Januvia™ Works For for First and Second-Line Management of Type 2 Diabetes

The FDA has approved sitagliptin for use with diet and exercise or in combination with metformin or the TZDs to improve glycemic control in adult patients with type 2 diabetes. According to a company news release, sitagliptin represents a new class of oral drugs called dipeptidyl peptidase-4 (DPP-4) inhibitors. These agents serve to increase the body’s active incretin hormone levels, which trigger the pancreas to increase insulin and signal the liver to stop glucose production. Adding sitagliptin to insulin sensitizers, such as pioglitazone or metformin, therefore addresses the 3 key defects of diabetes: insulin resistance, beta-cell dysfunction, and alpha-cell dysfunction.

Approval of sitagliptin monotherapy was based on data from 2 clinical studies of 24 and 18 weeks’ duration (n = 473 and 296, respectively) in patients with mild to moderate baseline hemoglobin A1c levels (mean, 8.0%; range, 7.0% – 10.0%). Results showed that once-daily sitagliptin therapy yielded significant decreases in hemoglobin A1c levels relative to placebo (-0.8% and -0.6%, respectively; P < .001).

The add-on indication for sitagliptin was based on separate 24-week studies, showing that the addition of sitagliptin to metformin or pioglitazone therapy yielded significant mean changes from placebo in hemoglobin A1c level (-0.7; P < .001 for both), with mean decreases of 0.7% and 0.9% from baseline hemoglobin A1c levels of 8.0% and 8.1% for metformin and pioglitazone, respectively.

Also, more than twice as many patients receiving sitagliptin add-on therapy achieved a hemoglobin A1c goal of less than 7% compared with those receiving metformin alone (47% vs 18%; P < .001). Similarly, 45% of patients receiving sitagliptin in addition to pioglitazone achieved this goal compared with 23% of those receiving pioglitazone alone (P < .001).

Sitagliptin has also been shown to provide a 24-hour glucose response at mealtime, between meals, and overnight. In a 24-week, placebo-controlled study of patients uncontrolled while receiving metformin, adding 100 mg of sitagliptin once daily substantially reduced postmeal and fasting plasma glucose levels by 51 and 25 mg/dL, respectively (P < .001 for both).

The recommended regimen of sitagliptin for all approved indications is 100 mg once daily with or without food. No dosage adjustments are required for patients with mild to moderate hepatic insufficiency or in patients with mild renal insufficiency (creatinine clearance [CrCl], > 50 mL/minute).

However, patients with moderate (CrCl, 30 to < 50 mL/minute) and severe (CrCl, < 30 mL/minute) renal insufficiency should receive reduced dosages of 50 and 25 mg once daily. Those with end-stage renal disease requiring hemodialysis should also receive daily doses of 25 mg. The FDA recommends that renal function be assessed prior to initiation of sitagliptin therapy and periodically thereafter.

The most commonly observed adverse events that occurred more often in the sitagliptin group vs placebo (incidence, > 5%) included stuffy or runny nose and sore throat, upper respiratory tract infection, and headache. Sitagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. Its safety and efficacy have not been established in patients younger than 18 years. Because there are no adequate and well-controlled studies in pregnant women, sitagliptin should only be used during pregnancy if clearly needed; caution should be exercised with use of sitagliptin in nursing women.

Additional studies of sitagliptin are planned to evaluate its safety and efficacy in combination with insulin and sulfonylureas.
In a news release, the company notes that 43 studies of sitagliptin have been completed or are underway (n = 6700 patients in the clinical studies; about 4700 patients from these trials are receiving sitagliptin); additionally, approximately 1100 patients thus far have been treated for more than a year. Four additional studies are set to begin this year, and use of sitagliptin as part of a single-tablet combination with metformin (MK-0431A) has been accepted for FDA review.

According to a news release from Novartis AG, the DPP-4 inhibitor vildagliptin (Galvus), a once-daily oral treatment option for people with type 2 diabetes, is also currently under review for approval by the FDA.

https://www.fda.gov/cder/whatsnew.htm