Sitagliptin (Januvia), the first in a new class of agents called dipeptidyl peptidase IV (DPP-4) inhibitors, received FDA approval late last year for the treatment of patients with type 2 diabetes. This once-daily oral therapy can be used as monotherapy or in combination with either metformin (Glucophage) or a thiazolidinedione (TZD). A second DPP-4, vildagliptin (Galvus), is currently under FDA review.

The DPP-4 inhibitors are not associated with hypoglycemia, a common side effect seen with many of the available antidiabetes drugs, especially at the beginning of treatment, when insulin secretion is unregulated, even though the glucose level is dropping.

One problem in diabetes is a defect in the incretin-signaling pathway, the hormones that are released by cells in the gut to facilitate digestion and metabolism. The focus of research has been on the incretin hormone, glucagonlike peptide-1 (GLP-1), which guards against excess increase in blood glucose and helps monitor the emptying of the stomach.

Patients with diabetes do not have enough GLP-1, which is rapidly metabolized by DPP-4. Because it is difficult to develop therapies that target GLP-1 directly, researchers began exploring ways to alter the effects of DPP-4. The first agent that addressed the incretin system defect was exenatide (Byetta). Known as an incretin mimetic, exenatide is similar in its structure to GLP-1 but resists breakdown in the body and thus lasts much longer.

The DPP-4 inhibitors approach GLP-1 insufficiency by enhancing incretin instead of mimicking it. By inhibiting DPP-4, agents such as sitagliptin can prolong the action of GLP-1 and increase circulating levels.

The mimetics and enhancers have potentially different side effects. Concerns about allergic reactions with exenatide injections turned out to be largely unfounded.

DPP-4 inhibitors tend to be weight neutral. They don’t promote weight loss, but they also don’t promote weight gain, which is something often seen with other diabetes treatments.

In clinical trials, the overall glycemic control seen with DPP-4 inhibitors was similar to that seen with exenatide. The importance of the DPP-4 inhibitors is that they lower glucose without causing hypoglycemia.

Sitagliptin is indicated for patients with type 2 diabetes, either as monotherapy or in combination with metformin or with a TZD. It should not be used in patients with type 1 diabetes or to treat diabetic ketoacidosis.

The recommended dosage is 100 mg/day, with or without food. The overall incidence of adverse reactions with sitagliptin alone or in combination with another drug has been similar to that with placebo. The main restriction involves reducing the dose in patients with significant kidney insufficiency.

Sitagliptin may not be a good option for patients with poorly controlled disease, that is, with HbA1cof 8.5% or more; a sulfonylurea may be a better choice.

It is reasonable to assume that many patients would prefer taking an oral tablet to an injection. Also, patients who report gastrointestinal side effects with metformin would be good candidates for sitagliptin.