Pharmacology Update
Saxagliptin Tablets (Onglyza™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship to this field of study.
The second competitive, reversible dipeptidyl peptidase-4 (DPP-4) inhibitor has been approved by the FDA for the treatment type 2 diabetes mellitus.1 Sitagliptin (Januvia®) was the first drug approved in this class.2 Inhibition of DPP-4 increases circulating levels of incretin hormones (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1) in response to meals. The resultant effect is increased insulin secretion and reduced glucagon secretion. Saxagliptin is marketed by Bristol-Myers Squibb as Onglyza™.
Indications
Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is approved as monotherapy or in combination with 3 types of commonly used oral anti-diabetic medications metformin, thiazolidinediones, and sulfonylureas when the single agent alone does not provide adequate glycemic control.1
Dosage
The recommended dose is 2.5 mg or 5 mg once daily. It may be taken without regard to meals.1 The lower dose (2.5 mg) is recommended for patients with moderate or severe renal dysfunction or coadministration with a CYP 3A4/5.
Saxagliptin is available as 2.5 mg and 5 mg tablets.
Potential Advantages
Saxagliptin is a potent and selective DPP-4 inhibitor.3,4
Potential Disadvantages
Saxagliptin is metabolized by CYP 3A4/5 to an active metabolite with 50% the potency of the parent compound. Strong inhibitors of CYP 3A4/5 increase systemic exposure of the parent compound.1 Sitagliptin does not appear to have any clinically important drug-drug interactions.4
Comments
The efficacy of saxagliptin was shown as monotherapy or in combination with metformin in treatment-naïve subjects or as add-on therapy to metformin, a sulfonylurea, or a thiazolidinedione.1,5-8 Approval was based on 3 randomized, double-blind, placebo-controlled, 24-week studies in type 2 diabetic subjects with a baseline HbA1c between 7% and 10%. The primary endpoint was change in HbA1c from baseline to week 24. Secondary endpoints included changes in fasting blood glucose and changes in postprandial glucose. As monotherapy in treatment-naïve subjects (n = 300), saxagliptin (2.5 mg or 5 mg) showed an adjusted mean change in HbA1c compared to placebo of -0.6% from a baseline of 7.9%-8.0%.1,6 The adjusted mean changes in fasting blood glucose were -21 mg/dL (95% confidence interval [CI], -31 to -10 mg/dL) and -15 mg/dL (95% CI, -25 to -4 mg/dL) for 2.5 mg and 5 mg. The adjusted mean changes in 2-hour postprandial glucose were -39 mg/dL and -37 mg/dL. Coadministration with metformin compared to metformin alone (n = 648) resulted in similar change in HbA1c (-0.6% and -0.7%).8 The addition of saxagliptin (2.5 mg or 5 mg) to metformin (n = 562), a thiazolidinedione (n = 565), and glyburide (n = 768) resulted in changes in HbA1c of -0.7% and -0.8%, -0.4% and -0.6%, and -0.6% and -0.7%, respectively.1,5,7 These changes are similar to results reported for sitagliptin.9 Saxagliptin appears to be well tolerated, is weight neutral. and does not cause hypoglycemia. In the placebo-controlled trials, adverse events that occurred more frequently than placebo were sinusitis (2.9% and 2.6% vs 1.6%), abdominal pain (2.4% and 1.7% vs 0.5%), gastroenteritis (1.9% and 2.3% vs 0.9%), and vomiting (2.2% and 2.3% vs 1.3%).1 The addition of saxagliptin 5 mg to a thiazolidinedione resulted in incidence of peripheral edema of 8.1% compared to 4.3% for placebo. There are no published direct comparisons between the two DPP-4 inhibitors.
Clinical Implications
Saxagliptin offers a second orally active DPP-4 inhibitor. There does not appear to be any clear clinical advantage of this agent over sitagliptin.
References
1. Onglyza Product Information. Princeton, NJ: Bristol-Myers Squibb; July 2009.
2. Januvia Product Information. Whitehouse Station, NJ: Merck and Co.; 2007.
3. Augeri DJ. 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. J Med Chem 2005;48:5025-5037.
4. Gallwitz B. Saxagliptin, a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. IDrugs 2009;12:200.
5. DeFronzo RA, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009;32: 1649-1655.
6. Rosenstock J, et al. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin 2009 Aug 4; Epub ahead of print.
7. Chacra AR, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: A randomised controlled trial. Int J Clin Pract 2009;63:1395-1406.
8. Jadzinsky M, et al. 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 Obes Metab 2009;11:611-622.
9. Ahren B. Emerging dipeptidyl peptidase-4 inhibitors for the treatment of diabetes. Expert Opin Emerg Drugs 2008;13:593-607.
The second competitive, reversible dipeptidyl peptidase-4 (DPP-4) inhibitor has been approved by the FDA for the treatment type 2 diabetes mellitus.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content. TESTING
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