Tuesday, May 26, 2009

Diabetes Conspiracy

I bought my Honda Civic Hybrid after watching Al Gore's An Inconvenient Truth and Who Killed the Electric Car, the latter of which tells how despite a overwhelming acceptance of consumers for an electric car, the project was killed. The documentary demonstrates that many had a role in killing the electric car including the government, car manufacturers and big oil; but never really gives an answer on who literally pulled the plug. In a similar fashion, the timeline below shows that there are many involved with various motivations and biases that have likely forever changed the way type 2 diabetes is managed. The cause for my concern is that important guidelines and public policy have been enacted and influenced by stakeholders with their own personal motivations and by using not entirely evidence based data to make these decisions; and these decisions (in my opinion) are not in the best interest of patients with type 2 diabetes.

August 22nd, 2001 -Nissen publishes Vioxx study
It is important to note that the Avandia story begins with Vioxx. Vioxx is an example of a drug that didn't have a lot of benefit over generic medications available, but was aggressively marketed by Merk and prescribed by millions of doctors. Unfortunately, it also carried some serious side effects, including heart attacks which seems to have been covered in some earlier publications. This JAMA article, whose second author was Dr. Steve Nissen, a cardiologist from the Cleveland Clinic, was the first sign of trouble. Though this study did some good by helping to pull a not very useful, quite expensive and likely dangerous drug from the market, Dr. Nissen quickly found that protecting the public from the harms of drugs garnered him lots of attention. Here is a Pharmalot post highlighting some of the conquests of Dr. Nissen. Though his intentions may be for the good, it is clear that with the publicity of this study and Vioxx, Dr. Nissen intended to make a name for himself warning the public of the dangers of some drugs.

August 26, 2004- Glaxo Agrees to Post Results Of Drug Trials on Web Site.

It is also important to note that the Avanida story also begins with Elliot Spitzer. Then attorney general Elliot Spitzer sued GlaxoSmithKline for fraud, because GSK publicized only one of five trials studying the effect of its antidepressant Paxil, in children. The other four not only failed to show a benefit, but also suggested a risk of suicide. As part of their settlement, which Spitzer claimed was "transformational", GSK agreed to post the results of ALL their trials for ALL their products on the web. Though a boxed warning was eventually added to ALL antidepressants in children, most experts believe that antidepressants still have substantial value in treating pediatric depression. Though GSK may have not been as brutally honest as possible with its data, fraud was a bit of a reach (and certainly nothing as bad as a Governor being involved with a prostitution ring). Whether Mr. Spitzer's zeal to sue GSK was due his desire to become Governor or to hide his own indiscretions, this settlement set the entire Avandia controversy into motion.

Septermber 30th, 2oo4- Vioxx Pulled from the Market

Here is a great recount of the whole Vioxx saga. That it took several years from Nissen's publication to Merk's pulling the product raised public concern. Vioxx was a game changer in that physicians, patients, policy makers, etc. are all now highly concerned about drug safety, and the FDA's ability to ensure it. The FDA is now under the gun, and thus highly sensitive to safety criticism.

November 18, 2004 - David Graham Testifies Before Congress. Enter Dr. David Graham, and FDA insider. After the Vioxx scare, he was called to congress to testify regarding what other drugs the public might be concerned about. Though Avandia wasn't named as one of Dr. Graham's five drugs to look out for, his testimony to congress against his own institution made it clear that Graham intended to be a whistle blower and would place the FDA safety folks at odds with the other branches of the agency. Here is the Washington Post Article as well as a Forbes article with more information about Graham the whistle blower. The theme here is that when you talk about drug safety after the Vioxx fiasco, a lot of people are willing to listen and give you lots of attention.

August, 2006- GlaxoSmithKline submits Avandia data to FDA

One known side effect of Avandia was fluid retention and the potential for congestive heart failure. After the product was approved in the late 90's, as part of due diligence, GSK agreed to perform a large randomized trial looking at heart benefits and risks of Avandia, as well as present the results of their planned studies, looking for any heart risks. The RECORD study was of particular interest because Avandia was also known to have potential heart benefits, including improving good cholesterol, lowering triglycerides, and reducing other markers of heart disease. The question was whether the potential heart benefits (reduced heart attacks) outweighed the potential heart risks (congestive heart failure). It is important to note that at no time did anyone predict that Avandia might cause heart attacks. If anything, it was thought that Avanida might reduce heart attacks.
In August of 2006, GSK submitted both a pooled analysis (meta-analysis) of 42 separate double-blinded, randomized, controlled clinical trials to assess the efficacy of rosiglitazone (Avandia) for treatment of type 2 diabetes as well as a population-based database of 33,363 patients looking for similar endpoints. The 42 studies showed a potential increase in myocardial ischemia in patients taking Avandia compared to placebo. There were no problems when Avandia was compared to other diabetes meds, no issues with death, heart attack, or other adverse events in the FDA's meta-analysis. In addition, the large data base showed no problems with ischemia.

The FDA also knew that two large, randomized trials (ADOPT and DREAM) were about to be published that could help shed some light on this surprising and potential safety signal. In addition, the RECORD study was a large, randomized trial designed specifically to answer the question of cardiovascular safety and Avandia. Though the results would not be available until 2009, the study had be going on for almost 2 years and an independent group which periodically looks at the study to assess safety (commonly done in safety studies) had not reported any problems. Given that GSK's data was inconsistent and that more data would soon be published, the FDA did not publicly disclose the findings of either the pooled data or population based data. This decision was made by the head of the FDA. There were some, as we will see, that probably didn't agree.

October, 2006. The results of the DREAM trial presented.

This was a study designed to see whether Avandia could prevent diabetes in patients with pre-diabetes. The study found that 8 mg daily of rosiglitazone given to 2365 patients resulted in 306 cases of diabetes or death (11.6%) compared with 686 cases of diabetes or death (26.0%) in 2634 patients given a placebo, a difference that was highly statistically significant at P < .0001. Also of note, there was no cardiovascular risk seen in these patients.

December 7th, 2006- ADOPT published

One of the largest diabetes studies ever done, the ADOPT trial showed that Avandia, a thiazolidinedione or TZD, substantially reduced loss of diabetes control compared to both metformin (Avandia 32% better) and sufonlyurea(Avandia 63% better). TZD's work by reducing insulin resistance, and also can improve beta cell dysfunction and both effects were seen in ADOPT. After 5 years of treatment, only 15% of patients failed on Avandia monotherapy. This is far better than the failures from UKPDS. the previous large study which looked at the commonly used drugs for type 2 diabetes, metformin and sufonlyurea. Though both lower blood sugar and reduced microvascular (eye and kidney problems) complications, about half of all patients taking either of these medications lost diabetes control by three years, with the vast majority losing control at 9 years. One would think these results would be exciting news; however, in his editorial to the ADOPT study, Dr. David Nathan, author of a recently published consensus statement that would soon be adopted as the American Diabetes Association's guidelines stated that "given the modest glycemic benefit of rosiglitazone and higher cost, metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes."

February 1st, 2007- Dr. David Nathan sees no need for new diabetes medicines.

However, only a few months later, despite the exciting results of DREAM and ADOPT, in response to the recent approval of Januvia, a new class of diabetes medicines called DPP4's, Dr. Nathan published this Perspective piece in the New England Journal of medicine , in which he railed against new diabetes medicines stating that newer diabetes drugs like Avandia and Januvia , "are generally no more potent, and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old. Moreover, the newer classes are uniformly more expensive and are associated with adverse effects — some that are shared by the older drugs, but others that are new." In essence, Dr. Nathan is suggesting (despite the problems with insulin and the failure of the older drugs mentioned above), that we just stick with the status quo, and use caution before approving newer diabetes medicine. See my Letter to the Editor in the NEJM criticising this position. Though old medicines certainly have a place, many diabetics do not have their diabetes under control, increasing the risk of things like blindness, amputations, and heart attacks.

January 2007- ADA Guidelines published

The ADA updates it's guidelines annually, and publishes them in the January issue of Diabetes Care. In January, 2007, the ADA guidelines adopted Dr. Nathan's consensus statement. This suggested that doctors start with metformin, and if that didn't work use insulin (best agent), sulfonylurea (like glimeperide) which was cheap though it caused low blood sugar or hypoglycemia, or the TZD's which were expensive, but didn't cause hypoglycemia. Dr. Nathan and company essentially left the newer drugs like Januvia and Byetta out of the picture. This is important because with limited options, patients failing on the available pills would need to start insulin, rather than trying the other agents.

*** Sometime between 8/2006 and 3/2007-Nissen tipped off to GSK's data****

I have no actual knowledge of any communication between someone inside the FDA and Dr. Nissen. However, this must have occured in order for Nissen to perform his own meta-analysis. Avandia had known potential problems with heart failure, but no one was thinking about risk for heart attacks, and if anything possibly preventing heart attacks. Even if Nissen has combed through all of GSK's data on his own, now publicly available thanks to Eliot Spitzer, finding heart attacks with Avandia would be like finding a needle in a haystack. Though I have no knowledge or any communication, I highly suspect that it was Dr. David Graham from the FDA who tipped off Nissen. From a safety standpoint, Graham was likely at odds with FDA Commissioner Andrew C. Von Eschenbach, who made the final call not to release the GSK data to the public. From his congressional testimony back in November, 2004 (see above), Graham had established himself as an FDA whistle blower. In addition, Nissen and Graham had certainly crossed paths back in February 2005 when discussing Vioxx. Whether Graham or someone else, it is unlikely that Nissen found the Avandia data on his own.

May 2007- Nissen Meta-Analysis. This date is referred to by GSK employees in a similar way the rest of us refer to 9/11. Nissen, likely tipped off by someone inside the FDA, performed his own meta-analysis of the GSK studies. His findings were rushed to press in the New England Journal of Medicine. I have posted on this article many times (see here specifically). Most peer review articles take about a year to publish, but this one only took a matter of weeks. Congressional hearings were called the next day. as if certain members of Congress knew about the results before they were published. The media had a huge field day with this. There are many flaws and critics of the particular study, as well as an alternative analysis that found completely different results. Of all the things about the study, the one thing that stands out most to me is that though Dr. Nissen found a 43% increase in risk of for myocardial infarction, the actual event rate was lower in the Avandia group. No statistician has ever been able to explain to me how this is possible. The bottom line is that this flawed study, motivated by Dr. Nissen's desire to get yet another drug off the market, bolstered by the New England's Journal willingness to publish this without a thorough peer review, and propelled to public attention by the media's appetite for a juicy story has forever changed the way diabetes is managed, and (in my opinion) to the detriment of patient care.

May 2007- RECORD interim Analysis published.

Because of fears that the RECORD study could be jeopardized as patients might pull out of the study if Avandia were dangerous, as well as a means to vindicate their medication, GSK felt obligated to publish the partial results of the RECORD study. Though only more than half way done, the study seemed to show no signs of heart attacks, thus refuting the Nissen publication. However, the study was accompanied by not one, but three editorials discrediting the study, one of which was by written by an obviously biased Dr. Nathan.

July 2007- FDA advisory board meets

Given the publicity of the Nissen study, the FDA met to discuss the safety of rosiglitazone. The consensus was mixed. After review of all of the FDA's (not Nissen's) data, they saw something that didn't make sense. Their own meta-analysis showed a signal of myocardial ischemia, but analysis of the ADOPT, DREAM and RECORD trials, as well as analysis of large claims databases showed nothing. It is important to note that using meta-analysis to draw conclusions have potential flaws (as I discuss here). One would think that the weight of severa large, randomized clinical trials would trump one meta-analysis that didn't seem make a lot of sense. However, some, including David Graham , did not agree. Interesting to see his name pop up in the news again, especially regarding this specific issue.

Nover 14th 2007 - Boxed warning added to Avandia.

In response to the July advisory meeting, the FDA ads a boxed warning to Avandia. This is one of the most confusing warnings ever seen. The warning essentially states that there is contradictory evidence so no conclusion can be made. Nevertheless, physicians who may have been on the fence about prescribing the drug, likely stopped writing prescriptions for Avandia.

February 6th, 2008- ACCORD study stopped

I blogged about this in my post ACCORD Study: Don't stop your diabetes medicines, Please! To recap, this study shocked the diabetes community, because the thought was that aggressively treating diabetes would finally show that controlling blood sugar in type 2 diabetics would prevent heart attacks. Previous studies had failed to show this, so perhaps sugar control was not aggressive enough. Instead, the ACCORD study showed the opposite. Patients in the more aggressively treated group had more heart attacks and deaths, and the study was halted ahead of schedule. The press had a field day, and suggested that treating blood sugar in diabetics may not be the best thing to focus on. Some were worried that since many of the patients in ACCORD were taking Avandia, that it might be the culprit. However, the NIH, who ran the study, saw no signs of increased heart attacks with Avandia. What was seen was that the patients in the intense group used more insulin, and had more episodes of hypoglycemia. Could it have been the aggressive use of insulin caused the problem? Interstingly, these adverse events were not seen in a similarly designed European study called ADVANCE, where less aggressive use of insulin ocurred. I talk more about this issue in my post The Problem With Insulin and The Problem with Insulin- Part 2

June 2008- ACCORD, ADVANCE , VADT presented

The results of 3 major trials were presented at the ADA meeting in June 2008 (I blogged about this here). The main problem seen was that despite agressive measures to control blood sugar, though microvascular (eye problems, kidney problems) were improved; macrovascular problems (heart attack and stroke) were not. However, as stated, it may not be how low you go, but how you get there. Regardless, with these studies, when it comes to Avandia safety, at this point in time, we now have randomized studies where over 26,000 patients that have been studied for over 3.5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks or myocardial ischemia.

Fall 2008- Januvia and Avandia get bashed as costly

As I pointed out in my post The Diabetes Conspiracy (Part I) , there are many that seem to be "out to get" the newer diabetes pills. In this example it is a study that points to the rising cost of diabetes care, and new medications like Januvia and Avandia as the culprits. However, two things are not mentioned. First, that the costs of the newer insulins are just as much as a contributor to costs as the newer pills, and unlike the newer pills which prescriptions have tapered off, the new insulins continue to climb in sales. Why do folks want to bash the cost of pills and not the newer insulins? The other point is that the older pills will almost always fail, whereas some newer pills (see the ADOPT study) don't. As I state in my post The Problem With Insulin, I believe certain (though not all) endocrinologists (and possibly drug makers of insulin products) do not want any new diabetes pills because they have a vested interest in keeping patients on injectible agents.

November, 2008- Nissen's name mentioned to head the FDA

Several sources (including the Wall Street Journal) name Steve Nissen as a top candidate to head the FDA. Though President Obama eventually chose another, Nissen remained at the top of the list for a while. How did Nissen garner so much attention and respect? Could aspirations to head the FDA have motivated Dr. Nissen to publish his controversial study?

December 17th, 2008- FDA makes it harder for new diabetes drugs to get approved
Here is the announcement from the FDA As this piece from the Wall Street Journal recounts, in response primarily to the Avandia issue, and despite data to the contrary, the FDA has decided to make it much tougher for ANY new diabetes products to become available. Looks like Dr. Nathan got his wish. Specifically, any new diabetes drug must now prove that it does not cause heart attacks before being approved by the FDA. All other drugs only need to show that they are relatively safe and better than placebo. Diabetes drugs now fall into a separate class of medications, needing to prove an additional level of safety. Proving that you don't cause heart attacks takes a lot of time, effort and energy and thus makes it harder for new diabetes medicines to get approved. I blog about this in more detail in my post Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III . The bottom line is that because of one highly controversial and politically motivated study, this new policy will now delay any new diabetes products unnecessarily. This is bad news for patients.

January 2009- ADA removes Avandia, states Januvia is not recommended

Though not part of the official guidelines, Dr. Nathan once again publishes a consensus statement. This time he goes even further. He states that the more evidenced based approach to type 2 diabetes treatment is to use metformin, sulfonylurea and eventualy insulin. He states that Actos (not Avandia) and Byetta (not Januvia) are less evidenced based alternatives. I am not exactly sure where he is getting his evidence from, but Dr. Nathan seems to reluctantly keep in Actos, while leaving Januvia and Avandia as non-recommended agents. It is interesting to me why Byetta gets a better position then Januvia, since the evidence behind each is about the same. Could it be that the endocrinologists (or at least Nathan and company) gave a more favored position to an injectible agent? It is interesting that the consensus statement appears in the same January 2009 issue of Diabetes Care that updates the guidelines. Will this new algorithm take the place of Nathan's old one in the ADA's guideline? Only time will tell.

March 2009-Alloglipitn gets delayed.

Here is the first sign of the effects of the new FDA policy. Again, prior to the Nissen publication, no one thought that Avandia might cause heart attacks. Prior to and since the Nissen publication, there have been multiple studies showing that Avandia does not cause heart attacks. Yet, any new diabetes drug must now prove that it too does not cause heart attacks. Allogliptin (ironically a drug made by Takeda-makers of Actos, Avandia's competitor) is a DPP4 inhibitor similar to Januvia. In addition to some potential safety benefits, because Takeda also makes Actos, allogliptin was to be eventually combined with Actos, giving doctors and patients and entirely new combination therapy. However, as noted by Heartwire, allogliptin was severely impacted by tougher restrictions and it's approval date was delayed until it could prove cardiovascular safety.

The Diabetes Conspiracy

According to dictionary.com, a conspiracy is an evil, unlawful, treacherous, or surreptitious plan formulated in secret by two or more persons; plot. Though I doubt there has been any legal wrong doing, and it is unclear whether or not the likes of Graham, Nissen, Spitzer, Nathan or others sat together to conspire to wipe out any new treatments for diabetes (though I suspect that it was Graham who tipped off Nissen to the GSK data), it seems clear that muliple players with their own interests, which are not necessarily in the best interest of patients with type 2 diabetes have created hysteria surrounding Avandia that has not only led to decreased use of this product, but also led to decreased use of other newer products and more importantly the delayed availability of newer products to market. It might be possible that we may never see a new diabetes product again, either because proving diabetes safety is too challenging, or the pharmaceutical companies choose to invest in "friendlier" areas.

Spitzer's biases are obvious. Nissen found the path to fame, and possibly to the head of the FDA, was through "busting" drugs. Graham found that best way to get what he wanted was to become a FDA whistle blower. The reasoning behind Nathan's dislike of all new diabetes agents remains unclear, but endocrinologists (who make their living by prescribing insulin) have a vested interest in seeing insulin prescribed.

Physicians, patients, policy makers and the public should be aware that the whole Avandia issue is a house of cards. Fortunately, this house of cards may soon come down with data to be published in a few weeks. More to come on that.


LaceyUnderall said...

Dr. Mintz -

If you are interested in conspiracy theories... you should investigate this ruse: Family Smoking Prevention and Tobacco Control Act (S982). Once you find out who is behind it and what the bill actually does, you will be stunned.

This is definitely along the lines of "Who Killed the Electric Car"...

Neil Curtis said...

Diabetes conspiracy has led to economic cost and fraudulent profits.

Neil Curtis said...

Read the congressional hearing information regarding Advandia and also read Dr. John Buse and others about how no other treatment is better than drugs for controlling diabetes. This does sound like a conspiracy. As a result, diabetic wife have to live in celibacy in trenchvillecity Iowa.

Unknown said...

Diabetic retinopathy could be associated with poorer memory and diminished brain power in people with Type 2 diabetes, according to a new research.