GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS
In type 2 diabetes, the release of glucagon-like polypeptide is diminished postprandially, which leads to inadequate glucagon suppression and excessive hepatic glucose output. Two synthetic analogs of glucagon-like polypeptide, exenatide and liraglutide, are commercially available to help restore GLP-1 activity. These therapies have multiple actions such as potentiation of glucose-mediated insulin secretion, suppression of postprandial glucagon release through as-yet unknown mechanisms, slowed gastric emp-tying, and a central loss of appetite. The increased insulin secre-tion is speculated to be due in part to an increase in beta-cell mass. The increased beta-cell mass may result from decreased beta-cell apoptosis, increased beta-cell formation, or both.
Exenatide, a derivative of the exendin-4 peptide in Gila monstervenom, was the first incretin therapy to become available for the treatment of diabetes. It has a 53% homology with native GLP-1, and a glycine substitution to reduce degradation by dipeptidyl peptidase-4 (DPP-4). Exenatide is approved as an injectable, adjunc-tive therapy in persons with type 2 diabetes treated with metformin or metformin plus sulfonylureas who still have suboptimal glycemic control. Exenatide is absorbed equally from arm, abdomen, or thigh injection sites, reaching a peak concentration in approximately 2 hours with a duration of action of up to 10 hours. It undergoes glomerular filtration, and dosage adjustment is required only when the creatinine clearance is less than 30 mL/min.
Exenatide is injected subcutaneously within 60 minutes before a meal; therapy is initiated at 5 mcg twice daily, with a maximum dosage of 10 mcg twice daily. When exenatide is added to preexist-ing sulfonylurea therapy, the oral hypoglycemic dosage may need to be decreased to prevent hypoglycemia. The major adverse effects are nausea (about 44% of users) and vomiting and diarrhea. The nausea decreases with ongoing exenatide usage. Exenatide mono- and com-bination therapy results in HbA1c reductions from 0.2% to 1.2%. Weight loss in the range of 2–3 kg is reported in some users, pre-sumably because of the nausea and anorectic effects. A serious and, in some cases, fatal adverse effect of exenatide is necrotizing and hemorrhagic pancreatitis. Antibodies to exenatide are formed with chronic use, the clinical significance of which is unclear.
Liraglutide is a long-acting synthetic GLP-1 analog with 97%homology to native GLP-1 but has a prolonged half-life that permits once-daily dosing. Liraglutide interacts with the GLP-1 receptor and acts to increase insulin and decrease glucagon release.
Liraglutide is approved for the treatment of type 2 diabetes as an injectable therapy in patients who achieve inadequate control with diet and exercise, and are receiving concurrent treatment with metformin, sulfonylureas, or Tzds. It is not recommended as a first-line therapy or for use with insulin. Treatment is initiated at 0.6 mg and is titrated in weekly increments of 0.6 mg as needed, and as tolerated, to achieve glycemic goals. Peak levels are obtained in 8–12 hours, and the elimination half-life is about 13 hours. Liraglutide therapy results in a reduction of HbA1c from 0.8% to 1.5%; weight loss ranges from nominal to 3.2 kg.. Experience with lira-glutide in patients with renal or hepatic impairment is limited and it should be used with caution in these populations.
Common side effects of liraglutide are headache, nausea, and diarrhea; antibody formation, urticaria, and other immune reactions also are observed Hypoglycemia can occur with concomitant sulfo-nylurea use and may require a dose reduction of the oral hypoglyce-mic agent. Pancreatitis is another serious adverse effect; liraglutide is contraindicated in individuals with a history of pancreatitis and should be permanently discontinued if pancreatitis develops. Because rodents exposed to liraglutide developed thyroid C-cell tumors, there is an FDA mandated “black box” warning that liraglutide is contrain-dicated in individuals with a personal or family history of medullary cancer or multiple endocrine neoplasia type 2.
Although they require injection, the GLP-1 receptor ligands have gained popularity because of the improved glucose control and associated anorexia and weight loss in some users. Safety issues, however, may deter future use.