Combination drug offers new option for diabetes

May 7, 2007

Merck has received FDA approval of combination drug Janumet, containing both sitagliptin and metformin. The new product utilizes three different mechanisms to improve glycemic control in type 2 diabetes.

Patients with Type 2 diabetes whose blood glucose is not adequately controlled with metformin or sitagliptin (Januvia, Merck) alone will now have a new option. Last month, the Food & Drug Administration approved a two-in-one product from Merck. Janumet, containing both metformin and sitagliptin, is also for use in patients already taking the two drugs separately.

Janumet improves glycemic control by three mechanisms. The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin works on the incretin pathway to increase circulating levels of incretin hormones, said Holly S. Divine, Pharm.D., CGP, CDE, associate professor at University of Kentucky College of Pharmacy. In this way, she said, sitagliptin "increases insulin release and decreases glucagon release in a glucose-dependent manner. Metformin primarily decreases hepatic glucose production." According to Merck, the metformin component also improves insulin sensitivity by increasing uptake and utilization of glucose by muscles and tissues.

Although no clinical efficacy studies were conducted with Janumet before its approval, bioequivalence with sitagliptin and metformin administered as separate tablets was demonstrated. A total of 701 patients took part in a 24-week study to evaluate the efficacy of the two drugs together. In combination with metformin, sitagliptin provided significant improvements in A1C, fasting plasma glucose, and two-hour postprandial glucose. More than twice as many patients on the combination therapy reached the A1C goal of < 7% compared with those patients on metformin alone.

Janumet, like metformin, is dosed twice daily with meals. The starting dose should be individualized and based on the patient's current regimen. However, the recommended initial dosage for patients not on prior metformin therapy and not adequately controlled on sitagliptin is 50 mg sitagliptin/500 mg metformin. Dosages can be increased gradually to reduce the incidence of gastrointestinal side effects due to metformin, but they should not exceed the maximum recommended daily dose of 100 mg of sitagliptin and 2000 mg of metformin. "If the dose is started low and increased no sooner than weekly, the effect is lessened," Divine said of the gastrointestinal upset.

The potential for developing lactic acidosis, due to an accumulation of metformin, appears in the prescribing information as a black box warning. According to Divine, "lactic acidosis is a serious but rare condition; however, it is more likely to occur if the patient has congestive heart failure or is renally or hepatically compromised." Other conditions that also increase the risk of lactic acidosis include sepsis, dehydration, and excess alcohol intake. Alcohol is known to increase the effect of metformin on lactate metabolism.

Janumet is contraindicated in patients with renal disease or renal dysfunction when serum creatinine levels are ≥ 1.5 mg/dL for males or ≥ 1.4 mg/dL for females. The drug should not be taken when abnormal creatinine clearance results from conditions such as acute myocardial infarction, shock, and septicemia or when acute or chronic metabolic acidosis exists, including diabetic ketoacidosis.

"Just as with metformin, if a patient is undergoing tests that include intravascular iodinated contrast dyes, Janumet should be temporarily discontinued prior to the test," Divine said. Janumet should also be avoided in patients with evidence of hepatic disease.

TIPS TO REMEMBER............... Janumet