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Diabetes Medications, One Old and One New, Run into Trouble


A potential new treatment for type 2 diabetes, dapagliflozin, recently failed to gain approval from the FDA. What makes this rejection noteworthy is that the new medication works by a completely new mechanism causing the kidney to excrete sugar from the blood into the urine. Reasons for the rejection were the increased risk of bladde and breast cancer in those taking the medication, increased urine and genital infections and possible liver toxicity. That list of problems seems pretty convincing to me. This is unfortunate because the drug appears to cause weight loss and does not cause low blood sugar (hypoglycemia). However, a drug that works by “poisoning” the kidney so that it dumps sugar into the urine strikes me as a drug that is going to cause a lot of other problems.

The other established diabetes medication generating new warnings is Actos (pioglitazone). I have written a number of articles on the sister drug Avandia, defending its usefulness despite possible cardiovascular risks, but the cancer warning for Actos is a new angle on this class of drugs (thiazolidinediones). Actos has been withdrawn in France due to concerns that it may cause bladder cancer but no such action has been taken in the U.S. The FDA this month did issue a warning that individuals with bladder cancer or at risk for bladder cancer, should be advised not to use Actos. If Actos is hit hard by these actions this whole class of diabetes drugs will have been eliminated from use.
A sure sign of trouble for Actos is that a “google search” for Actos is now showing lawyer websites as the first 5 citations.

Being sick is dangerous. Treating illness also has dangers. I am concerned that our cultural zeal for uncovering scandals and for pursuing litigation will lead us to sterile treatment options and doctors who are unwilling to risk helping.

Gary Pepper, M.D.
Editor in Chief, metabolism.com

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Avandia Law Suit Brings Out the Opportunists


The lawsuits against Avandia are being prepared and opportunists are lining up for a payday. Unfortunately, everyone else will wind up a loser, and here’s why.

Avandia, one of only two available medicines with unique properties to treat diabetes, was approved in 1999. From the very first day Avandia was approved a heated debate arose whether Avandia or its sister drug, Actos, was the better drug for diabetes treatment. Both had similar abilities to lower blood sugar and both had the same downside of causing significant weight gain and fluid retention. Avandia showed a slightly worse effect on cholesterol profiles which convinced many diabetes specialists to choose Actos over Avandia. The choice between drugs has also been heavily influenced by cost considerations such as whether the drug was covered by the patient’s insurance carrier. I personally treated numerous patients with both drugs and found them about equal in all respects.

The lawsuits against Avandia will contend that the medication caused heart attack or stroke. The truth of this contention is very much in question, but the murkiness of the water doesn’t stop the lawyers from trying to take a bite out of the flesh of GSK (GlaxoSmithKline), the maker of Avandia.

Several years ago research studies seemed to indicate a small increased risk of heart attacks in users of Avandia. Ever since there has been a heated debate about whether this was a true risk or just the result of overly aggressive interpretation of the available data. There are two major analyzes on the subject of heart attack risk with Avandia. One, written by a doctor on the payroll of a competing drug company, looked at results from 14 thousand patients on Avandia and found a small increased risk of heart attack or stroke and the other study analyzed another 14 thousand Avandia users and found no such association. Under pressure from the public, in 2007 the FDA placed a strong warning on the label of Avandia regarding the possibility of the drug causing heart disease, but Avandia was permitted to remain on the market. The FDA warning was updated and upgraded in 2010. The publicity surrounding Avandia’s potential risks basically halted the use of the drug in the U.S.

Now enter the opportunists. Advertisements fill my email in-box from lawyers looking for customers who want to sue the drug manufacturer in class action law suits. Try goggling “Avandia side-effects” and you will find the first several pages of results are ads looking for lawsuit clients. In the last month I received two requests for patient records from these lawyers. Both patients had heart disease at the time they started the medication. One patient who recently died was over 80 years old, and the other who had significant heart disease and other diabetes complication to begin with, is still alive more than 7 years after treatment with Avandia. I wonder how much benefit these patients received from the medication which allowed them to survive as long as they did despite all the other problems they had related to their diabetes.

Why should you care about whether a small army of opportunists each get a few thousand dollars from the drug manufacturer and a few lawyers become millionaires? Because it is just this sort of legal action which is convincing drug makers to back away from developing other potential diabetes treatments. It takes a decade and a billion dollars to bring a new drug in front of the FDA. This doesn’t include the cost of developing drugs which fail to even make it to FDA review. Then the FDA approval process is tortuous and uncertain. Passing this hurdle, any new drug can come under attack (like Avandia) for “possible” side effects making the company vulnerable to devastating legal costs and bad publicity. It isn’t economically feasible to develop new diabetes drugs in the United States. As a result, new drug development is grinding to a halt. We will all suffer due to lack of innovation, not only for diabetes treatment but for treatment of many other dangerous diseases.

Gary Pepper, M.D.
Editor in Chief, Metabolism.com

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Can Actos Really Prevent Type 2 Diabetes?


Diagnosing diabetes is simple. If the blood sugar is found to be elevated you are diabetic. Increasing or decreasing the cut off level between normal and diabetic will dramatically change the number of people diagnosed with diabetes. In 1997 the American Diabetes Association lowered the criterion of diabetes (type 2) to a fasting blood sugar above 126 mg/dl instead of 140 mg/dl. Suddenly 1.7 million Americans became “diabetic” under the new definition.

In the latest issue (March 24, 2011) of the New England Journal of Medicine research was published stating that Actos (pioglitazone), a popular medication used to treat type 2 diabetes, could substantially reduce the percentage of people at high risk for developing diabetes who progress to actual diabetes. 600 people with a form of pre-diabetes known as impaired fasting blood sugar (fasting blood sugar levels between 95 and 125), were divided into one group given placebo and the other group given Actos. After 2.5 years Actos reduced the incidence of developing type 2 diabetes by 72% compared to placebo. Initially, I was very impressed with these results.

Actos is the sister drug to Avandia and Rezulin. All of these drugs show similar ability to reduce blood sugar in diabetics. Rezulin and Avandia fell into disfavor due to the potential for side effects. Actos is considered safer.

It seems almost a little too obvious that if diabetes is defined as elevated blood sugar that if the test medication reduces blood sugar, diabetes can be “prevented”. Since Actos lowers blood sugar, the conclusion that Actos reduces the progression of pre-diabetes to actual diabetes seems inevitable. A substance that does not already lower blood sugar which prevented elevated blood sugar from developing would be far more impressive.

Side-effects of taking Actos need to be considered, as well. In this research study (New England J of Medicine 364; 12, 2011) the group taking Actos gained an average of about 9 pounds. That doesn’t include the 3% of test subjects who dropped out of the study because they gained too much weight. Edema (puffy ankles) was also more common in those taking Actos. We know that weight gain, particularly in pre-diabetics, is not a good thing. What are we hoping to accomplish by using Actos to prevent diabetes when at the same time, we make people chunkier and puffier?

To be fair, the family of medications known as “glitazones” which contain Actos, Avandia and Rezulin, have some intriguing properties. Years ago, the Triad Study, showed that women with gestational diabetes who received Rezulin, did not go on to develop type 2 diabetes nearly as often, even years after stopping this medication. This does seem like a true preventive benefit.

I am dubious about using Actos to prevent diabetes at this time. My patients, I suspect, will agree with that decision. I don’t think I would survive very long in practice, if my patients gain 10 or more pounds as I try to “prevent” their progression to diabetes.

This information is for educational purposes only and is not intended as medical advise or treatment. Always consult with your physician when deciding whether to use a prescription drug.

Gary Pepper, M.D.

Editor-in-Chief, Metabolism.com

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Old, Old News About Diabetes Medicine Danger Makes Headlines Again


In 2007 I published an article entitled, “Old News About Avandia and Actos Makes Front Page New York Times”. This article criticized the media for publishing an old story about the potential danger of Avandia, then a popular diabetes medication. Even in 2007 the potential hazard of Avandia was a story which had been beaten to death by experts with the conclusion that the hazard of using this drug was probably exaggerated by a few vocal critics. Since then much more information has come to light supportive of the safety of using Avandia. Just a week ago the whole issue again made front page news, making it seem as if something new had come to light on the safety issue. Close inspection of the reports show this to be virtually the same information that existed in 2007 without the benefit of more recent information, but now rehashed by a congressional committee. So here we have it…old, old news making headlines again but unenlightened by the passage of another 3 years.

Here is the original story about “old news” which I published at metabolism.com in 2007

Old News About Avandia and Actos Makes the Front Page NY Times

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.

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New Diabetes Treatment Guidelines Flawed


New Diabetes Treatment Guidelines Lack Credibility:

Recently the American Academy of Clinical Endocrinologists issued new treatment guidelines for treating Type 2 Diabetes. Complex medical guidelines are often referred to as a treatment algorithm. One of the stated goals of the AACE algorithm is to focus primarily on the theoretical ability of the diabetic medications to control blood sugar while ignoring the cost of the medication. The rationale to this approach is that controlling blood sugar with more expensive drugs will cost less in the long run since patients will be healthier and have less complications due better control of the blood sugar. On the surface this philosophy seems sound but digging beneath the surface reveals dangerous flaws in this thinking.

1. The first assumption, that newer medications for diabetes are better than older drugs is unsubstantiated. In fact there is ample evidence that newer diabetic drugs are no better than the older drugs for controlling blood sugar. The latest study finding no benefit of the newer diabetes medications is the FIELD study conducted outside of the U.S. This study showed that 5 years of treatment with the older diabetic drugs (sulfonylureas, metformin and insulin) resulted in adequate and prolonged control of blood sugar. In 2007 researchers from Johns Hopkins Bloomberg School of Public Health summarized the results of major studies using older and newer anti-diabetic medications and found no significant benefit of the newer medications.

2. The next assumption, that cost is not a key factor in treatment success contradicts most clinicians’ experience in diabetes care. It is clear to me, that patients are far less likely to comply with using expensive drugs than medications they can more easily afford. Looking at the numbers reveals the vast cost differences between the older (generic) versus the newer (brand) medications. Using figures provided by a local pharmacy I found that the retail cost of a typical two drug therapy for diabetes using older drugs is $59 per month. The retail cost of using two of the new drugs for a month ranges from $481 to $570. In more severe diabetes three drugs per day may be needed. The low cost alternative amounts to $185 per month while the high end alternative with new drugs is $610 per month. Looking at the cost of using insulin shows a similar vast cost difference between the older and newer drugs. Older forms of insulin may cost $100 for a month’s supply while a similar course of therapy with the newer insulin preparations will cost almost $250 per month. How many people will be willing and able to afford the new versus the old drugs, particularly knowing that there may be no health benefit to the more expensive drug combination?

The end result of not being able to afford these prices is non-compliance with medications and the result of non-compliance is higher costs passed on to the medical system. The Medco study from 2005 showed that the least compliant patients were more than twice as likely to be hospitalized compared to the most compliant, and that the yearly cost of caring for non-compliant patients is double that of compliant patients.

3. My next point is possibly the most contentious. The AACE guidelines were produced by a committee of physicians chaired by two distinguished endocrinologists, Dr. Paul Jellinger and Dr. Helena Rodbard. Both doctors are highly respected and accomplished. They are also both highly compensated consultants to the pharmaceutical companies which market the newest generation of diabetes medications. In the disclaimer attached to the committee’s recommendations, both Dr. Jellinger and Dr. Rodbard admit to consulting arrangements with virtually every one of the pharmaceutical companies whose interests are effected by their committee’s findings. I too am a consultant to many of these same companies (at least, until now), but I am not responsible for developing national guidelines for diabetes care. In my opinion the close association of both committee chairmen to the pharmaceutical companies detracts heavily from the credibility of their recommendations. The need for credibility is even more important when the AACE committee advises physicians to avoid using sulfonylureas, the only class of drugs not marketed by any of the big pharma companies. and which also happens to be the cheapest drug class, the drugs with the longest history of use, and the class of drugs many regard as the most effective at lowering blood sugar levels. The sulfonylurea class of drugs is so effective at lowering blood sugar, in fact, they are used as the gold standard by which the effectiveness of all new diabetic medications are compared.

4. In contrast with the AACE, the American Diabetes Association (ADA) has issued more conservative guidelines for diabetic therapy, preserving the role of the older generic drugs. My recommendation is that AACE go back to their committee and reconsider the way they have produced their algorithm. Appointing new leadership whose credentials do not lend themselves so readily to skepticism, would be an important first step in that process.

Gary Pepper, M.D.
Editor-in-Chief, Metabolism.com

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Al, Type 2 Diabetic, Shares His Thoughts on Treatment


Al is a type 2 diabetic. He has learned a lot about how diet and exercise can influence his blood sugar but still has frustrations with treatment options. He shares his thoughts with metabolism.com:

I am a male 47 years of age. 2 years ago my A1C was at 9.9 i was eating horribly and not exercising. Now my diet consists of South beach diet phase 2 my A1C is now 6.5 and my sugars are between 80 to 130 . My exercise routine is every other day due to my weight I am 5′ 7 1/2 lbs and at 282lbs my back is killing me.

I understand that there needs to be a lot of testing for these things and rightly so. Ive noticed that there is some hazards with Byetta and am glad im not on that and on avandia. I must point out that with the problems diabetics already have we do not need to compound it with more even though I do wish the testings would some how be able to go faster and that more and more research is done with stem cell testing.

My next option is to go for bariatric surgery..but my insurance wont cover it.

So here i am at a catch 22 . I hope they come up with something soon.

I am a male 47 years of age. 2 years ago my A1C was at 9.9 i was eating horribly and not exercising. Now my diet consists of South beach diet phase 2 my A1C is now 6.5 and my sugars are between 80 to 130 . My exercise routine is every other day due to my weight I am 5′ 7 1/2 lbs and at 282lbs my back is killing me.

I understand that there needs to be a lot of testing for these things and rightly so. Ive noticed that there is some hazards with Byetta and am glad im not on that and on avandia. I must point out that with the problems diabetics already have we do not need to compound it with more even though I do wish the testings would some how be able to go faster and that more and more research is done with stem cell testing.

My next option is to go for bariatric surgery..but my insurance wont cover it.

So here i am at a catch 22 . I hope they come up with something soon.

Al Lazzara

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Unreasonable Standards by the FDA for New Diabetes Drug Approval?


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

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Can Type 2 Diabetes Be Prevented?


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.

Metabolism.com

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Avandia Becomes The Britney Spears of Medicine


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.

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A Pyrrhic Victory for Avandia: FDA Releases New Statement


On November 14 the FDA released a new warning about potential heart complications of Avandia. After reading the statement which can be found at

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01743.html

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.

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