Do current incretin mimetics exploit the full therapeutic potential inherent in GLP-1 receptor stimulation?

Abstract

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are incretin-derived glucose-lowering agents that have been used for the treatment of type 2 diabetes since 2007. Agents such as exenatide (short-acting and once weekly preparations), liraglutide, taspoglutide, albiglutide and lixisenatide lower fasting glucose and HbA 1c upon subcutaneous injection, leading to glycaemic control that is equivalent to, or better than, that observed with other oral glucose-lowering agents or bedtime insulin. However, varying proportions of patients report nausea and vomiting, adverse events that typically narrow the therapeutic dose range. Furthermore, GLP-1 RAs reduce fasting glucose to a clinically meaningful extent, but not into the normal range. GLP-1: a parent compound for novel incretin-based glucose-lowering drugsGlucagon-like peptide-1 (GLP-1) has attracted attention because of its ability to stimulate insulin secretion in a glucose-dependent manner, to suppress glucagon release when glucose concentrations are not in the hypoglycaemic range, and to elicit a number of extra-pancreatic effects (on appetite/satiety, gastrointestinal motility and the cardiovascular system) [1]. This spectrum of biological activities addresses important deficits typical for patients with type 2 diabetes (impaired beta cell function, hyperglucagonaemia, overeating/obesity, excessive postprandial rises in glucoseElectronic supplementary material The online version of this article (doi:10.1007/s00125-013-2953-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

The Glucagon-Like Peptide 1 Receptor Agonist Exenatide Inhibits Small Intestinal Motility, Flow, Transit, and Absorption of Glucose in Healthy Subjects and Patients With Type 2 Diabetes: A Randomized Controlled Trial

“…Nausea is an established adverse effect of exenatide and is thought to be less with intravenous than subcutaneous administration (23). In our study, nausea tended not to occur with intravenous exenatide until the stimulus of intraduodenal glucose was added, perhaps due to synergy between central and gastrointestinal stimuli.…”

Response to Comment. Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes?

“…In either case, we agree with Deane and Horowitz that a gentler reduction in glycemia with avoidance of hypoglycemia "may lead to improved outcomes." We also agree that "there is no impediment to intravenous administration of GLP-1," as reviewed by Nauck et al (6). Further, as we pointed out (2), if GLP-1 therapy does not achieve the desired level of glycemic control, basal insulin therapy (both exenatide and liraglutide are approved with basal insulin) can be added without revising currently approved protocols for in-hospital insulin therapy.…”

Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes

“…There is also potential for a discordance between the effects of i.v. and s.c. administration of GLP-1 on BP, as appears to be the case for glucose lowering in patients with type 2 diabetes and, possibly, the induction of upper gastrointestinal symptoms [42].…”