I'm Your Cook, Not Your Doctor

Today on NBC's today show, celebrity chef Paula Deen confirmed she had Type 2 diabetes.  She was diagnosed 3 years ago, but only decided to come out today.  She also mentioned that she is a paid spokesperson for drug company Novo Nordisk, maker of several diabetes drugs. (Click here to view Al Roker's interview).

When the news started breaking earlier this week, I had mixed emotions about Deen as a spokesperson for diabetes. Blogger and health care marketer Richard Meyer at worldofdtcmarketing.com  posted This is a spokesperson for Novo?  Deen is of course known for her southern style of cooking, which typically involves very fattening ingredients. At one her restaurants she famously serves a hamburger with bacon and egg on a donut instead of a bun.

Rich correctly asks, "What message does this send to people ? That it’s OK to eat really bad food because diabetes can be treated with Rx drugs ?"


I commented on his blog that if Dean actually changes her ways, and focuses on healthier cooking, providing healthier recipes to her fans and other diabetics, she might actually make the perfect spokesperson.  Americans have not been paying attention to what we eat and obesity has now become an epidemic, leading to increasing numbers of patients with type 2 diabetes.


After seeing the Today show video, I remain on the fence.  Her interview was not the redemption story I was hoping for.  Give journalistic kudos to Al Roker who pressed Deen on whether she had changed her ways or changed her cooking. She responded essentially stating that she has always eaten (and suggested others eat) in moderation, claiming that her weekly cooking show is only 30 days out of a full year and that no one should eat that kind of food every day. According to Deen, when asked a similar line of questions from Oprah, she responded, "I'm your cook, not your doctor."


Deen did state that she and her sons would work to come up with lighter recipes (available on Novo's web site) and recommended people go to their doctor, get tested and "get on a program."   On the website diabetes in a new light,  Deen does say that she had to give up sweet tea.  In fact, rigid diet and exercise programs do not work all that well in reducing weight or improving diabetes, since patients have a hard time sticking to them, so her mantra "I wasn't about to change my life, but I have made simple changes in my life" may have some merit.


However, I believe there is still a difference between promotion of healthy lifestyle and realistic changes in diet and exercise and "everything in moderation" and "it's OK to have that little piece of pie." Paula doesn't have to become the next Richard Simmons or Jillian Michaels, but I would have liked to seen a little more "mea culpa." 
I am interested to see how this plays out in the media and in public opinion. This is a terrible disease and the prevalence is getting worse.  Ms. Deen has the potential to make a major impact.  I hope she takes her spokesperson role seriously. 

More Evidence that Lantus Causes Cancer

There is a new study reported in Bloomberg this morning that Sanofi’s Lantus Doubled Cancer Risk in Study of Diabetics. The study, which was presented yesterday at the San Antonio Breast Cancer Symposium retrospecitvely evaluated medical records of 23,266 patients in southern Sweden and determined that diabetics who used Lantus had a 2.9-fold greater chance of cancer, while those who took the generic drug metformin had an 8 percent lower risk.

I have previously blogged about this back in 2009 when the first reports surfaced about the link between Lantus and cancer. (See A New Problem With Insulin: Cancer ,  Lantus Causes Cancer! Why Doesn't Anyone Seem Care? and Lantus and Cancer- A Closer Look Is Not Reassuring )

Back in 2009, when the story broke, the FDA acknowledged the potential link but stated that the data was insufficient and recommended that patients not stop taking Lantus, at least without discussing this with their physicians. They stated that they were "currently reviewing many sources of safety data for Lantus, including these newly published observational studies, data from all completed controlled clinical trials, and information about ongoing controlled clinical trials, to better understand the risk, if any, for cancer associated with use of Lantus." However, we didn't hear much until January, 2011 when they released an update declaring that they had reviewed the four 2009 studies and has "determined that the evidence presented in the studies is inconclusive", and in addition had reviewed results from a 5 year study (sponsored by the makers of Lantus) which did not show an increased risk but was  "not specifically designed to evaluate cancer outcomes," concluding, "at this time, FDA has not concluded that Lantus increases the risk of cancer. Our review is ongoing, including review of information from a current clinical trial." With the new study reported today, it will be interesting to see whether the FDA chooses to give and update or reveals and additional information, such as a VA data set they are supposed to be evaluating.

According to the Bloomberg article, a Sanofi study from Sweden, Norway, Finland, Denmark and Scotland is complete and will be submitted to health authorities this month.  In addition,  U.S. study will be finished in early 2012, while a final report from Europe will come later. All of these studies combined will involve more than a million patients, which will hopefully be enough to give a more conclusive answer.

To be clear, I am not 100% convinced that Lantus causes cancer.  However, there is another long acting insulin (Levemir) which has similar efficacy to Lantus, has not been associated with cancer, and has a substantially different affinity for the insulin like growth factor (IGF) receptors that are implicated in the possible connection.  Given the mounting evidence of a cancer link with an equally effective product that appears to be safer, I can't see any reason to prescribe Lantus when Levemir is available.

Actos Causes Bladder Cancer. Maybe We Should Have Kept Avandia?

Both Germany and France have now suspended the marketing of Actos (pioglitazone) due to concerns of a link between Actos and  bladder cancer.  Though we have known about bladder cancer concerns for some time, these recent concerns about the bladder cancer link stem from a recent report analyzing the FDA's Adverse Event Reporting System (AERS), which found that 93 cases of cancer were recorded between 2004 and 2009 in patients treated with antidiabetic drugs of which 31 patients were treated with pioglitazone, representing a statistically significant increased risk of bladder cancer (ROR 4.30, 95% CI 2.82-6.52; p<0.0001). Interestingly, the FDA announced that it was going to look into the link between Actos and bladder cancer only a few days before it made it's final decision on what to do with Avandia (as if they didn't know about the Actos cancer risk before the July 2010 advisory board). 

Despite the many things you have heard about Avandia, back in July 2010, the FDA decided to severely restrict the use of Avandia for three reasons:
1. Despite limited and conflicting data, there seemed to be a signal of myocardial infarction for patients taking Avandia.
2.  The one study proving Avandia's safety, RECORD (see here for more details) was discredited by FDA scientists due to potential reporting errors.
3. The advisers on the panel felt strongly that despite limited and conflicting evidence, the signal was enough to be concerned AND because Actos (similar drug in same class) did not seem to show this signal, why would doctors ever want to prescribe Avandia?

I have blogged extensively about Nissen's meta-analysis that triggered the whole Avandia scare. Meta-analysis have major limitations.  Another group of researchers using the same data as Nissen's with different statistical  techniques concluded that Avandia did not cause heart attacks.  Large, randomized trials are the only way to determine certainty, and all available large trials (DREAM, ADOPT, ACCORD, etc.) with rosiglitazone showed no heart attack risk.  As mentioned above, the one study designed to definitively show whether or not Avandia led to cardiovascular risk (RECORD, which showed that Avandia did not cause cardiovascular risk, and in fact surpasses the FDA's standard for cardiovascular safety) was harshly criticized by those within the FDA that wanted to see Avandia pulled from the market.  Specifically, the FDA found that GSK had some errors in reporting the results of RECORD.  Though these types of errors are not uncommon in very large trials, and likely won't affect the overall results of the study, nonetheless, the deserve looking into.  However, the FDA promised to do a complete independent analysis of the RECORD results; a promise it has yet to deliver on.

The main issue here is #3: Actos appears to be safe, so let's dump Avandia. (Interestingly, independent cardiologists analyzed all the data and did not find a conclusive difference in cardiovascular risk between Actos and Avandia).  Here is the full transcript of the advisory board.  Since it is a very difficult document to read through, I have pasted some of the direct quotes below from some of the advisers who voted to either remove Avandia from the market or severely restrict its use. Based on these quotes, I feel pretty strongly that had the advisers known about Actos' bladder cancer risk, that they may have voted very, very differently.  However, the FDA did know about the association between Actos and bladder cancer.  They just chose not to mention it!   In fact, when one adviser brought up the question at the July advisory board, the FDA only briefly mentioned this and discussed it more as a class effect also seen with dual PPAR agonists.

Avandia and Actos help diabetics use their own insulin better by hitting a receptor called PPAR. There are three main PPAR receptors: Alpha, Gamma and Delta.  We don't know a whole lot about delta, but PPAR Gamma works on glucose, and PPAR alpha affects cholesterol.  Fibrates like gemfibrozil, which lower triglycerides and raise HDL or good cholesterol are PPAR alpha agonists.  Dual PPAR agonists were drugs that pharma were trying to develop that hit both alpha and gamma in order to help both with lipids and glucose.  They have not been able to make it to market due to safety concerns (raised by, guess who??? Dr. Nissen). One of the differences between Actos and Avandia, is that Actos has a higher affinity for the PPAR alpha receptor, which is why it likely does a better job on raising HDL and lowering triglycerides than Avandia.  Some have hypothesized that this might be the reason why Actos might not have the same cardiovascular issues as Avandia (though this has yet to be shown).  If in fact, as stated during the FDA meeting (I am not aware that this data is published) that the bladder cancer risk was seen in both Actos and the dual PPAR agonists.  Bladder cancer has not been seen with Avandia.  In other words, the evidence (both available and suggested by FDA quotes that are public record) suggest that Actos may have more of a bladder cancer risk than Avandia. 


Why the FDA in discussing to keep Avandia on the market would not extensively discuss the concerns of bladder cancer with Actos, paired with the weak and controversial data showing Avandia's cardiovascular risk and effort to discredit GSK's study proving Avandia's safety leads me to believe that the FDA's attack on Avandia was very much politically motivated.  Scientists look at all the available data and weigh the risks and benefits of all options before making a conclusion.  It is clear to me that the FDA's decision on severely restricting Avandia was more political then science. Based on the currently available data which now include bladder cancer risk, Avandia may actually be a better choice than Actos, but the FDA's restriction will essentially prevent any doctor from being able to prescribe Avandia after November.



Select quotes from advisers who voted to voted to either remove Avandia from the market or severely restrict its use:
DR. SCHAMBELAN: This is Morrie Schambelan. I voted E. (remove Avandia from the market) . I was one of the brain-dead kangaroos last time (meeting in 2007) who was on the fence, largely because I did see a signal for harm. I was led at that time by the comparison to active comparators, which I think is much more relevant to me than placebo. I wasn't swayed by the pioglitazone data that were presented at that time because they were pretty preliminary. I was much more persuaded this time, including Dr. Graham's analysis. I feel that pioglitazone is a perfectly acceptable alternative.

DR. SAVAGE: Peter Savage. I voted D (keep on the market with restrictions) I was also oscillating between D and E because I think that the evidence of potential harm associated with rosiglitazone is stronger now than it was in 2007. And very importantly, the evidence about pioglitazone is substantially greater than what we saw treat in 2007.

DR. FLEMING: Fleming. I voted E. My main sense about this is really explained in my answer to question number 7. There's very concerning data about safety with rosiglitazone. It's not definitive, but if TIDE is to provide that, we have many years before we're going to get that insight. We do have an alternative, pioglitazone, for which there is considerably strong safety experience. So I come down to, then, what is the continued role for rosiglitazone?

DR. THOMAS: Abraham Thomas. I voted E. The scientist in me says we should always seek the truth. But this isn't an NIH study section. This isn't the review of a journal for publication. Really, what this is is an intersection, as someone mentioned at lunch, between public policy and science. And when we look at it that way, we can't always have the absolute truth to make a decision. We have other classes that are available that we never had before for the treatment of diabetes. And if rosiglitazone was removed from the market, we still have another TZD, what has had a trial that does demonstrate no increased cardiovascular mortality, no increased cardiovascular events, in PROactive.

What to do about Niacin?

I have been getting a lot of questions regarding the use of Niacin since the media recently reported that the NIH had stopped their AIM-HIGH study. AIM-HIGH was designed to see if adding Niacin to patients on a statin who still had low HDL and high triglycerides would improve cardiovascular outcomes (heart attacks, strokes). Though we know that high triglycerides and low HDL are both strongly associated with heart disease, that Niacin will raise HDL and lower triglycerides and even few early studies did show raising the HDL with Niacin did work; this large, randomized NIH sponsored showed no evidence of improvement.  Though the actual data from the study has not been released, we do know that the NIH stopped the study a year early because there was no benefit seen and possibly some harm in the form of excess stroke.  One possibility is that patients were taking statins at doses that lowered their LDL to very aggressive levels (target range of 40-80). Some have postulated that with an LDL that low, you will never get a heart attack or stroke.  So, Niacin may indeed work, but not with super reductions of LDL's with statins.


One of the main points of from these findings is that we have to be careful when it comes to using surrogate endpoints (like LDL and HDL) for treatment.  For example, lowering the LDL with a statin reduces heart attacks and strokes. However, lowering the LDL with ezetimibe (Zetia) doesn't seem to do this (see here for more details)  This might be the case for Niacin and HDL as well. 

I have never been a big fan of Niacin because it causes pretty bad flushing, increases uric acid/gout, and most importantly raises blood glucose.  Most of my patients are diabetic/prediabetic, so raising their blood sugar is not something I am too fond of.  The other drugs that can raise HDL and lower triglycerides are fibrates. Gemfibrozil has clearly demonstrated this in a large VA study (VA-HIT).  The problem with gemfibrozil is that it can interact with statins, causing some serious side effects.  Statins are the one med that clearly works in just about everyone with increased cardiac risk.  Fenofibrate works the same way, but can be used safely with a statin.  However, when they tried to demonstrate cardiovascular improvements with fenofibrate (FIELD study), the primary outcome was not statistically significant.  One of the differences between VA-HIT and FIELD is that more patients were on statins in FIELD, since FIELD was a more recent study and regular use of statins had become standard of care.  However, in the diabetic patients with low HDL and high triglycerides, the FIELD study did show that fenofibrate reduced heart attacks and strokes. The ACCORD lipid study (another large, randomized, NIH sponsored trial), attempted to prove benefit by adding fenofibrate to all diabetics on a statin, but failed.  However, similar to FIELD, in those diabetics with low HDL and high triglycerides, fenofibrate added to a statin did reduce heart attacks and strokes. The consistency of these findings therefore have some merit. 

Bottom Line: Statins remain the first choice for patients at increased cardiovascular risk and should be used at doses that meet individual LDL goals and/or lower LDL by 30-40%.  After that, the rationale for treating low HDL/high trigs is now less clear. Before we see the actual data from the AIM-HIGH study, it would be premature to pull all patients off of Niacin.  That being said, in my opinion, Niacin's days are likely numbered.  Evidence for raising HDL and lowering triglycerides seems to be much stronger for fenofibrate, at least in diabetics, and fenofibrate does not seem to have the negative effects, specifically hyperglycemia, seen with Niacin. 

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

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

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

Using Actos to Prevent Diabetes

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

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

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

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

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

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

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

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

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

Study 175 and the Need for Comparative Effectiveness Research

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




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





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






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





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

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


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


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

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


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

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

One Patient Stays on Avandia, One Patient Switches to Actos

The calls/emails have already started to come in, and I expect more, as I have a lot of diabetes patients and have been an avid user of the TZD class. There are many reasons to like the TZD's:
1. The older, generic medicines like metformin and sulfonylureas are known to fail over time. After 3 years, most patients on one of these drugs lose control of their blood sugar. In contrast, patients on TZD's maintain glycemic control (at least up to 4-5 years which was shown in the ADOPT study).
2. The TZD's don't cause hypoglycemia, which is a really bad side effect of insulin and the sulfonylureas.
3. Many diabetic patients need more than one drug, so even if you start with metformin, you are going to have to choose between a TZD (well studied, no hypoglycemia), a sulfonylurea (well studied, causes hypoglycemia), or a DDP4 inbitor like Januvia/Ongyza (not as well studied, no hypoglycemia).
4. TZD's have other benefits that the other diabetes drugs don't, such as improving good cholesterol or HDL, and decreasing triglycerides or fats. In his presentation the Periscope study, which showed Actos prevented plaque build up, Dr. Nissen (wonder why he likes Actos?) compared these results to other similar cholesterol lowering studies and showed an ldl-independent effect of the TZD's in their ability to prevent plaque build up. He believed this was due primarily to increases in HDL.
5. Using a TZD, likely because of sustained glycemic control, prevents the need for insulin. This was shown in the recently maligned RECORD study and the NIH sponsored BARI-2D study. Insulin causes hypoglycemia and most of my patients would like to avoid insulin.

The first patient contacted me by email related what he had heard about the FDA panels finding. He understood that they recommended not to pull the drug, but also felt that there were enough concerns that he wanted to switch. He was on Avandia 4mg, so I switched him to Actos 45mg.

It is important to note that the TZD's have their maximal effect at the maximum dose. Though the maximum dose causes the most side effects, I have found that if used early in the course of disease, side effects are minimal. The most common side effect of the TZD's is edema, or fluid retention. Use of a low dose fluid pill (which many diabetics use anyway in order to keep their blood pressure controlled) seems to eliminate this problem. For metformin, the best dose is 2000mg a day (usually 1000mg twice a day).

This brings me to the second patient who called me with similar concerns. He had been taking Avandamet 4/1000mg twice a day for about 7 - 8 years with outstanding diabetes control. In discussing the switch to Actos, we uncovered a problem. The equivalent dose of Actos is 45mg. Like Avandia, Actos comes in combination with metformin, called Actoplusmet. Actoplusmet comes in 15/500mg and 15/850 and is to be taken twice a day. If you do the math, it is very hard to get the 45/2000mg a day that would be equivalent to the Avandamet dose that has kept this patient under control for so long. We could do two pills in the morning and one a night (a more complicated regimen), but would be over (more side effects) or under (less efficacy) on the metformin dose between the 850 and 500 versions. Actoplusmet was just approved as an extended release product. This can be taken once a day (easier regimen). Actoplusmet XR comes in 15/1000 and 30/1000. If we went this route we could have the patient take one of each. The problem is that his insurance company will consider this two different medications and charge him two separate co-pays. He could take the 30/1000 and use one and a half tablets a day (wouldn't cost him more), but we would be short on the metformin, and it is generally not a good idea to split extended release pills. After spending 10 minutes discussing the above dilemma, he decided that it was simply too complicated to switch and he would stick with the Avandamet, unless the FDA decided to pull it.

Actos and Avandia are both good medications. Many of the FDA panelists who voted to pull Avandia or severely restrict it, mentioned that they did so because Actos was available and they saw no clear avantage of Avandia over Actos. No one mentioned the dosing. This is likely because few on the panel actually treat patients with diabetes. The only panelist really pushing for options was the patient advocate.

In addition, there is really no compelling evidence to believe that Actos is any safer than Avandia. The AHRQ (government, non-pharma) commissioned a study to look at this, and they found no difference. A Science Advisory From the American Heart Association and American College of Cardiology Foundation also looked at this issue (most of the authors had no ties to either product) and similarly found no substantial difference between Actos and Avandia with regards to safety. This is also why the panel voted 19-10 to move forward with the TIDE study.

Though, I am sure I will continue to get emails and phone calls from worried patients, many of the patients I have on Avandia take Avandamet 4/1000mg twice a day. Hopefully, they will read my blog before calling as multiple 10 minute phone calls start to add up.

Avandia Smackdown!!

This is it. The final countdown.
The fate of Avandia will likely be decided in a matter of days.
The outcome will likely have long lasting impact regarding how the FDA manages potential safety issues with any current or future drugs on the market.
That is because on July 13th and July 14th, the FDA will hold an advisory committee to review the safety data on GSK's drug Avandia.
I have blogged on the Avandia topic extensively. (In particular see Avandia Vindicated and Diabetes Conspiracy).
Below is a re-cap of all the major events in the saga as well as possible outcomes and my prediction as to what will happen.


Prelude- Vioxx (2001 -2004)
It is important to note that the Avandia story begins with Vioxx. Prior to Vioxx, many doctors prescribed heavily marketed drugs with less concerns about safety, thinking that if a drug had been approved by the FDA, they were likely safe. One of the major studies that led to fall of Vioxx was published in JAMA on August 22nd, 2001 by Cleveland Clinic cardiologist Dr. Steve Nissen. It took nearly three years until September 30th, 2oo4, when Vioxx was finally pulled from the market. Dr. David Graham, an FDA insider who works on drug safety was clearly frustrated by the FDA's apparent lack of concern. He was called to congress in November of 2004 to testify regarding what other drugs the public might be concerned about. Though Avandia wasn't named as one of Dr. Graham's five drugs to look out for, his testimony to congress against his own institution made it clear that Graham intended to be a whistle blower and would place the FDA safety folks at odds with the other branches of the agency


August, 2006- FDA becomes aware of potential Avandia issue
In August of 2006, GSK submitted both a pooled analysis (meta-analysis) of 42 separate double-blinded, randomized, controlled clinical trials to assess the efficacy of rosiglitazone (Avandia) for treatment of type 2 diabetes, which surprisingly showed a potential increase in myocardial ischemia in patients taking Avandia compared to placebo. There were no problems when Avandia was compared to other diabetes meds, no issues with death, heart attack, or other adverse events in the FDA's meta-analysis. These results were surprising because though Avandia was known to cause fluid retention and a possible risk of congestive heart failure (CHF), due to some of Avandia's other properties (lowering triglycerides, increasing HDL, decreasing CRP), if anything, Avandia should have prevented heart attacks.

Rather than create a public hysteria and mass panic, the FDA decided to take a wait and see approach for several reasons. First, the FDA knew that two large, randomized trials (ADOPT and DREAM) were about to be published that could help shed some light on this surprising and potential safety signal. In addition, the RECORD study was a large, randomized trial designed specifically to answer the question of cardiovascular safety and Avandia. Though the results would not be available until 2009, the study had be going on for almost 2 years and an independent group which periodically looks at the study to assess safety (commonly done in safety studies) had not reported any problems. And in fact, both DREAM trial and the ADOPT trial not only showed that Avandia prevented diabetes and sustained glycemic control better than the other available diabetes agents respectively, there were NO signs of heart attack.

Thus, the FDA felt confident in their decision not to needlessly scare the public, but rather wait until about June, 2009 when the RECORD trial was likely to report out. Given that it was a large, randomized trial specifically designed to look at Avandia and cardiovascular safety, the RECORD study would be able to definitely answer the question once and for all.


May 2007- Nissen Meta-Analysis published.
Due to a previous settlement regarding their drug Paxil by then attorney general Elliot Spitzer, all GSK's clinical trial data was publicly available. Dr. Steve Nissen was therefore able to perform his own meta-analysis of the GSK studies. Given that there had been no public mention of Avandia heart attack concerns, I suspect someone inside the FDA tipped off Dr. Nissen. His controversial and often criticized findings of a 43% increase in heart attacks with Avandia were rushed to press and published in the New England Journal of Medicine. The news created a media frenzy. Congressional hearings were called for by Senator Charles Grassley the very next day (almost as if Sen. Grassley knew about the results before they were published). In the following week's issue of the New England Journal, the interim results of RECORD were published ahead of schedule, mainly due to concerns that the RECORD study itself could be jeopardized as patients might pull out of the study if Avandia were dangerous. Though only more than half way done, the study seemed to show no signs of heart attacks, thus refuting the Nissen publication. However, the study was accompanied by not one, but three editorials discrediting the study, and the controversy persisted.

July 2007- First FDA Advisory Committee Convened
Given the publicity of the Nissen study, the FDA met to discuss the safety of rosiglitazone. After review of all of the FDA's (not Nissen's) data, they saw something that didn't make sense. Their own meta-analysis showed a signal of myocardial ischemia, but analysis of the ADOPT, DREAM and RECORD trials, as well as analysis of large claims databases showed nothing. The FDA voted almost unanimously to keep Avandia on the market. However, they added a boxed warning to Avandia. This boxed warning remains one of the most confusing warnings I have ever seen, stating that there is contradictory evidence so no conclusion can be made. Nevertheless, physicians who may have been on the fence about prescribing the drug, likely stopped writing prescriptions for Avandia. The class of medications, called the TZD's, decreased in general use, and Actos, the competing TZD which had 50% of the market share of TZD prescriptions became the heavily favored product.

June 2009- RECORD study results published
During the ADA's annual meeting, the long awaited study results of the RECORD trial were finally published. The study that should have put the issue to rest showed absolutely no difference in cardiovascular issues with Avandia. In addition, patients who used Avandia had improved diabetes control and less use of insulin. At the previous years ADA meeting, two other randomized studies (ACCORD and VADT), which both used Avandia extensively also showed no issues related to Avandia. Given RECORD, ACCORD, ADOPT, DREAM and VADT there have been randomized, controlled trials of 26,000 patients that have been studied over 4 to 5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks. Yet, critics (mainly Nissen and Graham), still had their doubts. The FDA decided that they would meet in July 2010 to review all the newest data and re-look at the controversial issue of Avandia.



February 2010- Grassley releases investigation of FDA and GSK
As above, Sen. Grassley called for an investigation back in 2007, and it took three years to finally release his findings. The report is an indictment of both the FDA for not taking Avandia risk seriously and GSK for hiding data from the public. Interestingly, the report fails to mention any of the studies published since May, 2007 showing Avandia to be safe. It as if time stood still in the Grassley report. The other issue that the Grassely report raises is the ethics of the TIDE study. The TIDE study, which the FDA requested GSK perform is a head to head study comparing Actos and Avandia in regards to safety. Grassely contends that since Avandia risks are known, the TIDE study is unethical and should not be performed.



June 2010- Nissen and Graham take one more shot
In conjunction with the June ADA meeting and weeks before the July FDA advisory committee, both Dr. Nissen and Dr. Graham have separate publications once again questioning Avandia's safety. (Both claim publicly that the timing of the release of this data is coincidental). The Nissen study is an update of his 2007 study, which both addresses some previous criticism of the original study and adds new data, including the RECORD study. Since this is virtually the same study as he did in 2007, it is not surprising that his findings are the same. The Graham study analyzed Medicare claims databases comparing Actos and Avandia. Graham claimed that Avandia was far riskier than Actos when looking at stroke, heart failure and death. Retrospective reviews of databases are legitimate forms of research, but have even more limitations than meta-analaysis. More interesting (which no media seems to be reporting on) is that Graham's study showed no difference between Avandia and Actos when it came to heart attacks. Stroke had never been a question, and even Nissen's analysis showed Avandia didn't increase death; CHF is a risk for both with multiple studies suggesting the risk is similar. Nonetheless, both studies got major media attention, overshadowing a 3rd study presented at the ADA (analysis of BARI-2D) which showed Avandia prevented stroke, heart attacks and death!.


July 2010- FDA Advisory Commitee
The FDA will review all the data mentioned above and hopefully come up with some conclusion. The meeting was planned in advance of Sen. Grassley's report, and was timed such that RECORD, BARI-2D and Graham's review could be incorporated with existing data. Expect debate to be particularly heated.


What are the possible outcomes?

Avandia Gets Pulled from the Market ( Odds 30-1)

This would also be the end of the TIDE study. This is a relatively unlikely scenario given that, with the exception of Graham's retrospective reivew, the only new data since 2007 are RECORD and BARI-2D, which are large, randomized prospective trials specifically designed to look at cardiovascular safety, both showing no issues with Avandia. Another intersting aspect, (which I blogged about in Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III) is that because of the Avandia scare, the FDA developed new criteria requiring that ANY new diabetes drug that gets approved by the FDA must first show that it does not cause heart attacks. Specifically, the FDA now requires randomized clinical trials that show a drug does not cause heart attacks with the upper limit of confidence of 1.3. In other words, there needs to be 95% certainty that a diabetes drug couldn't possibly increase the risk of heart attacks by as much as 30%. The confidence intervals for the RECORD trial for heart attack fall under 1.3. Thus, Avandia has already fulfilled the FDA's own criteria of being a safe drug in regards to heart attack. How could they possibly pull it?

That said, removal of Avandia is not impossible. Folks like Graham, Nissen and Grassely have a lot at stake in this game. Avandia staying on the market might make them look pretty bad. Rest assured that they will not go down without a fight.


Avandia is exhonorated (10-1)

Given the results of RECORD and BARI-2D, along with analysis of the VADT and ACCORD trials and multiple data bases, the FDA could be so overwhelmed with Avandia safety data that it proclaims Avandia to have no risk of heart attack and pulls any mention of this from its label. However, with all the surrounding controversy, this seems a little unlikely. The FDA has been harshly criticized for being soft on safety. That said, the FDA might want to take a stand against outsiders (Nissen, Grassley) as well as insiders (Graham) trying to do their job for them.

Nothing Happens (1-1)

This is the most likley scenario. There are no clear winners or losers, so everyone can save face. In this scenario, the TIDE study would likely proceed as planned, but not necessarily. The problem with this scenario is that it leaves physicians and patients in the dark. Is Avandia safe or not? The FDA owes the public an actual opinion, unlike its stance in 2007, which essentially was "we dont' know." In this scenario, the devil is in the details. The FDA will have to update Avandia's label with regards to the cardiovascular safety . The label could be harsher towards Avandia (i.e. more studies suggest concern), reassuring (i.e. despite one meta-analysis a multitude of randomized trials show safety) or neutral.


Actos vs. Avandia?

Finally, I have been asked multiple time about Actos vs. Avandia regarding safety. The conventional wisdom is as follows: even if there probably isn't any cardiovascular risk with Avandia, why would you not just simply switch to Actos just in case? Why do we even have Avandia on the market if Actos exists?

I use both Acots and Avandia, and do believe there is a role for Avandia. There are two important things to consider with regards to this issue:

1. The absence of evidence does not equal the evidence of absence.
In other words, just because no concerns have been raised with Actos does not make it necessarily a safer choice. The vast majority of large, randomized clinical trials (the gold standard of science) have been done with Avandia and not Actos. Avandia beats Actos in trials almost 2:1. It would be like saying 5/10 studies show drinking Coke causes obesity in teens, but 0/5 studies show that drinking Pepsi does not cause obesity; therefore, we should have all teens drink Pepsi instead of Coke to avoid obesity. Some have argued that the reason there has been no signal seen in Actos is because of differences regarding each drug's affect on lipids, with Actos having slightly more benefit than Avandia. However, there has been no true head to head trial of both (which is why the TIDE trial would be scientifically beneficial), and the lipid data varies from study to study (cholesterol actually increased in Actos' one large, randomized trial called Proactive). Furthermore, since there are many more large, randomized trials with Avandia, none of which show an increased cardiovascular risk, one could make the argument that Avandia is the "safer" choice. I am not suggesting that Actos is dangerous. However, stating that Actos is a safer choice is not scientifically valid. The American Heart Association and the American College of Cardiology came to similar conclusions, stating no safety difference between the two products in their recent review of all the data (which was released ahead of schedule in response to the scathing Grassley report).

2. In my experience, the most effective dose of metformin is 1000mg twice daily. The most effective dose of each TZD is the maximum dose. If used early in the disease process, the typical side effects (edema) have been minimal, even at the maximum dose of each TZD. Thus, in my opinion, the perfect dose of Avandamet ( a product which combines Avandia and metformin) is 4/1000mg twice daily and the perfect dose of ActoPlusMet would be 22.5/1000mg. Avandamet is available in this does, ActoPlusMet is not. To give this dose of ActoPlusMet, patients would need two separate prescriptions, two separate pills, and two separate co-pays.

Addendum 7/9/2010
The FDA just posted the preliminary documents for next week's Avandia "smackdown."
A few tidbits:


1. I mentioned three possibilities for Avandia's fate: removal, label revision or no change. There is actually a little more subtlety regarding the label change. They might either remove altogether any mention of heart attack, add more warnings (such as recommending Avandia only be used if other meds fail), or add more warning AND restrictions to prescribing. See the FDA's exact wording below:

A. Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding an increased risk of ischemic CV events, or
B. Allow continued marketing and make no changes to the current label, or
C. Allow continued marketing and revise the current label to add additional warnings (e.g., contraindications for certain patient populations, recommendation for second-line use in patients intolerant of or uncontrolled on other anti-diabetic agents); or
D. Allow continued marketing, revise the current label to add additional warnings, and add additional restrictions on use (such as restricting prescribing to certain physicians or requiring special physician and patient education)
E. Withdrawal from the U.S. market.


2. One of the presentations regarding the TIDE study, talks about the importance of large randomized controlled trials, citing all the bad things we would still be doing without the data. I love this....

If modern medicine relied on epidemiologic data, administrative databases, & meta-analyses of small trials to identify effective therapies, we would be …
routinely using HRT (WHI)
suppressing VPBs post-MI (CAST)
doing internal carotid artery bypasses (EC-IC study)
using alpha blockers to prevent stroke (ALLHAT)
giving estrogen to men with CAD (CDP)
giving high-dose GIK infusions in the CCU (CREATE)
using perioperative beta blockers (POISE)

2. There is going to be considerable time spent on poking holes in the RECORD study, which is really the pivotal evidence for Avandia safety. One of the main criticisms of RECORD is that the expected number of events (which determines how many patients they need in a study) was much lower than expected. Some has therefore stated that RECORD was "underpowered" to show Avandia is safe. In fact, the AHA/ACC consensus statement hinges its findings on this. However, the study was indeed powered to show Avandia is safe. The FDA presentation looking at this issue confirms this stating "Despite the initial over-estimate of events, the trial had substantial power to achieve its specified goal." This bodes well for Avandia.

3. Dr. Unger, a cardiologist from the FDA states that "the results of RECORD do not substantiate the findings from the Nissen/Wolski meta-analysis on myocardial infarction and cardiovascular death." In other words, from a cardiologist's perspective, RECORD proved Nissen wrong.

4. Nissen is not going down without a fight. Nissen main tactics seem to be 1) poke holes in the RECORD study and 2) present Actos (using non-head to head comparisons, meta-analyses, and claims databases) as a much safer alternative. Again, note that Takeda (makers of Actos) fund his research.

Are Drug Reps and Free Samples Bad For Patients? It Depends

One of my favorite blogs, KevinMD, featured a post by Internist and fellow blogger Dr. Leslie Ramirez (founder of Leslie’s List, which helps the uninsured and underinsured find more affordable medications and health care services) on the true cost of free drug samples. Her point was that "free" drug samples may cost a patient in the long run if they are followed up with an expensive prescription that the patient can't afford. I posted a response on Kevin's site (more below) stating the issue was a little more complex, as Dr. Ramirez' example applied specifically to a patient who was paying out of pocket for medications, which is not usually the case. However, this post received numerous responses about the value/evils of both drug reps and the samples they provide. Below is an edited/expanded version of my replies.

The Benefit and Harm of Reps and Samples
Do drug reps/free samples…
-influence doctors? Absolutely.
-increase prescribing of non-generic meds? Absolutely.
-contribute to health care dollars spent on meds? Absolutely.
-harm or are bad for patients? It depends.

It is true that whenever a generic medication has equal safety and efficacy as a branded medication, the patient and public benefit when a generic is used. However, just because there are generic medications available, does not always mean that generics are the best choice for patients.

A good example is type 2 diabetes. The RECORD (see For the RECORD, Avandia does not cause heart attacks) study looked at cardiovascular safety of the much maligned drug Avandia. (RECORD showed it not to increase risk of CV death or hospitalization-something the media continues to ignore). The study took patients on a generic diabetes medication (either metformin or sulfonylurea) and randomized them to either an expensive, branded diabetes medicine (Avandia) or the other generic. Patients in the Avandia group who still had uncontrolled diabetes on Avandia + one generic could add the other generic. Patients in the other group who were uncontrolled on both generics had to go to insulin.


In addition to showing no difference in cardiovascular safety (primary endpoint), the patients in the Avandia group had better diabetes control, less weight gain, better cholesterol profiles, less hypoglycemia and less insulin use. In other words, though it certainly costs more money, (in this study) it was better to add Avandia then sticking with only generics. This should not be surprising since we know that the older diabetes drugs fail after a few years, and that TZD's like Avandia (seen now in ADOPT, RECORD, and BARI 2D) sustain glycemic control.



There are a few other examples where generic products exist, but branded products may be better. Branded statins (Crestor, Lipitor) are likely better then generics for patients with high cardiovascular risk who need to get their LDL (bad) cholesterol down more than 40%. In hypertension, losartan is the first generic angiotensin receptor blocker (ARB). Though there are several ACE inhibitors that are good once a day generics (lisinopril), up to 10% of patients will get a cough and need to be switched to an ARB. Now we finally have a generic ARB, except this one is not nearly as good as the other 4 branded products on the market. Because insurance companies will likely make it very difficult (higher co-pays and prior authorizations) to get one of the branded ARB's, patients will likely need to get a cough on an ACE and then fail losartan, before they are allowed to use the newer, better ARBs (and will still have a very high co-pay).



In addition, there are many medications that have no generics. All the respiratory medications (Advair, Symbicort, Spiriva, etc.) essentially have no generic equivalent. Having a drug rep provide samples of these meds will (as stated above) certainly increase prescriptions and therefore increase healthcare spending. However, asthma kills about 11 patients a day, COPD is the 4th leading cause of death, and both conditions are substantially under treated. Writing more prescriptions of these medications, and thus the reps that provide them, should therfore be a good thing. Even if the medicines are costly, their increased use will prevent exacerbations, hospitalizations, and even death (which have their own costs).



There is also the issue of direct cost to the patient (out of pocket costs) and the convenience factor. The FDA just approved a combination pill of Nexium and Naprosyn for rheumatoid arthritis. Many patients with rheumatoid arthritis need to take NSAIDs like naproxen on a regular basis. One of the side effects is stomach ulcers. Acid blocking proton pump inhibitors (PPI's) like Nexium can prevent these ulcers and guidelines recommend the use of PPI's with chronic NSAID therapy. The newly approved, branded pill will be an expensive, once a day pill that will treat the arthritis and protect the stomach. However, Prilosec (another PPI) and Naprosyn, are both over the counter. Why not just take two over the counter pills a day instead of an expensive branded pill? CVS brand naproxen would cost about 10 cents for two 22omg pills (prescription dose is 500mg), and one Prilosec 20mg OTC (not as strong as Nexium, but should do) is about 70 cents a day. Thus, a patient needing NSAIDs and stomach protection would need to take 3 pills at 80 cents/day, or $24/month. However, it is very likely that the drug company will provide coupons for patients that guarantee them that their co-pay is no more than $25/month. I would think that most patients would prefer the better, once a day pill than the 3 pills a day for about the same price. (There is also a potential safety benefit as combining the pills ensures the stomach is protected when taking an NSAID).

As already alluded to, the issue becomes further complicated when insurance coverage, samples and coupons create complex equations where decision making becomes a challenge. One example would be high cholesterol. Let’s say your bad cholesterol or LDL is 160 and your doctor tells you it needs to be under 100 based on your risk for heart attack and stroke. Simivastatin is generic and has been proven effective, but you will likely need the highest dose of 80mg to get to your goal (the higher the dose, the greater the likelihood of side effects). Generic simvastatin (no samples) costs you $10 month at your local CVS. There is also Lipitor, a branded drug that will get you to goal at a 20mg dose, but at a price of $25 per month. However, I can give you a four week sample of Lipitor to try (to make sure there are not side effects, etc.) and a coupon that will lower your monthly cost to $15. This will last for a year (at which point Lipitor should be generic). Using the branded product with samples and coupons, the additional out of pocket cost to the patient is only $50/year or an extra $4/month, but they get to try the med first, and received a drug that worked better, with fewer side effects. Which is better for the patient? (Before you say that $50/year is a lot for a poor person, keep in mind that very poor patients are on Medicaid and won't pay any difference for the medications, and people who do not have prescription coverage might have problems being able to afford either, as generic simvastatin 80mg is $33/month).


To be fair, there are PLENTY of examples where branded drugs are promoted heavily by the industry using drug reps and samples, where an equally safe and effective medications are available generically. Dr. Ramirez' post regarding generic citalopram and Lexapro is a great example. In addition, the argument can be made that drug companies should be putting their resources coming up with useful new agents, rather than re-packaging older medicines into one pill (like Naprosyn and Nexium).


The point is that the issue of the samples, drug reps and the industry is a complex one. The drug industry is one of the most profitable industries in the US. Their use of expensive, direct to consumer advertising may seem inappropriate to some, when so many in our country can not afford medications. Past excesses of lavish gifts to physicians (no longer allowed) and more recent settlements of off label promotions (see Pharma Should Not Settle Off-Label Promotional Suits) has certainly eroded trust in the industry from the public, patients and many physicians.

However, drugs save lives. Even in recent years, we have seen the remarkable difference prescriptions medications have made (HIV, cancer, heart attacks). Also, the majority of prescriptions being used today are now generic, and were made possible because they were once sold under a brand name. As stated above, generics are not always the best choice for patients, and while drug company promotional efforts will undoubtedly increase sales of expensive drugs, this is not necessarily a bad thing if patients' lives are improved. Finally, the way medications are covered and paid for create a sometime perverse set of circumstances where samples and coupons for expensive medicines may actually be in the patient's best interest even if similar medications are available generically or over the counter. Many (especially in the media) want to paint the influence of the pharmaceutical industry as black and white. However, this issue remains very, very grey.

Blood sugar, high blood pressure and cholesterol control still important for diabetics.

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.

Should all patients with metabolic syndrome or elevated HgA1c take statins?

Metabolic syndrome is a constellation of factors (increased waist circumference, high blood pressure, elevated fasting glucose, high triglycerides, low hdl) that are associated with increased cardiovascular risk. Metabolic syndrome is often called pre-diabetes both because sugars are high and because metabolic syndrome is related to insulin resistance, the primary mechanism of type 2 diabetes. Diabetes has been generally defined as having a fasting blood sugar of greater than 126, so patients with sugars between 100-125 have also been called pre-diabetics. Like diabetes, we know that metabolic syndrome is associated with increased cardiovascular risk (increased risk for heart attack and stroke). Men with three or more components of metabolic syndrome have more than double the risk for cardiovascular disease, and women with three or more factors have almost six times the risk for cardiovascular disease.

Because diabetes is associated with such a high cardiovascular risk, and because lowering cholesterol with statins in diabetics has proven to reduce these events, current guidelines recommend that virtually all diabetics take a statin, even for those patients with normal cholesterol levels. One question which remains is whether the same should be done for patients with elevated fasting blood sugars and/or metabolic syndrome.

A recent study in the New England Journal called Glycated Hemoglobin, Diabetes, and Cardiovascular Risk in Nondiabetic Adults may give us more reason to consider thinking about using cholesterol lowering agents in patients with elevated blood sugars, even if the cholesterol is normal. The study looked at the relationship of hemoglobin A1c (HbA1c) to development of diabetes and cardiovascular risk. It was not surprising that even high end normal HbA1c's predicted development of diabetes, but what was surprising was that high normal HbA1c was strongly associated with risk for heart attack and stroke.

In the study, patients with an HbA1c of less than 5.0% had 4% relative decreased risk of cardiovascular disease compared to patients with and A1c of 5.0 to 5.5%. However, those with A1c's from 5.5 to 6.0% had a 23% increase, those with A1cs of 6.0 to 6.5% had a 78% increased risk, and those with 6.5% or greater had an almost double risk of cardiovascular disease. This suggest a strong correlation between elevated blood sugar (pre-diabetic patients) and cardiovascular risk.

In the most recent updates to the ADA guidlines published in the January 2010 edition of Diabetes Care, the ADA now defines diabetes as patients with an A1c of >6.5%, and those patients with A1c's between 5.7–6.4% have been included in a category of increased risk for future diabetes. Thus, the last group in the recent study would now be considered to already have diabetes.

This study also made me think of the JUPITER trial. The JUPITER trial is a controversial trial which I have blogged about before (see Jupiter is Out, and the News is Good! and Crestor: Get Ready to Ask Your Doctor for the CRP Test). It showed that patients with relatively normal cholesterol levels, but high levels of CRP benefited from taking 20mg of Crestor. Crestor now has an FDA indication for primary prevention of heart disease.

Interestingly in the JUPITER study, 41% of patients had the metabolic syndrome. The median A1c was 5.7 (interquartile range was 5.4-5.9). This means that about half the patients in the study had an extra 23% increase for cardiovascular disease based on A1c alone, and about 25% of patients had a 78% additional risk or higher (with the new ADA definition, there was probably not an insignificant number of patients in the JUPITER study that had an A1c above 6.5% that would now be considered to be diabetic and should have been on a statin). The reason I bring up JUPITER is because we now have a primary prevention trial in which a substantial number of patients had metabolic syndrome or elevated sugar, and this trial showed that statins were beneficial.

Thus, there are compelling arguments that can be made to suggest that patients with either metabolic syndrome or an elevated HgA1c should be on a statin (similar to diabetics) regardless of their cholesterol number.

However........
1. In order to definitively make this case, you would need a large, randomized clinical trial of patients with metabolic syndrome (or A1c's between 5.5 and 6.5) and normal cholesterol, randomized to statin or no statin. I am hopeful that the NIH or some drug company is planning on doing this.
2. In a subgroup analysis of the JUPITER trial, the investigators looked to see whether metabolic syndrome was a factor in those patients that benefited from Crestor and didn't find a statistically significant difference. It appears that CRP levels and not sugar levels is what made the difference.
3. Though the presence of metabolic syndrome does predict cardiovascular disease, it predicts diabetes much better, and the Framingham risk score is a much better predictor of cardiovascular disease (see Metabolic Syndrome vs Framingham Risk Score for Prediction of Coronary Heart Disease, Stroke, and Type 2 Diabetes Mellitus )

Bottom Line: Elevated HgA1c levels and metabolic syndrome substantially increase risk for cardiovascular disease, and there are compelling reasons to consider statin therapy in these patients, though conclusive data is lacking. As per the new ADA guidelines, patients at risk for diabetes should be screened with a HgA1c, and if it is greater than 6.5%, these patients are now considered diabetic and should receive a statin.

Since the Framingham risk calculation is still the best predictor for cardiovascular risk, a reasonable approach might be to adjust the Framingham score for patients with HgA1c's between 5.5% and 6.5%. Currently, patients with a Framingham risk of greater than 10% are considered for more aggressive LDL goals (which usually means they need a statin). Based on the numbers from the recent New England Journal study, for patients with A1c's from 5.5 to 6.0%, more aggressive goals should be considered when these patients have a Framingham score of 8% (instead of 10%), and for those with A1cs of 6.0 to 6.5%, more aggressive goals should be considered for a Framingham score above 6%.

More Avandia Scare- Again, Unwarranted.

Here we go again......


A piece recently published in the New York Times and cited by others has just kicked up the Avandia controversy again. As usual, this is both unnecessary, and will likely scare patients and cause more harm than it is trying to prevent. (In many ways like the current LABA scare).

I have blogged extensively on Avandia safety.
The Avandia Scare: Why it Matters, Who's Responsible, and What to Do ,For the RECORD, Avandia does not cause heart attacks, Avandia Vindicated, and The Diabetes Conspiracy.



Before going diving into what the hubub is about it is important to note two extremely important facts:

1. There is no new data or information here. Everything being discussed is old news.

2. The one thing NOT being discussed in all these reports is that the question of Avandia safety was answered this past July at the American Diabetes Association's annual meeting when the RECORD trial was presented which definitively showed that Avandia did not cause heart hospitalizations, cardiac deaths, or any heart problems.


What's this all about?

The New York Times got a hold of a report that is now public from Senators Grassley and Baucus. What is available is the Press release and the full report of their two year investigation into the FDA and GSK's handling of Avandia safety. Their letter to the FDA states that GSK knew that that there were cardiac risks associated with Avandia and did not make these risks known to the public or the FDA soon enough. The second charge they make is that the study the FDA has requested GSK conduct to test safety differences between their product Avandia and their competitor's (Takeda) product Actos called the TIDE study is unethical, because two FDA safety officers felt that since there was no benefit of Avandia over Actos, and that Avandia had heart concerns that Actos did not, the study would needlessly harm patients. One of those safety officers was Dr. David Graham.

The full report is a 342 page document that includes publications, FDA data and internal communications at GSK. One of the main focuses of their concern is that the RECORD trial was continuing when GSK knew that the initial heart attack rates were low, so low in fact that it was unlikely that when finished, the RECORD trial would have enough events (statistical power) to show whether or not Avandia was safe. What is not highlighted in the report (which comes out 6 months after RECORD was presented) is that RECORD actually did meet criteria for statistical power. In other words, all their worry was for naught. Another focus of the report was study 211, which as a study on using Avandia in patients with heart failure. (More on that later).

You can argue whether or not the Senators have a point regarding what the FDA and GSK should have done and by when; however, from a clinical perspective there is nothing new in this report. More importantly, it was irresponsible of them not to discuss the final results of RECORD in this context.


Study 211
Study 211 was actually published in the well respsected Journal of the American College of Cardiology. It showed that when giving Avandia to patients with class 1 and 2 heart failure (a relative contraindication) that Avandia did not statisctically increase the rates of heart failure, death or heart attack. The only differences seen were more edema (a known side effect of Avandia, especially for patients with heart failure) and more need for medications. The essential findings of the study is that Avandia increases fluid retention (we know this, Actos does this as well) but does not actually have any effects on the heart. Why the senators want to make a big deal of study 211 is beyond me. If anything it shows that even in patients who you shouldn't give the drug to, there were no real problems.


What about the recommendation to take Actos instead of Avandia?

This is probably the scariest and most harmful outcome of the report and the media attention surrounding it. Every media outlet has not publisehd the following quote: "if every diabetic now taking Avandia were instead given a similar pill named Actos, about 500 heart attacks and 300 cases of heart failure would be averted every month because Avandia can hurt the heart"

This statistic comes from a letter written by Dr. David Graham to the FDA expressing concerns about Avandia over Actos. What Dr. Graham did is compared two Avandia meta-analysis with one meta-analysis on Actos. The two Avandia analysis used were Nissen's and the Singh meta-analysis published in JAMA. The Singh meta-analysis looked at ADOPT, RECORD and DREAM (which the FDA did a meta-analysis on and showed NO PROBLEMS with Avandia), and added study 211, which is a focus of the Grassley report. As mentioned, study 211 was a study done in 200 patients with heart failure, and since we know that Avandia does in fact increase the risk of heart failure, the patients in this study are not ones that you would normally give Avandia. Nonetheless, the Singh meta-analysis, unlike the FDA's, showed problems with Avandia, consistent with Nissen. ADPOT, DREAM and RECORD had thousands of patients. Study 211 had only 200. In other words, the only reason the Singh meta-analysis was positive and the FDA's was negative is that Dr. Singh added the 200 patients from study 211.

The Actos meta-analysis was published in JAMA, and found no heart attacks with Actos. One needs to note that one of the authors on the Actos meta-analysis is Dr. Nissen. Also, one should note that Takeda, the makers of Actos, gave Dr. Nissen and colleagues $25,000 in funding. In other words, Dr. Nissen has two published meta-analyses, one that is not funded that finds heart attacks in Avandia, and one funded by the makers of Actos that finds no heart attacks in Actos. As Arsenio Hall used to say, this is something that makes you go "hmmmmmmm."


Dr. Graham's conclusion is that comparing the Actos and Avandia meta-analyses, there were excess heart attacks and heart failures in Avandia over Actos, so that for every 63 patients taking Avandia instead of Actos for 1 year, there would be an additional heart attack. He then looked at the number of patients taking Avandia and came up with the 500/300 cases.

In addition to jumping to major conclusions from meta-analyses, one of the bigger problems here is comparing results from separate studies. This is breaking a cardinal rule of evidence based medicine. Doctors should be familiar with this because drug company reps do this all the time. They say, "my drug's studies show that my drug does X and my competitor's studies only show that their drug does Y, so you should use my drug." The astute clinician should politely ask the drug rep about head to head studies. Most often, the response will be that there are none. It is critical when making comparisons between to therapies, that head to head studies are done. Unfortunately, head to head comparisons are often not done by the drug companies because there is a huge financial risk if the results show that your company's drug is inferior. This is why proposed legistlation is rightfully calling for funding of comparative effectiveness research. In other words, Dr. Graham is stating that Actos is safer then Avandia WHEN THERE ARE NO HEAD TO HEAD STUDIES COMPARING THE SAFETY OF BOTH DRUGS. Unfortunately, this incorrect and inflammatory statement is what gets picked up by all the media. To be clear, I don't believe that Actos is harmful. I think both drugs are safe, though they both show similar side effects (fluid retention, edema and osteoporosis) and should be used with caution in certain patients (HCF).

A Diabetes Conspiracy?

This report if anything give more credibility to my postulations.
- It was Grassely and Baucus that called for congressional hearings back in May 2007, the day of the Nissen publication was announced. It was as if they new about the controversy before the story broke. The fact that they continue to draw attention to this issue (and themselves) despite the fact that the issue has been scientifically resolved and that health care reform is on life support is a concern.
- We again hear the name of Dr. David Graham, the FDA insider on Vioxx. I contend that somehow Nissen was tipped off from someone inside the FDA to publish the Avandia data himself, since the FDA decided to keep this data from the public. After this report, Graham continues to be my likely suspect. Regardless, if anything should be looked into, it should be whether or not classified FDA documents or conversations were leaked to Dr. Nissen. I am not a lawyer, but I think this is illegal.


Bottom Line
1. Nothing new here. Avandia does not cause heart attacks, as proven by the RECORD trial.
2. Quote on Actos safety over Avandia is based on no truly comparative (head to head) studies, and thus should not bebelieved, especially given #1.
3. Don't the Senators have other things to worry about....like fixing health care?

4. Someone should take a closer look at how Nissen "discovered' the link between Avandia and heart attacks. This is the congressional hearing I would like to see.