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.

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

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

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


Here's why:





Why it matters?


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




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

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

2. We need Avandia (and medicines like it)
Most diabetics are not able to be controlled on only one pill. In fact, of the two older, generic pills; we know that most patients on these medicines will eventually fail therapy. Analysis have shown that though both metformin and sufonlyurea lower blood sugar; about half of all patients taking either of these medications lost diabetes control by three years, with the vast majority losing control at 9 years.

Avandia, was the first medicine to show that it could keep patients' diabetes under control. The ADOPT trial showed that Avandia, a thiazolidinedione or TZD, substantially reduced loss of diabetes control compared to both metformin (Avandia 32% better) and sufonlyurea (Avandia 63% better). TZD's work by reducing insulin resistance, and also can improve beta cell dysfunction. Both effects were seen in ADOPT. The recent RECORD trial has now also showed this effect. Actos, another TZD, also seems to do this as well. Finally, some of the newer DPP4 medications like Januvia and (hopefully) soon to be available saxagliptin (Onglyza) have shown to preserve pancreas beta cell function in animals and human studies are only now just getting under way.

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

3. Patients were harmed.

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

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

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

Dr. Nathan, an endocronologist from Harvard, is basically the current architect of the ADA's guidelines for the management of type 2 diabetes. In a Perspective piece in the New England Journal of medicine , he shows that he does not like new diabetes medicines stating that newer diabetes drugs like Avandia and Januvia , "are generally no more potent, and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old. Moreover, the newer classes are uniformly more expensive and are associated with adverse effects."

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

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

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

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




Who is to blame?

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

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

3. An FDA insider. Until the Nissen publication, Avandia had known potential problems with heart failure, but no one was thinking about risk for heart attacks, and if anything possibly preventing heart attacks. Even if Nissen has combed through all of GSK's data on his own, now publicly available thanks to Eliot Spitzer, finding heart attacks with Avandia would be like finding a needle in a haystack. The only folks who knew about the problem were the FDA, and they decided not to release the data to the public, because other data was contradictory. The fact that 42 studies (not all the same) were used in both the Nissen and FDA meta-analysis seems more than just coincidental. I have no actual knowledge of any communication, but I strongly suspect that someone inside the FDA tipped off Nissen to the data that GSK submitted to the FDA, because they did not agree with the head of the FDA's decision not to make this data public.

4. The FDA in general.

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

What should be done?

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

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.