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• By
• SHIRLEY S. WANG
• CONNECT

AMSTERDAM—A new class of diabetes drug doesn't appear to increase patients' risk of heart attack, stroke or death, according to two large studies, offering some reassurance to doctors and patients concerned about possible negative heart effects.

But there was a signal in one of the trials—which were presented at an international cardiology meeting Monday—that the drug might increase patients' risk of heart-failure hospitalizations. Heart failure is a complex, chronic condition in which the heart doesn't pump enough blood to the body.

The findings also raise questions about whether drugs that only lower blood sugar, without addressing cholesterol, blood pressure or lifestyle factors, are enough to improve heart health. Previous small trials had suggested a possible benefit from lowering blood sugar.

Scrutiny about diabetes drugs' possible deleterious cardiovascular effects arose in recent years after a controversy about whether a diabetes medicine of a different class, GlaxoSmithKline PLC's Avandia, was linked to a rise in patients' risk of an acute cardiovascular event, such as a heart attack.

In 2008, the U.S. Food and Drug Administration issued guidance that drug makers needed to demonstrate that new diabetes drugs wouldn't lead to an "unacceptable increase in cardiovascular risk." In 2010, Avandia was removed from the market in Europe and use in the U.S. was restricted. But in June, a Duke University study suggested cardiovascular events didn't increase with Avandia, and an expert committee advised the FDA to ease curbs.

The studies presented Monday at the European Society of Cardiology Congress investigated a newer class of drugs known as DPP-4 inhibitors, which are supposed to help bring diabetics' blood sugar into normal range. Both studies were published Monday in the New England Journal of Medicine.

One of the trials, known as Savor Timi-53, was a 16,492-patient study on the medication saxagliptin, marketed by Bristol-Myers Squibb Co. and AstraZeneca PLC as Onglyza. Patients with Type 2 diabetes and a history of, or at risk for, cardiovascular events were randomly given the medicine or a placebo as well as other standard treatment and were followed for two years on average.

The other study, called Examine, was a randomized study of alogliptin—Takeda Pharmaceutical Co. and Sanofi SA's Nesina—in nearly 5,400 patients for an average of 18 months.

The studies, conducted independently of each other, found similar outcomes on the main endpoint of heart attack: The gliptins didn't increase heart-attack risk compared with a placebo but also didn't lower risk. However, there was a statistically significant difference in heart-failure hospitalizations with Onglyza: 3.5% for the group taking it, compared with 2.8% for the control group.

"I think what we have provided in this trial is a great deal of clarity with respect to heart-attack risk," said Deepak Bhatt, a senior physician at the Brigham & Women's Hospital in Boston who presented the Savor data on Monday. "But this heart-failure finding was unexpected. For that reason, it's important to be a little bit cautious in interpreting it."

The finding needs further examination to verify it and understand which patients might be susceptible to heart failure, Dr. Bhatt said. "What we need to do, and in fact what we're doing, is really trying to drill down on that and see exactly who might be at risk for heart failure." said Dr. Bhatt.

Overall, however, experts who weren't involved in the study said the data largely put to rest concerns about the possible heart-attack risk with DPP-4 inhibitors. "I personally feel a certain amount of reassurance," said Anthony DeMaria, a professor of medicine at the University of California, San Diego, and editor in chief of the Journal of the American College of Cardiology. "Gliptins can be incorporated into overall diabetes treatment without excessive concern about cardiac effects."

It remains a question whether diabetes drugs that lower blood sugar can benefit the heart. Some experts said they were discouraged by findings that suggest DPP-4 inhibitors don't cut heart-attack risk. Others said they never expected a benefit because a multipronged approach is necessary.

The DPP-4 inhibitors tend to be mild in their effect but well tolerated, but it is "not very logical" to think that lowering blood glucose alone would translate into reduction in heart-attack risk, said Heinz Drexel, chairman of the department of medicine and cardiology at Feldkirch Hospital in Austria and president of the Austrian Diabetes Association. He wasn't involved in these trials but has been an investigator on various clinical trials of diabetes drugs.

"Glucose lowering should be accompanied by cholesterol lowering through statins and by blood-pressure control," Dr. Drexel said.

In addition, these latest findings suggest that the FDA needs to think about a new way of assessing diabetes drugs, according to Sanjay Kaul, a cardiologist at Cedars-Sinai Medical Center in Los Angeles, who wrote an accompanying editorial in Monday's New England Journal of Medicine.

Currently, a blood-based marker of glucose control called HbA1c, which serves as a proxy for how well the diabetes is controlled, is used as a primary outcome measure on which approvals are based. But "it is time for the FDA to consider a patient-oriented clinical outcome of benefit," such as prevention of kidney failure or blindness, Dr. Kaul said in an email.

"While it is reassuring that evidence does not suggest [cardiovascular concerns], it is disappointing that none of these therapies provide CV benefit," Dr. Kaul said.

Write to Shirley S. Wang at shirley.wang@wsj.com