Pharmacology Update

Sitagliptin and Metformin Tablets (Janumet™)

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 relationship to this field of study.

The FDA has approved a new combination product for the treatment of type 2 diabetes mellitus. Sitagliptin, the recently approved dipeptidyl peptidase-4 (DPP-4) inhibitor is combined with metformin in two different dose configurations. Sitagliptin/metformin is marketed by Merck & Co., Inc as Janumet.

Indications

Sitagliptin/metformin is indicated as an adjunct to diet and exercise for the treatment of type 2 diabetics in patients who are not adequately controlled on either drug alone or who are already being treated with both drugs.1

Dosage

The starting dose of sitagliptin/metformin should be individualized based on the patient's current regimen. The dose may be titrated upward but should not exceed 100 mg of sitagliptin or 2000 mg of metformin daily. The tablets should be taken twice daily with meals.1

Sitagliptin/metformin is available as 50 mg sitagliptin/500 mg metformin and 50 mg sitagliptin/1000 mg metformin.

Potential Advantages

Sitagliptin/metformin provides a product with two different mechanism of action. The addition of sitagliptin to patients inadequately controlled on metformin alone improves glycemic control with a reduction of HbA1c of 0.65%,1,2 and may improve compliance.

Potential Disadvantages

The most common adverse events are gastrointestinal related associated with metformin (eg, nausea, vomiting, diarrhea). The combination has little flexibility in individualizing the dose. The effect of long-term 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).3,4

Comments

Sitagliptin/metformin is a new combination product with two distinct mechanisms of action. Sitagliptin is a DPP-4 inhibitor prolonging the action of incretin hormones. This results in glucose dependent insulin release, inhibition of glucagon release, delayed gastric emptying, and increases satiety.5 Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity.

The fixed combination has not been studied in any clinical trial. The approval was based on a 24-week study (n = 701) with sitagliptin (100 mg daily) added to metformin (1500 mg daily or higher) in patients inadequately controlled on metformin alone.1,2 This addition resulted in a placebo-adjusted reduction of HbA1c of 0.65%. The mean baseline HbA1c was 8%. Adjusted reductions in fasting plasma glucose and 2-hour postprandial glucose were 25 mg/dL (baseline 170) and 51 mg/dL (baseline 275).

Hypoglycemia and weight gain are not associated with these two drugs. The daily wholesale cost is about $5, similar to the sitagliptin alone.

Clinical Implications

Sitagliptin/metformin is the newest combination product to be approved for the treatment of type 2 diabetes. There are currently many combinations available including sulfonylurea metformin combinations, glitazone/metformin and glitazone/sulfonylurea combinations. The combinations may be more convenient for those who are already taking the two drugs separately.

References

1. Janumet Product Information. Merck & Co., Inc. March 2007.

2. Charbonnel B, et al. Diabetes Care. 2006;29:2638-2643.

3. Mentlein R. Regul Pept. 1999;30:9-24.

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

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