User's guide to mechanism of action and clinical use of GLP-1 receptor agonists

Postgrad Med. 2015;127(8):818-26. doi: 10.1080/00325481.2015.1090295. Epub 2015 Sep 15.


Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved for the treatment of adult patients with type 2 diabetes mellitus (T2DM). This article provides practical information to guide primary care physicians on the use of GLP-1RAs in patients with T2DM. Two short-acting (once- or twice-daily administration; exenatide and liraglutide) and three long-acting (weekly administration; albiglutide, dulaglutide and exenatide) GLP-1RAs are currently approved in the US. These drugs provide levels of GLP-1 receptor agonism many times that of endogenous GLP-1. The GLP-1RAs have been shown to significantly improve glycemic parameters and reduce body weight. These agents work by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release-responses that are both glucose-dependent-with a consequent low risk for hypoglycemia. Effects on GLP-1 receptors in the CNS and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying. The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs. GLP-1RAs are recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones or basal insulin, providing a means of enhancing glucose control while offsetting the weight gain associated with insulin and some oral agents. GLP-1RAs represent a useful tool that the primary care physician can use to help patients with T2DM achieve their therapeutic goals.

Keywords: Glucagons; glucagon-like peptide-1; insulin; receptor agonist; type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Blood Glucose
  • Delayed-Action Preparations
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Therapy, Combination
  • Energy Intake / drug effects
  • Gastric Emptying / drug effects
  • Glucagon-Like Peptide 1 / metabolism
  • Glucagon-Like Peptide-1 Receptor / agonists*
  • Glycated Hemoglobin
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / adverse effects
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use*
  • Incretins / pharmacology
  • Incretins / therapeutic use
  • Medication Adherence
  • Metformin / administration & dosage
  • Pancreas / metabolism
  • Primary Health Care*
  • Weight Loss / drug effects


  • Blood Glucose
  • Delayed-Action Preparations
  • Glucagon-Like Peptide-1 Receptor
  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Incretins
  • Glucagon-Like Peptide 1
  • Metformin