Reviewed By Charlotte Grayson
The traditional medical approach to diabetes is simply to manage it after it has been diagnosed. Because there isn't a cure, the emphasis is on keeping blood sugars as close to normal as possible -- usually with exercise and weight loss coupled with medication -- and dealing with complications as they arise. But while this sort of treatment can allow people with diabetes to have full and relatively normal lives, it doesn't get at the root causes of the illness.
Thomas Buchanan, MD, professor of medicine at the University of Southern California, believes this is precisely why the thrust of diabetes treatment needs to be changed.
"Typically, in diabetes treatment, the whole focus is on blood sugar," says Buchanan, who is also director of the clinical research center at the Keck School of Medicine. "But people aren't thinking enough about the actual disease that's causing the problem."
To address this issue, Buchanan led the Troglitazone in Prevention of Diabetes (TRIPOD) study, which treated women at risk of developing type 2 diabetes with a class of drugs called glitazones or thiazolidinediones, or more commonly, TZDs. The results were dramatic: The drugs were apparently effective in preventing the onset of the disease.
Given that an epidemic of type 2 diabetes may be on the horizon -- due primarily to the increasing levels of obesity in the U.S. and around the world -- preventing diabetes is an urgent public health priority. TZDs could be part of the solution.
TZDs and the TRIPOD Study
Unlike some drugs used to treat diabetes, the main strength of TZDs as treatment doesn't lie in their ability to directly boost insulin production or lower glucose levels. Instead, TZDs work on a different level by affecting the beta cells in the pancreas.
For the body to use blood glucose as energy, beta cells secrete the hormone insulin. As insulin circulates throughout the body, it attaches itself to individual cells; once the insulin is attached, the cell becomes receptive to glucose and absorbs it, providing itself with energy. In many people developing type 2 diabetes, the body becomes less sensitive to insulin -- a condition called insulin resistance -- making the absorption of glucose from the bloodstream more difficult.
The pancreatic cells respond by producing more insulin to make up for this resistance. While the beta cells may be able to produce enough insulin to keep blood glucose at normal levels for a time, the increased production of insulin eventually may take a toll. The beta cells may become compromised and their ability to produce insulin will diminish, causing insulin deficiency. The body will become less capable of processing blood sugar, blood sugar levels will rise, and type 2 diabetes can follow. About 70 to 80 million Americans are estimated to have insulin-resistance syndrome and 17 million have type 2 diabetes.
Buchanan believes that TZDs might prevent beta cells from becoming overloaded and wearing out. By averting this, insulin resistance wouldn't worsen and, by extension, the development of type 2 diabetes could be stopped.
In the TRIPOD study, 235 Hispanic women who previously had gestational diabetes -- diabetes that develops during pregnancy -- and were at high risk of developing type 2 diabetes were treated with the TZD Rezulin (troglitazone), then another TZD, Actos. Buchanan and his colleagues found that the TZDs stabilized beta-cell function and led to a 55% reduction in diabetes compared with a placebo group. Startlingly, the benefits of the drugs seemed to last even after use was stopped.
"That was one of the most striking results," Buchanan tells WebMD. "We found that in people who didn't have diabetes, the preventative effect of the drug persisted eight months after it was stopped."
The Technical Details: How TZDs Work
The exact mechanism of how TZDs improve beta-cell function isn't entirely understood. The most widely accepted theory is that TZDs activate a receptor common in fat cells called the nuclear peroxisomal proliferator-activated receptors-gamma, or PPAR-gamma. These receptors affect how glucose and fats are metabolized, and once they are activated, the uptake or absorption of fat cells is increased; this also stimulates the metabolism of glucose and lessens the liver's production of new glucose.
What's particularly interesting is that TZDs may actually increase the total amount of fat on a person, but they appear to cause a redistribution of fat in ways that may help increase insulin sensitivity. Visceral fat -- fat surrounding the organs of the abdomen -- seems to be connected to the development of insulin resistance while subcutaneous fat -- fat beneath the skin in other parts of the body -- is not. TZDs appear to decrease the amount of visceral fat and increase the amounts of subcutaneous fat.
Unrelated to its effects on beta cells, TZDs may lower the cardiovascular risks of diabetes. Given that heart problems and strokes are among the most deadly complications of diabetes, this may prove an important effect of the drugs.
While TZDs also have the ability to lower glucose, their abilities to do so are modest compared with other medications.
"TZDs are not very potent when used as monotherapy," says David Nathan, director of the diabetes center at Massachusetts General Hospital and a professor of medicine at Harvard Medical School. "In fact, they are considerably less potent than the sulfonylureas or metformin [standard diabetes drugs]." Nathan tells WebMD the greatest benefit may come by combining TZDs with other drugs, although he cautions that the results of doing so are not yet fully understood.
Another potentially significant benefit of TZDs is that they appear to lower the levels of free fatty acids in the bloodstream, a new focus of attention for diabetes experts because of their connection to diabetic complications. "I think that's an important aspect of TZDs," says Paul Jellinger, MD, past president of the American Association of Clinical Endocrinologists. "It's one of the apparent benefits of TZDs that hasn't been widely appreciated yet."
A New Direction?
Based in part on the results of the TRIPOD study, Buchanan believes the emphasis of diabetes treatment needs to be shifted.
"Basically, right now, we treat people whose glucose levels are already high enough to cause long-term complications and we try to get their levels lowered," he says. "But by the time someone has gotten to the point of diabetes, they've probably lost about 80% of their beta-cell function. Someone with just Impaired glucose tolerance [an aspect of pre-diabetes] has already lost about 50% of their beta-cell function."
Buchanan wants diabetics and doctors to understand better the difference between the manifestations of disease -- heightened glucose levels -- and the loss of beta-cell function that may be causing them.
"The current paradigm of diabetes treatment is focused on the sprint -- what your glucose levels are -- instead of the marathon, which is how the disease is progressing," he says.
However, other experts caution that the results of the TRIPOD study and the effectiveness and safety of TZDs need to be confirmed.
"TZDs are an incredibly important addition to our set of tools," says Fran Kaufman, president of the American Diabetes Association and division head of endocrinology at the Children's Hospital Los Angeles. But she cautions that more studies need to be done. "Whether other studies will show a similarly robust effect of TZDs [as the TRIPOD study did] is something we just don't know."
The Risks and The Costs
There are potential dangers to TZDs. This was most evident in 2000, when the Food and Drug Administration asked the manufacturer of Rezulin to withdraw it after reports of severe and sometimes fatal liver poisoning. The two other TZDs that are currently available, Actos and Avandia, have not shown the same risks and other TZDs are currently in various stages of development. However, the FDA still recommends that liver function of people using TZDs be tested regularly.
The problems with Rezulin illustrate the risks of using any newly developed drug. "Like any drug that's only been used for a short time, we just don't know what the long-term risks might be of TZDs," Buchanan says.
As noted, TZDs have also been connected with weight gain. While the extra fat may be subcutaneous, and thus not as dangerous as visceral fat, the long-term effects of the weight increase aren't known; some patients gain so much weight that treatment needs to be stopped. Studies have also shown an increase in the risk of edema -- the build-up of fluid in tissue -- from TZD use.
There have been reports of other potential problems, and one survey of patients using TZDs found that the risk of congestive heart failure actually increased, in contrast to studies demonstrating the cardio-protective characteristics of the drugs.
Finally, the financial costs of TZDs may hamper their usefulness; they are significantly more expensive than other drugs used to treat diabetes. While Kaufman hopes that prices will drop as more TZDs are released, Buchanan is concerned that this may not happen until the patents on particular TZDs expire.
Who Needs TZDs?
Given the possible benefits of TZDs, you may wonder whether you should be using them yourself. They aren't appropriate in all cases, and many of their benefits need to be confirmed.
For instance, despite the promise of the TRIPOD study, TZDs are not recommended for the treatment of pre-diabetes. "I get asked a lot whether you should treat everybody with insulin-resistance syndrome with a TZD," says Buchanan, "and the answer is no." Buchanan notes that insulin resistance is really marked by a cluster of things, and treatment should be based on what symptoms an individual has.
It is also crucial to know that other studies, such as the Diabetes Prevention Program (DPP), have demonstrated the effectiveness of behavioral interventions -- such as regular exercise and weight loss -- in slowing or preventing the progress of pre-diabetes to type 2 diabetes. Depending on your case, changes in your diet and an increase in exercise may be the best medicine.
For the time being, doctors are generally advised to use TZDs cautiously because of their potential risks. But the beneficial effects of TZDs point to a possible future in the treatment of diabetes.
"I think that if nothing else, TRIPOD showed that by focusing on the relieving the stress on beta cells, we can slow the progress of IGT and type 2 diabetes," Buchanan says. "We can stabilize the process."
Originally published March 17, 2003.
Medically updated June 18, 2004.
SOURCES: Thomas Buchanan, MD, director of the clinical research center at the Keck School of Medicine; professor of medicine at the University of Southern California; leader of the Troglitazone in Prevention of Diabetes (TRIPOD) study. Om Ganda, MD, associate clinical professor of medicine at Harvard Medical School; senior physician and director of the lipid clinic at the Joslin Diabetes Center; attending physician at Beth Israel-Deaconess Medical Center, Boston. David E. Goldstein, MD, chair of the NGSP Steering Committee; professor of child health and principal investigator at the health sciences center at the University of Missouri School of Medicine. Paul Jellinger, MD, past president of the American Association of Clinical Endocrinologists (AACE); clinical professor in the department of medicine at the University of Miami School of Medicine. Fran Kaufman, MD, president of the American Diabetes Association (ADA); head of the division of endocrinology and metabolism and director of the comprehensive childhood diabetes center at the Children's Hospital in Los Angeles; professor of pediatrics at the Keck School of Medicine. David M. Nathan, MD, director of the general clinical research center and of the diabetes center at Massachusetts General Hospital; professor of medicine at Harvard Medical School; chairman of the Diabetes Prevention Project (DPP).
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