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.
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