The secondary findings of the ACCORD trial reported out today, and already the media is buzzing. Though the news was disappointing, the results are not nearly as bad as some of the media headlines are making it out to be. ABC News is reporting: ACCORD Study: Cholesterol, BP Control Does Little Good for Diabetics and MSNBC states that Intense treatment hopes for diabetics dashed. If I were a diabetic, I might think that controlling blood pressure and cholesterol was not important. However, this couldn't be further from the truth.
The same thing happened when the media first reported that the ACCORD study was stopped.
( See ACCORD and ADVANCE: Good News for Type 2 diabetes...really). This first part of the study was looking at whether or not intense lowering of blood sugar to normal (A1c less than 6%) prevented heart attacks and strokes more than the current standard of care (A1c less than 7%) which had not proven to reduce heart attacks or strokes. The study was stopped early because there were more heart attacks and deaths in the intense group. However, though the media headlines similarly questioned the role of blood sugar control back then, the good news was that the rate of heart attacks and strokes were much lower than expected. In other words, good sugar control in diabetics is likely important in preventing cardiovascular disease; however, intensely lowering blood sugar is probably not a good idea.
What was reported today at the American College of Cardiology meeting was the blood pressure and cholesterol arms of the study. The blood pressure arm similarly looked at getting the blood pressure to normal (120/80) compared to standard care. Again, both groups had fewer heart attacks and strokes than expected. Thus, blood pressure control is important, just not continuing to add medicines until the BP is normal. The cholesterol arm of the study looked at something different. All the patients were given statins, but half were randomized to fenofibrate, a different kind of cholesterol medicine that doesn't affect bad cholesterol too much (LDL), but does raise good cholesterol (HDL) and lowers fats (triglycerides). Unfortunately, there was no difference in heart attacks or strokes in either group. However, when you looked at diabetics with low HDL and high triglycerides, there was an improvement. In other words, unlike statins which should be given to every diabetic, fibrates should be used only in diabetics with low HDL and high triglycerides. Again, this reinforces the importance of cholesterol lowering in diabetics, despite what the headlines may read.
Bottom Line: If you are a diabetic, try and keep your A1c under 7%, and don't take any more medicines (especially insulin) to try to get the A1c any lower. Blood pressure and cholesterol control are also very important. Diabetics should keep the blood pressure under 130/80, but don't need to keep adding medications to get it perfect (under 120/80). All diabetics should take a statin medications (regardless of LDL number), and if your triglycerides are above 200 and HDL is below 35, add a fibrate to the statin.
Showing posts with label blood glucose. Show all posts
Showing posts with label blood glucose. Show all posts
Sunday, March 14, 2010
Wednesday, July 1, 2009
Lantus Causes Cancer! Why Doesn't Anyone Seem Care?
The answer is probably money, but more on that later.
I recently posted on the Lantus/cancer connection in my post A New Problem With Insulin: Cancer. The concern was triggered in a press release about a recent European report based on one earlier and three new studies which show a link between Lantus, a long acting insulin, and cancer. As I mentioned, I though it was interesting that more alarm has not been raised, particularly here in the US. Nissen's poorly done Avandia study got major press, and people stopped taking the drug (He was recently proven wrong- see here fore more info). Yet, for Lantus, the report is not about one study, but four studies that show similar findings that Lantus increases rates of cancer. In addition there are some biologically plausible reasons (more later) and a clear dose response. If you look at the criteria for causation, the Lantus/cancer connection seems to ring true. Yet, there seems to be not that much in the press and little public outcry to pull the medication from the market. This may be in part to the fact that the news cycle is now 24/7 Michael Jackson, but other medical stories, like the FDA and Tylenol, seem to be getting some attention, so this can't be the entire reason.
What do the experts say? The Europeans are making "an urgent call for more research". Yet, the US response is much more subdued. The official response from the American Diabetes Association (ADA) stated that findings from these research papers are conflicting and inconclusive, and cautioned against over-reaction until more information is available. A similar response can be found from The American Association Of Clinical Endocrinologists (AACE), the smaller but more academic group of diabetes specialists.
Where is the media attention on this? Where is the warning to patients? Why doesn't anyone seem to care?
MJ aside, here are some reasons:
1. The US experts don't want to say too much because of their ties to the drug companies. Both the ADA and AACE receive huge amounts of money from corporate sponsors, specifically the drug companies. In fact, back in 5/07 the experts issued a joint statement that had similar comments on the Avandia scare (which turned out to be correct). Sanofi-Aventis, the maker of Lantus, gives money to both of the ADA and AACE, and their members are unlikely to bite the hand that feeds them.
2. Though not all endocrinologists think alike, based on national and international diabetes recommendations, the expert guidelines recommend the use of insulin in type 2 diabetes much sooner than I would recommend. I have blogged in the past that I believe the endocrinologist making these recommendations may have a conflict of interest in that they have an incentive to make recommendations that will lead more patients toward insulin is because insulin use in type 2 diabetics is how they make their living. It is possible that the endocrinology experts are cautious about scaring the public about Lantus, because this may cause concern about all insulins, which they believe is the best treatment for diabetes.
3. The reason why Avandia drew more attention is because Dr. Nissen and some Congressmen were the ones making the noise, not the specialty societies. The Nissen meta-analysis on Avandia, from the data analyzed, to the publication, to the media frenzy had political motivations, whereas the Lantus studies do not. (See a timeline of the politics of the Avandia study in my post Diabetes Conspiracy )
What now?
Thanks to a comment on my previous post, I looked into the matter a little more. One of the problems with insulin is that is that it is related to insulin like growth factor (IGF-1) which has been shown to stimulate tumor growth. Regular human insulin has some affinity for the IGF-1 receptor, but Lantus has a much greater affinity, which is the likely reason more cancers were seen. There happens to be another long acting insulin on the market called Levemir that has very little affinity for the IGF-1 receptor (less than even human insulin) and is as effective as Lantus. In 2008, Lantus just missed the top 25 most commonly prescribed branded drugs at #26 with over 10.25 million prescriptions that year. Levemir came in at #170 with only 1.3 million prescriptions. Though I doubt this is public knowledge, I would guess that Novo Nordisk (the company that makes Levemir) is not giving nearly as much to these organizations as Sanofi Aventis (makers of Lantus), but I could be wrong. Since Levemir is a newer drug, is was not included in these studies and one can not rule out potential harm. That said, its low affinity for IGF-1 is reassuring. Thus, upon further reflection, I think that all diabetic patients who are on Lantus should talk to their doctor about insulin use, and if they need it, ask their doctor to consider switching them to Levemir.
Update: Via Med Page today, FDA just announced they were going to look into this. Not sure how much press this will garner. Certainly more valuable use of their time then trying to take down Tylenol.
I recently posted on the Lantus/cancer connection in my post A New Problem With Insulin: Cancer. The concern was triggered in a press release about a recent European report based on one earlier and three new studies which show a link between Lantus, a long acting insulin, and cancer. As I mentioned, I though it was interesting that more alarm has not been raised, particularly here in the US. Nissen's poorly done Avandia study got major press, and people stopped taking the drug (He was recently proven wrong- see here fore more info). Yet, for Lantus, the report is not about one study, but four studies that show similar findings that Lantus increases rates of cancer. In addition there are some biologically plausible reasons (more later) and a clear dose response. If you look at the criteria for causation, the Lantus/cancer connection seems to ring true. Yet, there seems to be not that much in the press and little public outcry to pull the medication from the market. This may be in part to the fact that the news cycle is now 24/7 Michael Jackson, but other medical stories, like the FDA and Tylenol, seem to be getting some attention, so this can't be the entire reason.
What do the experts say? The Europeans are making "an urgent call for more research". Yet, the US response is much more subdued. The official response from the American Diabetes Association (ADA) stated that findings from these research papers are conflicting and inconclusive, and cautioned against over-reaction until more information is available. A similar response can be found from The American Association Of Clinical Endocrinologists (AACE), the smaller but more academic group of diabetes specialists.
Where is the media attention on this? Where is the warning to patients? Why doesn't anyone seem to care?
MJ aside, here are some reasons:
1. The US experts don't want to say too much because of their ties to the drug companies. Both the ADA and AACE receive huge amounts of money from corporate sponsors, specifically the drug companies. In fact, back in 5/07 the experts issued a joint statement that had similar comments on the Avandia scare (which turned out to be correct). Sanofi-Aventis, the maker of Lantus, gives money to both of the ADA and AACE, and their members are unlikely to bite the hand that feeds them.
2. Though not all endocrinologists think alike, based on national and international diabetes recommendations, the expert guidelines recommend the use of insulin in type 2 diabetes much sooner than I would recommend. I have blogged in the past that I believe the endocrinologist making these recommendations may have a conflict of interest in that they have an incentive to make recommendations that will lead more patients toward insulin is because insulin use in type 2 diabetics is how they make their living. It is possible that the endocrinology experts are cautious about scaring the public about Lantus, because this may cause concern about all insulins, which they believe is the best treatment for diabetes.
3. The reason why Avandia drew more attention is because Dr. Nissen and some Congressmen were the ones making the noise, not the specialty societies. The Nissen meta-analysis on Avandia, from the data analyzed, to the publication, to the media frenzy had political motivations, whereas the Lantus studies do not. (See a timeline of the politics of the Avandia study in my post Diabetes Conspiracy )
What now?
Thanks to a comment on my previous post, I looked into the matter a little more. One of the problems with insulin is that is that it is related to insulin like growth factor (IGF-1) which has been shown to stimulate tumor growth. Regular human insulin has some affinity for the IGF-1 receptor, but Lantus has a much greater affinity, which is the likely reason more cancers were seen. There happens to be another long acting insulin on the market called Levemir that has very little affinity for the IGF-1 receptor (less than even human insulin) and is as effective as Lantus. In 2008, Lantus just missed the top 25 most commonly prescribed branded drugs at #26 with over 10.25 million prescriptions that year. Levemir came in at #170 with only 1.3 million prescriptions. Though I doubt this is public knowledge, I would guess that Novo Nordisk (the company that makes Levemir) is not giving nearly as much to these organizations as Sanofi Aventis (makers of Lantus), but I could be wrong. Since Levemir is a newer drug, is was not included in these studies and one can not rule out potential harm. That said, its low affinity for IGF-1 is reassuring. Thus, upon further reflection, I think that all diabetic patients who are on Lantus should talk to their doctor about insulin use, and if they need it, ask their doctor to consider switching them to Levemir.
Update: Via Med Page today, FDA just announced they were going to look into this. Not sure how much press this will garner. Certainly more valuable use of their time then trying to take down Tylenol.
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.
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 .
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.
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.
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.
Tuesday, May 26, 2009
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.
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.
January 2009- ADA removes Avandia, states Januvia is not recommended
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.
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
*** 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
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.
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.
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