This post is the third in a series under the title: 2009. Another Troubled Year for Endocrinologists.
This year the FDA has instituted new standards for diabetes drugs coming up for approval. These new standards require that each new drug prior to approval must demonstrate the lack of any negative impact on cardiovascular (heart and blood vessel) health. While this may seem a legitimate requirement, in reality it requires thousands of patients be treated for many more years in research settings to acquire this information. So far three new diabetes medications from Takeda Pharmaceuticals, Novo Nordisk and Bristol Myers have all been put in limbo due to delays on their approval based on the new requirements.
I would point to the case of Avandia as an example of how difficult it is to prove that a drug has negative cardiovascular effects. In 2007 an alarm was sounded by several outspoken critics, whose analysis pointed to increased cardiovascular risk from Avandia. At that time Avandia was a key diabetes medication on the market for over 5 years with millions of individuals treated. Although the diabetes community remained split on the truth of these assertions major medical organizations such as the American Diabetes Association placed a virtual ban on the use of this medication and the FDA placed its highest “black box” level warning on Avandia use. At that time the FDA was criticized widely for allowing this supposed public danger to go unrecognized for so long. Many think that it is in response to this criticism that the FDA was forced to add the new much more stringent requirements on new drug approval.
Since 2007 however, a large V.A. study (the VADT study) and the 2009 RECORD study both found no evidence of cardiovascular risk with Avandia use. The belief is growing that the FDA was initially correct in allowing Avandia to come to market, although so much negative publicity has hurt the use of Avandia and led the FDA to take a highly defensive approach to new drug approval.
Some pharmaceutical executives believe the new FDA requirements will double the cost of bringing a new drug to market. Approval of several promising new diabetes treatments has already been stalled and the companies developing new medical therapies are beginning to move diabetes treatment to the back-burner. It is likely that it will takes years to reverse this trend, if a reversal is possible at all.
Gary Pepper, M.D. Editor-in-Chief, Metabolism.com
How do I prevent type 2 diabetes?
If you have a close relative with type 2 diabetes (the kind that usually develops in adulthood), you are at risk for developing diabetes yourself.
1. The most important way to avoid developing diabetes is to pay close attention to nutrition and exercise and to maintain a healthy weight. The particular food groups you eat may not be as important as how many calories you consume. Once obesity develops the risk of type 2 diabetes goes way up.
2. Exercise not only helps prevent obesity but the muscle you develop through exercise helps your body to metabolism blood sugar. This lowers your diabetes risk.
3. Recent studies have shown that some medications used at the first sign of high blood sugar can prevent or delay the onset of type 2 diabetes. Among these medications are acarbose (Precose) which blocks absorption of carbohydrates from the intestine, rosiglitazone (Avandia) which makes the body more sensitive to insulin, and orlistat (Xenical or Ali) which blocks absorption of fat from the intestine. These drugs are not yet approved by the FDA for the purpose of preventing type 2 diabetes. For each individaul with prediabetes only a health care professional can determine if such medication is appropriate.
Gary Pepper, M.D.
Terms of Service apply to this post https://www.metabolism.com/2008/09/06/terms-conditions-service-agreement/
Once the superstar of the medical world and the number one darling of doctors for the treatment of diabetes, Avandia is now a big disgrace. The image of Britney Spears comes to mind when considering this story. After all, the rise and fall of Avandia does make for great tabloid reading. Avandia reached the market as a one of a kind treatment for diabetes and within a few years was at the top of the heap making billions of dollars for its maker GlaxoSmithKline. In the past few years there has been a vague undercurrent of trouble with this drug including limited availability, due to what Glaxo said were problems with its manufacture. The company blamed it on hurricane damage to its factory. Then came the sudden, dramatic tumble from the top when the media broke the story of a possible ugly side to this beauty (http://blog.metabolism.com/2007/10/01/the-avandia-debate-common-sense-required/).
Now Avandia and its maker can’t seem to get out of their own way. Stories have circulated about mishandling of data, and intimidation of Avandia’s critics by Glaxo. Most recently the search for culprits has brought other celebs such as Bill Gates into the circus spotlight.
Meanwhile, not even a kind word from the FDA can restore Avandia’s former glitter. Doctors all over the country have turned their backs on their former darling and are even snickering among themselves about the scandal. It seems like Avandia has followed closely in the footsteps of Britney Spears. I wonder when it will be that the paparazzi snaps a picture of the Avandia box in a compromised position in a seedy nightclub.
On November 14 the FDA released a new warning about potential heart complications of Avandia. After reading the statement which can be found at
I was most impressed by the reserved tone the FDA used in describing the risk. Based on the types of articles already published by some leaders in the field of diabetes, it wouldn’t have been out of the question for the FDA to have Avandia withdrawn from the market. Instead the FDA chose to include the term “potential” when describing the risk of heart attack associated with using Avandia. The FDA also explains that there isn’t enough data at present to say that Avandia creates an increased risk of heart attack compared to other diabetes drugs and that further studies are necessary to clarify this.
Finally, the FDA adds that at present no diabetes drug is associated with a reduced risk of heart attack. In my opinion this is a slap at the makers of Actos (Takeda Pharmaceuticals) , the direct competitor of Avandia in the diabetes market. Takeda has recently been heavily promoting a single study which seems to indicate a potential heart benefit of their drug, Actos.
My overall impression is that this is a win for GSK, the makers of Avandia in that the warning is a lot milder than it might have been and that it moves to silence the makers of Actos who appear to be making the most of the negative publicity surrounding the Avandia controversy.
More on the Avandia Debate: Common Sense vs. the Statisticians
I previously addressed the issue of “relative risk” in this blog, as it applies to the perceived hazard of using Avandia (rosiglitazone) to treat diabetics. To gain a better understanding of the true Avandia risk, I went back to the actual data submitted by Dr. Nissan et. al. in the meta-analysis which ignited this controversy. What I found supports my notion that the real risk is allowing statisticians to bludgeon common sense into immediate submission with a few technical terms.
In Nissan’s meta-analysis of 42 studies which compared Avandia to other diabetes treatments (“other”), results from a total of 27,843 diabetics were analyzed (15,560 received Avandia and 12,283 “other” treatments). During the study period there were a total of 158 heart attacks (M.I.’s) and 58 deaths from cardiovascular causes. Compared to “other” treatments there were 14 extra M.I’s in the Avandia group then the “other” group. If your first reaction is “gee…14 extra deaths seem unacceptable”, remember there were 2300 more people in the Avandia group for bad things to happen to….see the blog on “relative risk” for more on that issue).
The over-all incidence of cardiovascular death for diabetics in the U.S. is generally accepted as 65% or more and the incidence of heart attack (M.I.) substantially higher. In Nissan’s study of 27,843 total diabetics 65% is equivalent to 17,730 total M.I.’s. The 14 extra M.I.’s in the Avandia group would make the M.I. rate 65.09%. Not a very alarming increase if it were true. In the “other” group if we equalize for the smaller number of participants in that group, we find the M.I. incidence would be higher at 65.12%. ( 72 M.I.’s for Avandia, 91 M.I.’s for “other” treatment).
Another way to look at the magnitude of the supposed increase in Avandia related events,
we find the “excess” number of M.I.’s is equivalent to 1 per 1250. For practitioners who treat diabetes and understand the enormous degree of variation between diabetic patients, trying to pin-point the factors accounting for one M.I. per 1250 in this group would be like trying to isolate one snowflake in a blizzard.
I simply do not believe that there is a way to validate the results of Nissan’s study. Believing the use of statistics can correctly pin-point the cause of 1 in 1250 M.I.’s within the chaos that is diabetes care, in my opinion, is being naïve to the true complexity of this disease and its treatment.
Gary Pepper, M.D.
Today’s NY Times carries a front page article about the dangers of Actos and Avandia, two popular diabetes medications. The reason behind the news story is that the FDA has finally required the two companies that make these diabetes drugs to carry a “black box” warning (the strongest labeling warning that can be applied) about the potential for congestive heart failure (overload of fluid in the heart and lungs) in diabetics using these drugs. Is this warning really news? Not to doctors.
I have been to numerous seminars on the use of these two diabetes drugs and have been paid by the companies that manufacture these drugs to educate other health care professionals about the use and hazards of these drugs. Both companies gave all representatives and speakers the strictest instructions regarding their obligation to carefully mention the potential for fluid overload and congestive heart failure associated with the use of these drugs. I know that my colleagues, particularly the cardiologists (heart doctors) and endocrinologists (diabetes doctors), have been acutely aware of this information for years.
Did you know that the type of drugs known as sulfonylureas that have been used to treat diabetes since the 1960’s and remain popular today carry a “black box” warning since the 1970’s about the potential for causing heart disease? This class of drug include Diabinese, Orinase, DiaBeta, Micronase, glyburide, and glipizide. Why are these drugs still in widespread use, and where are the stories notifying the public about this? What’s the big deal about the black box warning on Actos and Avandia?
I think I smell some politics going on. The Commissioner of the FDA, Dr. von Eschenback, was appointed by President Bush in 2005. The harshest critics of the FDA on this issue are the Democrats on the House Panel. Coming out of the woodwork are various “injured” parties who were criticised by company representatives for speaking out against these drugs in 1999. These stories warrant a separate column in The Times today.
Are there real risks to taking Actos and Avandia in the treatment of diabetes. Of course there are, just as there is a real risk of treating diabetes with just about any drug. It is up to the medical profession to remain vigilant and educated about these risks and to balance them with the benefits. Inflammatory front page news stories which create an atmosphere of mistrust and hysteria may serve only narrow political purposes.
This blogged comment at metabolism.com is not intended to convey medical advice. Diabetics are encouraged to contact their own healthcare professional about advice about what to do at this time. Most authorities encourage the public not to panic and to wait instructions from their physician before altering their medical treatment.