Following the Twists and Turns of Type 2 Medications

| May 1, 1999

A type 2 medication can reap huge sales, and the world's pharmaceutical businesses compete fiercely for a part of the type 2 market of 14 million people. The push for these sales has brought out many new drugs during recent years. Yet, the recent Rezulin controversy serves as a reminder that knowing all you can about your medication can improve your health.

The type 2 treatments all have different functions, and what your physician prescribes is related to the underlying cause of your diabetes. Knowing your own body and the drug's specific function can help you understand your doctor's prescription, and better treat your diabetes. This is a guide to all of the treatments, including the latest developments in this dynamic area of health care.

Diet and Exercise

You often hear it said, "If diet and exercise fail..." then type 2 people go on an oral medication. Yet, it seems that most type 2s are on an oral medication, so do "diet and exercise" really work?

The number one prescription for type 2 diabetes is weight loss through reformed eating habits and exercise. With early type 2 diabetes, the body is still producing insulin, but it resists the insulin's effects. The goal of this "diet and exercise" therapy is to reduce the body size, making it a more manageable job for the insulin.

"It's do-able," says Terry Zierenberg, RN, CDE, program coordinator for the Diabetes Care Center at Encino-Tarzana Regional Medical Center in Los Angeles. "It's especially do-able for people who've just been diagnosed. It's definitely do-able, but we're talking about aerobic activity every day."

A Mouthful of Oral Choices for Type 2

Still, for many, lifestyle changes after many years are too hard. Exercise becomes too painful because of neuropathy, or it's just not enough, and drugs are then necessary to bring down glucose levels.

With all the different diabetes drugs out there, your doctor must choose one for you based on the underlying causes of your diabetes.

Sulfonylureas: Buying Time

In the past, before other drugs were available, sulfonylurea drugs were the first choice of treatment. They work on people who are still producing insulin in the pancreas, acting like a whip to a pancreas, encouraging it to make more insulin.

"If a person with type 2 diabetes is not overweight, a sulfonylurea may still be the first choice," states R. Keith Campbell, RPh, CDE, professor of pharmacy at Washington State University, "although a controversy still exists."

Campbell reports that sulfonylureas stimulate the body's potassium channels to bring out more insulin from the pancreas. "But if the potassium channels in the heart are stimulated, it could result in an increased risk of cardiovascular problems." Campbell believes in the sulfonylurea glimepiride, brand name Amaryl, because Amaryl does not affect the heart.

For years, sulfonylureas were the only type 2 treatment, but science created others, because eventually sulfonylureas stop working.

According to Zierenberg, "When you're on a sulfonylurea after a number of years, it will tend to wear out the pancreas, because it's asking it to work harder. It's trying to buy people a little more time before they end up on insulin."

Repaglinide: More Help for the Pancreas

Repaglinide, brand name Prandin, arrived in 1998 with a similar goal to sulfonylureas-to stimulate the pancreas' beta cells in producing more insulin. But it was marketed as working differently from sulfonylureas.

"There are two phases of insulin release-a first phase and a second phase. Prandin seems to work on that first phase response, which helps postprandial [after meals] hyperglycemia. In other words, it works a little bit faster. It only works in the presence of glucose, so, if the blood sugar doesn't go really high after lunch, Prandin doesn't do anything. If the blood sugar goes up, the Prandin will kick in and do what it's supposed to do," reports Zierenberg.

One drawback Zierenberg names is that it must be taken with every meal, and people can easily forget to do this. Users of repaglinide should be warned that if they take a pill but do not eat, they risk hypoglycemia.

Insulin Resistance

Yet, if your underlying problem is insulin resistance, you don't need more insulin, you need to help it work. According to Zierenberg, more than 75 percent of type 2s produce adequate insulin but the body cannot properly use it.

Metformin: Works While You Sleep

"Early type 2 people have more insulin in their system than they can even use. It's an insulin resistance disease. So, why not take a different drug that may ask the body to utilize the insulin better," says Zierenberg, who often chooses metformin, or Glucophage, first for people who are insulin resistant.

"If someone is healthy, with normal kidney function, Glucophage is my favorite first. It tells the liver not to put out so much sugar while the person is sleeping."

Zierenberg describes how it works, saying, "What's common in type 2 diabetes is central obesity, which is fat through the middle. In these patients, the liver likes to put out sugar while they are asleep. Glucophage tells it to slow down and tends to make the muscles a little more sensitive to the glucose uptake, and the insulin. It will also, in some patients, help their lipids. It's one of my favorite, first-line therapies, after diet and exercise."

Metformin is often prescribed for people who wake up with high glucose levels. This is the sign that the liver is putting out sugar during the night. Others, however, have normal sugars in the morning, but they rise during the day, after eating. For these people, therapy is different.

Troglitazone: "It's a Food Thing"

"If you see a patient that's waking up with good blood sugars but then climb throughout the day, it's a food thing," reports Zierenberg.

For these people, troglitazone, or Rezulin, can be a first line of defense.

Says Zierenberg, "Rezulin makes the muscles more sensitive to the insulin that's already on board. It also doesn't ask the pancreas to make more insulin. Again, that's for people with normal liver function, under the guidance of a physician. Take it only one month at a time, with liver function tests every month, as the package recommends."

Acarbose: Working On the Intestines

Acarbose, brand name Precose, began a class of type 2 drugs called the alpha-glucosidase inhibitors. It works in the intestines on carbohydrate digestion so that post-meal BGs don't shoot up so drastically.

Zierenberg says Precose "inhibits the absorption of carbohydrate from the small intestine."

Combination Therapy

Your physician may try to fight your diabetes on several different fronts, using a combination of drugs. The FDA also approves combinations, ruling on which drugs are safe together.

"Many of the drugs work nicely together, in that they all have different approaches to diabetes management," says Zierenberg.

Latest on Type 2 Oral Prescriptions

Competitors have taken advantage of the Rezulin controversy, hoping that people will be scared away by the liver deaths and run to their promises of a medication "not associated with liver toxicity."

(For those who haven't heard, the immensely popular oral treatment Rezulin has caused somewhere around 30 deaths due to liver toxicity. Warner-Lambert, Rezulin's maker, the FDA, and many doctors and patients continue to endorse Rezulin and tout its success at controlling diabetes.)

A number of new type 2 treatments are available, or are in the approval process with the FDA:

Miglitol

Miglitol, brand name Glyset, arrived in February for treatment of mildly elevated glucose levels in people recently diagnosed with diabetes. Its manufacturer, Pharmacia & Upjohn, calls Glyset "nonsystemic" because it works in the small intestine. The company recommends Glyset to supplement diet and sulfonylureas.

Glyset is an alpha-glucosidase inhibitor (AGI). When a person eats carbohydrates, an AGI stops the small intestine from converting all of those carbohydrates into glucose.

In clinical trials, 41 percent of people who took Glyset experienced flatulence, and 28 percent reported diarrhea as a side effect. Pharmacia & Upjohn says that these side effects "are usually mild to moderate and diminish over time and with dosage adjustment."

Rezulin's Cousins

Two potential drugs of the same class as Rezulin, hinting at fewer liver problems, are being fast-tracked by the FDA, meaning an approval decision should be made by early May. Rezulin's scientific name is troglitazone, and its two cousins are rosiglitazone, brand name Avandia, and pioglitazone hydrochloride, brand name Actos. All three fight diabetes by battling insulin resistance.

Avandia is made by SmithKline Beecham, while Actos comes from a Japanese company called Takeda Pharmaceuticals in a joint venture with Eli Lilly. Both companies are trying to distance the products from Rezulin's liver controversy.

"Avandia is metabolized differently in the liver," says Barry Goldstein, MD, PhD, director of endocrinology and diabetes at Thomas Jefferson Medical College in Philadelphia. Goldstein was part of the team that performed clinical trials of Avandia.

The "-glitazone" part of the drugs is only half of the molecule, according to Goldstein. The other half of troglitazone is a compound that looks like vitamin E, and it is more easily dissolved in fat. The problem, according to Goldstein, is that the liver is a fatty organ.

"The other part of the rosiglitazone molecule doesn't make it want to stay in fat," he continues. "It's much more soluble in the blood and water. It doesn't accumulate in the liver."

Goldstein says that in clinical trials, rosiglitazone lowered fasting blood sugars by 75 mg/dl. Side effects were weight gain and a "slight drop in red blood cell counts," producing "very slight anemia."

Because neither drug has yet been approved, long-term side effects are difficult to determine.

A New Combination-Amaryl and Glucophage

In March, the FDA approved the combination of Amaryl (glimepiride) and Glucophage (metformin) for fighting type 2 diabetes. This combination treatment uses Amaryl to help the body produce more insulin, while Glucophage fights the body from resisting the insulin that is produced.

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Categories: Blood Sugar, Diabetes, Food, Insulin, Low Blood Sugar, Type 2 Issues, Type 2 Medications


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