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Therapeutic advantages of saxagliptin, the newest DPP-IV inhibitor on the market
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Saxagliptin was approved by the FDA in July and represents the second DPP-IV inhibitor to reach the U.S. market for the treatment of type 2 diabetes. DPP-IV is the enzyme responsible for the rapid degradation of glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide. Patients with type 2 diabetes demonstrate reduced GLP-1 concentrations after meals as compared with healthy individuals. GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells and slows gastric emptying time.
Clinical trial data
Rosenstock and colleagues studied saxagliptin (Onglyza, Bristol-Myers Squibb) in a dose-ranging study. They enrolled 423 drug-naïve patients with type 2 diabetes. This was a 12-week, multicenter, randomized, parallel-group, double-blind, placebo-controlled trial. Patients received 2.5 mg, 5 mg, 10 mg, 20 mg or 40 mg of saxagliptin once daily or placebo for 12 weeks. In another cohort, patients were assigned to 100-mg daily of saxagliptin or placebo for six weeks. Saxagliptin reduced HbA1c by 0.7% to 0.9% from an average baseline of 7.9%. Placebo reduced HbA1c by 0.3% in the low-dose cohort. One-hour postprandial glucose was reduced 24 mg/dL to 41 mg/dL as compared with placebo. Saxagliptin did not result in any significant changes in weight, and adverse events were similar across groups.
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In another randomized, placebo-controlled study, researchers assigned 743 patients with uncontrolled diabetes to saxagliptin 2.5 mg, 5 mg, 10 mg or placebo — all once daily. The patients had already been assigned metformin. Baseline HbA1c ranged from 7% to 10% (mean, 8%) and metformin doses ranged from 1,500 mg/day to 2,550 mg/day. Baseline mean fasting plasma glucose was 176 mg/dL. After 24 weeks, patients assigned once-daily saxagliptin 2.5 mg (0.73%), 5 mg (0.83%) and 10 mg (0.71%) showed reductions in HbA1c compared with placebo (P<.0001). FPG was also reduced (P<.0001) for patients assigned saxagliptin 2.5 mg (16 mg/dL), 5 mg (24 mg/dL) or 10 mg (21 mg/dL) daily. Saxagliptin also decreased postprandial glucagon and increased postprandial insulin and C-peptide after oral glucose tolerance tests when compared with placebo. No increase in hypoglycemia was observed with saxagliptin as compared with placebo. Weight changes were similar for all patients: 2.5 mg (–1.5 kg), 5 mg (–0.9 kg), 10 mg (–0.5 kg) and placebo (–1.0 kg).
The manufacturer also reported that saxagliptin has been studied in combination with pioglitazone (Actos, Takeda) and rosiglitazone (Avandia, GlaxoSmithKline). Patients with type 2 diabetes (n=565) participated in a 24-week, randomized, double-blind, placebo-controlled trial. The researchers conducted the trial to evaluate the efficacy and safety of saxagliptin in combination with a thiazolidinedione in patients with inadequate glycemic control (HbA1c ≥7% to ≤10.5%) assigned to a TZD alone. Saxagliptin 2.5 mg and 5 mg add-on to TZD provided significant improvements in HbA1c (0.7%-0.9%) as compared with placebo add-on (0.3%). Postprandial glucose also significantly decreased with the addition of saxagliptin (55 mg/dL to 65 mg/dL) as compared with placebo (15 mg/dL).
Dosing
Saxagliptin is indicated as monotherapy or in combination with other drugs used to treat type 2 diabetes. The recommended dose is 2.5 mg to 5 mg by mouth once daily. Patients with a creatinine clearance <50 mL/minute or those also assigned a medication that is a strong inhibitor of CYP3A4/5 (eg, ketoconazole) should be assigned 2.5 mg daily. It has not been studied in combination with insulin.
Adverse events
Saxagliptin is generally well tolerated. The three most commonly reported adverse reactions in clinical trials were upper respiratory tract infection, urinary tract infection and headache. The overall incidence of hypoglycemia in patients treated with saxagliptin was similar to the incidence in patients treated with placebo.
Saxagliptin may cause lymphopenia. Compared with data from placebo recipients, the mean decrease in absolute lymphocyte count was 100 cells/mcL among saxagliptin 5-mg daily recipients. In one trial, a lymphocyte count of 750 cells/mcL or less occurred in 0.5% of saxagliptin 2.5-mg recipients, in 1.5% of saxagliptin 5-mg recipients and in 0.4% of placebo recipients.
No increased risk for cardiovascular disease was seen in trials involving relatively low–risk patients. Trials involving those at higher CV risk are ongoing.
Place in therapy
Saxagliptin appears to significantly reduce HbA1c and postprandial glucose when used as monotherapy and in combination with other agents. At this point, it is generally well tolerated, and there is no evidence that it affects CVD risk. Since it is a CYP3A4/5 substrate, it is potentially affected by other drugs that are strong 3A4/5 inhibitors. It is not clear at this time if saxagliptin presents any advantages or disadvantages as compared with sitagliptin, the first DPP-IV inhibitor to hit the market.
James R. Taylor, PharmD, CDE, is a Clinical Associate Professor in the Department of Pharmacy Practice at the University of Florida.
For more information:
- Defronzo RA. Saxagliptin added to metformin improves glycemia control in patients with type 2 diabetes. Presented at: American Diabetes Association 67th Annual Scientific Sessions; June 22-26, 2007; Chicago.
- Rosenstock J. Diabetes Obes Metab. 2008;10:376-386.