The potent insulin-stimulating properties of native GLP-1 and GLP-1R agonists raise a legitimate question about the potential for GLP-1therapy in human subjects to cause hypoglycemia. Furthermore, the ability of GLP-1 to suppress glucagon secretion further raises the possibility that GLP-1-treated patients may exhibit defective glucagon responses to hypoglycemia, with potentially deleterious consequences due to delayed counter-regulatory responses designed to raise blood glucose. On the other hand, the observations that GLP-1 actions on the β cell are tightly coupled to the level of ambient glucose argue for a reduced risk of hypoglycemia, as the insulinotropic actions of GLP-1 should be rapidly diminished or terminated once the plasma glucose falls into the normal range.

It has been argued that exogenous GLP-1 might cause reactive hypoglycemia in healthy normal subjects Subcutaneous glucagon-like peptide-1 (7-36) amide is insulinotropic and can cause hypoglycaemia in fasted healthy subjects. Clin Sci (Lond). 1998 Dec;95(6):719-24. however this depends on the rate and amount of GLP-1 administration No increased risk of hypoglycaemic episodes during 48 hours of subcutaneous glucagon-like-peptide-1 administration in fasting healthy subjects Clin Endocrinol (Oxf). 2008 Dec 15. [Epub ahead of print] and exogenous GLP-1 is much less likely to cause hypoglycemia in patients with Type 2 diabetes who are not treated with other anti-diabetic medications prone to causing hypoglycemia No reactive hypoglycaemia in Type 2 diabetic patients after subcutaneous administration of GLP-1 and intravenous glucose. Diabet Med. 2001 Feb;18(2):144-9.

Are there conditions, independent of exogenous GLP-1 administration, that might shed light on this issue? Patients with very rapid gastric emptying, often associated with or secondary to partial gastrectomy, may develop hypoglycemia following rapid transit of nutrients from the stomach to the small bowel, and an exaggerated release of insulin. Although GLP-1 administration should independently reduce the rate of gastric emptying, exaggerated GLP-1 secretion and hypoglycemia has been observed in postgastrectomy patients as described in Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987 Dec 5;2(8571):1300-4. and Emptying of the gastric substitute, glucagon-like peptide-1 (GLP-1), and reactive hypoglycemia after total gastrectomy. Dig Dis Sci. 1991 Oct;36(10):1361-70and Increased glucagon-like Peptide-1 secretion and postprandial hypoglycemia in children after nissen fundoplication. J Clin Endocrinol Metab. 2009 Jan;94(1):39-44. Indeed there are now numerous reports associating increased plasma levels of GLP-1 with hypoglycemia in subjects following gastric bypass.

Similarly, infusing GLP-1 into normal subjects to achieve the same types of levels seen in patients with dumping syndrome produced hypoglycemia in some subjects as described in Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia. Diabetologia. 1998 Oct;41(10):1180-6

In contrast, other studies have used graded stepwise induction of hypoglycemia to show that the GLP-1-dependent suppression of GLP-1 administration at various glucose concentrations was employed to assess whether GLP-1 restrained the glucagon response to hypoglycemia in normal human subjects. Although GLP-1 suppresses glucagon secretion at hyper and euglycemia, GLP-1 does not suppress glucagon secretion, under these experimental conditions, once the blood glucose falls below 3. 7 mM. See Effects of Glucagon-Like Peptide 1 on Counterregulatory Hormone Responses, Cognitive Functions, and Insulin Secretion during Hyperinsulinemic, Stepped Hypoglycemic Clamp Experiments in Healthy Volunteers. J Clin Endocrinol Metab. 2002 Mar;87(3):1239-46 

Similar experiments carried out in insulin-sensitive lean diabetic subjects with normal or near normal body weight demonstrated that an acute bolus of GLP-1 does not cause hypoglycemia in lean diabetic subjects or in patients with diabetes secondary to pancreatectomy. See  No hypoglycemia after subcutaneous administration of glucagon-like peptide-1 in lean type 2 diabetic patients and in patients with diabetes secondary to chronic pancreatitis. Diabetes Care. 2003 Sep;26(9):2581-7

The question of GLP-1-related hypoglycemia becomes more clinically relevant in patients taking anti-diabetic medications which by themselves, are known to cause hypoglycemia. GLP-1 is known to enhance the insulin-stimulatory effects of sulfonylurea agents Glucagon-like peptide I enhances the insulinotropic effect of glibenclamide in NIDDM patients and in the perfused rat pancreas. Diabetes Care. 1996 Aug;19(8):857-63, and thus in predisposed patients with Type 2 diabetes, the combination of a GLP-1R agonist and a SU agent will carry an increased risk of hypoglycemia. Indeed, in Phase 2 and Phase 3 studies of Exenatide, hypoglycemia was seen only in patients treated with a combination of Exenatide and a SU, whereas metformin-treated (plus Exenatide) subjects showed no significant hypoglycemia. Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care. 2003 Aug;26(8):2370-7.

Although GLP-1R agonists administered alone rarely cause significant hypoglycemia, a combination of a GLP-1R agonist and a sulfonylurea can certainly be associated with an increased risk of hypoglycemia, as seen in the AMIGO studies with Exenatide Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004 Nov;27(11):2628-35

Although the actions of GLP-1 to stimulate insulin secretion are normally highly glucose-dependent, administration of GLP-1 in the presence of a sulfonylurea agent leads to enhanced insulin secretion even at normal or low glucose concentrations. Studies in the perfused rat pancreas demonstrate that GLP-1 augments the tolbutamide-mediated stimulation of insulin secretion at 3 mM glucose. GLP-1 also increased somatostatin and decreased glucagon secretion at both 3 and 11 mM glucose in the same experiments and the secretion of SMS and glucagon were inversely correlated. These findings confirm that substantial inhibition of the KATP channel by an agent such as tolbutamide uncouples the glucose-dependent action of GLP-1 on the b-cell. See Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like Peptide 1. Diabetes. 2007 Feb;56(2):438-43

The potential importance of the GLP-1-associated hypoglycemia is theoretically exemplified by a report of a single patient with a neuroendocrine tumor that secreted both GLP-1 and somatostatin. The patient developed reactive hypoglycemia following meal ingestion, that was attributed to high levels of tumor-derived GLP-1. Nevertheless, the concomitant production of somatostatin by the tumor completely inhibited the counterregulatory glucagon in human subjects. Hence GLP-1 associated hypoglycemia when GLP-1 is the only drug on board is theoretically possible, but unlikely if counterregulatory mechanisms are functioning normally. See A tumour that secretes glucagon-like peptide-1 and somatostatin in a patient with reactive hypoglycaemia and diabetes. Lancet. 2003 Jan 18;361(9353):228-30