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Sat 1 Sep 2007 04:00 AM

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Outlook on diabetes drug less than rosy

Early work suggests that rosiglitazone (Avandia) may not be the best drug for the heart.

In May 2007, millions of people with diabetes got something extra to worry about - the possibility that a drug they were taking to control blood sugar might be harming their hearts. According to a report in the New England Journal of Medicine (NEJM) that touched off a media firestorm, Avandia (rosiglitazone) increases the chances of having a heart attack or dying of cardiovascular disease. The news prompted many people to call their doctors.

The cardiovascular safety of Avandia and other diabetes drugs is an important issue, since heart disease is the most common cause of death among people with diabetes. More than 16 million Americans have the disease, and the number is growing fast. The preliminary finding certainly sounds a note of caution about this new drug.

Controlling blood sugar

Avandia makes liver and muscle cells more sensitive to insulin.

Type 2 diabetes often starts when the body's tissues lag in responding to insulin. This hormone unlocks the molecular doors through which blood sugar enters a cell.

Resistance to insulin means that sugar builds up in the bloodstream after a meal or snack, instead of being efficiently and relatively rapidly absorbed by cells to meet their energy needs. The body responds by making extra insulin in an effort to force open those doors.

Avandia makes liver and muscle cells more sensitive to insulin. The FDA approved the drug in 1999 based on clinical trials showing that it reduces blood sugar levels in people with type 2 diabetes.

That's a good thing, and it is the most immediate goal of diabetes drugs. But none of the trials lasted long enough to show if Avandia prevents what actually matters to people with diabetes - heart disease, damage to blood vessels or nerves, or cardiovascular-related death.

Some early signs hinted at problems with the drug. It can increase LDL (bad) cholesterol by 15% to 20% and slightly reduce the amount of oxygen-carrying haemoglobin. Bothered by these and other hints of trouble, two Cleveland Clinic researchers combed the results of 42 clinical trials that tested Avandia against a placebo for cardiovascular problems.

After adjusting for age, level of diabetes, how long the medication was taken, and other factors, the researchers determined that those taking rosiglitazone had a 43% higher risk of having a heart attack and a 64% higher risk of dying from cardiovascular disease.

Keep in mind that those are relative risks - they compare problems with Avandia against problems with placebo. The absolute risks are a bit more reassuring. Among the 15,560 volunteers who took Avandia, 86 (0.55%) had heart attacks and 39 (0.25%) died. Among the 12,283 who took a placebo, 72 (0.58%) had heart attacks and 22 (0.18%) died. It is also worth noting that none of the trials included in this study were designed to look at the drug's effect on the heart.

A large trial that began in 2000, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD), is looking specifically at the cardiovascular impact of the drug. A week after the NEJM report appeared, the journal published a midstream analysis of RECORD conducted by the independent board that monitors the trial for safety. It didn't show a big hazard with Avandia, but it didn't show a cardiac benefit from the drug, either.
More to the story

Stories like this one - problems surface with a drug after it has been approved and has been used by millions of people - aren't new. In fact, they are fairly common. Since the early 1980s, about 10% of all new drugs approved eventually acquired a "black box" warning because of safety problems. Nearly two dozen were pulled from the market, including the painkillers Vioxx and Bextra, Baycol (a statin), Seldane (an antihistamine), and Posicor (a blood pressure medicine).

Since the early 1980s, about 10% of all new drugs approved eventually acquired a “black box” warning because of safety problems.

Why does this happen? In large part it's because the trials used to test a new drug are small and short, while eventually millions of people may take the drug for years. Another problem is that drug trials often exclude people of a certain age or with certain conditions, while after its approval almost anyone can take it.

Patience pays off

It's hard to say what will happen with Avandia. As we were going to press, the FDA announced that it would require the labels of Avandia and a similar drug, Actos (pioglitazone), to display a prominent black box warning of possible problems with heart failure. Whether that warning will be extended to heart attack risk remains to be seen.

The Avandia story offers once again an important lesson for doctors and the rest of us: Don't be too eager to try a brand-new drug when you can use an equally effective alternative that has been around for a while. There are many diabetes drugs on the market. Most lower blood sugar as effectively as Avandia without the potentially harmful changes in LDL and haemoglobin. Whether Actos is safer for the cardiovascular system than Avandia is grist for future studies.

The new findings make it clear that Avandia isn't good for the heart, something researchers had suggested might be a possibility when it was under development. Older medications, such as metformin, have a better track record for safety and possible benefits in cardiovascular disease.

Patients taking Avandia, should not automatically stop taking it. The increased cardiovascular risk, if it exists, is exceedingly small for an individual. If a patient were to stop the drug without having an alternative in place, the prolonged increase in blood sugar and insulin would be worse than a small and theoretical risk from Avandia. Look at the various benefits, risks, and alternatives. Everyone is different. Some people do fine with metformin or another diabetes medication to control their blood sugar; others need extra help. Whatever a patient and their doctor decides to do, they should not overlook exercise, the most potent anti-diabetes therapy around.

This article is provided courtesy of Harvard Medical International. © 2007 President and Fellows of Harvard College.

Options for controlling blood sugar

A variety of drugs are available to help people with diabetes control their blood sugar. They are listed here from the oldest to the newest. The last three were approved in 2005 and 2006.

Drug class

Insulin
Examples: Injectable insulin was recently joined by Exubera, the first inhaled form

Sulfonylureas
Examples: glimepiride (Amaryl), glipizide (Glucotrol), glyburide (Diabeta, Glynase, Micronase), tolbutamide (Orinase)

Biguanides
Examples: metformin (Glucophage)

Alpha-glucosidase inhibitors
Examples: acarbose (Precose), miglitol (Glyset)

Glinides
Examples: nateglinide (Starlix), repaglinide (Prandin)

Thiazolidinediones
Examples: pioglitazone (Actos), rosiglitazone (Avandia)

GLP-1 analogue
Examples: exenatide (Byetta)

Amylin analogue
Examples: pramlintide (Symlin)

DPP-IV inhibitor
Examples: sitagliptin (Januvia)

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