Pharmacology Update

Sitagliptin Phosphate Tablets (Januvia™)

By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD, Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.

The FDA has approved the first of a new class of drugs for the treatment of type 2 diabetes. Sitagliptin is a dipeptidyl peptidase-IV (DPP-4) inhibitor. Inhibition of DPP-4 prolongs the action of incretin hormones resulting in improved glycemic control. Sitagliptin is marketed by Merck & Co as Januvia™.


Sitagliptin is indicated as adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. It may be used as monotherapy or in combination with metformin or a thiazolidinedione (ie, pioglitazone, rosiglitazone).1


The recommended dose is 100 mg once daily taken with or without food. In patients with moderate renal insufficiency (CrCl 30 mL/min to < 50 mL/min) the dose should be reduced to 50 mg once daily. In patients with severe renal insufficiency (CrCl < 30 mL/min) the dose should be 25 mg once daily.1

Sitagliptin is available as 25 mg, 50 mg, and 100 mg tablets.

Potential Advantages

Sitagliptin is an orally active drug with a different mechanism of action compared to existing therapy and, therefore, its action may be additive to other therapy such as metformin or a thiazolidinedione. It does not cause hypoglycemia or weight gain.1,2 Currently available data suggest that the drug is well tolerated and has a low potential for drug-drug interactions.

Potential Disadvantages

As monotherapy, the magnitude of improvement in glycemic control as measured by reduction in HbA1c and fasting plasma glucose levels appears to be less than that obtained with sulfonylureas, metformin, and possibly thiazolidinediones.1-3 The long-term effect of inhibition of DPP-4 is not known, as DPP-4 plays an important role in the regulation of differentiation and growth of T lymphocytes and inactivation of bioactive peptides (eg, neuropeptides, circulating peptide hormones, growth hormone-releasing hormone).4,5


Sitagliptin is the first DPP-4 inhibitor to be marketed. Inhibition of this enzyme prolongs the activity of incretin hormones such as glucagon-like peptide-1 and gastric inhibitory polypeptide. These are released in response to oral ingestion of nutrient. The resultant effect is inhibition of glucagon release, delay in gastric emptying, and increase in satiety.6 Monotherapy efficacy was shown in two double blind, placebo-controlled studies, for 18 weeks (n = 296) and 24 weeks (n = 273). Patients inadequately controlled with diet and exercise and with HbA1c of 7% to 10% were randomized to sitagliptin (100 mg) or placebo. Those who received sitagliptin showed a placebo-adjusted difference in HbA1c of -0. 6% (95% CI, -0.4 to -0.8) and -0.8 (95% CI, -0.6 to -1.0) respectively).1,2 Mean placebo-subtracted reductions in fasting plasma glucose (FPG) were -20 mg/dL and -17 mg/dL respectively. Two-hour mean adjusted postprandial glucose was reduced by 47 mg/dL in the 24-week study. Identical mean reductions (-0.7 %) were reported when sitagliptin (100 mg daily) was added to metformin (at least 1500 mg) (n = 677) or pioglitazone (30-45 mg daily) (n = 337).1 Sitagliptin appears to be well tolerated. Adverse effects compared to placebo include nasopharyngitis (5.2% vs 3.3%), upper respiratory tract infection (6.3% vs 3.4%), headache (5.1% vs 3.9%), nausea (1.4% vs 0.6%), and diarrhea (3.0% vs 2.3%). A small increase in white blood counts (200 cells/microL) has been reported.1 DPP-4 has a dual function as a regulatory protease as well as a binding protein.4 The effect of long-term inhibition of DPP-4 is not known. There are currently no published studies comparing sitagliptin with other first line agents such as a sulfonylurea or metformin. The cost of sitagliptin is about $5 per day.

Clinical Implications

Sitagliptin provides a new oral antidiabetic drug with a novel mechanism of action. Improvement in glycemic control as monotherapy appears to be modest (-0.6 % to - 0.8% in HbA1c and 17-20 mg/d in FPG). In contrast, reductions of 1 to 2% in HbA1c are expected with sulfonylurea or metformin monotherapy along with a reduction of FPG of 36-72 mg/dL.3 For thiazolidinediones monotherapy, a 0.5 to 1.5% reduction is reported for HbA1c. Given the experience with established agents, lack of comparative studies, unknown long-term effects, sitagliptin should be reserved a second-line therapy.


1. Januvia Product Information. Merck & Co. October 2006.

2. Raz I, et al. Diabetologia. 2006;49:2564-2571.

3. Krentz AJ, Bailey CJ. Drugs. 2006;65:385-411.

4. Mentlein R. Regul Pept. 1999;85:9-24.

5. Reinhold D, et al. Biol Chem. 2002;383:1133-1138.

6. Gallwitz B. Treat Endocrinol. 2005;4:361-370.