Actos Causes Bladder Cancer. Maybe We Should Have Kept Avandia?

Both Germany and France have now suspended the marketing of Actos (pioglitazone) due to concerns of a link between Actos and  bladder cancer.  Though we have known about bladder cancer concerns for some time, these recent concerns about the bladder cancer link stem from a recent report analyzing the FDA's Adverse Event Reporting System (AERS), which found that 93 cases of cancer were recorded between 2004 and 2009 in patients treated with antidiabetic drugs of which 31 patients were treated with pioglitazone, representing a statistically significant increased risk of bladder cancer (ROR 4.30, 95% CI 2.82-6.52; p<0.0001). Interestingly, the FDA announced that it was going to look into the link between Actos and bladder cancer only a few days before it made it's final decision on what to do with Avandia (as if they didn't know about the Actos cancer risk before the July 2010 advisory board). 

Despite the many things you have heard about Avandia, back in July 2010, the FDA decided to severely restrict the use of Avandia for three reasons:
1. Despite limited and conflicting data, there seemed to be a signal of myocardial infarction for patients taking Avandia.
2.  The one study proving Avandia's safety, RECORD (see here for more details) was discredited by FDA scientists due to potential reporting errors.
3. The advisers on the panel felt strongly that despite limited and conflicting evidence, the signal was enough to be concerned AND because Actos (similar drug in same class) did not seem to show this signal, why would doctors ever want to prescribe Avandia?

I have blogged extensively about Nissen's meta-analysis that triggered the whole Avandia scare. Meta-analysis have major limitations.  Another group of researchers using the same data as Nissen's with different statistical  techniques concluded that Avandia did not cause heart attacks.  Large, randomized trials are the only way to determine certainty, and all available large trials (DREAM, ADOPT, ACCORD, etc.) with rosiglitazone showed no heart attack risk.  As mentioned above, the one study designed to definitively show whether or not Avandia led to cardiovascular risk (RECORD, which showed that Avandia did not cause cardiovascular risk, and in fact surpasses the FDA's standard for cardiovascular safety) was harshly criticized by those within the FDA that wanted to see Avandia pulled from the market.  Specifically, the FDA found that GSK had some errors in reporting the results of RECORD.  Though these types of errors are not uncommon in very large trials, and likely won't affect the overall results of the study, nonetheless, the deserve looking into.  However, the FDA promised to do a complete independent analysis of the RECORD results; a promise it has yet to deliver on.

The main issue here is #3: Actos appears to be safe, so let's dump Avandia. (Interestingly, independent cardiologists analyzed all the data and did not find a conclusive difference in cardiovascular risk between Actos and Avandia).  Here is the full transcript of the advisory board.  Since it is a very difficult document to read through, I have pasted some of the direct quotes below from some of the advisers who voted to either remove Avandia from the market or severely restrict its use. Based on these quotes, I feel pretty strongly that had the advisers known about Actos' bladder cancer risk, that they may have voted very, very differently.  However, the FDA did know about the association between Actos and bladder cancer.  They just chose not to mention it!   In fact, when one adviser brought up the question at the July advisory board, the FDA only briefly mentioned this and discussed it more as a class effect also seen with dual PPAR agonists.

Avandia and Actos help diabetics use their own insulin better by hitting a receptor called PPAR. There are three main PPAR receptors: Alpha, Gamma and Delta.  We don't know a whole lot about delta, but PPAR Gamma works on glucose, and PPAR alpha affects cholesterol.  Fibrates like gemfibrozil, which lower triglycerides and raise HDL or good cholesterol are PPAR alpha agonists.  Dual PPAR agonists were drugs that pharma were trying to develop that hit both alpha and gamma in order to help both with lipids and glucose.  They have not been able to make it to market due to safety concerns (raised by, guess who??? Dr. Nissen). One of the differences between Actos and Avandia, is that Actos has a higher affinity for the PPAR alpha receptor, which is why it likely does a better job on raising HDL and lowering triglycerides than Avandia.  Some have hypothesized that this might be the reason why Actos might not have the same cardiovascular issues as Avandia (though this has yet to be shown).  If in fact, as stated during the FDA meeting (I am not aware that this data is published) that the bladder cancer risk was seen in both Actos and the dual PPAR agonists.  Bladder cancer has not been seen with Avandia.  In other words, the evidence (both available and suggested by FDA quotes that are public record) suggest that Actos may have more of a bladder cancer risk than Avandia. 


Why the FDA in discussing to keep Avandia on the market would not extensively discuss the concerns of bladder cancer with Actos, paired with the weak and controversial data showing Avandia's cardiovascular risk and effort to discredit GSK's study proving Avandia's safety leads me to believe that the FDA's attack on Avandia was very much politically motivated.  Scientists look at all the available data and weigh the risks and benefits of all options before making a conclusion.  It is clear to me that the FDA's decision on severely restricting Avandia was more political then science. Based on the currently available data which now include bladder cancer risk, Avandia may actually be a better choice than Actos, but the FDA's restriction will essentially prevent any doctor from being able to prescribe Avandia after November.



Select quotes from advisers who voted to voted to either remove Avandia from the market or severely restrict its use:
DR. SCHAMBELAN: This is Morrie Schambelan. I voted E. (remove Avandia from the market) . I was one of the brain-dead kangaroos last time (meeting in 2007) who was on the fence, largely because I did see a signal for harm. I was led at that time by the comparison to active comparators, which I think is much more relevant to me than placebo. I wasn't swayed by the pioglitazone data that were presented at that time because they were pretty preliminary. I was much more persuaded this time, including Dr. Graham's analysis. I feel that pioglitazone is a perfectly acceptable alternative.

DR. SAVAGE: Peter Savage. I voted D (keep on the market with restrictions) I was also oscillating between D and E because I think that the evidence of potential harm associated with rosiglitazone is stronger now than it was in 2007. And very importantly, the evidence about pioglitazone is substantially greater than what we saw treat in 2007.

DR. FLEMING: Fleming. I voted E. My main sense about this is really explained in my answer to question number 7. There's very concerning data about safety with rosiglitazone. It's not definitive, but if TIDE is to provide that, we have many years before we're going to get that insight. We do have an alternative, pioglitazone, for which there is considerably strong safety experience. So I come down to, then, what is the continued role for rosiglitazone?

DR. THOMAS: Abraham Thomas. I voted E. The scientist in me says we should always seek the truth. But this isn't an NIH study section. This isn't the review of a journal for publication. Really, what this is is an intersection, as someone mentioned at lunch, between public policy and science. And when we look at it that way, we can't always have the absolute truth to make a decision. We have other classes that are available that we never had before for the treatment of diabetes. And if rosiglitazone was removed from the market, we still have another TZD, what has had a trial that does demonstrate no increased cardiovascular mortality, no increased cardiovascular events, in PROactive.

One Patient Stays on Avandia, One Patient Switches to Actos

The calls/emails have already started to come in, and I expect more, as I have a lot of diabetes patients and have been an avid user of the TZD class. There are many reasons to like the TZD's:
1. The older, generic medicines like metformin and sulfonylureas are known to fail over time. After 3 years, most patients on one of these drugs lose control of their blood sugar. In contrast, patients on TZD's maintain glycemic control (at least up to 4-5 years which was shown in the ADOPT study).
2. The TZD's don't cause hypoglycemia, which is a really bad side effect of insulin and the sulfonylureas.
3. Many diabetic patients need more than one drug, so even if you start with metformin, you are going to have to choose between a TZD (well studied, no hypoglycemia), a sulfonylurea (well studied, causes hypoglycemia), or a DDP4 inbitor like Januvia/Ongyza (not as well studied, no hypoglycemia).
4. TZD's have other benefits that the other diabetes drugs don't, such as improving good cholesterol or HDL, and decreasing triglycerides or fats. In his presentation the Periscope study, which showed Actos prevented plaque build up, Dr. Nissen (wonder why he likes Actos?) compared these results to other similar cholesterol lowering studies and showed an ldl-independent effect of the TZD's in their ability to prevent plaque build up. He believed this was due primarily to increases in HDL.
5. Using a TZD, likely because of sustained glycemic control, prevents the need for insulin. This was shown in the recently maligned RECORD study and the NIH sponsored BARI-2D study. Insulin causes hypoglycemia and most of my patients would like to avoid insulin.

The first patient contacted me by email related what he had heard about the FDA panels finding. He understood that they recommended not to pull the drug, but also felt that there were enough concerns that he wanted to switch. He was on Avandia 4mg, so I switched him to Actos 45mg.

It is important to note that the TZD's have their maximal effect at the maximum dose. Though the maximum dose causes the most side effects, I have found that if used early in the course of disease, side effects are minimal. The most common side effect of the TZD's is edema, or fluid retention. Use of a low dose fluid pill (which many diabetics use anyway in order to keep their blood pressure controlled) seems to eliminate this problem. For metformin, the best dose is 2000mg a day (usually 1000mg twice a day).

This brings me to the second patient who called me with similar concerns. He had been taking Avandamet 4/1000mg twice a day for about 7 - 8 years with outstanding diabetes control. In discussing the switch to Actos, we uncovered a problem. The equivalent dose of Actos is 45mg. Like Avandia, Actos comes in combination with metformin, called Actoplusmet. Actoplusmet comes in 15/500mg and 15/850 and is to be taken twice a day. If you do the math, it is very hard to get the 45/2000mg a day that would be equivalent to the Avandamet dose that has kept this patient under control for so long. We could do two pills in the morning and one a night (a more complicated regimen), but would be over (more side effects) or under (less efficacy) on the metformin dose between the 850 and 500 versions. Actoplusmet was just approved as an extended release product. This can be taken once a day (easier regimen). Actoplusmet XR comes in 15/1000 and 30/1000. If we went this route we could have the patient take one of each. The problem is that his insurance company will consider this two different medications and charge him two separate co-pays. He could take the 30/1000 and use one and a half tablets a day (wouldn't cost him more), but we would be short on the metformin, and it is generally not a good idea to split extended release pills. After spending 10 minutes discussing the above dilemma, he decided that it was simply too complicated to switch and he would stick with the Avandamet, unless the FDA decided to pull it.

Actos and Avandia are both good medications. Many of the FDA panelists who voted to pull Avandia or severely restrict it, mentioned that they did so because Actos was available and they saw no clear avantage of Avandia over Actos. No one mentioned the dosing. This is likely because few on the panel actually treat patients with diabetes. The only panelist really pushing for options was the patient advocate.

In addition, there is really no compelling evidence to believe that Actos is any safer than Avandia. The AHRQ (government, non-pharma) commissioned a study to look at this, and they found no difference. A Science Advisory From the American Heart Association and American College of Cardiology Foundation also looked at this issue (most of the authors had no ties to either product) and similarly found no substantial difference between Actos and Avandia with regards to safety. This is also why the panel voted 19-10 to move forward with the TIDE study.

Though, I am sure I will continue to get emails and phone calls from worried patients, many of the patients I have on Avandia take Avandamet 4/1000mg twice a day. Hopefully, they will read my blog before calling as multiple 10 minute phone calls start to add up.

Avandia Smackdown!!

This is it. The final countdown.
The fate of Avandia will likely be decided in a matter of days.
The outcome will likely have long lasting impact regarding how the FDA manages potential safety issues with any current or future drugs on the market.
That is because on July 13th and July 14th, the FDA will hold an advisory committee to review the safety data on GSK's drug Avandia.
I have blogged on the Avandia topic extensively. (In particular see Avandia Vindicated and Diabetes Conspiracy).
Below is a re-cap of all the major events in the saga as well as possible outcomes and my prediction as to what will happen.


Prelude- Vioxx (2001 -2004)
It is important to note that the Avandia story begins with Vioxx. Prior to Vioxx, many doctors prescribed heavily marketed drugs with less concerns about safety, thinking that if a drug had been approved by the FDA, they were likely safe. One of the major studies that led to fall of Vioxx was published in JAMA on August 22nd, 2001 by Cleveland Clinic cardiologist Dr. Steve Nissen. It took nearly three years until September 30th, 2oo4, when Vioxx was finally pulled from the market. Dr. David Graham, an FDA insider who works on drug safety was clearly frustrated by the FDA's apparent lack of concern. He was called to congress in November of 2004 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


August, 2006- FDA becomes aware of potential Avandia issue
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, which surprisingly 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. These results were surprising because though Avandia was known to cause fluid retention and a possible risk of congestive heart failure (CHF), due to some of Avandia's other properties (lowering triglycerides, increasing HDL, decreasing CRP), if anything, Avandia should have prevented heart attacks.

Rather than create a public hysteria and mass panic, the FDA decided to take a wait and see approach for several reasons. First, the FDA 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. And in fact, both DREAM trial and the ADOPT trial not only showed that Avandia prevented diabetes and sustained glycemic control better than the other available diabetes agents respectively, there were NO signs of heart attack.

Thus, the FDA felt confident in their decision not to needlessly scare the public, but rather wait until about June, 2009 when the RECORD trial was likely to report out. Given that it was a large, randomized trial specifically designed to look at Avandia and cardiovascular safety, the RECORD study would be able to definitely answer the question once and for all.


May 2007- Nissen Meta-Analysis published.
Due to a previous settlement regarding their drug Paxil by then attorney general Elliot Spitzer, all GSK's clinical trial data was publicly available. Dr. Steve Nissen was therefore able to perform his own meta-analysis of the GSK studies. Given that there had been no public mention of Avandia heart attack concerns, I suspect someone inside the FDA tipped off Dr. Nissen. His controversial and often criticized findings of a 43% increase in heart attacks with Avandia were rushed to press and published in the New England Journal of Medicine. The news created a media frenzy. Congressional hearings were called for by Senator Charles Grassley the very next day (almost as if Sen. Grassley knew about the results before they were published). In the following week's issue of the New England Journal, the interim results of RECORD were published ahead of schedule, mainly due to concerns that the RECORD study itself could be jeopardized as patients might pull out of the study if Avandia were dangerous. 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, and the controversy persisted.

July 2007- First FDA Advisory Committee Convened
Given the publicity of the Nissen study, the FDA met to discuss the safety of rosiglitazone. 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. The FDA voted almost unanimously to keep Avandia on the market. However, they added a boxed warning to Avandia. This boxed warning remains one of the most confusing warnings I have ever seen, stating 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. The class of medications, called the TZD's, decreased in general use, and Actos, the competing TZD which had 50% of the market share of TZD prescriptions became the heavily favored product.

June 2009- RECORD study results published
During the ADA's annual meeting, the long awaited study results of the RECORD trial were finally published. The study that should have put the issue to rest showed absolutely no difference in cardiovascular issues with Avandia. In addition, patients who used Avandia had improved diabetes control and less use of insulin. At the previous years ADA meeting, two other randomized studies (ACCORD and VADT), which both used Avandia extensively also showed no issues related to Avandia. Given RECORD, ACCORD, ADOPT, DREAM and VADT there have been randomized, controlled trials of 26,000 patients that have been studied over 4 to 5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks. Yet, critics (mainly Nissen and Graham), still had their doubts. The FDA decided that they would meet in July 2010 to review all the newest data and re-look at the controversial issue of Avandia.



February 2010- Grassley releases investigation of FDA and GSK
As above, Sen. Grassley called for an investigation back in 2007, and it took three years to finally release his findings. The report is an indictment of both the FDA for not taking Avandia risk seriously and GSK for hiding data from the public. Interestingly, the report fails to mention any of the studies published since May, 2007 showing Avandia to be safe. It as if time stood still in the Grassley report. The other issue that the Grassely report raises is the ethics of the TIDE study. The TIDE study, which the FDA requested GSK perform is a head to head study comparing Actos and Avandia in regards to safety. Grassely contends that since Avandia risks are known, the TIDE study is unethical and should not be performed.



June 2010- Nissen and Graham take one more shot
In conjunction with the June ADA meeting and weeks before the July FDA advisory committee, both Dr. Nissen and Dr. Graham have separate publications once again questioning Avandia's safety. (Both claim publicly that the timing of the release of this data is coincidental). The Nissen study is an update of his 2007 study, which both addresses some previous criticism of the original study and adds new data, including the RECORD study. Since this is virtually the same study as he did in 2007, it is not surprising that his findings are the same. The Graham study analyzed Medicare claims databases comparing Actos and Avandia. Graham claimed that Avandia was far riskier than Actos when looking at stroke, heart failure and death. Retrospective reviews of databases are legitimate forms of research, but have even more limitations than meta-analaysis. More interesting (which no media seems to be reporting on) is that Graham's study showed no difference between Avandia and Actos when it came to heart attacks. Stroke had never been a question, and even Nissen's analysis showed Avandia didn't increase death; CHF is a risk for both with multiple studies suggesting the risk is similar. Nonetheless, both studies got major media attention, overshadowing a 3rd study presented at the ADA (analysis of BARI-2D) which showed Avandia prevented stroke, heart attacks and death!.


July 2010- FDA Advisory Commitee
The FDA will review all the data mentioned above and hopefully come up with some conclusion. The meeting was planned in advance of Sen. Grassley's report, and was timed such that RECORD, BARI-2D and Graham's review could be incorporated with existing data. Expect debate to be particularly heated.


What are the possible outcomes?

Avandia Gets Pulled from the Market ( Odds 30-1)

This would also be the end of the TIDE study. This is a relatively unlikely scenario given that, with the exception of Graham's retrospective reivew, the only new data since 2007 are RECORD and BARI-2D, which are large, randomized prospective trials specifically designed to look at cardiovascular safety, both showing no issues with Avandia. Another intersting aspect, (which I blogged about in Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III) is that because of the Avandia scare, the FDA developed new criteria requiring that ANY new diabetes drug that gets approved by the FDA must first show that it does not cause heart attacks. Specifically, the FDA now requires randomized clinical trials that show a drug does not cause heart attacks with the upper limit of confidence of 1.3. In other words, there needs to be 95% certainty that a diabetes drug couldn't possibly increase the risk of heart attacks by as much as 30%. The confidence intervals for the RECORD trial for heart attack fall under 1.3. Thus, Avandia has already fulfilled the FDA's own criteria of being a safe drug in regards to heart attack. How could they possibly pull it?

That said, removal of Avandia is not impossible. Folks like Graham, Nissen and Grassely have a lot at stake in this game. Avandia staying on the market might make them look pretty bad. Rest assured that they will not go down without a fight.


Avandia is exhonorated (10-1)

Given the results of RECORD and BARI-2D, along with analysis of the VADT and ACCORD trials and multiple data bases, the FDA could be so overwhelmed with Avandia safety data that it proclaims Avandia to have no risk of heart attack and pulls any mention of this from its label. However, with all the surrounding controversy, this seems a little unlikely. The FDA has been harshly criticized for being soft on safety. That said, the FDA might want to take a stand against outsiders (Nissen, Grassley) as well as insiders (Graham) trying to do their job for them.

Nothing Happens (1-1)

This is the most likley scenario. There are no clear winners or losers, so everyone can save face. In this scenario, the TIDE study would likely proceed as planned, but not necessarily. The problem with this scenario is that it leaves physicians and patients in the dark. Is Avandia safe or not? The FDA owes the public an actual opinion, unlike its stance in 2007, which essentially was "we dont' know." In this scenario, the devil is in the details. The FDA will have to update Avandia's label with regards to the cardiovascular safety . The label could be harsher towards Avandia (i.e. more studies suggest concern), reassuring (i.e. despite one meta-analysis a multitude of randomized trials show safety) or neutral.


Actos vs. Avandia?

Finally, I have been asked multiple time about Actos vs. Avandia regarding safety. The conventional wisdom is as follows: even if there probably isn't any cardiovascular risk with Avandia, why would you not just simply switch to Actos just in case? Why do we even have Avandia on the market if Actos exists?

I use both Acots and Avandia, and do believe there is a role for Avandia. There are two important things to consider with regards to this issue:

1. The absence of evidence does not equal the evidence of absence.
In other words, just because no concerns have been raised with Actos does not make it necessarily a safer choice. The vast majority of large, randomized clinical trials (the gold standard of science) have been done with Avandia and not Actos. Avandia beats Actos in trials almost 2:1. It would be like saying 5/10 studies show drinking Coke causes obesity in teens, but 0/5 studies show that drinking Pepsi does not cause obesity; therefore, we should have all teens drink Pepsi instead of Coke to avoid obesity. Some have argued that the reason there has been no signal seen in Actos is because of differences regarding each drug's affect on lipids, with Actos having slightly more benefit than Avandia. However, there has been no true head to head trial of both (which is why the TIDE trial would be scientifically beneficial), and the lipid data varies from study to study (cholesterol actually increased in Actos' one large, randomized trial called Proactive). Furthermore, since there are many more large, randomized trials with Avandia, none of which show an increased cardiovascular risk, one could make the argument that Avandia is the "safer" choice. I am not suggesting that Actos is dangerous. However, stating that Actos is a safer choice is not scientifically valid. The American Heart Association and the American College of Cardiology came to similar conclusions, stating no safety difference between the two products in their recent review of all the data (which was released ahead of schedule in response to the scathing Grassley report).

2. In my experience, the most effective dose of metformin is 1000mg twice daily. The most effective dose of each TZD is the maximum dose. If used early in the disease process, the typical side effects (edema) have been minimal, even at the maximum dose of each TZD. Thus, in my opinion, the perfect dose of Avandamet ( a product which combines Avandia and metformin) is 4/1000mg twice daily and the perfect dose of ActoPlusMet would be 22.5/1000mg. Avandamet is available in this does, ActoPlusMet is not. To give this dose of ActoPlusMet, patients would need two separate prescriptions, two separate pills, and two separate co-pays.

Addendum 7/9/2010
The FDA just posted the preliminary documents for next week's Avandia "smackdown."
A few tidbits:


1. I mentioned three possibilities for Avandia's fate: removal, label revision or no change. There is actually a little more subtlety regarding the label change. They might either remove altogether any mention of heart attack, add more warnings (such as recommending Avandia only be used if other meds fail), or add more warning AND restrictions to prescribing. See the FDA's exact wording below:

A. Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding an increased risk of ischemic CV events, or
B. Allow continued marketing and make no changes to the current label, or
C. Allow continued marketing and revise the current label to add additional warnings (e.g., contraindications for certain patient populations, recommendation for second-line use in patients intolerant of or uncontrolled on other anti-diabetic agents); or
D. Allow continued marketing, revise the current label to add additional warnings, and add additional restrictions on use (such as restricting prescribing to certain physicians or requiring special physician and patient education)
E. Withdrawal from the U.S. market.


2. One of the presentations regarding the TIDE study, talks about the importance of large randomized controlled trials, citing all the bad things we would still be doing without the data. I love this....

If modern medicine relied on epidemiologic data, administrative databases, & meta-analyses of small trials to identify effective therapies, we would be …
routinely using HRT (WHI)
suppressing VPBs post-MI (CAST)
doing internal carotid artery bypasses (EC-IC study)
using alpha blockers to prevent stroke (ALLHAT)
giving estrogen to men with CAD (CDP)
giving high-dose GIK infusions in the CCU (CREATE)
using perioperative beta blockers (POISE)

2. There is going to be considerable time spent on poking holes in the RECORD study, which is really the pivotal evidence for Avandia safety. One of the main criticisms of RECORD is that the expected number of events (which determines how many patients they need in a study) was much lower than expected. Some has therefore stated that RECORD was "underpowered" to show Avandia is safe. In fact, the AHA/ACC consensus statement hinges its findings on this. However, the study was indeed powered to show Avandia is safe. The FDA presentation looking at this issue confirms this stating "Despite the initial over-estimate of events, the trial had substantial power to achieve its specified goal." This bodes well for Avandia.

3. Dr. Unger, a cardiologist from the FDA states that "the results of RECORD do not substantiate the findings from the Nissen/Wolski meta-analysis on myocardial infarction and cardiovascular death." In other words, from a cardiologist's perspective, RECORD proved Nissen wrong.

4. Nissen is not going down without a fight. Nissen main tactics seem to be 1) poke holes in the RECORD study and 2) present Actos (using non-head to head comparisons, meta-analyses, and claims databases) as a much safer alternative. Again, note that Takeda (makers of Actos) fund his research.

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.

Statins Don't Cause Diabetes

As of this morning, the only major source reporting the results of a recent study from Lancet is Business Week. However, the headlines that will likely pop up in the next few hours will likely be similar to theirs: "Cholesterol-Cutting Drugs Raise Diabetes Risk by 9% in Study." In my last post I discussed how the media likes bad news stories, so even though this is not yet all over the headlines, I will take a preemptive strike for potentially concerned patients.
The Lancet study is a large major meta-analysis of major statin trials, looking to see if there is a risk associated with statins and the development of diabetes.

The authors likely got the idea to do a meta-analysis from the JUPITER trial which showed that Crestor reduced heart attacks in patients who wouldn't have generally gotten a statin, except they had an elevated CRP (see Crestor: Get Ready to Ask Your Doctor for the CRP Test. ) One thing seen in this study was a potential increased risk of the development of diabetes. I mentioned this in my blog post when the data was first released that physician report of diabetes was increased in the Crestor group (270 reports of diabetes, vs. 216 in the placebo group; P=0.01). I stated that though one might be concerned about this, these were physician reports without confirmation. When looking at the study lab values in Jupiter, there were no significant differences with respect to the fasting blood glucose level, and the A1c level was pretty much the same (5.9% and 5.8%). I also mentioned that there was no biologically plausible reason to suspect Crestor, or any statin, as a cause of diabetes. In addition, both groups of patients in the JUPITER study had a 41% prevalence of metabolic syndrome, which is a pre-diabetic state. Therefore it should not have been surprising to find an increase in diabetes in both groups.

The meta-analysis looked at Jupiter and several other studies combined and found a 9% increase in the development of diabetes in patients taking statins.
So if this is true, how can you say that statins don't cause diabetes????
1. The 9% value is a relative risk, not an absolute risk. If 1/100 patients taking placebo have a side effect, and 2/100 patients taking a statin have a side effect, the relative risk increase is a doubling or 100%, but the real or absolute risk is only 1%. Drug companies and the media (and unfortunately some authors, as was the case in this study) like to talk about relative risk instead of absolute risk, because it makes there drug/data/news story look better. In this study, the actual increase in diabetes was 0.38% or about one third of 1%. Even though the result is statistically significant (true by scientific standards), the magnitude of the increase is so small that there is a high possibility that this is not true.
2. The study is a meta-analysis, which by design can not prove causation. The only way to really find this out is to do a large, randomized controlled study to specifically look at whether or not statins cause diabetes. This will never happen because 1) given the low absolute risk, the number of patients needed in this study would be tens to hundreds of thousands, which means the study would be ridiculously expensive and 2) with Lipitor going generic, no drug company is going to fund such a study. I spoke of the dangers of meta-analysis many times, specifically in talking about Nissen's meta-analysis of Avandia (multiple posts on this). Even in Nissen's own meta-analysis showing a "40% increase in heart attacks" in patients taking Avandia (relative risk), there was really NO DIFFERENCE in the absolute risk in his study! Of course that didn't stop the press, and millions of patients stopped taking Avandia. Unlike the randomized, controlled trial for statins and diabetes we will never see, there was a randomized controlled trial on cardiac safety and Avandia called the RECORD trial which was presented at the ADA this past summer. It showed NO RISK of heart attacks with Avandia. Don't be surprised if you never hear about this, since the press does not seem to be too fond of reporting good news.
3. As above, there is no biologic reason to believe that a statin medication would cause diabetes.

In other words, what you are seeing in the headlines is statistical garbage, that really doesn't mean anything. An incredibly low absolute risk found in a meta-analysis without a biologic reason to support a connection between statins and diabetes should not be cause for concern.

The Avandia Scare: Why it Matters, Who's Responsible, and What to Do

We now know that Avandia is not associated with increased cardiovascular risk.

I have blogged quite a lot regarding Avandia. You might ask why would I so strongly support and blog about a drug/medication that, even if it doesn't seem to cause heart attacks, is expensive and is known to have other side effects, like congestive heart failure and bone fractures?


Here's why:





Why it matters?


1. Patients, doctors and the public were unnecessarily scared. You only need to recall the story of the boy who cried wolf to know why false alarms can be problematic. There were many patients who were unnecessarily worried that the medication their doctors prescribed might be killing them. Similarly, physicians were worried that a medication they thought they were giving their patients to help them, might have caused harm. The reaction can be seen in the precipitous drop in Avandia sales. However, it wasn't just that patients stopped taking Avandia and switched to its competitor Actos. Though there are now far many more prescriptions written for Actos than Avandia (was about 50/50 before the Nissen article), the entire class of TZD medications declined. Also, though there were increases in other drugs like metformin, many patients simply stopped taking their diabetes medications, and many of those patients did not tell there doctor about this. (We have documented this in our large, academic faculty practice and are in the process of publishing the results).




In addition, the Avandia scare was probably one of the key events that prompted the FDA to start warning the public about issues they were looking into BEFORE their analysis was complete. I blogged about this in March, 2008 in my post More FDA warnings should not be cause for worry. Thusfar, all of these "early warnings" have not panned out, and have undoubtedly scared more than a few concerned patients. Spiriva and Stroke? Doesn't' seem to be associated. Singulair and Suicide? Well the FDA just released their findings and though the label to Singulair was changed, the data does not seem to support a major concern, and the FDA's concerns were significanatly downgraded from the original warning. In other words, asthmatic and COPD patients on these drugs would have never needed to worry about these "warnings" if it wasn't for the Avandia scare.

This is not to say that we shouldn't take adverse effects of drugs seriously. Vioxx taught us that lesson. The Vioxx scare made everyone take a careful look at drug safety including the reporting and approval process. However, the Avandia scare added unnecessary fuel to the fire to the point of hysteria. Now, many patients will question the necessity of every medication a doctor prescribes. This itself is not inherently bad (an activated, inquistive patient is a plus), but it's the fear that causes this questioning that is problematic.

2. We need Avandia (and medicines like it)
Most diabetics are not able to be controlled on only one pill. In fact, of the two older, generic pills; we know that most patients on these medicines will eventually fail therapy. Analysis have shown that though both metformin and sufonlyurea lower blood sugar; 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.

Avandia, was the first medicine to show that it could keep patients' diabetes under control. 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. Both effects were seen in ADOPT. The recent RECORD trial has now also showed this effect. Actos, another TZD, also seems to do this as well. Finally, some of the newer DPP4 medications like Januvia and (hopefully) soon to be available saxagliptin (Onglyza) have shown to preserve pancreas beta cell function in animals and human studies are only now just getting under way.

The point is that though the older medications are needed, they are not enough. Newer medications like Avandia have value, most importantly keeping blood sugar under control and preventing the need for insulin.

3. Patients were harmed.

The damage done to patients from the Nissen publication is hard to quantify, but in addition to unnecessarily worrying patients, patients were definitely harmed by this poorly done study and the subsequent media frenzy. As mentioned, many patients simply stopped taking their medications. It is not known what ill effects this might have caused. More importanly, those doctors who stopped using the TZD class altogether likely started prescribing more and more insulin. We now know from both RECORD and BARI 2D that not using TZD's like Avandia can double to triple the amount of patients needing insulin. Though the exact number from RECORD is not published, based on the what was presented at the ADA, I calculate that it takes at most 10 patients treated with Avandia for 5 years to prevent at least one patient from needing insulin. Put another way, for every 10 patients who stopped Avandia, one likely needed to go on insulin. Based on pharmacy data (via drugtopics.com, thank Mr. Medsaver) , there weree 11,331,000 prescriptions for Avandia and 11,329,000 for Actos in 2006. In 2008, that dropped to 3,103,000 and 12,518,000 respectively. Assuming that both Actos and Avandia prevent the need for insulin, and assuming that about every 6 scripts written represents one individual patient, over one million diabetics likely stopped taking Avandia or Actos, and thus the Avandia scare likely caused over 100,000 type 2 diabetic patients to need insulin, which could have been avoided.

Patients don't like insulin. There is the cost of not only the medications (most doctors are using the newer, expensive insulins, not the older ones), but also the strips and the machines to check blood sugar. In addition, patients fear low blood sugar, or hypoglycemia, which can be fatal. I have blogged about The Problem With Insulin (as well as The Problem with Insulin- Part 2)

4. The entire approach to the way diabetes is managed has forever changed.

Dr. Nathan, an endocronologist from Harvard, is basically the current architect of the ADA's guidelines for the management of type 2 diabetes. In a Perspective piece in the New England Journal of medicine , he shows that he does not like 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."

Despite the results of ADOPT, in an early guideline, Nathan stated that TZD's were merely a secondary option. In the newer consensus statement, mostly because of the Avandia scare, he further pushes for the older medicines (metformin, sulfonylurea, and insulin) as the preferred medications to use, leaving Actos as only a second line alternative, and taking Avandia and Januvia off the map. Though not all endocrinologists necessarily agree with this approach, many primary care physicians follow what the ADA recommends. In addition to TZD benefits presented at the recent ADA meeting, there are other examples of gains for diabetic patients, specifically saxagliptin, which is now proven to show no cardiovascular side effects and may even prevent strokes, and once weekly exenatide (Byetta). This insulin before newer medications approach, which is promoted by Nathan and the ADA is, in my opinion, not good for patients.

5. It is now much harder for ANY new diabetes medications to be availble for patients.

The Avandia scare had another MAJOR impact. Because of this supposed risk of increased heart attacks, the FDA now requires ANY new diabetes medicine to prove that it doesn't cause heart attacks. I talk about this in more detail in Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III. This finally came to fruition several months ago when allogliptin got it's approval delayed. (This is somewhat ironic since alloglipitin's maker is Takeda, who also makes Actos, Avandia's competitor. Takeda was banking on alloglipitin more than GSK was counting on Avandia for it's future, so even though many docs switched from Avandia to Actos, it is possible that in the long run, the Avandia scare will hurt Takeda far worse than GSK).

6. The false alarm was motivated by politcs, ego and greed. Not all false alarms are bad. However, there is a difference between someone yelling "fire" when they smell smoke, and the school boy pulling the fire alarm to get an earlier recess. Prior to the Nissen meta-analysis, no one thought that Avandia would cause heart attacks. In fact, if anything, the thought was that TZD's like Avandia might actually prevent heart attacks. In fact, in one of Nissen's own studies Actos (a competitor to Avandia) was shown to decrease the progression of plaque build up. (Yes, this might be a conflict of interest if Nissen is attacking a drug whose competitor funds his research). To further describe those who may have less than pure motivations, see below.




Who is to blame?

1. There is no questio n that cardiologist Dr. Steve Nissen is in part to blame. He is very smart and an excellent researcher. He knows that some of the techniques he used in his analysis were not up to par, such as excluding any Avandia study where there were no heart attacks from him analysiss. There are many flaws and critics of the this meta-analysis, as well as an alternative analysis that found completely different results.

2. The New England Journal of Medicine is also to blame. This is one of the most prestigious medical journals. To ensure the studies they publish are of the highest quality, they use a process of peer review. This means that when a study comes into a journal for publication, the editors first look at this to see if it is of interest to the journal and if so, sends it out to several experts in the field. These experts comment on the study, and based on these comments, the journal chooses whether or not to publish. Before publication, the author needs to address the comments by the peer reviewers and re-submit to the editor. This process generally takes several months. The New England Journal released the study to the public in just 3 weeks after Nissen submitted it. It seems impossible to me that The New England Journal followed it's own policies, especially with such an important, confusing and flawed study. The study was so confusing that one of the reviewers contacted GSK to make sense of the data (this was a major no-no, and the doctor got a lot of negative publicity about this move, but the point is that one of the experts could not make sense of a study that was published in just 3 weeks). Had the peer review process been followed strictly, the study may never have been published or the results would have been modified and likely gotten much less publicity.

3. An FDA insider. Until the Nissen publication, 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. The only folks who knew about the problem were the FDA, and they decided not to release the data to the public, because other data was contradictory. The fact that 42 studies (not all the same) were used in both the Nissen and FDA meta-analysis seems more than just coincidental. I have no actual knowledge of any communication, but I strongly suspect that someone inside the FDA tipped off Nissen to the data that GSK submitted to the FDA, because they did not agree with the head of the FDA's decision not to make this data public.

4. The FDA in general.

The FDA made the right decision to hold off on any conclusions regarding GSK's surprising meta-analysis, since it knew DREAM and ADOPT would soon be published and there was no problems with RECORD study currently underway. When the Nissen paper was published in the NEJM , the FDA could have come out strongly stating it's reasoning for not acting on GSK's meta-analysis, and because by this time ADOPT and DREAM were published and showed no increased cardiovascular risk, the FDA could have clearly shown why their decision was right. In addition, another opportunity for the FDA to make a strong statement reassuring the public came the following week when the RECORD interim analysis also showed no increased cardiovascular risk. Instead, the FDA just bent over and took the criticism from the media, bloggers, Congress and others.

What should be done?

Because the Avandia scare caused unnecessary worry for doctors and patients, harmed patients, forever changed the way diabetes is managed, and made it more difficult for new diabetes medicine to be approved; because we need medicines like Avandia; and because the motivations behind the Avandia scare may not have been in the best interest of patients; something must be done. I believe a full investigation is in order, starting with the FDA. I would like to know whether Nissen communicated with anyone inside the FDA that leaked confidential information. I would also like an investigation into the New England Journal of Medicine. Though we do have freedom of the press, medical journals must be held to a higher standard, since doctors use information published in these journals to make life and death decisions. If the New England Journal has policies in place to ensure only high quality data is published and they did not follow these policies when publishing Nissen's study, they too should also be held accountable. I have sent emails to the Department of Health and Human services. I hope they respond.

For the RECORD, Avandia does not cause heart attacks.

Those people who know me would probably agree that I am not one to say "I told you so," but in this case I will make and exception.

The RECORD study, as I described the other day, was just presented and the results are GOOD. Dr. Home, the lead author of the study (from Med Page Today), stated, "in terms of overall cardiovascular risk, the drug is safe. There's no increased risk, no decreased risk. And that includes the heart failure element."

I told you in one of my first posts that the Nissen article was likely a lot of media hype.

I told you when the VADT trial came out that Avandia had been vindicated, and did not cause heart attacks.

I told you all about the flaws of the Nissen study and how politically motivated the entire Avandia scare really was, outlined in my post Diabetes Conspiracy

I told you before the results were presented in my post Get Ready for RECORD the likely outcomes of the study, which I also warned that the naysayers would be out in full force (more below)

Here's the actual results which can be found in The Lancet
- For the primary outcome of combined cardiovascular hospitalization and cardiovascular death- they were exactly the same
-for cardiovascular death alone, no difference (avandia slightly favored)
-for heart attack - no difference
- for stroke no difference (avandia slightly favored)
-diabetes was also better controlled in the avandia group (though we don't know by how much...yet.
-the only bad thing was that heart failure causing admission to hospital or death occurred in 61 people in the rosiglitazone group and 29 in the control group. However, this is not unexpected, since heart failure is a known risk for the drug. In fact, it is comforting to know that even with a double risk of heart failure, there was no overall increase in risk of hospitalization or death from cardiovascular causes in the study- which was the whole point of the study to begin with.

As mentioned, it should not be surprised that certain people are going to try to raise doubts about the study. Dr. Steve Nissen, whose meta-analysis is essentially completed refuted by the study claims that it is still unresolved is whether rosiglitazone is associated with an increased risk of myocardial infarction stating, "In The Lancet manuscript, the authors don't reveal the number of patients who were still taking Avandia by the end of the study. Obviously, it is impossible to assess the safety of a drug when patients are not actually taking it."

Guess what Dr. Nissen? At the end of the study, 1,344 patients 61% of the Avandia group were still on the drug, while 1,131 patients, or 51% of the control group, remained on their medicines (from Forbes). In other words, there was high and similar drop out in both groups. It is actually surprising that even more patients didn't drop out, given your study unnecessarily scared the socks of these folks!

Dr. David Nathan is another likely naysayer, given that his newest guidelines recommend that Avandia shouldn't be used.

From MedPageToday: Although the data released today showed no associated risk of overall cardiovascular morbidity or mortality, Dr. Nathan noted that the study still doesn't put to rest the concerns about the drug
This should not come as a surprise from someone who believes we need no more new diabetes medicines.


If you are still skeptical, I encourage you to read all my diabetes posts, particular the Diabetes Conspiracy, as it outlines how flawed and political the whole controversy is.

In addition, please consider that gold standard of science is not a meta-analysis, but large, randomized controlled trials designed to answer a specific question like RECORD. Given RECORD, ACCORD, ADOPT, DREAM and VADT there have been randomized, controlled trials of 26,000 patients that have been studied over 4 to 5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks .

Major Diabetes Study to Be Presented! Get Ready for RECORD

The American Diabetes Association's annual meeting starts this week, and there will be some major studies that will be reporting out. One of the biggest is going to be the RECORD study, which will present at 4:15 on Friday June 5th, in New Orleans. This study will likely put to rest the Avandia controversy and either prove Dr. Steve Nissen to be a hero and cause Avandia to be pulled from the market...OR prove that Nissen's data was full of holes, completely vindicate Avandia as safe and effective and have major implications for the treatment of type 2 diabetes.



I have blogged multiple times about what I call the Diabetes Conspiracy and the Avandia saga. Please check out this time line which shows that the Avandia scare is much more about politics then science, and really starts with both Vioxx and Elliot Spitzer (yes, that Elliot Spitzer).



Briefly, Avandia was known to increase fluid retention and may have the potential for congestive heart failure, so 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 called RECORD (pronounced like the noun, i.e. LP and not the verb) , as well as present the results of their planned studies, looking for any heart risks. The RECORD study was a large, randomized trial designed specifically to answer the question of cardiovascular safety and Avandia. 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 had be going on for almost 2 years, and even though the results would not be available until 2009, 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.



Coincidentally, the issue of releasing this data was just discussed in the New York times as the FDA, under scrutiny, is reconsidering some of these policies. However, there might be a plus side to not releasing data before a scientific conclusion can be made. Due to an earlier settlement regarding Paxil (find out who was the prosecutor behind this case by reading the Diabetes Conspiracy ), all of GSK's studies were available online. Dr. Steve Nissen, cardiologist from the Cleveland Clinic and known champion of dangerous drugs like Vioxx went and got the data himself and published it in the New England Journal of Medicine. ( I suspect that he was tipped off from someone inside the FDA who did not want to wait for RECORD, ADOPT and DREAM to finish before letting the public know about a potential danger- read here for more info). The Nissen article created a media storm, and patients and doctors got scared about using Avandia, since Nissen claimed Avandia caused a 43% increase in heart attacks.



Because of fears that the ongoing 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, and claiming that it proved nothing about the safety regarding Avandia.



However, the final results of the RECORD study will be at 4:15 on Friday June 5th, at the ADA meeting in New Orleans and we should hopefully know once and for all whether or not Avandia is safe or increases the risk of heart attacks.



What are the possible results?

1. Avandia does in fact cause an increase risk of heart attack. If this is the case, GSK will likely pull Avandia from the market and spend billions of dollars settling law suits. However, this is HIGHLY unlikely, mainly because 1) the interim results did not show this 2) a data safety monitoring board has been independently watching the study closely and would have pulled the plug (like the ACCORD study) at the first warning signs, and 3) every large major randomized trial such as ACCORD, ADOPT, DREAM, VADT. etc show no increase risk of heart attacks.



2. It is not clear whether or not Avandia causes an increase risk in heart attacks.

This is a possibility (probably the most likely) for a variety of reasons. First, the primary outcome of the study is hospitalization (for acute myocardial infarction, congestive heart failure, stroke, unstable angina pectoris, transient ischemic attack, unplanned cardiovascular revascularization, amputation of extremities, or any other definite cardiovascular reason) or death from cardiovascular causes (including heart failure, acute myocardial infarction, sudden death, and death caused by acute vascular events including stroke). Hospitalization and death from cardiovascular causes individually, as well as each of the individual components (heart attacks, heart failure, etc.) are secondary endpoints. Since we know that Avandia can increase the risk of heart failure (possibly hospitalization, much less likely death) it is possible that the primary endpoint will not meet the study's statistically significant number, even though death might actually be reduced on Avandia and/or hearts attacks are clearly no different. When the results come out, should some of these endpoints go in opposite direction, be aware that the people who staked their reputation on NEJM meta-analysis (Dr. Nissen, Dr. Graham, Dr. Nathan) will likely come out and say that the entire study shows nothing. However, this is just simply not the case. It would be reasonable to expect that the primary endpoint of the study did not clearly indicate safety from the combination of hospitalization and death, but if all the hospitalizations are due to heart failure ( a known complication), there are no more deaths (possibly fewer) and there are no more heart attacks (possibly fewer); these are very meaningful and positive results.

Secondly, the study is designed to show with more than 95% certainty that Avandia would not increase the risk of BOTH cardiovascular hospitalization AND death by more than 20%. If the results show that the combination increases the risk by 21%, the general findings will be considered inclusive even if some of the findings of the study show Avandia to be clearly beneficial. Again, look for the naysayers to focus on this should the primary endpoint fail to meet this criteria. However, what you shold focus on is whether or not there is a difference in what everyone was worried about in the first place: heart attacks.

Finally, the study may not be powered to make a conclusion. For the RECORD study, the patients not on Avandia need to have the 11% events per year ( 3% with deaths from cardiovascular causes and 8% with hospitalizations from cardiovascular causes). In the interim analysis of RECORD, the event rate was much, much lower at 3.1%. This is likely due to much better diabetes care occurring then when the study was originally designed, for example more diabetics being put on statin medications. This was a HUGE criticism when the interim analysis was published, and will likely be a huger criticism on Friday. Power calculations are used to estimate how many patients would be needed in a study to show a difference. A well powered study increases the confidence that the results are true if a difference is shown. That said, if there are differences (or in this case no difference is shown, the study's primary goal), even if the study is not adequately powered, it does not make the results untrue. All it does is decreases the level of confidence that these results are true. Power calculations for RECORD were based on a 99% certainty. If the results are 85% certain, then this is probably good enough.

3. Avandia does not cause an increase risk of heart attacks. This was the primary goal of the study was to show that Avandia does not increase hospitalizations or deaths from cardiovascular causes. If the study shows with statistical confidence that there is no difference in both this primary outcome AND there is no statistically different risk of heart attacks between Avandia containing regimens and non-Avandia containing regimens, then this should be the end of the Avanida controversy. Case closed. Again, given that the primary outcome includes heart failure and the issue of statistical power mentioned above, it may be hard to show this. That said, even if the primary outcome is inconclusive, if both death from cardiovascular cause and heart attack are no different, along with data from other studies, this should be enough evidence to put the issue to rest, though it will leave enough room for folks like Nissen, Graham, and Nathan to be critical.



4. Avandia actually DECREASES the risk of heart attacks. I might be the only one in the country (including the drug company that makes Avandia), but I am not going to be surprised if the data shows that Avandia prevents heart attacks. I realize I am going out on a limb here, and making a prediction that is not likely to come true, days before we will actually know the results. However, there are several reasons that this might occur. First based on all the data we have up to this point, it is clear that Avandia doesn't cause heart attacks. As I have blogged before, the Nissen study itself is riddled with problems. However, the way the study is designed, the patients in the group who are NOT taking Avandia will be more likely to take insulin.In my previous posts The Problem With Insulin and The Problem with Insulin- Part 2 , I explain that though insulin is life saving for type 1 diabetics, and can be life saving for some type 2 diabetics, it is not without complications. In the ACCORD study where diabetics who were actually treated more aggressively to get their sugars to normal had more heart attacks and death. They also had more hypoglycemia or low blood sugar, which could be a cause of heart attack or death as well. It may be that because Avandia has properties that might actually prevent heart attacks (improved good cholesterol or HDL for example) and because the patients not taking Avandia would be more likely to need insulin, that Avandia might be shown to actually reduce heart attacks!


Bottom Line
Even if scenario #2 or #3 (3 obviously preferred) turns out to be the result, and their is a mix of finding BUT no difference in heart attacks, death, and only an increase in the risk for the known complications of CHF; AND in addition to this there turns out to be less use of insulin and less hypoglycemia in the Avandia group, isn't that reason enough to use Avandia (or Actos, the other TZD on the market)? For most of my diabetic patients, the thing they are most afraid of is needing insulin. How wonderful would it be to know that I can spare many patients the need for starting insulin by using pills (and not just the generic ones that although cheap, are known to fail over the long term)? Yet, current recommendations suggest that doctors should use JUST the old, generic diabetes medicine (there are only two) and if these fail, go right to insulin. This is why the RECORD study is so important. It is more than just about vindicating a maligned drug or making a cardiologist who likes the limelight look foolish. It's is about whether or not we should use insulin early in the game or as a last resort. Thus, the results of the study should have profound implications for the management of all patients with type 2 diabetes.

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.