed with semaglutide vs placebo (AUC_0-1h ; estimated treatment ratio: 0.73 [0.61, 0.87]); this may have contributed to the lower postprandial glucose increase in semaglutide-treated subjects. Overall gastric emptying (AUC_0-5h ) was not statistically different between treatments. Fasting and postprandial PYY responses were significantly lower with semaglutide vs placebo (P = .0397 and P = .0097, respectively).

Conclusion: Semaglutide improved fasting and postprandial glucose and lipid metabolism. Overall gastric emptying was similar to that with placebo; however, the observed first-hour delay with semaglutide may contribute to a slower entry of glucose into the circulation.

Keywords: GLP-1 analogue; glucose metabolism; incretin therapy; insulin analogues; obesity therapy; phase I-II study.

Figure 1

Mean glucose metabolism profiles after standardized, carbohydrate‐rich breakfast. Error bars represent standard error

Figure 2

Mean lipid metabolism profiles after standardized, fat‐rich breakfast. Error bars represent standard error. Abbreviation: VLDL, very‐low‐density lipoprotein

Figure 3

Gastric emptying: A, mean paracetamol profiles following standardized, carbohydrate‐rich breakfast. B, Mean PYY profile following standardized, carbohydrate‐rich breakfast. Error bars represent standard error. Abbreviation: PYY, peptide YY