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Medical Areas: Endocrinology | Family Medicine
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The following drug information is obtained from various newswires, published
medical journal articles, and medical conference presentations.
Company: Bristol-Myers Squibb
Approval Status: Approved July 2009
Treatment Area: type 2 diabetes mellitus
Onglyza (saxagliptin) is an orally-active inhibitor of the DPP4 enzyme. D-PP4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through increasing insulin production in the pancreas, and by reducing production of sugar by the liver.
Onglyza is specifically indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Onglyza is supplied as a 5 mg and 2.5 mg tablet designed for oral administration. The recommended initial dose of the drug is 2.5 mg or 5 mg once daily taken regardless of
meals. The 2.5 mg daily dosage is recommended for 1) patients with moderate or severe renal impairment or end-stage renal disease and 2) for patients also taking strong cytochrome
P450 3A4/5 (CYP3A4/5) inhibitors.
The FDA approval of Onglyza was based on monotherapy trials and in trials combining Onglyza with metformin, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone) therapy.
A total of 766 subjects with type II diabetes inadequately controlled on diet and exercise participated in two 24-week, double-blind, placebo-controlled trials.
Following a 2-week single-blind diet, exercise, and placebo lead-in period, 401 subjects were randomized to 2.5 mg, 5 mg, or 10 mg of Onglyza or placebo. Subjects who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy, added on to placebo or Onglyza. Treatment with Onglyza 2.5 mg and 5 mg daily provided significant improvements in A1C, FPG, and PPG compared to placebo. The percentage of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 16% in the Onglyza 2.5 mg treatment group, 20% in the Onglyza 5 mg treatment group, and 26% in the placebo group.
This 24-week monotherapy trial enrolled 365 treatment-naive subjects with inadequately controlled diabetes. Following a 2-week, single-blind diet, exercise, and placebo lead-in period, the subjects were randomized to 2.5 mg every morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every morning, or 5 mg every evening of Onglyza or placebo. Treatment with either Onglyza 5 mg every morning or 5 mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of -0.4% and -0.3%, respectively). Treatment with Onglyza 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of 0.4%).
In trials evaluating Onglyza in combination with metformin, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone), Onglyza 2.5 mg and 5 mg plus combination provided significant improvements in A1C, FPG, and PPG compared with placebo plus combination.
Adverse events associated with the use of Onglyza may include, but are not limited to, the following:
- Upper respiratory tract infection
- Urinary tract infection
Mechanism of Action
Onglyza (saxagliptin) is an orally-active inhibitor of the DPP4 enzyme. D-PP4 inhibitors work by affecting the action of natural hormones in the body called incretins .Increased concentrations of the incretin hormones such as glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. This saxagliptin is a competitive DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner
Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R; for the CV181-011 Study Investigators Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Current Medical Research and Opinion 2009 Aug 4
Jadzinsky M, Pfützner A, Paz-Pacheco E, Xu Z, Allen E, Chen R; CV181-039 Investigators Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes, Obesity and Metabolism 2009 Jun;11(6):611-22
Defronzo RA, Hissa MN, Garber AJ, Gross JL, Duan RY, Ravichandran S, Chen RS; for the Saxagliptin 014 Study Group The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes on Metformin Alone. Diabetes Care 2009 Jun 23
Rosenstock J, Sankoh S, List JF Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes, Obesity and Metabolism 2008 May;10(5):376-86
Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Journal of Medicinal Chemistry 2005 Jul 28;48(15):5025-37
For additional information regarding Onglyza or type II diabetes, please visit the Onglyza web page.