More Avandia Scare- Again, Unwarranted.

Here we go again......


A piece recently published in the New York Times and cited by others has just kicked up the Avandia controversy again. As usual, this is both unnecessary, and will likely scare patients and cause more harm than it is trying to prevent. (In many ways like the current LABA scare).

I have blogged extensively on Avandia safety.
The Avandia Scare: Why it Matters, Who's Responsible, and What to Do ,For the RECORD, Avandia does not cause heart attacks, Avandia Vindicated, and The Diabetes Conspiracy.



Before going diving into what the hubub is about it is important to note two extremely important facts:

1. There is no new data or information here. Everything being discussed is old news.

2. The one thing NOT being discussed in all these reports is that the question of Avandia safety was answered this past July at the American Diabetes Association's annual meeting when the RECORD trial was presented which definitively showed that Avandia did not cause heart hospitalizations, cardiac deaths, or any heart problems.


What's this all about?

The New York Times got a hold of a report that is now public from Senators Grassley and Baucus. What is available is the Press release and the full report of their two year investigation into the FDA and GSK's handling of Avandia safety. Their letter to the FDA states that GSK knew that that there were cardiac risks associated with Avandia and did not make these risks known to the public or the FDA soon enough. The second charge they make is that the study the FDA has requested GSK conduct to test safety differences between their product Avandia and their competitor's (Takeda) product Actos called the TIDE study is unethical, because two FDA safety officers felt that since there was no benefit of Avandia over Actos, and that Avandia had heart concerns that Actos did not, the study would needlessly harm patients. One of those safety officers was Dr. David Graham.

The full report is a 342 page document that includes publications, FDA data and internal communications at GSK. One of the main focuses of their concern is that the RECORD trial was continuing when GSK knew that the initial heart attack rates were low, so low in fact that it was unlikely that when finished, the RECORD trial would have enough events (statistical power) to show whether or not Avandia was safe. What is not highlighted in the report (which comes out 6 months after RECORD was presented) is that RECORD actually did meet criteria for statistical power. In other words, all their worry was for naught. Another focus of the report was study 211, which as a study on using Avandia in patients with heart failure. (More on that later).

You can argue whether or not the Senators have a point regarding what the FDA and GSK should have done and by when; however, from a clinical perspective there is nothing new in this report. More importantly, it was irresponsible of them not to discuss the final results of RECORD in this context.


Study 211
Study 211 was actually published in the well respsected Journal of the American College of Cardiology. It showed that when giving Avandia to patients with class 1 and 2 heart failure (a relative contraindication) that Avandia did not statisctically increase the rates of heart failure, death or heart attack. The only differences seen were more edema (a known side effect of Avandia, especially for patients with heart failure) and more need for medications. The essential findings of the study is that Avandia increases fluid retention (we know this, Actos does this as well) but does not actually have any effects on the heart. Why the senators want to make a big deal of study 211 is beyond me. If anything it shows that even in patients who you shouldn't give the drug to, there were no real problems.


What about the recommendation to take Actos instead of Avandia?

This is probably the scariest and most harmful outcome of the report and the media attention surrounding it. Every media outlet has not publisehd the following quote: "if every diabetic now taking Avandia were instead given a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart"

This statistic comes from a letter written by Dr. David Graham to the FDA expressing concerns about Avandia over Actos. What Dr. Graham did is compared two Avandia meta-analysis with one meta-analysis on Actos. The two Avandia analysis used were Nissen's and the Singh meta-analysis published in JAMA. The Singh meta-analysis looked at ADOPT, RECORD and DREAM (which the FDA did a meta-analysis on and showed NO PROBLEMS with Avandia), and added study 211, which is a focus of the Grassley report. As mentioned, study 211 was a study done in 200 patients with heart failure, and since we know that Avandia does in fact increase the risk of heart failure, the patients in this study are not ones that you would normally give Avandia. Nonetheless, the Singh meta-analysis, unlike the FDA's, showed problems with Avandia, consistent with Nissen. ADPOT, DREAM and RECORD had thousands of patients. Study 211 had only 200. In other words, the only reason the Singh meta-analysis was positive and the FDA's was negative is that Dr. Singh added the 200 patients from study 211.

The Actos meta-analysis was published in JAMA, and found no heart attacks with Actos. One needs to note that one of the authors on the Actos meta-analysis is Dr. Nissen. Also, one should note that Takeda, the makers of Actos, gave Dr. Nissen and colleagues $25,000 in funding. In other words, Dr. Nissen has two published meta-analyses, one that is not funded that finds heart attacks in Avandia, and one funded by the makers of Actos that finds no heart attacks in Actos. As Arsenio Hall used to say, this is something that makes you go "hmmmmmmm."


Dr. Graham's conclusion is that comparing the Actos and Avandia meta-analyses, there were excess heart attacks and heart failures in Avandia over Actos, so that for every 63 patients taking Avandia instead of Actos for 1 year, there would be an additional heart attack. He then looked at the number of patients taking Avandia and came up with the 500/300 cases.

In addition to jumping to major conclusions from meta-analyses, one of the bigger problems here is comparing results from separate studies. This is breaking a cardinal rule of evidence based medicine. Doctors should be familiar with this because drug company reps do this all the time. They say, "my drug's studies show that my drug does X and my competitor's studies only show that their drug does Y, so you should use my drug." The astute clinician should politely ask the drug rep about head to head studies. Most often, the response will be that there are none. It is critical when making comparisons between to therapies, that head to head studies are done. Unfortunately, head to head comparisons are often not done by the drug companies because there is a huge financial risk if the results show that your company's drug is inferior. This is why proposed legistlation is rightfully calling for funding of comparative effectiveness research. In other words, Dr. Graham is stating that Actos is safer then Avandia WHEN THERE ARE NO HEAD TO HEAD STUDIES COMPARING THE SAFETY OF BOTH DRUGS. Unfortunately, this incorrect and inflammatory statement is what gets picked up by all the media. To be clear, I don't believe that Actos is harmful. I think both drugs are safe, though they both show similar side effects (fluid retention, edema and osteoporosis) and should be used with caution in certain patients (HCF).

A Diabetes Conspiracy?

This report if anything give more credibility to my postulations.
- It was Grassely and Baucus that called for congressional hearings back in May 2007, the day of the Nissen publication was announced. It was as if they new about the controversy before the story broke. The fact that they continue to draw attention to this issue (and themselves) despite the fact that the issue has been scientifically resolved and that health care reform is on life support is a concern.
- We again hear the name of Dr. David Graham, the FDA insider on Vioxx. I contend that somehow Nissen was tipped off from someone inside the FDA to publish the Avandia data himself, since the FDA decided to keep this data from the public. After this report, Graham continues to be my likely suspect. Regardless, if anything should be looked into, it should be whether or not classified FDA documents or conversations were leaked to Dr. Nissen. I am not a lawyer, but I think this is illegal.


Bottom Line
1. Nothing new here. Avandia does not cause heart attacks, as proven by the RECORD trial.
2. Quote on Actos safety over Avandia is based on no truly comparative (head to head) studies, and thus should not bebelieved, especially given #1.
3. Don't the Senators have other things to worry about....like fixing health care?

4. Someone should take a closer look at how Nissen "discovered' the link between Avandia and heart attacks. This is the congressional hearing I would like to see.

More problems with insulin

I have previously blogged about my concerns with the use of insulin therapy in patients with type 2 diabetes (The Problem With Insulin and The Problem with Insulin- Part 2). Several studies show new concerns using insulin to treat type 2 diabetes. The most notable is the ACCORD study which investigated intensive diabetes treatment and was stopped early because patients in the intensive treatment group had more heart attacks and death. Many experts suspect that even though controlled blood sugar is desirable, blood sugar that is too low may cause problems. This seems to be especially true for insulin, most likely because insulin causes hypoglycemia, or blood sugar that is too low. Hypoglycemia can be dangerous and may explain the excess deaths seen in the ACCORD and other studies. One of the main reasons for my concern is that some recent recommendations from worldwide experts in diabetes suggest that we are not using insulin enough! These guidelines dismiss or leave out altogether newer and potentially safer agents, suggesting that the older (all be it cheaper) diabetes pills which are known to fail over time continued to be used with advancement to insulin once they have failed.

However, a new study from the Lancet gives further evidence to more cautious use of insulin in type 2 diabetes. This UK study looked at two groups of diabetics. One group of about

28,000 patients were already on a diabetes pill (metformin or sulfonylurea) and had their regimen adjusted by adding another pill (metformin plus sulfonylurea). In the second group of about 20,000 patients, patients on one pill that were not under control were either switched to insulin alone, or insulin was added to their diabetes pill. The chart is below, but as you can see the higher your A1c (high A1c means that diabetes is under poor control) is, the greater your chance of death (and heart attack, seen in similar graphs), EXCEPT when your A1c is too low (under 7) and you have a greater risk of death. This is known as a U shaped curve, which means that treatment works, but you need to be careful because over-treatment can cause harm. Both groups saw this effect, but the effect was much greater in the second group that got insulin. In other words, similar to what waas seen in the ACCORD study, if you are on a diabetes pill and you need to get to a goal of below 7, you should probably reserve insulin as a last resort, since it will increase the likelihood of killing you compared to a diabetes pill. In addition, one of the side effects of sulfonylureas is hypoglycemia. It would be very interesting to see how these curves look when non-sulfonylurea drugs such as the TZD's (Avandia, Actos), DPP4 inhibitors (Januvia, Onglyza) or even incretin mimetics (Byetta and just approved Victoza) that DON"T cause hypoglycemia were used. I would suspect the difference would be even greater.

Again, this study lends further evidence that insulin should be used cautiously and other agents should be considered to get diabetes under control before going to insulin. This is in stark contrast to the recently released consensus as mentioned above. I have previously speculated ( here, here, here, and here) why certain experts continue to recommend older drugs and insulin when evidence continues to point to the benefit of some of the newer drugs

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.