The FDA has approved Merck's Januvia (sitagliptin phosphate), the first dipeptidyl peptidase-4 (DPP-4) inhibitor to be marketed in the United States for the treatment of type 2 diabetes in adults.¹ As a class, DPP-4 inhibitors have been shown to improve hemoglobin A1C (HbA_1C) without causing weight gain or hypoglycemia.² Januvia will be available in a convenient once-daily tablet and can be used either alone or in combination therapy with metformin or a thiazolidinedione (TZD) agent. Januvia may be taken with or without food.¹

Mechanism of Action

Incretin hormones are secreted by the gut in response to food intake to maintain the body's balance of insulin release and hepatic glucose production.³ The glucagon-like peptide 1 (GLP-1) impacts the body by stimulating insulin secretion and suppressing the release of glucagon from the pancreas, which in turn decreases hepatic glucose production.^4,5 The inhibition of DPP-4 by Januvia results in increased levels of incretin hormones, such as GLP-1 and glucose-dependent insulinotropic polypeptide, thus increasing endogenous insulin release and suppressing glucose production by the liver.⁵

Clinical Trials

Januvia was studied as monotherapy in 2 clinical trials in a total of 1262 patients with type 2 diabetes. The 18-and 24-week studies were both double-blind and placebo-controlled. Patients were randomized to receive placebo, Januvia 100 mg daily, or Januvia 200 mg daily. Both studies determined Januvia 100 mg to effectively lower hemoglobin A_1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) when compared with placebo. The 200-mg dose was not more effective than the 100-mg dose.⁵

The efficacy of Januvia in combination with metformin was evaluated in a randomized, double-blind, placebo-controlled study in type 2 diabetic patients. Patients already using at least 1500 mg of metformin were randomly assigned either placebo or Januvia 100 mg daily.At the conclusion of the 24-week study, the Januvia group was found to have more significant decreases in HbA_1C, FPG, and PPG than the placebo group.⁵

Januvia was evaluated as combination therapy with the TZD pioglitazone in a 24-week, randomized, double-blind, placebo-controlled study. Type 2 diabetic patients already using pioglitazone in doses of 30 to 45 mg daily were randomized to receive either placebo or Januvia 100 mg daily. The Januvia group was determined to have better glycemic control than the placebo group, as evaluated by reduction in HbA_1C and FPG.⁵

Dosing

Januvia is dosed as 100 mg daily either as monotherapy or in combination with metformin or TZD. Patients with moderate renal disease (creatinine clearance [CrCl] between 30 mL/min and 50 mL/min) should receive Januvia 50 mg daily; patients with severe renal disease (CrCl <30 mL/min) should receive Januvia 25 mg daily.⁵

Warnings, Precautions, and Adverse Effects

Januvia should not be used for type 1 diabetes or for diabetic ketoacidosis. The use of Januvia has not been studied with agents other than metformin or TZDs; its use with other hypoglycemic medications is not recommended. Patients using digoxin with Januvia experienced a slight increase in the area under the curve and mean peak drug concentration. Although dosage reductions in either medication are not recommended, patients using both Januvia and digoxin should be monitored appropriately. Januvia is not approved for use in pediatric patients.⁵

In clinical trials, the most common adverse effects included upper respiratory tract infection, nasopharyngitis, and headache.⁵

Dr. Holmberg is a pharmacist with Phoenix Children's Hospital, Phoenix, Ariz.

References

1. FDA approves once-daily Januvia, the first and only DPP-4 inhibitor available in the United States for type 2 diabetes. Available at: www.januvia.com/januvia/hcp/documents/press_release10172006.pdf. Accessed November 2006.

2. Barnett A. DPP-4 inhibitors and their potential role in the management of type 2 diabetes. Intl J Clin Pract. 2006;11:1454-1470.

3. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic {beta}-cell mass and function in a rodent model of type 2 diabetes. Diabetes. 2006;55(6):1695-1704.

4. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368(9548):1696-1705.

5. Januvia complete prescribing information. Available at: www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf. Accessed November 2006.