Sitagliptin (Januvia) is an incretin enhancer and the first medication from the gliptin class to be marketed. Incretin hormones are released from intestinal cells in response to carbohydrate- or fat-rich meals and stimulate pancreatic beta cells to release insulin, which stops hepatic glucose production. Sitagliptin prolongs the action of incretin hormones by prohibiting their degradation through inhibition of the dipeptidyl peptidase-4 enzyme. Sitagliptin is labeled as adjunct therapy to diet and exercise, metformin (Glucophage), or thiazolidinediones in adults with type 2 diabetes.

SAFETY

Two large trials have assessed the effectiveness and safety of sitagliptin alone or in combination with metformin in adult patients with type 2 diabetes. Hypoglycemia rates in patients receiving sitagliptin were similar to those in patients receiving placebo or metformin alone, with no incidents of severe hypoglycemia^1–3; however, it is unknown whether sitagliptin will increase hypoglycemic events when combined with sulfonyl-ureas or insulin.

Hepatic insufficiency appears to have minimal effect on sitagliptin concentrations and requires no dosage adjustment. Patients with moderate renal insufficiency (creatinine clearance of 30 to 50 mL per minute [0.50 to 0.83 mL per second]) should reduce daily dosages to 50 mg, and patients with severe kidney dysfunction (creatinine clearance of less than 30 mL per minute [0.50 mL per second]) should take 25 mg daily.^4,5 Sitagliptin is U.S. Food and Drug Administration pregnancy category B.⁵

TOLERABILITY

Overall, reports of side effects with sitagliptin are similar to those reported with placebo. Respiratory symptoms (e.g., nasopharyngitis, respiratory tract infection, cough) occur more often with sitagliptin than with placebo or other oral hypoglycemics; however, those rates are still low. Gastrointestinal side effects are uncommon, and weight gain does not occur.^1–3,5 None of these side effects resulted in discontinuation of treatment.^1,2

EFFECTIVENESS

Only three clinical trials evaluating the effectiveness of sitagliptin have been published, with a total enrollment of fewer than 2,000 patients.^1–3 The trials showed that after six months of monotherapy with sitagliptin, A1C levels decreased by an average of 0.8 percent in patients with a baseline A1C of 8.1 percent.^1,4 In patients with moderately uncontrolled diabetes (baseline A1C of less than 8 percent but at least 7 percent), sitagliptin decreased the A1C level by 0.6 percent; in patients with a higher baseline A1C (9 percent or greater), it decreased the A1C level by 1.5 percent.¹ Adding sitagliptin to either metformin or pioglitazone (Actos) will decrease the A1C level by an additional 0.7 percent.^2,4 Average fasting blood glucose will decrease by 17 to 25 mg per dL (0.9 to 1.4 mmol per L), and postprandial levels will decrease by approximately 47 to 50 mg per dL (2.6 to 2.8 mmol per L).^1–3

Studies have not evaluated the effects of sitagliptin on microvascular or macrovascular complications or mortality. Likewise, no information is available regarding the effectiveness of treatment lasting longer than six months. Study participants had diabetes for an average of 4.5 to 6.0 years; the effect of sitagliptin on patients with long-standing diabetes may not be as pronounced.^1–3

PRICE

A one-month supply of sitagliptin (30 tablets) costs approximately $175. In comparison, a one-month supply of generic metformin costs $40 to $42, and a one-month supply of Glucophage costs $57. The injectable incretin mimetic exenatide (Byetta) costs about $202 per month.

SIMPLICITY

Sitagliptin is available in 25-mg, 50-mg, and 100-mg tablets taken once daily, regardless of meals or time of day.⁵

Bottom Line

Sitagliptin may be useful as second-line or third-line therapy in patients with a mildly elevated A1C level (less than 9 percent) who do not reach their A1C goal with first-line therapy (metformin). Sitagliptin will decrease postprandial blood glucose and mildly lower fasting blood glucose for a total A1C reduction around 0.8 percent. It is more expensive than other options, such as sulfonylurea hypoglycemics. It is not known whether sitagliptin has any effect on diabetes-related morbidity or mortality.