Friday, July 16, 2010

Study 175 and the Need for Comparative Effectiveness Research

Though I am not going to say that the New York Times lied, they either purposely and grossly misrepresented the truth or did a horrible job of reporting. In their article "Diabetes Drug Maker Hid Test Data, Files Indicate" the Times states that Avandia maker GSK "secretly began” a study which ”provided clear signs that it (Avandia) was riskier to the heart.” In fact, the study in question, called study 175, was a small, short study, that had no cardiovascular outcomes (only lipid data) and was not a comparison of Actos and Avandia. In fact, there were no patients taking Avandia in this study! In addition, from pages and pages of documents, the Times took an out of context comment about the study (a GSK memo which read that study 175 shouldn't see the “light of day”) to make their charges sound even more damning. The New York Times should be above this kind of sensationalist journalism.

Let me give you a breakdown of study 175, why it was done, what it showed, and most importantly how this relates to the need for comparative effectiveness. You can read the official GSK statement about study 175 here, or look at the data yourself, which comes from a letter to the FDA from Senator Grassley (via Pharmalot).

Both Avandia (GSK) and its competitor Actos (Takeda) came out around the same time in the late 90's. Both were insulin sensitizers or TZD's, a new class of drugs for diabetes; a disease which hadn't seen any new drugs in a while. Not surprisingly, the two companies with their respective products were pretty competitive. The Takeda drug reps were usually quick to point out that though both products improved diabetes control, Actos did a better job on lipids. (Note that in addition to improving diabetes, the TZD's have a positive effect on lipids). The Actos people were able to make this claim because in their studies, Actos lowered triglycerides or fats by about 9% and in the GSK studies, Avandia didn't have much of an effect on triglycerides. This is a common tactic used by drug reps and breaks a cardinal rule of evidence based medicine: you can not compare products across studies, because in each study the populations and circumstances might be different. The only real way to make a comparison is in a head to head comparative trial. (This point remains very relevant, because the recent FDA advisory committee somehow concluded that Actos was safer than Avandia without one head to head trial!)

However, GSK noted an additional flaw in the Takeda claims. In the Actos studies, the patients started out with an average triglyceride level of about 260 mg/dL, where the patients in the Avandia studies had baseline triglyceride levels closer to 180mg/dL. In other words, if you start with worse numbers, you are more likely to show a bigger improvement. How well would Actos do on triglycerides in patients with closer to normal levels of triglycerides (normal is less than 150mg/dL)? One way to find out would be to do a head to head study comparing Actos to Avandia in patients with similar cholesterol and triglyceride levels. GSK could have certainly done this, but what would happen if the GSK study proved that Actos did indeed work better on triglycerides? Before spending a substantial amount of time and money on a study that could ultimately hurt the company, GSK did study 175 which looked at lipid levels in patients taking Actos who started with relatively normal cholesterol levels. Though they compared this to historical Avandia data, this was not a true head to head comparison, but likely enough information to tell them whether or not to proceed with the head to head.

I have pasted the main results from study 175 below (though you are welcome to go through the entire 158 Grassley letter). What you can see is that the higher dose of Actos dropped triglycerides about 16 points (or about 10%) and Avandia at the higher dose raised triglycerides by about 11 points. Study 175 also showed that Avandia raised the LDL or bad cholesterol by about 10%, where Actos didn't have any change (advantage Actos) and that Avandia raised HDL or good cholesterol by about 4 points (roughly 10%), whereas Actos didn't really raise the HDL (advantage Avandia). Given that these results might put Avandia at a competitive disadvantage, GSK decided not to publish their findings and did not to go forward with the head to head study. Thus, the company did not secretly hide data that Avandia was dangerous (as Grassely and the Times suggest). Rather, GSK chose to not to publish an Actos study that didn't make Avandia look any better.

Now you might argue (am I am guessing that this is Grassley's point) that since Actos did better with triglycerides and LDL cholesterol than Avandia, that this shows Avandia might pose a cardiac risk. In fact, many have argued this as the very reason that Avandia seems to show safety signals in meta-analyses and Actos doesn't. However, time and time again, surrogate markers have shown us that they don't translated into outcomes. First, all diabetics should be on statins, so these minimal changes in lipids seen by both TZD's probably don't matter clinically. Second, both the FIELD trial and the recently published lipid arm of the ACCORD study showed that even if you treat diabetic patients with medicines that truly lower triglycerides (fenofibrate), it doesn't reduce heart attacks. Furthermore, though there are only a few studies in diabetics showing raising the HDL decreases heart attacks, even Dr. Steve Nissen in his PERISCOPE trial that showed Actos to reduce plaque build up compared to the older sulfonylurea drug, suggests this may have been due to the HDL effect. In other words, if HDL is more important in preventing heart attacks in diabetics than triglycerides, maybe Avandia is the real winner of study 175. Though I am not going to suggest (similar to the Times and Grassley) that study 175 showed Actos to be more dangerous to the heart due to Avandia's HDL benefit, it is clear that study 175 does not show in any way, shape or form, that Avandia is more dangerous than Actos.

However, if you still feel the public has a right to know all the data (which is a valid point), GSK didn't just "hide" the data; they had an obligation NOT to publish it. GSK (and every drug company) is a for profit business. Though they have an obligation to patients to make safe and effective products, they also have a fiduciary obligation to their shareholders to make money. Similarly, though Toyota has an obligation to warn the public about any safety issue with its cars, it can not publicly declare that their Sienna minivan has fewer cup holders than Honda's Odyssey mini-van. Nor should Starbuck's need to announce that in a blinded taste test, most people preferred the cheaper McDonald's coffee. In all three cases, share holders could sue the company.

The main problem is that the majority of pharmaceutical studies are done by the pharmaceutical companies. The purpose of these studies are to get their drug approved for initially for availability on the market and eventually use in other indications. In 2005, pharma spent nearly $40 billion in research. This dwarfed the entire NIH budget that year of $28 billion dollars, and the NIH does very little research on drug therapies. You can't have your cake and eat it to. If you want unbiased studies, and if you want science and not marketing to determine what studies get done, then someone besides the industry is going to have to do the work.

Indeed, it is rare that industry published head to head studies. In some cases, such as Merk's ENHANCE study which showed its expensive product Vytorin to be no better a reducing plaque buildup thant its recently generic simvastatin, the company lost big time. Use of Vytorin decreased dramatically, and Merk's stock plummeted. In fact, the TIDE study comparing Actos to Avandia (which the FDA advisory committee approved to go foward with 19 to 10), only got started in the first place because the FDA mandated that GSK do this study. Ironically, in this Avandia "win" from this past week, GSK is footing the bill for TIDE, spending millions while sales of Avandia will likely plummet. If we had comparative effectiveness research in place back in the 90's the TIDE study would likely have already been completed and we would know with 100% certainty whether there was any TZD risk for heart attacks and any difference between Actos and Avandia.

This is why comparative effectiveness research is so important, and why it is a much needed improvement that came out of the recently passed health care reform bill. The health care reform act included about $500 million for a Patient-Centered Outcomes Research Institute
to do comparative effectiveness research. The funding builds on about a $1 billion dedicated to comparative effective research from the stimulus package. However, though an important start, $1.5 billion over the next decade is a drop in the bucket compared to the funding needed to answer important clinical questions about which medications are best in which patients. One possibility would be to have industry and government partner in such a way that the industry kicked in with only limited input into the research, which would also absolve them from their fiduciary responsibility to their shareholders. Other agreements could include more data transparency and independent analysis of drug company sponsored studies before publication.

The recent Avandia hearing with its media sensationalism from the Times and politicking by folks like Grassley and insiders within the FDA shows that when science, politics and media mix; patients lose. Not only is more transparency needed in both the FDA and the industry, but we have not been wise to allow industry to foot the bill for most of our research on therapeutics. Comparative effectiveness research provided in the health care reform bill is a start, but is grossly underfunded for what is really needed.

Thursday, July 15, 2010

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.

Wednesday, July 14, 2010

FDA Panel Recommends Keeping Avandia on the Market

As I mentioned in my post Avandia Smackdown!! , I suspected that Avandia would likely stay on the market. The story is all over the headlines, including the Wall Street Journal's FDA Panel Backs Keeping Avandia on the Market. The 12 panel members wanted to pull Avandia, but 20 said it should stay on the market. More interestingly, though the majority of the members felt there were signals of risk, the vote was 20 to 10 to proceed with the controversial TIDE trial, which Drs. Graham and Sen. Grassley said were unethical.

I have been following the hearing closely for the past few days via Twitter and live video feeds from CNN. Here are some initial thoughts.

1. Despite the panel's concerns about Avandia safety, the clear majority felt that there was simply not enough data. Many were concerned that studies like Nissen's meta-analysis were just not strong enough. Though they favored long term, randomized trials to definitely answer these questions, unfortunately, there were enough concerns about the RECORD study by some (low events, withdrawals, and some missing data) to be convincingly reassured.
2. The sentiment of many was because Actos didn't show as strong signals, it remained a better option. Many who chose to pull Avandia stated for the RECORD that Actos' availability was a deciding factor. This is concerning because the data for Actos safety is extremely weak (not that I think Actos is dangerous). One panelist stated what I have heard before, that "the absence of evidence does not equal the evidence of absence."
3. Many panelist stated that they were putting on their "public health" hats, meaning that even though scientifically they were not convinced of real harm, because there was a possibility of harm, they voted to remove or proceed with caution. This is VERY important, because as a clinician (which many on the panel were not), you have to balance risk and benefit every day. Is the side effects of a particular medicine worth the benefits of the medicine? Is the potential harm of radiation worth the need for a CT scan? I think if more practicing doctors were on the panel, fewer would have voted to remove the drug.

What now?
Ultimately, the FDA will decide what to do. Since the FDA doesn't have to agree with the panel and especially since the panel seemed split, the FDA could decide to remove Avandia anyway or keep on the market with certain restrictions. Given that 10 voted to have very strict warnings, it is likely that's what the FDA will do. These stricter warnings will likely include something like requiring only a diabetes specialist, i.e. an endocrinologist be able to write a prescription for Avandia. This language will be crucial, because even if Avandia stays on the market, if the restrictions are tough enough, no doctor will ever write for the prescriptions.

Despite all the holes that Avandia's opponents poked in the data, I remained convinved that the preponderance of the data points in Avandia's favor. It doesn't appear to cause increased heart attacks, it certainly doesn't cause increased death, seems to decrease stroke, and clearly decreases the use of insulin. I will continue to write for the product unless it is pulled from the market, newer restrictions make it virtually impossible to prescribe, or my patients request being placed on a different medicine.

Sunday, July 4, 2010

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.