The safety of most diabetes drugs are time-tested — insulin was discovered in the early 1920s, and two of the other most commonly prescribed, metformin and sulfonylurea, have been around since the 1950s.
Avandia is different. The drug landed with a splash on the market 11 years ago and quickly became the top-selling diabetes drug in the world. It's used by Type 2 diabetics to help improve blood sugar control in a different way than most other diabetes medications. Instead of causing the body to make more insulin, it works to use what is naturally made more efficiently.
But when studies began to link it to an increased risk of heart attacks and strokes, its fortunes quickly reversed. Now an advisory panel to the Food and Drug Administration has recommended that the drug be slapped with stricter warnings and increased supervision.
That doesn't mean diabetes patients taking Avandia should necessarily stop. Or that there are no options for those who choose to do so. Far from it. Rather, it offers a lesson in how medications are prescribed for Type 2 diabetes, which accounts for 90% to 95% of the 23.7 million diagnosed diabetes cases in the U.S.
As with high blood pressure and cholesterol, there is no silver-bullet, cure-all medication for either type of diabetes, said Daniel Einhorn, president of the American Assn. of Clinical Endocrinologists. Treatment for Type 1 (in which the body produces no insulin) largely amounts to taking insulin and maintaining a healthy lifestyle. But treatment for Type 2 (in which the body does not produce enough insulin or is resistant to what is produced) often includes a combination of drugs, which can produce varying results among different patients or even in the same person over a number of years.
Neither doctors nor their patients have to wade through the offerings on their own. They have a long history of data on which to draw. Avandia's rapid rise and fall highlights the importance of knowing what to expect.
To improve medication management for diabetics, professional associations such as the American College of Endocrinology and the International Diabetes Center have created charts detailing how and when to prescribe the drugs based on myriad factors, including a patient's weight, fitness level, health conditions, other medications and ability to control blood glucose levels.
"Doctors can take many paths down the road, but the road maps give you advice," Einhorn said. "They like the ability to choose a plan for patients, but many are kind of glad to have the guidance of general principles."
The charts provide information on target glucose levels, potential side effects and benefits of the drugs, and suggestions on when to add new medications.
When first diagnosed with Type 2 diabetes, most patients are advised to regulate blood sugar with exercise, diet and stress management. If that fails, the first medication that they receive is usually metformin, said Sanjay Kaul, a cardiologist at the Cedars-Sinai Heart Institute and member of the FDA's Avandia panel.
Metformin has the five characteristics physicians look for in diabetes medications, Kaul said: few potential complications, safety, tolerability, ease of use and a low cost.
"Metformin is preferred by professional societies as the treatment of first choice for diabetic patients," he said. "It is relatively safe, without side effects, well tolerated, weight neutral and inexpensive. And evidence shows it may save lives."
It decreases the amount of sugar (glucose) the body takes from foods and the amount of glucose produced by the liver. About 15% to 20% of diabetes patients cannot tolerate the drug because of gastric side effects or kidney problems, said Richard Bergenstal, president of medicine and science for the American Diabetes Assn. and executive director of the International Diabetes Center.
When first starting diabetes medications, some patients experience side effects such as water retention. These are usually seen within a week or so, and three months is sufficient time to see if a drug is affecting glucose reduction, Bergenstal said.
If a patient can't tolerate the drug or it doesn't decrease blood sugar adequately, a second medication is typically added to the regimen. About a dozen categories of drugs are available in the second class of medications, Bergenstal said, but four of them make up about 90% of prescriptions.
One group is sulfonylureas (such as Amaryl, or glimepiride), which help the pancreas release more insulin. A second is DPP-4 inhibitors (such as Onglyza, or saxagliptin). DPP-4 is an enzyme that blocks the secretion of the hormone GLP-1, which stimulates the release of insulin. The third is GLP-1 agonists (such as Byetta, or exenatide), which mimic the actions of GLP-1. And lastly, thiazolidinediones (such as Avandia, or rosiglitazone, and Actos, or pioglitazone), which increase the body's sensitivity to insulin.
If patients still don't meet their target glucose levels, a third medication is added to the regimen. This could be another of the drugs not used in the second tier, background insulin (long-acting, which stays in the bloodstream for 24 hours) or a thiazolidinedione. If patients continue to have problems, the fourth, and final, level of treatment is insulin therapy.
But doctors can, and obviously should at times, move beyond the guidelines. Among the most important factors in doing so are patient preferences and needs.
Treatments should not just be safe but manageable over the long term. That often amounts to a limit of one or two doses a day, Einhorn said. Further, they should be as effective as possible so patients aren't forced to monitor glucose too frequently.
Many patients don't want to give themselves shots and look at insulin as "the end of the road," so doctors may try to avoid insulin when possible, Bergenstal said. Others may need to lose weight, so doctors might choose drugs less likely to cause weight gain.
"Knowing your patient is really critical," he said. "As much as we put algorithms out … if you match them to patients' best preferences, you will get the best outcome."
And monitoring is crucial — both of the patient and of the drugs on, and coming to, the market, as the troubles with Avandia so aptly highlighted.
"Even when a drug gets approved for sure, maybe 5,000 people have taken it, so now we have 1 million who will be using it," Bergenstal said. "We have to have good surveillance and be willing to change our mind and modify things."
Even after a drug is approved by the FDA, doctors and medical associations gather data to see how it affects patients before relying on it too heavily, he said. Sometimes the data are inconclusive, as with Avandia — even the FDA panel that waded through numerous studies could not decide if there was enough of a cardio risk to pull it from the market.
This is where physicians help decide the risks and benefits to their patients, Kaul said. When an FDA advisory committee meeting was held in 2007 to look at Avandia studies, physicians had already started curtailing the use of the medication, he said. The market share of thiazolidinediones that year was essentially split 50-50 between GlaxoSmithKline's Avandia and its competitor, Takeda Chemical's Actos. Avandia's market share is about 10% now and "rapidly shrinking," Kaul said.
"Physicians have already decided what to do with Avandia," he said. "They use their clinical judgment and are obligated to protect patients from potentially harmful therapies."