Page 776 - Basic _ Clinical Pharmacology ( PDFDrive )

762 SECTION VII Endocrine Drugs

GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) Liraglutide at a dose of 3 mg daily has been approved for weight
and by other enzymes such as endopeptidase 24.11 and is also loss.
cleared by the kidney. The native peptide therefore cannot be used Albiglutide is a human GLP-1 dimer fused to human albu-
therapeutically. One approach to this problem has been to develop min. The half-life of albiglutide is about 5 days and a steady state
metabolically stable analogs or derivatives of GLP-1 that are not is reached after 4–5 weeks of once weekly administration. The
subject to the same enzymatic degradation or renal clearance. Four usual dose is 30 mg weekly by subcutaneous injection. The drug
such GLP-1 receptor agonists, exenatide, liraglutide, albiglutide, is supplied in a self-injection pen containing a powder that is
and dulaglutide are available for clinical use. The other approach reconstituted just prior to administration. Weight loss is much less
has been to develop inhibitors of DPP-4 and prolong the action of common than with exenatide and liraglutide. The most frequent
endogenously released GLP-1 and GIP. Four oral DPP-4 inhibi- adverse effects were nausea and injection-site erythema.
tors, sitagliptin, saxagliptin, linagliptin, and alogliptin, are avail- Dulaglutide consists of two GLP-1 analog molecules cova-
able in the United States. An additional inhibitor, vildagliptin, is lently linked to an Fc fragment of human IgG4. The GLP-1 mol-
available in Europe. ecule has amino acid substitutions that resist DPP-4 action. The
half-life of dulaglutide is about 5 days. The usual dose is 0.75 mg
weekly by subcutaneous injection. The maximum recommended
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) dose is 1.5 mg weekly. The most frequent adverse reactions were
RECEPTOR AGONISTS nausea, diarrhea, and vomiting.
All of the GLP-1 receptor agonists may increase the risk of
Exenatide, a derivative of the exendin-4 peptide in Gila monster pancreatitis. Patients on these drugs should be counseled to seek
venom, has a 53% homology with native GLP-1 and a glycine immediate medical care if they experience unexplained persistent
substitution to reduce degradation by DPP-4. Exenatide is severe abdominal pain. Cases of renal impairment and acute renal
approved as an injectable, adjunctive therapy in persons with type injury have been reported in patients taking exenatide. Some of
2 diabetes treated with metformin or metformin plus sulfonyl- these patients had preexisting kidney disease or other risk factors
ureas who still have suboptimal glycemic control. for renal injury. A number of them reported having nausea, vom-
Exenatide is dispensed as fixed-dose pens (5 mcg and 10 mcg). iting, and diarrhea and it is possible that volume depletion con-
It is injected subcutaneously within 60 minutes before breakfast tributed to the development of renal injury. Both exenatide and
and dinner. It reaches a peak concentration in approximately liraglutide stimulate thyroidal C-cell (parafollicular) tumors in
2 hours with a duration of action of up to 10 hours. Therapy rodents. Human thyroidal C cells express very few GLP-1 recep-
is initiated at 5 mcg twice daily for the first month and if toler- tors, and the relevance to human therapy is unclear. The drugs,
ated can be increased to 10 mcg twice daily. Exenatide LAR is a however, should not be used in persons with a past medical or
once-weekly preparation that is dispensed as a powder (2 mg). It family history of medullary thyroid cancer or multiple endocrine
is suspended in the provided diluent just prior to injection. When neoplasia (MEN) syndrome type 2.
exenatide is added to preexisting sulfonylurea therapy, the oral
hypoglycemic dosage may need to be decreased to prevent hypo-
glycemia. The major adverse effect is nausea (about 44% of users), DIPEPTIDYL PEPTIDASE 4 (DPP-4)
which is dose dependent and declines with time. Exenatide mono- INHIBITORS
therapy and combination therapy results in HbA1c reductions of
0.2–1.2%. Weight loss in the range of 2–3 kg occurs and contrib- Sitagliptin is given orally as 100 mg once daily, has an oral
utes to the improvement of glucose control. In comparative trials bioavailability of over 85%, achieves peak concentrations within
the long-acting (LAR) preparation lowers the HbA level a little 1–4 hours, and has a half-life of approximately 12 hours. It is
1c
more than the twice-daily preparation. Exenatide undergoes glo- primarily excreted in the urine, in part by active tubular secretion
merular filtration, and the drug is not approved for use in patients of the drug. Hepatic metabolism is limited and mediated largely
with estimated GFR of less than 30 mL/min. by the cytochrome CYP3A4 isoform and, to a lesser degree, by
High-titer antibodies against exenatide develop in about 6% of CYP2C8. The metabolites have insignificant activity. Dosage
patients, and in half of these patients an attenuation of glycemic should be reduced in patients with impaired renal function (50 mg
response has been seen. if estimated GFR is 30–50 mL/min and 25 mg if <30 mL/min.
Liraglutide is a soluble fatty acid-acylated GLP-1 analog. The Sitagliptin has been studied as monotherapy and in combination
half-life is approximately 12 hours, permitting once-daily dosing. with metformin, sulfonylureas, and thiazolidinediones. Therapy
It is approved in patients with type 2 diabetes who achieve inad- with sitagliptin has resulted in HbA reductions of 0.5–1.0%.
1c
equate control with diet and exercise and are receiving concurrent Common adverse effects include nasopharyngitis, upper respi-
treatment with metformin, sulfonylureas, or thiazolidinediones. ratory infections, and headaches. Hypoglycemia can occur when
Treatment is initiated at 0.6 mg and increased after 1 week to the drug is combined with insulin secretagogues or insulin. There
1.2 mg daily. If needed the dosage can be increased to 1.8 mg have been postmarketing reports of acute pancreatitis (fatal
daily. In clinical trials liraglutide results in a reduction of HbA and nonfatal) and severe allergic and hypersensitivity reactions.
1c
of 0.8–1.5%; weight loss ranges from none to 3.2 kg. The most Sitagliptin should be immediately discontinued if pancreatitis or
frequent adverse effects are nausea (28%) and vomiting (10%). allergic and hypersensitivity reactions occur.