Merck's Januvia

The FDA has approved Merck's Januvia(sitagliptin phosphate), the first dipeptidylpeptidase-4 (DPP-4) inhibitor to be marketedin the United States for the treatmentof type 2 diabetes in adults.¹ As aclass, DPP-4 inhibitors have been shownto improve hemoglobin A1C (HbA_1C) withoutcausing weight gain or hypoglycemia.² Januvia will be available in aconvenient once-daily tablet and can beused either alone or in combination therapywith metformin or a thiazolidinedione(TZD) agent. Januvia may be takenwith or without food.¹

Mechanism of Action

Incretin hormones are secretedby the gut in response to foodintake to maintain the body's balanceof insulin release andhepatic glucose production.³ Theglucagon-like peptide 1 (GLP-1)impacts the body by stimulatinginsulin secretion and suppressingthe release of glucagon from thepancreas, which in turn decreaseshepatic glucose production.^4,5The inhibition of DPP-4 byJanuvia results in increased levelsof incretin hormones, such asGLP-1 and glucose-dependentinsulinotropic polypeptide, thusincreasing endogenous insulinrelease and suppressing glucoseproduction by the liver.⁵

Clinical Trials

Januvia was studied as monotherapyin 2 clinical trials in a total of 1262patients with type 2 diabetes. The 18-and 24-week studies were both double-blindand placebo-controlled. Patientswere randomized to receive placebo,Januvia 100 mg daily, or Januvia 200 mgdaily. Both studies determined Januvia100 mg to effectively lower hemoglobinA_1C, fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) whencompared with placebo. The 200-mgdose was not more effective than the100-mg dose.⁵

The efficacy of Januvia in combinationwith metformin was evaluated in a randomized,double-blind, placebo-controlledstudy in type 2 diabetic patients.Patients already using at least 1500 mgof metformin were randomly assignedeither placebo or Januvia 100 mg daily.Atthe conclusion of the 24-week study, theJanuvia group was found to have moresignificant decreases in HbA_1C, FPG, andPPG than the placebo group.⁵

Januvia was evaluated as combinationtherapy with the TZD pioglitazone in a 24-week, randomized, double-blind, placebo-controlled study. Type 2 diabeticpatients already using pioglitazone indoses of 30 to 45 mg daily were randomizedto receive either placebo or Januvia100 mg daily. The Januvia group wasdetermined to have better glycemic controlthan the placebo group, as evaluatedby reduction in HbA_1C and FPG.⁵

Dosing

Januvia is dosed as 100 mg daily eitheras monotherapy or in combination withmetformin or TZD. Patients with moderaterenal disease (creatinine clearance[CrCl] between 30 mL/min and 50mL/min) should receive Januvia 50 mgdaily; patients with severe renal disease(CrCl <30 mL/min) should receive Januvia25 mg daily.⁵

Warnings, Precautions, andAdverse Effects

Januvia should not be used for type 1diabetes or for diabetic ketoacidosis.The use of Januvia has notbeen studied with agents otherthan metformin or TZDs; its usewith other hypoglycemic medicationsis not recommended.Patients using digoxin withJanuvia experienced a slightincrease in the area under thecurve and mean peak drug concentration.Although dosagereductions in either medicationare not recommended, patientsusing both Januvia and digoxinshould be monitored appropriately.Januvia is not approved foruse in pediatric patients.⁵

In clinical trials, the mostcommon adverse effects includedupper respiratory tractinfection, nasopharyngitis, andheadache.⁵

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

References

1. FDA approves once-daily Januvia, the first and only DPP-4 inhibitor available in the UnitedStates for type 2 diabetes. Available at:www.januvia.com/januvia/hcp/documents/press_release10172006.pdf. Accessed November2006.

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

3. Mu J, Woods J, Zhou YP, et al. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptinanalog 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 anddipeptidyl 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 November2006.