Orlistat Augments Postprandial Increases in Glucagon-Like Peptide-1 in Obese Type 2 Diabetic Patients

Response to Damci et al.

Damci et al. (1) suggest that the lipase inhibitor, orlistat, stimulates the postprandial secretion of glucagon-like peptide-1 (GLP-1) after meals containing fat and speculate that this may lead to reductions in both postprandial glycemia and energy intake. The authors observed (in a cohort of 29 type 2 diabetic patients) that after ingestion of a 600 kcal breakfast (comprising 38% fat, 50% carbohydrate, and 12% protein), the increases from baseline in plasma GLP-1 and serum C-peptide were slightly greater and that of serum glucose slightly less, as measured in a single blood sample taken 60 min after commencement of the meal. The authors have apparently failed to appreciate the following: 1) While fat is a potent stimulant of GLP-1 secretion, the latter appears to be dependent on the digestion of fat to fatty acids (2,3), e.g., in healthy subjects, the stimulation of GLP-1 by intraduodenal triglyceride is abolished by concomitant administration of orlistat (2). 2) As the regulation of gastric emptying of fat is also dependent on lipolysis (4,5), orlistat may accelerate gastric emptying of meals containing fat (4). If the meal also contains carbohydrate, orlistat has the capacity to exacerbate overall postprandial glycemic excursions in type 2 diabetic patients by this mechanism (3). Even relatively minor variations in gastric emptying of carbohydrate are now known to potentially have a major effect on postprandial glycemia and insulin responses in both healthy subjects and type 2 diabetic patients (6,7). 3) In healthy subjects, acute lipase inhibition with orlistat attenuates rather than increases the inhibitory effects of fat on subsequent energy intake (2,8).

The effects of orlistat on glycemic, insulin, and incretin responses to a meal, including the time course of these effects, are likely to be critically dependent on both the macronutrient composition and energy content of a meal, perhaps particularly the ratio of fat to carbohydrate. It should also be recognized that in patients with type 2 diabetes, gastric emptying is frequently abnormal and may influence these responses (7). In relation to the study by Damci et al. (1), we would offer an alternative interpretation, i.e., after administration of orlistat, the carbohydrate, fat, and protein components of their meal (the type of meal is not described) initially emptied from the stomach more rapidly, and this was reflected in a relative increase in C-peptide and GLP-1 at 60 min and a slight reduction in plasma glucose at that time. The stimulation of GLP-1 would reflect the greater small intestinal carbohydrate load during this time as well as the presence of fatty acids that escaped lipase inhibition. We would anticipate that the overall GLP-1 response to the meal would be less and initial postprandial glycemia worse. It would require more frequent blood sampling over a longer period of time to fully interpret the action of orlistat on incretin and insulin secretion and to draw conclusions about GLP-1 as a mediator of the effects of orlistat on body weight in obesity.