Life is getting more complicated for people with type 2 diabetes and the doctors who treat them. But that's good. If you think you and your doctor have a lot of glucose-lowering drugs to choose from now, hang onto your hat as we look at what the biotech companies are developing.
‘We use all the combinations.’
Until 1995, the sulfonylurea class of drugs was the only choice other than insulin for treating type 2 diabetes. Certainly you had a choice of brand, but they all work the same way, by squeezing more insulin out of your beta cells and improving insulin's ability to get glucose into the rest of your body. Sulfonylurea drugs include Glucotrol (glipizide) and Diaßeta, Glynase, and Micronase (glyburide).
The explosion of drugs available for controlling blood glucose began when Glucophage (metformin) became available in 1995, quickly followed by Precose (acarbose). Bristol-Myers Squibb's Glucophage works differently from the sulfonylureas by keeping the liver from making too much sugar. Bayer Corporation's Precose, a third class of drugs, slows carbohydrate digestion.
The fourth choice hit the market a year ago. Parke-Davis's Rezulin (troglitazone) makes the body more sensitive to its insulin. In spite of reports of liver damage in some people, the drug continues to be available here with warnings that people who use it need very frequent liver tests. [On March 21, 2000, Parke-Davis withdrew Rezulin from the market in the United States.]
Rezulin remains on the market here because it works well for most folks. In one study, average levels of HbA1c dropped 1.4 percent. For example, if you have an HbA1c level of 8, you might expect it to come down to 6.4.
Rezulin works even better in combination with a sulfonylurea. In fact, "Any one of these drugs can be used in combination with any other," says Dr. William W. Quick, a board-certified endocrinologist practicing near Kansas City. "The research studies are a bit stronger for some of the combinations than they are for others, but out here in clinical practice we use all the combinations."
"Vegetable soup" is what Dr. Quick calls the choices open to him and his type 2 patients. "We can add any of several different ingredients and come up with a slightly a slightly different flavor for individualized therapy with the drugs that are available now. I am very impressed that we are doing a heck of a lot better than we did in the past when we had just one flavor to our soup."
Now, a fifth class of drugs hit the market in April, when Novo Nordisk and Schering-Plough jointly launched Prandin (repaglinide). It works by stimulating insulin secretion from the beta cells and differs from earlier drugs both in its structure and how it is eliminated. It needs to be taken just before each meal because it is so fast-acting.
Prandin may be even more effective than Rezulin. It reduced HbA1c levels by 2.1 percent in one study reported in the package insert that will come with the drug.
Beyond Prandin, there is an explosion of research on glucose control drugs. "As someone who has had diabetes for 48 years, I don't think that I have ever seen a more exciting time," says Dr. Keith Campbell, associate dean and professor of pharmacy practice at Washington State University College of Pharmacy and a Certified Diabetes Educator.
The glucose control drug probably closest to market after Prandin is Ergoset. The FDA is considering its approval after receiving a New Drug Application from its manufacturer, Ergo Science Corporation, in October.
"We are probably looking at an early 1999 launch," says Donna LaVoie, Ergo Science's executive director, corporate communications and investor relations. Johnson & Johnson will market Ergoset under the terms of a multimillion dollar deal the two companies signed this February.
Ergoset is a low-dose and fast-acting formulation of bromocriptine, which doctors have prescribed for years in a different form to treat Parkinson's disease. Unlike other diabetes control drugs that work at the gut level, Ergoset's action is through the brain, resetting the body's clock that regulates daily metabolic activity.
Studies of Ergoset show an average drop in HbA1c of 1.04 percent. But unlike other studies, that's a measure only of the patients who responded well to it, excluding the 36 percent who didn't.
The drug also has a lipid-lowering effect and is in Phase II trials for obesity. And that's another problem in understanding its effectiveness. Since patients on Ergoset lose weight, there's a question whether it lowers HbA1c directly or because of weight loss, says Dr. Dan Baker, director of drug information at Washington State University in Spokane.
"It is an interesting product, and it will be useful," he believes. He notes that two other weight-control drugs close to market may also help people with diabetes reduce their blood glucose, Meridia and Xenical (see following table).
Like Ergoset, Targretin's original target was another disease. And like Ergo Science, Targretin's developer has a powerful corporate alliance that is some indication of the likelihood the drug will actually come to market.
Ligand Pharmaceuticals developed Targretin to fight certain cancers, but serendipitously discovered that it is also an insulin sensitizer. Ligand has licensed marketing rights to Eli Lilly and Company for $99 million.
"Targretin is a Vitamin A derivative," says Henry Niman, an associate professor in the University of Pittsburgh's epidemiology department and the scientific founder of Ligand's parent company.
The drug is in phase II trials for diabetes and probably won't be on the market until three to four years from now, he says. "In animals it worked great. It was as effective as one of the second generation compounds in Rezulin's class, which are even more effective than Rezulin itself." It also reduced triglyceride levels.
The second generation compound Dr. Niman is talking about is BRL 49653. SmithKline Beecham, which developed the drug says that it is an insulin sensitizer and is in Phase III trials.
Beyond that, the company releases little additional information. "It's frustrating to us in pharmacy and in medicine to project what is going to happen in the future with drug therapy," Dr. Campbell says. "For almost every new drug that comes out there is almost nothing in the scientific literature until about the time the FDA recommends it for approval."
Among all the other drugs now in clinical and preclinical trials to reduce blood glucose levels perhaps the most interesting is SP-134101, which Shaman Pharmaceuticals is developing. The drug just started Phase I trials and probably won't hit the market until about 2003, according to Vice President J. D. Haldeman.
What makes SP-134101 exciting is that it is the first of 21 compounds the company found in tropical plants that lower blood glucose levels in animal models. "SP-134101 comes from a plant that grows in the southeastern part of the U.S. and Mexico," she says. "We will be isolating it directly from the plant."
Even if all of these drugs prove effective in reducing blood glucose, that's not the end of the story. "I consider effectiveness as only a minor factor in my decision-making," Dr. Quick says. "Other factors to consider include cost, side effects, rules about time of administration, taste and other eccentricities of the pill, and contraindications."
An edited version of this article appeared as "Beyond Sulfonylureas" in Diabetes Wellness Letter, May 1998, pages 1-4.
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