Glucagon-like peptide 1 (GLP-1)-based therapies (eg, GLP-1 receptor agonists, dual-acting GLP-1 and glucose-dependent insulinotropic polypeptide [GIP] receptor agonists) affect glycemia through several mechanisms, including increased glucose-dependent insulin secretion, slowed gastric emptying, and reduced food intake and postprandial glucagon secretion. This topic will review the mechanism of action and therapeutic utility of GLP-1-based therapies for the treatment of type 2 diabetes mellitus. The use of GLP-1-based therapies for weight loss in adults without diabetes is covered separately.
Dipeptidyl peptidase 4 (DPP-4) inhibitors increase endogenous GLP-1 by inhibiting DPP-4. These agents, as well as the initial management and management of persistent hyperglycemia in adults with type 2 diabetes, are also presented separately.
Glucose homeostasis depends on a complex interplay of several hormones: insulin and amylin, produced by pancreatic beta cells; glucagon, produced by pancreatic alpha cells; and gastrointestinal peptides, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP; formerly called gastric inhibitory polypeptide). GLP-1 and GIP are incretin hormones that link the absorption of nutrients from the gastrointestinal tract with pancreatic hormone secretion. They are released in the setting of a meal, after the ingestion and absorption of glucose, protein, and fat, and provide one of the physiologic connections between eating and insulin release. Abnormal regulation of these peptides may contribute to the development of type 2 diabetes.
GLP-1 is produced from the proglucagon gene in L cells of the small intestine. After processing from proglucagon, the active 30-amino acid polypeptide GLP-1 (7-37) binds to a specific GLP-1 receptor, which is expressed in various tissues, including pancreatic beta cells, pancreatic ducts, gastric mucosa, kidney, lung, heart, skin, immune cells, and the hypothalamus. GLP-1 stimulates glucose-dependent insulin release from the pancreatic islets. It also slows gastric emptying, inhibits inappropriate post-meal glucagon release, and reduces food intake. In patients with type 2 diabetes, the insulin response to GLP-1 is impaired, possibly due to reduced postprandial GLP-1 secretion or to other mechanisms. Although GLP-1 has been shown to promote beta cell proliferation and mass in animal models of prediabetes and diabetes, these findings have not been replicated in humans.
GLP-1 has a half-life of only one to two minutes due to N-terminal degradation by the enzyme dipeptidyl peptidase 4 (DPP-4). Synthetic GLP-1 receptor agonists are variably resistant to degradation by the enzyme DPP-4, and therefore have a longer half-life, facilitating clinical use. Longer-acting GLP-1 receptor agonists can be administered once daily or once weekly. Like native GLP-1, all synthetic GLP-1 receptor agonists bind to the GLP-1 receptor and stimulate glucose-dependent insulin release from the pancreatic islets as their primary glucose-lowering effect. See Administration below and Glycemic efficacy below.
GIP is produced in the K cells of the small intestine. It binds to a specific GIP receptor, which is expressed in various tissues, including pancreatic beta cells, pancreatic alpha cells, subcutaneous and visceral adipose tissue, bone, and heart. In the postprandial state, GIP is cosecreted with GLP-1, and they may synergistically promote glucose-induced insulin secretion. However, GIP exhibits different effects from GLP-1 on glucagon secretion. In the euglycemic or hypoglycemic states, GIP enhances glucagon activity.
A synthetic dual-acting GIP and GLP-1 receptor agonist (tirzepatide) is available for the treatment of hyperglycemia in patients with type 2 diabetes. The extent to which GIP receptor activation contributes to the therapeutic effects of tirzepatide is uncertain and the subject of ongoing investigation. Tirzepatide has a half-life of five days, allowing for once-weekly administration. See Glycemic efficacy below and Weight loss below.
Glucagon-like peptide 1 (GLP-1)-based therapies are particularly appropriate for use alone or in combination with other glucose-lowering agents in certain clinical settings that include the following:
Prior to initiation of GLP-1-based therapy, we perform the following assessments:
We assess all patients for a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia types 2A or 2B. We also ask about a prior diagnosis of acute pancreatitis or gastroparesis and any symptoms that suggest one of these conditions. The diagnostic evaluation for suspected gastroparesis is reviewed separately. See Gastroparesis: Etiology, clinical manifestations, and diagnosis, section on Evaluation.
We perform a physical examination, including assessment of thyroid size and the presence of palpable nodules. We also evaluate for other stigmata of multiple endocrine neoplasia (eg, mucosal neuroma). See Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2, section on Clinical features.
We obtain a baseline retinal examination if not performed within the prior 12 months, particularly before initiating subcutaneous semaglutide or tirzepatide or in the presence of symptoms suggesting new or worsening retinopathy.
Progression of retinopathy has been observed with subcutaneous semaglutide. This is likely a consequence of rapid glycemic lowering rather than a direct effect of the drug. In patients with a history of diabetic retinopathy, consider slower titration of subcutaneous semaglutide or tirzepatide to avoid rapid declines in A1C. Retinal screening within six months of drug initiation should be performed to detect progression of retinopathy. The caution regarding rapid lowering of glycemia and risk of retinopathy applies to all glucose-lowering medications. See Monitoring below and Microvascular outcomes below.
We measure serum creatinine to calculate estimated glomerular filtration rate (eGFR) if a recent value is not available or any suspicion exists for worsening or advanced kidney disease.
GLP-1-based therapies should not be used in patients with:
Some of the salutary effects of these agents are independent of beta cell function (eg, decreased glucagon, weight loss, cardiovascular and kidney protection) and might benefit selected individuals with type 1 diabetes. Until further data are available, however, we do not use GLP-1-based therapies in patients with type 1 diabetes specifically for glycemic management. See Management of blood glucose in adults with type 1 diabetes mellitus, section on Adjunctive therapy not recommended.
Most experts would not prescribe any GLP-1-based therapy for patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B. See Uncertain risks.
