General Information

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.

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.

Side Effects

Adverse events associated with the use of Onglyza may include, but are not limited to, the following:

• Upper respiratory tract infection
• Urinary tract infection
• Headache
• Nasopharyngitis

Dosing/Administration

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.

Clinical Trial Results

FDA Approval
The FDA approval of Onglyza was based on monotherapy trials and in trials combining Onglyza with metformin, glyburide and thiazolidinedione (pioglitazone and rosiglitazone) therapy.

Monotherapy
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.
 

Study One
Following a two-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 percent in the Onglyza 2.5 mg treatment group, 20 percent in the Onglyza 5 mg treatment group and 26 percent in the placebo group.
 

Study Two
This 24-week monotherapy trial enrolled 365 treatment-naive subjects with inadequately controlled diabetes. Following a two-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 percent and -0.3 percent, respectively). Treatment with Onglyza 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of 0.4 percent).

Combination Therapy
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.