Monday, June 29, 2009

A New Problem With Insulin: Cancer.

Followers of this blog will note that my approach to the management of Type 2 diabetes is different then currently recommended guidelines. Unlike current recommendations which seem to push insulin after the failure of two older oral agents (which are known to fail), I recommend that multiple agents be used, reserving insulin as a last resort. I have blogged before about my concerns with insulin (The Problem With Insulin , The Problem with Insulin- Part 2 ). While life-saving for all type 1 diabetics and many type 2 diabetics, insulin causes many problems including the need to frequently monitor finger stick glucose, costs, inconvenience, weight gain, and hypoglycemia which can lead to death.

However, a new concern regarding glargine insulin (trade name Lantus) seems to be emerging. This press release best explains it. In summary, a recent study confirmed earlier findings between increased rates of cancer in diabetes taking glargine insulin and regular insulin, in particular, a doubling risk of breast cancer.

Why might this be true?
Human and even porcine insulin has a long track record of safety. However, glargine insulin is different in that it is not "natural" but a manufactured insulin, specifically modified to last longer. While insulin has been used for decades, glargine has only been used since 2000. Other reasons to consider this more than just a concern include that the findings are reproduced in multiple studies of tens of thousands of people, and that the finding seem dose dependent. In other words, the higher the dose of glargine one takes, the higher the risk of cancer. In order to know for sure, we need a randomized, controlled trial of thousands of patients to prove this is the case. This is exactly what the European Diabetes Association is calling for. However, those findings will not be available for years.

Why be concerned?
Most guidelines for type two diabetes recommend that long acting insulins be started first, and most clinicians usually start with the synthetic, glargine type of insulins. In fact, the preferred regimen for insulin in type 2 diabetics by most endocrinologists is a combination of a long acting insulin like glargine given once a day with very short acting insulins (lispro) at meal times. This approach, called basal-bolus, is supposed to mimic what the pancreas naturally does. Though I am glad that the European endocrinologists have raised concern and are calling for more data, I find it interesting that more alarm has not been raised, particularly here in the US. One very poorly done study which has now been proven to be false, caused so much uproar that people simply stopped taking Avandia. Yet, study after study shows a compelling and dose responsive relationship between glargine and cancer, and there seems to be little in the press.

What should you do?
If you are on Lantus, don't stop!!!! Please discuss this with your doctor first. There are other options other than Lantus, and even with an increased cancer risk, Lantus still may be the best option for you. If you are diabetic, but not yet on insulin, first do everything you can to avoid this. First and foremost, diet and exercise are key and critical. If that doesn't work, in addition to lifestyle changes, consider using multiple pills before resorting to insulin. If injections are needed, talk to your doctor about the incretin mimetics, like Byetta as alternatives to insulin. Studies of shown that in patients who failed diabetes pills, Byetta performed similarly to glargine in controlling diabetes but with less hypoglycemia and weight gain.

Tuesday, June 23, 2009

Why aren't medical students taught about health care policy?

Happy to have been interviewed by and mentioned in this very timely article at which asks the question "Why aren't medical students taught about health care policy?"

There is so much to cram into 4 years of medical school, it's hard to imagine that we could teach students more. However, some basic understandings of health care policy are needed. Students need to know a little about policy because:
1. The way medicine is practice is (for the most part) dependent on how health care is paid for, which comes from health care policy. In primary care, we need to rush and see patients in 15 minute slots not because we want to, but because we have to see that many patients to make ends meet. The medical home is one of many policy solutions that might fix this.
2. Policy makers listen to physicians, especially when we tell them what is good for patients (and not just our own interests). Having a voice is really not that hard. Through minimal participation in medical societies, like the America College of Physicians for Internal Medicine (my specialty), you can get behind those who share your opinions and can go up on the hill and fight for you.
3. Students in particular need to know about policy that regards to work force issues. Though we have a shortage of physicians, with calls to expand medical school class size, there is not likely going to be an increase in residency slots. This means that it is going to be much harder for students to get into the lucrative specialties they might desire.

I am very proud of some the initiatives we have taken at our institution, including bringing the entire 3rd year class to the Hill. However, we need to do more to incorporate policy into the current curriculum (and we will0>

Tuesday, June 16, 2009

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, 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.

Sunday, June 7, 2009

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.

Friday, June 5, 2009

For the RECORD, Avandia does not cause heart attacks.

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

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

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

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

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

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

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

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

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

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

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

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

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

Wednesday, June 3, 2009

Major Diabetes Study to Be Presented! Get Ready for RECORD

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

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

Briefly, Avandia was known to increase fluid retention and may have the potential for congestive heart failure, so after the product was approved in the late 90's, as part of due diligence, GSK agreed to perform a large randomized trial looking at heart benefits and risks of Avandia called RECORD (pronounced like the noun, i.e. LP and not the verb) , as well as present the results of their planned studies, looking for any heart risks. The RECORD study was a large, randomized trial designed specifically to answer the question of cardiovascular safety and Avandia. The RECORD study was of particular interest because Avandia was also known to have potential heart benefits, including improving good cholesterol, lowering triglycerides, and reducing other markers of heart disease. The question was whether the potential heart benefits (reduced heart attacks) outweighed the potential heart risks (congestive heart failure). It is important to note that at no time did anyone predict that Avandia might cause heart attacks. If anything, it was thought that Avanida might reduce heart attacks.

In August of 2006, GSK submitted both a pooled analysis (meta-analysis) of 42 separate double-blinded, randomized, controlled clinical trials to assess the efficacy of rosiglitazone (Avandia) for treatment of type 2 diabetes as well as a population-based database of 33,363 patients looking for similar endpoints. The 42 studies showed a potential increase in myocardial ischemia in patients taking Avandia compared to placebo. There were no problems when Avandia was compared to other diabetes meds, no issues with death, heart attack, or other adverse events in the FDA's meta-analysis. In addition, the large data base showed no problems with ischemia.
The FDA also knew that two large, randomized trials (ADOPT and DREAM) were about to be published that could help shed some light on this surprising and potential safety signal. In addition, the RECORD study had be going on for almost 2 years, and even though the results would not be available until 2009, an independent group which periodically looks at the study to assess safety (commonly done in safety studies) had not reported any problems. Given that GSK's data was inconsistent and that more data would soon be published, the FDA did not publicly disclose the findings of either the pooled data or population based data. This decision was made by the head of the FDA.

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

Because of fears that the ongoing RECORD study could be jeopardized as patients might pull out of the study if Avandia were dangerous, as well as a means to vindicate their medication, GSK felt obligated to publish the partial results of the RECORD study. Though only more than half way done, the study seemed to show no signs of heart attacks, thus refuting the Nissen publication. However, the study was accompanied by not one, but three editorials discrediting the study, and claiming that it proved nothing about the safety regarding Avandia.

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

What are the possible results?

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

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

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

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

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

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

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

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

Monday, June 1, 2009

More on Electronic Cigarettes or E-cigs

I continue to receive multiple comments on my original post Electronic Cigarettes and appreciate them all. There is an avid group of e-cig users that does not appreciate my opinion on this topic. Rather than respond to several recent comments on the original post, I thought it would be more effective to just generate a brand new post. Here are my responses to some general concerns/criticisms.

If electronic cigarettes are a safer alternative to tobacco cigarettes, why do you oppose them?
I think most people, even tobacco cigarette smokers, will agree that tobacco cigarettes are harmful in many ways. E-cigarettes may be safer than tobacco cigarettes. However, I have no way of knowing this. There is simply no published studies in the medical literature (and the few in existence are from the manufacturers). Yes, e-cigs don't have the carcinogens that tobacco cigarettes contain, and it is most likely that they pose no more dangers than those we already know to be attributed to nicotine. However, without regulation and research, I can not recommend these to patients. My opposition is more with the regulators than the electronic cigarettes. First, e-cigs are drugs by definition. Therefore, the fall within the jurisdiction of the FDA, who has turned a deaf ear to this issue. Many users buy these products online from China, and there have been several recent health related risks with products from China. In addition, many of the e-cigs sold in the US are sold in retail shopping malls. Since the FDA has chosen to ignore e-cigarettes, there is nothing really stopping vendors from selling these to minors. I strongly believe that the FDA should regulate these products as the drugs they are, which would include ensuring that they are safe. If patients choose to use e-cigarettes as tobacco cigarette alternatives, I would rather them purchase this from behind the counter of a CVS then from a questionable online site selling non-US made products.

There are plenty of nicotine replacement products out there. These are safe, so why do you think electronic cigarettes post a threat?
First, all nicotine replacement products (patch, gum, etc.) are regulated by the FDA and have been proven to be safe. E-cigarettes have not been proven safe. Secondly, nicotine has risks associated with it. These risks are clearly labeled on all nicotine replacement products. Every medicine we dispense has risks and benefits. With nicotine replacement products, the risk of short term nicotine use is outweighed by the benefits of stopping (hopefully permanently) tobacco cigarette smoke. No nicotine replacement product is intended for long term use. Caffeine also has side effects. Though I think it is OK for patients (without certain health conditions) to drink a cup or two a day, I would not recommend six or seven cups of coffee a day because of adverse effects. Thus, even if e-cigarettes are proven as safe as nicotine replacement products, I still would not recommend their regular use (though if studies were done, I would agree that this would be preferred to tobacco smoke).

I have tried everything to stop smoking. Electronic cigarettes were the only thing that worked for me. Why do you oppose e-cigs when current methods don't work and some, especially Chantix, might even be dangerous.
Current methods do work and about double your chance of successfully quitting. E-cigarettes may be effective smoking cessation devices, but they have not yet proven to be effective. Also, there is a difference between quitting tobacco cigarettes and quitting nicotine products. Nicotine replacement products like the patch are not intended for permanent use. E-cigarettes were designed to be tobacco cigarette replacement products, not smoking cessation aides. It is also possible that smokers will use e-cigarettes in place of SOME of their tobacco cigarettes. Although this does decrease exposure to known dangerous products, e-cigarettes might therefore actually prolong tobacco cigarette smoking.
Lastly, Chantix has gotten a bad rap. have posted several times about Chantix here, here, here, and here and most recently in the post Prescription Drugs: Risk vs. Benefit vs Cost- The Chantix Example . Chantix is the most effective smoking cessation agent available. Though post-marketing safety data suggest that Chantix may be associated with depressed mood, agitation, and suicidal behaviour or ideation; these also occur with smoking cessation alone. Thus, it is unclear if some these reports are due to taking Chantix or stopping smoking. Since there was at least one report of these side effects with a patient who was taking Chantix, but still smoking, the FDA appropriately decided to add this to the warnings section on Chantix' label and is currently conducting an extensive safety review. Again, all medications have risks and benefits. Being the most effective agent, these potential and rare risks are likely worth the benefit. E-cigarettes have not been tested so the risk is not known, and it is unclear whether they are effective in smoking and nicotine cessation.