Why the FDA Should Lift Warnings on Avandia, Even if No One Will Use It

Today was day #1 of the FDA's two day hearing on Avandia. The reason for the meeting is a review of the controversial RECORD trial.  I have blogged about Avandia extensively. In case you are not up to speed on what's happening, Matthew Herper at Forbes has one of the best summaries I have read called "Battleground FDA: How Tomorrow's Avandia Panel Could Help Shape The Future Of Diabetes."

The decision by tomorrow's FDA advisory committee could range from lifting restrictions, to removing Avandia from the market entirely, to doing absolutely nothing.  And regardless of their recommendation, the FDA may do something different.  However, even if Avandia is cleared of all harm, and restored as a safe product in the eyes of the FDA, few doctors will likely ever prescribe this medication.  Since rosiglitazone is off patent, it could be generic, but it is unlikely that any generic company will invest in bringing it to market. For the same reason, it is unlikely the GSK will start marketing the medication again.  However, I believe there are important reasons why Avandia should be exonerated, even if few additional patients end up taking it.

1. The un-blinded RECORD analysis is enough reassurance
What we learned today was that the re-analysis of RECORD was consistent with the original findings that Avandia did not lead to cardiovascular death or heart attacks. In addition, the Duke group that did the re-analysis did a pretty darn thorough job.  Thus, the central issue in tomorrow's discussion will be whether an un-blinded, large randomized trial is enough to prove safety and negate the results of a meta-analysis.
The gold standard for science is the double-blinded, randomized control trial.  Double blinded means that when the researchers are analyzing the data, they don't know which group is the treatment group and which is the control, and patients don't know whether they are taking the experimental drug or a placebo.  The reason for blinding is that it reduces potential bias.  When patients are enrolled in a study, if they think they are taking a medication that will help them, it will help them, even if the drug is a placebo. The more they think the drug is helping the more it is likely to help. So, if you did a headache study and gave half the patients Tylenol and half the patients nothing, the patients taking Tylenol would surely do better, but you couldn't prove that Tylenol relieves headaches because your results might have just been due to the placebo effect. In other words, in a study of efficacy, not blinding patients to a treatment may bias a study in favor of that treatment. 
In the RECORD study, the investigators were blinded to the results (single blinded), but patients knew whether or not they were taking Avandia. There were several reasons the investigators did this, one being that in Europe (RECORD was an international study), Avandia was not indicated with insulin.  However, having open label treatments in RECORD should not effect the results, primarily because record is a safety study. If anything, if you are patient in a safety study and you know you are taking the drug they are studying (must be something wrong with it if they are studying safety), you would be more likely to have adverse events.  This is known as the nocebo effect. It is the reason why if you read the all the information they give you at the pharmacy when picking up a prescription, you are much more likely to think you have one of the millions of side effects listed. In other words, in a study of safety, not blinding patients to a treatment may bias a study in favor of the control. However, in spite of this bias, the RECORD study still showed no harmful effects of Avandia. Thus, if anything, the un-blinded design of the RECORD study should lead the FDA to be even more assured about Avandia's safety.

2. The TZD class is good for treatment of diabetes.
When the Nissen publication was released and the Avandia storm began, patients got worried.  Some patients simply stopped taking Avandia altogether, without substitution.  Many doctors switched their patients to Actos, the other thiazolidinedione or TZD available. Merck got lucky and launched Januvia around this time, so when physicians were looking to add a medication to metformin, due to TZD fear, and presumed safety of a new class of medications, they started prescribing Januvia.  In other words, while Actos ended up getting most of the TZD scripts, fewer doctors were writing for TZD's. This is a shame because the TZD's are the only class of medications to show that they keep a diabetics sugar under control for many years.  Older drugs like metformin and sulfonylureas usually fail after three to six years.  TZD's also don't cause hypoglycemia.  They also have positive benefits on lipids (raising good cholesterol and lower tirglycerides). The TZD's are not perfect drugs.  They increase fluid retention and can lead to congestive heart failure in patients who have decreased heart function.  There is a small risk of osteoporosis, and with Actos there may be an increase in bladder cancer. Yet, while not perfect, most of these risks are manageable.  Heart attacks are not, and so due the Avandia fiasco, the TZD class is likely underutilized.  Pioglitazone is available without restrictions and is now generic. Thus, exoneration of Avandia would likely (and appropriately) increase prescriptions of this medications.

3. Other options may be less safe than once thought.  
There are two reasons why in 2010, the FDA chose to severely restrict Avandia.  The first was due to concerns of missing data and a non-independent analysis in the RECORD trial (which we now know was unfounded).  Second was the notion that Actos seemed just as good as Avandia, but didn't have the risks, and therefore many saw no reason to keep Avandia on the market. However, what we now know is that Actos may be associated with bladder cancer.  (In fact the FDA knew about this in 2010, but brushed it under the rug at the July meeting- see page 213 of the original transcript).  While pioglitazone may have a slight edge over rosiglitazone in a number of areas, in patients with a higher risk of bladder cancer (smokers), I might use Avandia over Actos.
Also, the new agents (DPP4's like Januvia and GLP-1's like Victoza) were new at the time.  We now know that these agents may have risks of their own including pancreatitis, and the FDA is even looking into pancreatic cancer as highlighted by a recent New York times article. Now there are pro's and con's to all agents.  A physician's job is to weigh the risks and benefits of each medication and choose the most appropriate product. However, this is made particularly difficult for diabetes when the specter of heart attack looms over the TZD class.  Lifting the heart attack risk from Avandia will truly give diabetics more options (even if they don't take Avandia).

4. Clearing Avandia may help restore public confidence in the FDA, and possibly pharma. 
The problem with the whole Avandia fiasco was it decreased the public's confidence in both the FDA and the pharmaceutical industry.  The heavily marketed Vioxx was a lesson in caution.  However, certain doctors and journalists made a name for themselves looking for the next Vioxx, and Avandia was a great target.  The FDA knew about the risk seen in their own meta-analysis but wisely chose to wait on any restrictions or warnings until other trials, including RECORD, were complete.  We now know that this was the correct decision.  However, some inside the FDA were not happen with this decision and made sure that the data got to the public. Hysteria ensued.
While industry watchdogs are necessary, they can sometimes to more harm than good. Ask any physician, and they will tell you that, in general, most patients are afraid to take any medications. This was not nearly as true 10 years ago. Today, patients don't trust drug companies or the FDA. The Avandia fiasco played a major role in this.  The FDA can now right this wrong.

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.

Metformin is first, but what diabetes medicine is #2?

Most experts seem to agree that for type 2 diabetes, metformin should be the first line therapy for most patients, but there is significant disagreement for which agent holds the #2 spot.  Recently, the NY Times wrote a piece "For Those With Diabetes, Older Drugs Are Often Best." claiming that docs should stick with the older, cheaper drugs.  This may be true for metformin, but likely not for sulfonylureas which cause hypoglycemia, weight gain and do not sustain glycemic control. This means the next agent will need to be a branded drug.  DPP4's likely Januvia and Onglyza and TZD's like Actos are but possibilities, and each has advantages and disadvantages over the other.  The DPP4's are the newest agents and therefore have the shortest track record.  We don't know whether they can sustain glycemic control, but 2 year data looks promising.  However, they are very clean with essentially no side effects.  The TZD's have been the best studied, and really the only drugs that have shown sustained glycemic control.  However, they have more side effects including edema, weight gain, a very small risk of non-vertebral fractures, a very small risk of heart failure in those at risk, and of course the FDA's concern about myocardial ischemia with Avandia (though not a concern with Actos per the FDA).   Both classes also come in combination with metformin.

For a more complete discussion, see my Medscape blog post "Metformin is first, but what diabetes medicine should be your second choice?" (You will need to create a log in and password for Medscape in order to see this).

Using Actos to Prevent Diabetes

Recently, the New England Journal of Medicine published a study showing that Actos prevented the development of diabetes in patients at risk for developing diabetes (Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance). Though this has not generated significant mainstream media buzz, bloggers Matthew Herper from Forbes (Why You Don’t Want A Pill To Prevent Diabetes) and Amy Tenderich from Diabetes Mine (10 Reasons Why The Actos Pre-Diabetes Study is Dumb) strongly disagree. Since many patients follow these popular blogs (far more popular than mine), I thought it would be important to throw a clinician's point of view into the ring.

The NEJM study randomized over 600 patient who were at high risk for developing diabetes to pioglitazone (Actos) or placebo and found that after about 2.5 years, 2.1% in the pioglitazone group and 7.6% in the placebo group progressed to diabetes (which is a relative 72% risk reduction). On the down side, patients on pioglitazone gained about 7 pounds more and about 7% more had edema.

To assess the value of using TZD's like Actos to prevent diabetes, it is important to understand what diabetes really is, how it is defined, and why TZD's might be a very important option despite the associated risks. Unlike type 1 diabetes which is mostly about the destruction of the beta cells in the pancreas and subsequent lack of insulin, type 2 diabetes is a long process that is about much more than blood sugar. Type 2 diabetes is a result of genetic factors that control how individuals utilize glucose, about age, and about obesity. These factors combine to cause much more than just the body's impaired ability to utilize sugar. There is increased inflammation, worsening of cholesterol, increased blood pressure and increased blood clotting, just to name a few. All of these factors, including elevated sugar, combine over years and years to increase the risk of microvascular complications (eye, kidney, nerves) and macrovascular complications (heart attack and stroke). The process occurs for many years, and it is estimated that at the time of diagnosis of diabetes, the process (let's call it metabolic syndrome) has been going on for about a decade and that about half of the pancreas' function is lost despite having relatively high levels of insulin. Men who meet the diagnostic criteria for metabolic syndrome have three times the risk of heart attack and stroke and women who meet this criteria have six times the risk.

When we call a diabetic a diabetic is quite arbitrary. The guidelines used to classify diabetes as a fasting glucose of 140. This was lowered several years ago to 126 recognizing that complications were occurring at sugar levels lower than 140, and the cut off of 140 was too high because it was delaying treatment. More recently, in 2010 the ADA recommended that diabetes be diagnosed at a hemoglobin A1c of 6.5% or greater, recognizing a fasting glucose of 126 missed many of the diabetics with impaired post-prandial glucose, thus leading to possible delays in therapy. In fact, based on this new criteria, some of the patients in the Actos study who were not classified as having diabetes, would now be called diabetics. It is not inconceivable in the near future, that the threshold for diagnosis and treatment of diabetes occurs at an even lower fasting glucose number, A1c, or some constellation of markers. In other words, whether or not we are really preventing diabetes or just delaying the time to reach an arbitrary threshold is more of semantics. The bottom line is that in patients with impaired fasting glucose, there is an underlying disease process leading to complications that ought to be addressed.

To make an informed decision, one has to review the three main studies that looked at drugs for the "prevention" of diabetes. The study above for Actos, was very similar in design and findings to the other TZD rosiglitazone or Avandia called the DREAM study. The other major study, called the Diabetes Prevention Program (or DPP) looked at metformin vs. diet and exercise vs. placebo. Interestingly, diet and exercise beat metformin for preventing diabetes. Why would this be? It has to do with the fact that diet and exercise reverses the process of insulin resistance whereas metformin merely lowers blood sugar. Metformin was not included in the rosi or pioglitazone studies, nor was there a diet and exercise arm, so it is hard to compare all three interventions (diet/exercise, metformin, TZD) in preventing diabetes complared to placebo. However, troglitazone, an early TZD which was pulled from the market for liver complications (Actos and Avandia have not shown these problems) was initially used in the Diabetes Prevention Program (DPP), but was stopped after less than a year. Interestingly, in that short time, troglitazone did better than both metformin and diet and exercise. In other words, when you address insulin resistance and metabolic syndrome either by diet and exercise or with a TZD, you prevent diabetes much better than with a drug like metformin that only addresses blood sugar or placebo. This is important because the Actos study not only showed decreased rates of diabetes, but also showed statistically significant decreases in blood pressure, plaque build up, and increases in HDL or good cholesterol.

This begs the question, if you can prevent diabetes (or treat the underlying process that has not yet met the arbitrary criteria to be called diabetes) with Actos or lifestyle modications, why would you choose a drug? The answer is that lifestyle modifications is always preferred, but often not practical or easy to do. For the lifestyle intervention group in the DPP, participants were instructed to limit their calories to 1200-1800, get 150 minutes of exercise a week, had 16 sessions of counselling, and access to nutritionists, personal trainers, and behavioral counsellors. Another way to look at this is that anyone can go on "The Biggest Loser" and lose weight if they are given that amount of support (and time to take off from work), but this is not always practical. Interestingly, much of this support is not covered by traditional health insurance (where medication is), and once could argue that this is where we ought to devote our precious health care dollars (topic for another post).

As a physician, I need to help my patient the best way I can. I need to be practical. For all patients, diet and exercise is clearly the first step and always encouraged at every step. However, practically speaking, this just doesn't work all the time. It takes a highly motivated patient with a lot of resources and support to do this. Thus, if I can use a medication that will help reverse the underlying disease process of insulin resistance and delay the diagnosis of overt diabetes (along with diet and exercise), then I believe I am ethically obligated to do so.

Finally, the big issue that has been brought up is side effects. Mainly weight gain and heart failure. First, the TZD's do not "cause" heart failure. What I mean by this is that Actos has no direct effect on the heart. What is does do is increase fluid retention. For patients whose hearts are not working that great (pre-heart failure), a little extra fluid can push them into heart failure. Though this is a serious risk, it is not that common and can be addressed by carefully monitoring patients before and after treatment. Secondly, weight gain is a real issue. There are two components of weight gain caused by TZD's. The first is the aforementioned fluid retention. The second has to do with reversing the underlying disease process. Patients with diabetes and metabolic syndrome do not utilize glucose correctly. This causes subsequent increases in insulin and eventual pancreas failure leading to the need (over years) of supplemental insulin. By not using sugar, weight is not gained. By correcting the process, the sugar goes to where it is supposed to, which leads to weight gain. However, it is not clear that this weight gain is necessarily "bad." Studies show that TZD treated patients shift their fat from the dangerous visceral abdominal fat (associated with high cardiovascular risk) to more centralized fat stores. In other words, though not proven by a randomized control trial, reversing the disease process (glucose, cholesterol, blood pressure, weight gain) is likely to prevent more adverse events (heart attack and stroke) then events caused by additional weight.

Bottom line: Obesity is an epidemic in our country and will soon be the single leading cause of preventable death in the US. Along with obesity comes diabetes, which takes years to develop and is defined by arbitrary criteria. This diease process (metabolic syndrome) is associated with it's own consequences. Diet and exercise leading to subsequent weight loss and improved cardiovascular health is clearly the best choice. However, for most patients for very practical reasons, this method is not successful. Until there are changes to our health care system and/or public health initiatives that make intense lifestyle modifications more reasonable, pharmacotherapy to prevent diabetes has an important role. Pioglitazone has demonstrated that it can effectively prevent diabetes in most patients with known but manageable side effects, and therefore should be considered a useful tool.

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.

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.

Comparative Effectiveness Can Be a Win for the Drug Companies

One of the Obama administration's major initiatives as part of health care reform is comparative effectiveness. Currently, the drug and device companies do almost all of the research. NIH and other government agencies don't often compare which treatments work best and the industry usually only sponsors studies that it knows will make their product come out on top. Thus, it is not surprising that many drug companies do not support this comparative effectiveness. However, their position may be misguided.

A great example of comparative effectiveness was just presented this afternoon at the American Diabetes Association and simultaneously published ahead of press in the New England Journal of Medicine. The trial is called BARI 2D and is a 5 year comparative effectiveness study in over 2,000 type 2 diabetics sponsored by the good old USA (via NIH). In this case, the drug companies won not just once, but twice!

1. Drugs beat interventions. BARI 2D was designed to look at two things. First, in patients with type 2 diabetes who have atherosclerosis (blocked heart arteries), do they do better with interventions like surgery (coronary artery bypass) or percutaneous coronary intervention (where the cardiologist goes in with a catheter to open up a blocked artery with a balloon, often leaving a stent in place) or no interventions and just medications. Previous studies had shown no difference between medical therapy and intervention for stable patients, but the question remained whether or not this would hold true for type 2 diabetics, who are at even higher risk for heart related events. However, the same results were seen. Optimal medical management (think lots of pills) is better than angioplasty and bypass surgery. If I was the head of a drug company, I would be pretty happy with these results.

2. New medicines beat (sort of) old medicines. The second question BARI 2D tried to answer was whether the greatest benefit in this very high risk group of type 2 diabetics would come from insulin providing medicines (insulin, sulfonylurea-which are older drugs) or insulin sensitizing medicines (metformin, and thiazolidinediones or TZD's, which are newer). Again, there was essentially no difference in the primary outcomes of death or major cardiovascular events.

Having the old drugs show no difference then then newer drugs might at first seem like a loss for the drug companies. However, severe hypoglycemia was more frequent among patients assigned to receive insulin provision than among those who received insulin sensitization.This is important, because severe hypoglycemia is bad, and can be life threatening. Even more important, at the 3-year follow-up, the most frequently used drugs in the insulin-provision group were insulin (60.7%) and sulfonylurea (52.0%); in the insulin-sensitization group, the most frequently used drugs were metformin (74.6%) and a thiazolidinedione (62.1%- of which most (55%)was rosiglitazone or Avandia). Specifically, the use of insulin was double in the insulin providing group. If you can achieve the same results without using insulin why wouldn't you? My patients don't like taking insulin. The strips are expensive, checking your blood sugar frequently has been proven to reduce your quality of life, and I already mentioned severe hypoglycemia. This is a loss for those drug companies that make insulin products, but a real win for those drug companies that make pills and other newer insulin sensitizing products. Finally, more than half of the patients in the insulin sensitizing group took Avandia and virtually none took it in the insulin providing group. Guess what? In this group of type 2 diabetics who were at extremely high risk for death and heart attacks, there was absolutely no difference. Thus, BARI 2 D trial confirms what the RECORD trial clearly showedjust the other day: there is no cardiovascular risk associated with Avandia. This is a win for GSK (makers of Avandia) and Takeda (makers of Actos, another TZD).

BARI 2D represents comparative effectiveness at work. It tells us that we should be using medicines (even if some of them are expensive) instead of doing angiography and surgery (even more expensive) in certain patients who are commonly using the later. BARI 2D also shows us that newer (even if some of them are expensive) insulin sensitizing drugs provide equal cardioprotective benefits, but less hypoglycemia and less need for insulin which has many costs associated with it. The drug companies should re-consider their stance on this issue. If they are making novel and useful products, comparative effectiveness will likely be a win for them.

ADDENDUM- In the middle of writing this post, the Wall Street Journal published Diabetes Study Questions Expensive Treatments on this exact same issue. However, they got it wrong on Avandia and Actos. These medicines were shown to provide better sugar control, less hypoglycemia, and less need for insulin. It was indeed disappointing that there was not a statistically significant reduction in death or cardiovascular events. It is possible that longer studies would be needed to show this effect. However, even with no difference in the primary outcome; better glucose control, less hypoglycemia and less use of insulin is a win for these medications, not a loss.

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.