Sitagliptin: Novel Once-Daily Oral Therapy for Diabetes

Sitagliptin (Januvia; Merck) is the first of a new class of agents, dipeptidyl peptidase IV (DPP-4) inhibitors, to be approved for the treatment of patients with type 2 diabetes. The new once-daily oral therapy can be used as monotherapy or in combination with either metformin (Glucophage) or a thiazolidinedione (TZD).

"We really need drugs like the DPP-4 inhibitors," Barry J. Goldstein, MD, PhD, says. The problem with other drugs, such as most of the commonly used sulfonylureas, is that "as you use them aggressively, especially early in diabetes, it's fairly common to get low blood sugar reactions, because you get unregulated insulin secretion, even though the glucose is dropping."

DPP-4 inhibitors are different, says Dr Goldstein, who is director of the Division of Endocrinology, Diabetes and Metabolic Diseases at Jefferson Medical College, Philadelphia. "With DPP-4 inhibitors, the beta-cells in the pancreas turn off their insulin secretion when the glucose starts to fall into the normal range. They help the beta-cells perform in a smarter way, and they're not associated with significant hypoglycemia. I think that's really key."

The Incretin-Signaling Pathway

One of the problems 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. Of the different hormones involved, the main focus has been on the incretin, glucagonlike peptide-1 (GLP-1), which guards against too much increase in blood glucose and helps control the emptying of the stomach.

Patients with diabetes do not have enough GLP-1 to exert its normal effects. "If you could give back this GLP-1, you could restore this aspect of what has gone awry in diabetes," says Dr Goldstein. But GLP-1 is rapidly metabolized by DPP-4, making it ?difficult to develop therapies that target GLP-1 directly, so researchers began exploring ways to alter the effects of DPP-4.

The first agent that addressed the incretin system defect was exenatide (Byetta), which received FDA approval last year. 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. Exenatide reduces the secretion of another hormone, glucagon, which works against insulin. "By reducing glucagon levels?which are also known to be elevated in type 2 diabetes?exenatide helps reduce glucose production from the liver, which is another important part of what causes the blood sugar to go up in people with diabetes," says Dr Goldstein.

Mimetics versus Enhancers

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

One of the major differences between the incretin mimetics and the incretin enhancers is that the former are proteins that must be injected, and the latter are chemicals that can be taken in pill form. Also, exenatide must be kept in the refrigerator. In development are longer-acting incretin mimetics, including a once-weekly injection.

The mimetics and enhancers have potentially different side effects. "They're all very new," Dr Goldstein reminds, although concerns about allergic reactions with exenatide injections turned out to be largely unfounded. "One of the advantages of exenatide is that it seems to promote some weight loss, even though it's relatively modest? 5 or 10 lb after 1 or 2 years of treatment. In my experience, the more overweight patients tend to lose more weight."

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 you often see with other diabetes treatments."

Glycemic Control

In clinical trials, the overall glycemic control seen with DPP-4 inhibitors is similar to that seen with exenatide. "We were hoping for a more robust lowering of hemoglobin [Hb]A_1c," admits Dr Goldstein, who was one of the investigators in the sitagliptin trials. Most studies found about 1% reduction of HbA_1c. "DPP-4 inhibitors are generally contributing about as much as the other agents," he says, emphasizing that the key is that they lower glucose without causing hypoglycemia.

Dr Goldstein contends that "we have to?really think about getting patients to glucose goals and getting the blood sugar normalized." But none of the available drugs performs for any length of time as a single therapy. "Every drug that's available has a unique mechanism, and it seems as though only by putting together some of the complementary mechanisms can we hope to get patients to normal blood glucose."

The problem is that there are several defects to target. "If the GLP-1 system was the major defect in type 2 diabetes, then you would expect DPP-4 inhibitors to completely normalize the ongoing disease process. They don't. No drug does."

Who Is a Candidate for Sitagliptin?

Sitagliptin is indicated to improve glycemic control, in association with diet and exercise, in patients with type 2 diabetes, either as monotherapy or in combination with metformin or 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 as combination therapy has been similar to that with placebo. "As far as we know now, and obviously it's very early, sitagliptin is extremely well tolerated, without any really significant side effects," Dr Goldstein says.?

"I think you would be hard-pressed to say that someone would not be a candidate for sitagliptin therapy, because there aren't really any restrictions other than reducing the dose in patients with significant kidney insufficiency." The one exception is patients with poorly controlled disease. "For anyone who has an HbA1c?of 8.5% or greater, sitagliptin is not going to get them to goal," and a sulfonylurea may be a better choice.

Findings reported at the European Association for the Study of Diabetes meeting did show that when sitagliptin was used as initial therapy in combination with metformin, HbA1c?levels dropped by a mean of 2.1% from a baseline of 8.8%. "I think we're going to be seeing more of this initial coadministration of these drugs, because you get additive effects," he says.

Noting the lack of a good postapproval surveillance system, Dr Goldstein believes that "it's fully appropriate for people to hold off and keep their eyes open. When drugs are approved, and sitagliptin is a good example, several thousands of patients have already taken them." But this is "a pretty trivial number of human exposures," since there could be a rare but devastating side effect, and a pattern might not be evident until after 50,000 or 100,000 people have taken the drug."

As we gain more experience, he said, "I hope that the safety profile of sitagliptin is going to hold up. With every set of another 10,000 people, it's much more reassuring."