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Harvard Research on Glaxo's Avandia May Point Way to New Diabetes Options
Harvard University researchers discovered how GlaxoSmithKline Plc’s diabetes drug Avandia works to prevent the illness, a step that may show the way to develop less-toxic drugs that are just as effective.
The study identified how Avandia and similar drugs work by blocking a cell process involved in diabetes, and suggests that side effects may come from a separate action also triggered by the pill. That opens the door to developing newer treatments without the toxic activity, the researchers say.
Sales of Avandia, once the world’s best-selling diabetes medicine, plunged after a 2007 analysis linked the medicine to a 43 percent increased risk in heart attacks. A U.S. advisory panel’s call for stronger warnings about heart risks tied to Avandia may eliminate 95 percent of the drug’s use, said Steven Nissen, head of cardiology at the Cleveland Clinic in Ohio, in a interview last week.
“The mechanism of action in terms of these drugs is not the function that people thought,” Bruce Spiegelman of Harvard Medical School said in an interview from Boston. “The benefits are largely due to modification of the protein, not just generally activating it.”
Avandia, known by the generic name rosiglitazone, also decreases hemoglobin levels, may raise cholesterol and can cause swelling and weight gain, according to previous studies.
New Generation
Almost 21 million Americans and 170 million people worldwide have diabetes, according to the National Institutes of Health. There is an epidemic of type 2 diabetes under way, fueled by rising obesity rates, age and sedentary lifestyles, public health officials said.
The cells of those patients don’t properly use insulin, a hormone that turns blood sugar into energy. Persistent high blood sugar eventually damages the nerves and blood vessels,leading to blindness, kidney failure and death.
Avandia belongs to a family of medicines known as thiazolidinediones, or TZDs, that have been taken by more than 15 million people since they were made available in 1999.
They work by activating a cell protein known as PPAR that makes diabetics more sensitive to the hormone insulin, while also triggering side effects including higher blood lipids and heart failure risk. Today’s study found that some TZDs other than Avandia may mobilize PPAR in a way that still increases insulin sensitivity without causing the side effects.
Benefit Without Harm
Subtle modifications to Avandia and other medicines in the class to circumvent the side effects could lead to a new generation of diabetes drugs, Spiegelman said.
“Avandia has very good effects clinically, there is a good reason to try to see how we get the benefit without the negative effects,” Spiegelman said. “This should point the way to how one can separate the good and bad effects of these drugs. At least that’s the hope.”
Takeda Pharmaceutical Co.’s rival pill Actos, which is in the same family of diabetes medicines as Avandia, has been shown to work as well as Avandia without the same risks. It is not clear why.
“Different compounds don’t have to be in lockstep,” he said. “Since the beneficial effects are not coming from the mechanism that was previously thought you can understand how you could get different ratios of risk and benefit.”
Speigelman said new compounds taking the research into account could enter clinical trials within one to three years. “How to move this forward becomes pretty obvious,” he said.
To contact the reporter on this story: Trista Kelley in London at tkelley2@bloomberg.net.
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