Januvia is an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The DPP-4 enzyme inactivates incretin hormones, which are involved in the physiologic regulation of glucose homeostasis. By inhibiting DPP-4, Januvia increases and prolongs active incretin levels. This in turn increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner.

Januvia is specifically indicated for the improvement of glycemic control in patients with type II diabetes mellitus as monotherapy or combination therapy with metformin or a peroxisome proliferatoractivated receptor gamma (PPAR) agonist (e.g., thiazolidinediones) when the single agent does not provide adequate glycemic control.

Januvia is supplied as 25 mg, 50 mg or 100 mg tablets designed for oral administration. The recommended initial dose of the drug is 100 mg once daily.

FDA Approval
FDA approval of Januvua was based on the pooled results of two double-blind, placebo controlled monotherapy studies and two double-blind, placebo controlled combination therapy studies.

Monotherapy Trials

The Januvia monotherapy trials had one with an 18 week duration and one with a 24 week duration. In the 18-week study, 521 subjects were randomized to placebo, Januvia 100 mg, or Januvia 200 mg, and in the 24-week study 741 subjects were randomized to placebo, Januvia 100 mg, or Januvia 200 mg. In both trials subjects went under a 7 week washout period then completed a 2-week, single-blind, placebo run-in period, before receiving treatment. Treatment with Januvia at 100 mg daily provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo. In the 18-week study, 9% of patients receiving Januvia 100 mg and 17% who received placebo required rescue therapy. In the 24-week study, 9% of patients receiving Januvia 100 mg and 21% of patients receiving placebo required rescue therapy. The 200 mg daily dose did not provide greater glycemic efficacy than the 100 mg daily dose in either trial.

Combination Therapy Trials

The first randomized, double-blind, placebo-controlled trial enrolled 701 subjects. It was designed to compare Januvia in combination with metformin as treatment for 24 weeks. Subjects already on metformin at a dose of at least 1500 mg per day were randomized after completing a 2-week single-blind placebo run-in period. Subjects on metformin and another antihyperglycemic agent and subjects not on any antihyperglycemic agents (off therapy for at least 8 weeks) were randomized after a run-in period of approximately 10 weeks on metformin (at a dose of at least 1500 mg per day) in monotherapy. Subjects were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. This combination provided significant improvements in A1C, FPG, and 2-hour PPG compared to placebo with metformin. Rescue glycemic therapy was used in 5% of those treated with Januvia 100 mg and 14% of those treated with placebo.

The second randomized, double-blind, placebo-controlled trial enrolled 353 subjects. It was designed to evaluate Januvia in combination with pioglitazone as treatment for 24 weeks. Patients on any oral antihyperglycemic agent in monotherapy or on a PPAR agent in combination therapy or not on an antihyperglycemic agent (off therapy for at least 8 weeks) were switched to monotherapy with pioglitazone (at a dose of 30-45 mg per day), and completed a run-in period of approximately 12 weeks in duration. After the run-in period on pioglitazone monotherapy, patients were randomized to the addition of either 100 mg of Januvia or placebo, administered once daily. This combination therapy demonstrated significant improvements in A1C and FPG compared to placebo with pioglitazone. Rescue therapy was used in 7% of patients treated with Januvia 100 mg and 14% of patients treated with placebo.

Ongoing Study Commitments

• Merck has agreed to conduct a deferred pediatric study under PREA for the treatment of type 2 diabetes in pediatric patients ages 11 to 16, inclusive.
  Protocol Submission: March 2008
  Study Start: June 2008
  Final Report Submission: December 2010
• Merck has agreed to a clinical safety and efficacy study of sitagliptin as add-on therapy to insulin.
  Protocol Submission: March 2007
  Study Start: June 2007
  Final Report Submission: March 2009
• Merck has agreed to conduct a clinical safety and efficacy study of sitagliptin as add-on therapy to sulfonylureas. (A study protocol was previously submitted and the study recently completed.)
  Final Report Submission: March 2007

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

• Upper Respiratory Tract Infection
• Nasopharyngitis
• Headache.

Januvia is an an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. The DPP-4 enzyme inactivates incretin hormones, which are involved in the physiologic regulation of glucose homeostasis. Januvia slows the inactivation of incretin hormones and thus increases and prolongs their action. By inhibiting DPP-4, Januvia increases and prolongs active incretin levels. This in turn increases insulin release and decreases glucagon levels in the circulation in a glucose-dependent manner

Herman GA, Bergman A, Yi B, Kipnes M; The Sitagliptin Study 012 Group Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes. Current medical research and opinion 2006 Oct;22(10):1939-47

Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H; Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006 Nov;49(11):2564-71.

Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, Snyder K, Hilliard D, Tanaka W, Zeng W, Tanen M, Wang AQ, Chen L, Winchell G, Davies MJ, Ramael S, Wagner JA, Herman GA. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clinical Therapeutics 2006 Jan;28(1):55-72.

Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clinical pharmacology and therapeutics 2005 Dec;78(6):675-88.

For additional information regarding Januvia or type II diabetes, please visit the Januvia web page.