Experts predict the role new agents could play in managing type 2 diabetes

DPP-IV inhibitors improve beta-cell function.

Issue: November 2006

The recent FDA approval of an innovative new agent as well as the potential approvals of further novel treatments have triggered much anticipation of a new frontier in type 2 diabetes management.

Publications such as The New York Times and the Boston Globe have already coined the new class of DPP-IV inhibitors as bonafide blockbusters before long-term data are even available. To obtain a more grounded perspective on treatment options, Endocrine Today referred to various experts and trial data to assess the state of diabetes management following the approval of sitagliptin (Januvia, Merck).

Last month the FDA approved sitagliptin as monotherapy and as an adjunct to either metformin or thiazolidinediones to improve glucose control in patients with type 2 diabetes (for more on sitagliptin’s approval, see related article “FDA approves DPP-IV inhibitor sitagliptin for type 2 diabetes.”).

Because many of the candidate drugs address abnormalities of prandial physiology in diabetes that are inadequately treated by other therapies, they are all likely to contribute to the treatment of diabetes, Matthew C. Riddle, MD, of the section of diabetes at Oregon Health and Science University of Portland, said of pramlintide (Symlin, Amylin), exenatide (Byetta; Amylin, Eli Lilly), liraglutide (NN2211, Novo Nordisk), vildagliptin (Galvus, Novartis) and sitagliptin.

“I believe that most of the medications on the market are crucial in diabetes management,” Osama Hamdy, MD, PhD, told Endocrine Today. Hamdy is the director of the Obesity Clinical Program at Joslin Diabetes Center and staff endocrinologist at Beth Israel Deaconess Medical Center, both in Boston. “The DPP-IV inhibitors will definitely find their way into routine care with better understanding of the drug mechanism.”

Sitagliptin works directly on the beta cells and improves the beta-cell function, especially the early-phase insulin secretion, which is crucial for controlling the high postprandial blood glucose, Hamdy said. “We didn’t have any effective oral medication that could correct the postprandial blood glucose levels until now.”

Hamdy predicted possible market competition between DPP-IV inhibitors and metformin. “Metformin is an inexpensive, generic medication. It is a medication that has been on the market for a long time and physicians are confident in using it, which will make it tough for DPP-IV to replace it as initial monotherapy,” he said.

Because metformin and TZDs target insulin sensitivity, new medications that target beta-cells should be combined with them to improve both insulin sensitivity and beta-cell function. “I see, in the future, possibly a combination pill of metformin and the DPP-IV inhibitor,” Hamdy said. “Because metformin is generic, I believe a combination pill will be extremely beneficial as initial management for diabetes.”

Enrico Cagliero, MD, from the Massachusetts General Hospital Diabetes Center and assistant professor of medicine at Harvard Medical School, cautioned that the new DPP-IV inhibitors are not as powerful as some of the older drugs. “Being new and expensive, I am sure that patients will not start on these as soon as they develop diabetes,” he said. “Because [people with diabetes] tend to progress to different medications, I see a clear role for these drugs.

“It is always nice to have another option,” Cagliero said. “Some physicians might want to wait for more data before they start prescribing these medications.”

DPP-IV crash course

In the late 1980s, professor Jens Holst, MD, a medical physiologist from Copenhagen University, discovered glucagon-like peptide 1, a potent incretin hormone. The next logical step was to develop an injectable that patients could take with a meal.

“That is the direction a number of drug companies have gone,” said Edwin Villhauer, PhD, a principal fellow research scientist for Novartis. However, researchers learned that GLP-1 degrades quickly with both impact and degraded product secreted rapidly.

The concept of a small molecule GLP-1 receptor agonist fell through because nausea and vomiting would likely occur without very tight control on such receptor agonism, he said.

Edwin Villhauer, PhD [photo]
Edwin Villhauer

In 1993, researchers found that raising circulating levels of GLP-1 twofold with subcutaneous administration led to a significant reduction in glucose excursion. Two years later, Holst found that DPP-IV was the major degradating pathway for GLP-1, meaning one could potentially increase the circulating levels of postprandial GLP-1 two- to fivefold, Villhauer said.

In this 1995 paper published in Diabetes, Holst predicted, “DPP-IV inhibition may be an effective supplement to diet and exercise treatment in attempts to prevent the deterioration of glucose metabolism associated with the Western lifestyle.”

Using combinatorial chemistry, Villhauer designed a library of DPP-IV inhibitors, including DPP728. At the American Diabetes Association annual meeting in 2000, colleagues from Novartis exhibited that DPP728 increased endogenous GLP-1 levels in normal patients.

“At the ADA meeting in 2002, we were the first to show that the DPP-IV inhibitor was as potent as any oral anti-diabetic agent that was present on the market, without many adverse effects,” Villhauer said.

With some modification, DPP728 evolved into vildagliptin, which is expected to provoke FDA action by the end of 2006.

DPP-IV inhibitors improve the beta cell’s ability to synthesize insulin and proper meal-driven insulin release. Villhauer is hoping that, as research continues, these drugs will restore the normal beta-cell function by reducing apoptosis and increasing the number of new normal functionalized beta cells. In addition, DPP-IV inhibitors reduce glucagon secretion in the alpha cell, therefore reducing glucose production in the liver.

Current/future contenders

Another major player in diabetes care is the GLP-1 analog exenatide, which binds to the GLP-1 receptor. Sitagliptin and vildagliptin block the enzyme that degrades GLP-1.

“Both approaches [of exenatide and DPP-IV inhibitors] work off the idea of boosting levels of GLP-1,” Cagliero said.

“When Byetta came on the market, it was a new class of drugs. There was nothing else that worked in the same way. Everyone was excited,” he said. Exenatide is a twice-daily injectable drug that is used in conjunction with oral therapies, such as metformin and/or a sulfonylurea. Nausea is a common adverse effect, Cagliero said.

Exenatide is not the most powerful diabetes drug, in terms of glucose control, according to Cagliero. However, exenatide was the first diabetes drug to be associated with weight loss. “Though the documented weight loss among patients was minor, it was progressive,” he said. “Patients lost a little bit of weight at six months, and after a year, they lost a little bit more weight with no sign of rebound.” Weight loss continued through two years of follow-up.

Although DPP-IV inhibitors are weight-neutral, patients might prefer to receive a pill than an injection, even with the benefit of potential weight loss. Amylin and Eli Lilly are working to make exenatide a once-a-week injection, Cagliero said. “Many patients might opt for a once-a-week injection with the potential for weight loss over a weight-neutral pill.” Amylin also manufactures the incretin mimetic pramlintide.

Weight gain is a common problem associated with various diabetes medications, such as insulin, secretagogues and TZDs. Multiple injections of insulin can cause up to 16 lb of weight gain. This effect can be greatly reduced with concurrent metformin treatment, according to Riddle.

Presently in the pipeline, liraglutide is a GLP-1 receptor agonist administered with a single daily injection. As with pramlintide and exenatide, the most common adverse event is nausea. A 24-hour glycemic profile of 13 patients treated with placebo or liraglutide for one week led to lower basal and preprandial values, with small reductions of postprandial increments. Although the glucagon profile was reduced, insulin levels were not different between treatment arms, Riddle said.

The differences in action of the three types of drugs targeting the GLP-1 system — exenatide, liraglutide and DPP-IV inhibitors — highlight that there is much to discover. Researchers have yet to determine whether these diverse approaches are due to differences in pharmacokinetics or mechanisms of action, Riddle reported in Diabetes Care.

Only time can reveal the long-term benefits and risks of each agent and, ultimately, that treatment’s role in the management of type 2 diabetes. – by Rebekah Cintolo

For more information:

Kuehn BM. New diabetes drugs target gut hormones. JAMA. 2006;296:380-381.

Riddle MC, Drucker DJ. Emerging therapies mimicking the effects of amylin and glucagon-like peptide 1. Diabetes care. 2006;29:435-449.

Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes. 1998;47:1663-1670.