Actos Effective in Late-Stage Type 2 Diabetes

16% Lower Combined Risk of Death, Heart Attack, Stroke

Medically Reviewed by Louise Chang, MD on October 06, 2005
From the WebMD Archives

Oct. 6, 2005 -- The drug Actos cuts the risk of death, heart attack, and stroke in people with advanced type 2 diabetes, a large clinical trial shows.

Actos is a new-generation diabetes drug. It lowers blood sugar levels. It also thought to lower patients' risk of heart disease, the No. 1 reason why people with diabetes tend to die far too soon.

But there's never been any direct evidence that Actos really helps prevent heart attacks or stroke. That's why John A. Dormandy, MD, University of London professor of vascular sciences, led a 19-nation study in which 5,238 patients with diabetes added either Actos or a placebo to their treatment regimen. All of these volunteers already had serious arterial disease and/or a previous heart attack or stroke.

"This study is the first evidence in a prospective clinical trial that [Actos] does decrease arterial disease in terms of heart attacks, strokes, and death," Dormandy tells WebMD. "This is the first drug for blood sugar also shown to affect heart attacks, strokes, and death."

The benefit wasn't gigantic; only a 16% lower combined risk of death from any cause, heart attack, or stroke. If 1,000 high-risk people took Actos for three years, it would prevent about 20 of these events.

Dormandy and colleagues report the findings in the Oct. 8 issue of The Lancet.

Heart Failure a Downside?

There are two major downsides to taking Actos, Dormandy says. The first is water retention and weight gain.

"These drugs are known to retain water in the body, but it varies among patients," he says. "People who take Actos are going to retain water, and some will get swelling of the ankles. On average, patients taking Actos will put on a bit of weight. That is a downside. But if that is all it is, it is better to put on weight than to have heart attack and die."

That brings up the second problem: increased heart failure in patients taking Actos.

"Is it better to have healthy arteries in the heart than a failing heart?" asks an editorial accompanying the study. Editorialist Hannele Yki-Järvinen, MD, PhD, heads the division of diabetes at the University of Helsinki, Finland.

"There was two times more heart failure in patients taking Actos," Yki-Järvinen tells WebMD. "Heart failure caused by this drug may not be as bad as heart failure in general. But we don't know how bad this is when the drug causes it."

Since patients treated with Actos were less likely to die from any cause -- and no more likely to die of heart failure than those who took a placebo -- Dormandy says this risk isn't particularly significant for most people with diabetes. And it may be that doctors overdiagnosed heart failure in Actos patients because drug-associated water gain causes swollen ankles - which may also be a symptom of heart failure.

"The crucial fact is that the number of people dying from heart failure in the two groups is identical," he says. "So even if you accept that Actos causes heart failure, it obviously isn't heart failure in any serous sense because it doesn't seem to cause death."

Since only a minority of patients develops heart failure, doctors obviously would like to avoid giving Actos to those most at risk of this apparent side effect.

"But we cannot predict who that will be," Yki-Järvinen says.

Good for Late Diabetes, Good for Early Diabetes?

If Actos helps people with advanced diabetes, might it be more useful earlier in the course of the disease?

The current study does not answer this question. It does, however, provoke speculation.

"The trial was carried out in end-stage diabetics: those who already had evidence of heart disease or minor strokes or whatever," Dormandy says. "If it works for them, it would be extraordinary if it didn't work in type 2 diabetes patients who were earlier in the course of the disease. But that remains speculation. We didn't prove it in this study."

Dormandy notes that during the three-year study, patients who took Actos were only half as likely to start taking insulin as those receiving placebo. That's good news for patients who want to avoid the daily shots.

Yki-Järvinen, however, says patients really should not fear insulin. It's a natural product, she says, and works much better than diabetes drugs.

"The evidence for insulin reducing heart attacks is much better than for this drug," Yki-Järvinen says. "If you use modern, long-lasting insulin, you get good results. And insulin is a natural drug. Of course if you use this pill, it is going to postpone the start of insulin therapy. But insulin itself is not something you have to avoid. One shot a day is no big deal. But this pill is an alternative."

Do Actos Findings Apply to Avandia?

Actos is a member of a family of drugs sometimes called glitazones and sometimes called thiazolidinediones or TZDs. Avandia is another member of this family, and is also currently used to treat high blood sugar in diabetes.

But all these drugs don't work exactly the same. Another glitazone, Rezulin, had to be taken off the market because of severe liver toxicity. Actos and Avandia aren't nearly as hard on the liver -- and Actos actually helps rid the liver of excess fat.

"Although Actos and Avandia are in the same class, there are very significant differences," Dormandy says. "So I think to say that other TZDs necessarily have the same benefit as Actos would be very rash. But they are testing it, and I hope it works."

It's not an academic question. More than one in five Americans with diabetes takes a glitazone drug. Many combine it with insulin -- yet no clinical trial has yet shown whether this actually works.

"This is in a way scary, because there is no study of this," Yki-Järvinen says. "Everyone would like to know if you can use Actos safely when combined with insulin. Unfortunately, this study did not address that question."

The Dormandy study was funded by Takeda Pharmaceuticals and Eli Lilly Co., which jointly market Actos. Eli Lilly is a WebMD sponsor.

Show Sources

SOURCES: Dormandy, J.A. The Lancet, Oct. 8, 2005; vol 366: pp 1279-1289. Yki-Järvinen, H. The Lancet, Oct. 8, 2005; vol 366: pp 1241-1242. John A. Dormandy, MD, professor of vascular sciences, St. George Hospital, University of London, U.K. Hannele Yki-Järvinen, MD, PhD, director, division of diabetes, University of Helsinki, Finland.
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