New Weapons To Cut Diabetes' Toll

Breakthrough drugs may help stem the surging epidemic

For Raquel Palmerin, there seemed to be few options. In May, 1997, when she was 63, Palmerin was hospitalized with a kidney infection, a complication of her type II diabetes. Existing drugs were not controlling her blood sugar levels, and it was likely she would have to resort to insulin injections. But her physician suggested she join the trials of a new oral drug called Avandia--and she did, with dramatic results. Palmerin is no longer plagued by headaches. Not only has she controlled her blood sugar without insulin injections, but also she has regained her energy, walks a mile and a half daily, and has lost 20 pounds. "It was almost an immediate improvement," she says now.

For the 16 million Americans suffering from diabetes, tales like Palmerin's are providing long-overdue encouragement. A series of new drugs that will help diabetes sufferers better control the disease, including Avandia from SmithKline Beecham, are likely to hit the market in the next few years. And these drugs are just the beginning. Researchers at big companies like Eli Lilly & Co., Pfizer Inc., and Novartis AG are studying everything from how to restore insulin's effectiveness in the body, to how much of a role obesity plays in the disease, to how to prevent the disease's deadly complications. Taken together, these developments mark "a revolution in our understanding and ability to treat diabetes," says Dr. Mitchell A. Lazar, director of the Diabetes Center at the University of Pennsylvania Medical Center.

That progress comes as the toll from diabetes mounts. The death rate from diabetes has jumped 50% since 1985, at a time when death rates from heart disease and stroke have been declining (chart). That bad news stems from a number of factors--including a growing number of people who are eating too much and exercising too little and the lack of new drugs to overcome those trends. Diabetes led to an estimated 67,000 amputations between 1993 and 1995, and nearly 28,000 cases of end-stage kidney disease in 1995. And it causes as many as 24,000 new cases of blindness each year. The result: Diabetes contributes to an estimated 193,000 deaths annually.

TWO DISEASES. The direct and indirect costs of the disease are estimated at close to $100 billion annually. And that tab is likely to grow. With sedentary lifestyles and high-fat diets adding to the incidence of the disease, the number of diabetes sufferers is expected to hit 22 million by 2010. "Diabetes is an epidemic," says Lars Rebien Srensen, corporate executive vice-president of Novo Nordisk A/S, a leading insulin maker.

One complication is that diabetes isn't simply one disease. About 5% to 10% of diabetes patients suffer from type I diabetes. In those patients, the immune system destroys cells in the pancreas that make insulin, a hormone that helps the body metabolize sugar. But most diabetes patients suffer from what is called type II diabetes, in which the body produces insulin but the hormone simply doesn't do the job of controlling blood-sugar levels--a condition known as insulin resistance. In both types of diabetes, high levels of blood sugar cause deadly complications.

Until recently, diabetes sufferers relied on old and often ineffective therapies. Type II diabetes patients usually tried to control their disease through diet and exercise or the use of drugs called sulfonylureas, which stimulate the pancreas to make more insulin. For type I patients, and for many with advanced type II, insulin injections were needed to keep blood sugar in check. And historically, potential new treatments often fizzled in development because they disrupted other critical functions, producing nasty side effects.

LIVER TROUBLES. In the mid-1990s, however, new therapies finally emerged from the laboratory. Among them was Warner-Lambert Co.'s Rezulin, part of a class of drugs called thiazolidinediones, or TZDs. The TZDs latch onto a particular receptor on muscle, fat, and liver cells called PPAR. For reasons that are not entirely clear, stimulating that receptor helps insulin do its job better. Thanks to the success of drugs like Rezulin, the U.S. market for diabetes treatments has nearly doubled since 1994, hitting $3 billion in 1998.

But after Rezulin was approved in March, 1997, a number of people taking it developed life-threatening liver complications. The FDA is meeting on Mar. 26 to reexamine Rezulin's safety, and the drug's future is uncertain. Glaxo Wellcome, which sold the drug in the U.K., withdrew it from that market in December, 1997; nonetheless, it hopes to reintroduce it soon. But two new TZDs are expected to hit the market this summer--SmithKline's Avandia and Actos from Takeda Pharmaceuticals America Inc. And many analysts are betting, based on early testing, that these new drugs will not lead to the type of liver problems seen among Rezulin users.

The TZDs are just the first in a stream of new drugs aimed at one thing: making insulin work again. Insulin latches onto cells via a sort of docking station called an insulin receptor. When insulin hits that receptor, it triggers the passage of messages into the cell, stimulating it to take up blood sugar. In diabetes, something goes wrong in that chain of events. Either there isn't enough insulin, or the receptor is malfunctioning, or the mechanism for passing messages into the cell is faulty. Researchers are now studying the entire insulin pathway to figure out where the defects occur--and how to repair them. "This is where the real breakthroughs will come," says Dr. C. Ronald Kahn of the Joslin Diabetes Center in Boston.

The biotech company Insmed Pharmaceuticals Inc. is studying a compound that looks as if it may bypass problems with the insulin receptor, stimulating glucose absorption in another way. And a team of Canadian researchers working with Merck & Co. has identified a protein that might turn off the insulin receptor. A drug that blocks that protein could put the insulin receptor back in business. As those efforts identify new targets for drugs, the race will be on to develop those compounds. "The companies that are successful at getting to market fastest win out," says Stefan D. Loren, analyst at Legg Mason Wood Walker Inc. "It is not necessarily those who spot it first."

Advances in genetics will yield an opportunity to get at the root causes of the disease. Researchers at companies such as Incyte Pharmaceuticals Inc. are trying to identify genes that are turned on or off only in individuals with diabetes. Once those genes are identified, it might be possible to develop drugs, based on that knowledge, that could cure or alleviate the symptoms of the disease.

THE FAT FACTOR. Diabetes patients may also benefit from the huge amount of research directed toward discovering and developing new obesity drugs. Obesity has long been known to be a risk factor for type II diabetes. Trega Biosciences Inc. is one of a number of companies that sees a big opportunity in that connection. It has a partnership with Novartis to identify drugs that stimulate sites in the brain called melanocortin receptors, which appear to suppress appetite. Trega research chief Lawrence D. Muschek says these drugs might also prove useful in treating diabetes.

But until diabetes can be stopped in its tracks, patients need better tools to fight its effects. Eli Lilly & Co. is testing a drug that may help prevent eye damage in diabetics. The drug is intended to slow or stop the growth of excess blood vessels in the eye caused by the disease, which can lead to blindness. Warner-Lambert and Pfizer are testing drugs that act on another enzyme to prevent damage to the kidneys, nerves, and eyes. And if final clinical trials go well, Genentech Inc. could be on the market as early as next year with a drug that promotes nerve growth and protects existing nerves from damage. If these companies succeed, they will be tapping into a market that "is as big as any market can possibly be," says SG Cowen analyst Stephen M. Scala.

Many complications of diabetes could be avoided if patients were religious about taking their insulin injections. But people often tire of injecting themselves. One solution could be new inhaled and oral forms of insulin from companies such as Inhale Therapeutic Systems and Generex Pharmaceuticals Inc. Physicians hope these new, easy-to-use forms of insulin, which are in the final phase of testing, will encourage patients to become more aggressive about keeping their blood sugar at safe levels.

Such advances have been a long time in coming. But for the 16 million Americans with diabetes, they are reason to hope that the frightening rise in deaths may soon be history.

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