DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
Sitagliptin, saxagliptin, and linagliptin are inhibitors of DPP-4,the enzyme that degrades incretin hormones. These drugs increase circulating levels of native GLP-1 and glucose-dependent insulino-tropic polypeptide (GIP), which ultimately decreases postprandial glucose excursions by increasing glucose-mediated insulin secretion and decreasing glucagon levels. They are approved as adjunctive therapy to diet and exercise in the treatment of individuals with type 2 diabetes who have failed to achieve glycemic goals.
Sitagliptin has an oral bioavailability of over 85%, achievespeak concentrations within 1–4 hours, and has a half-life of approximately 12 hours. It is primarily (87%) excreted in the urine in part by active tubular secretion of the drug. Hepatic metabolism is limited and mediated largely by the cytochrome CYP3A4 isoform and, to a lesser degree, by CYP2C8. The metab-olites have insignificant activity. The usual dosage is 100 mg orally once daily. Sitagliptin has been studied as monotherapy and in combination with metformin, sulfonylureas, and Tzds. Therapy with sitagliptin has resulted in HbA1c reductions of between 0.5% and 1.0%.
Common adverse effects include nasopharyngitis, upper respi-ratory infections, headaches, and hypoglycemia when the drug is combined with insulin secretagogues or insulin. There are postmar-keting reports of acute pancreatitis (fatal and nonfatal) and severe allergic and hypersensitivity reactions. Sitagliptin should be imme-diately discontinued if pancreatitis or allergic and hypersensitivity reactions occur. Dosage should be reduced in patients with renal impairment and may need to be adjusted to prevent hypoglycemia if there is concurrent insulin secretagogue or insulin therapy.
Saxagliptin is given orally as 2.5–5 mg daily. The drug reachesmaximal concentrations within 2 hours (4 hours for its active metabolite). It is minimally protein bound, and undergoes hepatic metabolism by CYP3A4/5. The major metabolite is active, andexcretion is by both renal and hepatic pathways. The terminal plasma half-life is 2.5 hours for saxagliptin and 3.1 hours for its active metabolite. Dosage adjustment is recommended for individuals with renal impairment and concurrent use of strong CYP3A4/5 inhibitors such as antiviral, antifungal, and certain antibacterial agents.
Saxagliptin is approved as monotherapy and in combination with biguanides, sulfonylureas, and Tzds. It has not been studied in combination with insulin. During clinical trials, mono- and combination therapy with sitagliptin resulted in an HbA1c reduc-tion in the range of 0.4–0.9%.
Adverse effects include an increased rate of infections (upper respiratory tract and urinary tract), headaches, peripheral edema (when combined with a Tzd), hypoglycemia (when combined with a sulfonylurea), and hypersensitivity reactions (urticaria, facial edema). The dose of a concurrently administered insulin secret-agogue or insulin may need to be lowered to prevent hypoglycemia.
Linagliptin is the most recently introduced drug in this classand appears to have properties similar to sitagliptin and saxaglip-tin. It is approved for use as monotherapy and in combination with metformin, glimepiride, and pioglitazone.