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Specialists mull incretin-based therapies for diabetics

From the September ACP Observer, copyright © 2007 by the American College of Physicians.

By Deborah Gesensway

TORONTO—Endocrinologists from around the world debated whether the time is right to start their type 2 diabetes patients on the new incretin-based medications and how to counter the growing problem of vitamin D insufficiency among the population at large, and seniors in particular.

Debate about diabetes

The examination of new diabetes therapies comes on the heels of the rosiglitazone furor fueled by evidence that the thiazolidinedione (TZD)-type drug is associated with a significantly increased risk of myocardial infarction among some patients with type 2 diabetes. The FDA in late May ordered the makers of rosiglitazone maleate (Avandia) and pioglitazone hydrochloride (Actos) to add a black box warning—the agency's strongest—about heart disease risks to their products.

In terms of long-term safety of the new incretin therapies, whether they are GLP-1 agonists like exenatide (Byetta) or DPP-IV inhibitors like sitagliptin (Januvia), "We just don't know yet what the unanticipated long-term side effects might be," said Edward S. Horton, FACP, professor of internal medicine and endocrinology at Harvard Medical School, Brigham & Women's Hospital and the Joslin Diabetes Center, at a special symposium on the new diabetes therapies.

"It is still uncertain where they will fit in, but I think they are very encouraging," he said. These drugs seem to work as well as many other types of type 2 diabetes drugs to reduce HbA1c levels while causing fewer short-term gastrointestinal side effects and having a lower risk of inducing dangerous hypoglycemia, he said, adding that they also do not promote weight gain and perhaps may help to protect beta cells. In addition to exenatide and sitagliptin, there are a number of other variants in various stages of testing and several are on track to be approved by the FDA.

Julio Rosenstock, ACP Member, director of the Dallas Diabetes and Endocrine Center at Medical City and also a clinical professor of medicine at the University of Texas Southwestern Medical School in Dallas, added that "the potential is that we should start with combination therapy much earlier, even right from the outset, and in the future, we will use this incretin-based therapy much more aggressively once long term safety data are available." All of the presenters discussed using the new incretin-type drugs in combination with other diabetes drugs, including metformin, various sulfonylureas, TZDs and insulin.

Taking the other side of the debate was David Nathan, MD, director of the Diabetes Center at Massachusetts General Hospital, professor of medicine at Harvard Medical School and lead author of the American Diabetes Association's (ADA) 2006 consensus algorithm for how to manage type 2 diabetes (published in the August 2006 Diabetes Care.)

He told meeting attendees that although the new medications appear to be safe and seem to be well tolerated, the real concern is that they don't work better than existing drugs in lowering HbA1c levels and are very expensive. Moreover, he said, "there is always the concern that we are going to get bitten by one of these new drugs" in terms of their long-term safety. "One would hate to see the same thing happen to them as happened to troglitazone or rosiglitazone."

Although the newer, less powerful and more expensive drugs may be acceptable when starting at a relatively low A1c, there is little or no evidence that they lower A1c to 7%, Dr. Nathan said. And their effect on weight loss, although real and important, he said, is not nearly as great for most patients as the drugs' manufacturers advertise.

According to the ADA algorithm, all patients diagnosed with type 2 diabetes should be started on metformin immediately along with lifestyle interventions. A1c levels should be checked every three months and if levels are above 7%, additional drugs should be added. Up to three oral agents (a glitazone, a sulfonylurea and metformin) can be used at once. Beyond that, the algorithm states, "initiation and intensification of insulin therapy is preferred based on effectiveness and expense."

Given patients' aversion to going on insulin therapy, however, there appears to be a place for drugs like these new incretins, others contended. Yes, insulin works the best in reducing hemoglobin A1c levels to recommended targets, explained Robert Ratner, FACP, of the Medstar Research Institute in Hyattsville, Md., and professor of medicine and endocrinology at Georgetown University, "but we need options for our patients."

Since achieving blood sugar control requires individualized therapy regimens that each patient can abide by, Dr. Ratner said, "The more options you have the better off you are going to be."

Contrary to the assumptions underlying the ADA algorithm, he said, glycemic control has to be considered only one goal of therapy.

"Patient acceptance is critical," he said, as is "minimal risks of severe or symptomatic hypoglycemia." Other goals include weight control or weight loss and modifying cardiovascular risks and outcomes, he said. The new incretin-based therapies, Dr. Ratner argued, have an increasing place in a doctor's armamentarium as the costs of the newer drugs drop.

In addition, he observed, "we aren't spending enough on drug therapy that will keep patients out of the hospital. Hospitalizations and complications—that's where the costs related to diabetes care are."

Vitamin D

Several sessions about vitamin D focused on study results documenting low blood levels of vitamin D in the population, plus a number of groundbreaking discoveries about the role of vitamin D and its analogues in regulating everything from immune function to diabetes and cancer. Vitamin D insufficiency, as it is now known, affects more than bone health.

Data indicate that about two-thirds of the adult white population in the U.S. have insufficient levels of vitamin D in their blood, with the numbers even higher for blacks (88%) and Hispanics (82%).

"What this means is almost everyone who comes into your office, especially 65 and older people, will fail to meet the target" of about 30 ng/mL 25-hydroxy vitamin D levels, explained Daniel D. Bikle, MD, PhD, professor of medicine and dermatology at the University of California, San Francisco.

Very few foods have vitamin D in them and it's difficult get enough from sunlight in the northern half of the U.S., particularly during the winter months. Physicians also should be aware that adults with otherwise unexplained vitamin D deficiency may be suffering from an undiagnosed gastrointestinal disorder affecting absorption, such as Celiac or Crohn's diseases, he said.

"We're finding that a substantial proportion of people coming into clinics with osteopenia have Celiac disease," Dr. Bikle said.

Other people showing up with severe vitamin D deficiency, he said, are those bariatric surgery patients whose GI tract was seriously altered.

About 15-20 observational studies indicate that vitamin D status is inversely related to diabetes, according to Anastassios G. Pittas, MD, assistant professor of medicine and endocrinology at Tufts-New England Medical Center in Boston. Vitamin D and calcium supplementation seem to affect insulin sensitivity, he said.

In addition, vitamin D may have anti-inflammatory and antiproliferative effects. According to David Feldman, MD, professor of medicine and endocrinology at Stanford University School of Medicine, vitamin D may be protective against nearly all cancers. Most research to date has focused on the relationship of vitamin D to prostate, breast and colon cancer, but many cells have the ability to make their own calcitrial from circulating vitamin D.

Giving patients combination therapy of vitamin D and an anti-inflammatory drug is now being studied in prostate cancer and "looks hopeful in delaying progression of the disease," he said. "Combination therapy is probably going to be key."

Although many questions remain about optimal doses, Dr. Pittas said, if everybody were to take " 1,000 to 2,000 units of vitamin D daily, there would be benefit with low risk for harm” The U.S. and Canadian recommended daily allowance currently is 200 units for people up to age 50, 400 units for people age 51-70 and 600 units for people older than 71.

Dr. Bikle added that vitamin D insufficiency is not difficult to treat with supplements. The problem is how to give patients enough vitamin D to make a difference in raising blood levels of 25 hydroxy d. To raise blood levels by 1 ng/mL, he said, a patient needs to consume 100 units of vitamin D3 (cholecalciferol).

The only supplement available in a large dose amount, however, is vitamin D2 (ergocalciferol), which is cleared by the body much faster than vitamin D3. As a result, Dr. Bikle recommended giving such patients D2 for six to eight weeks until the levels of hydroxy d increase significantly, and then 2,000 units a day of vitamin D3 from supplements, sunlight and foods, such as dairy and cold water fish or fish oil.

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