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. 

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. 

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.

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%.

Statins Don't Cause Diabetes

As of this morning, the only major source reporting the results of a recent study from Lancet is Business Week. However, the headlines that will likely pop up in the next few hours will likely be similar to theirs: "Cholesterol-Cutting Drugs Raise Diabetes Risk by 9% in Study." In my last post I discussed how the media likes bad news stories, so even though this is not yet all over the headlines, I will take a preemptive strike for potentially concerned patients.
The Lancet study is a large major meta-analysis of major statin trials, looking to see if there is a risk associated with statins and the development of diabetes.

The authors likely got the idea to do a meta-analysis from the JUPITER trial which showed that Crestor reduced heart attacks in patients who wouldn't have generally gotten a statin, except they had an elevated CRP (see Crestor: Get Ready to Ask Your Doctor for the CRP Test. ) One thing seen in this study was a potential increased risk of the development of diabetes. I mentioned this in my blog post when the data was first released that physician report of diabetes was increased in the Crestor group (270 reports of diabetes, vs. 216 in the placebo group; P=0.01). I stated that though one might be concerned about this, these were physician reports without confirmation. When looking at the study lab values in Jupiter, there were no significant differences with respect to the fasting blood glucose level, and the A1c level was pretty much the same (5.9% and 5.8%). I also mentioned that there was no biologically plausible reason to suspect Crestor, or any statin, as a cause of diabetes. In addition, both groups of patients in the JUPITER study had a 41% prevalence of metabolic syndrome, which is a pre-diabetic state. Therefore it should not have been surprising to find an increase in diabetes in both groups.

The meta-analysis looked at Jupiter and several other studies combined and found a 9% increase in the development of diabetes in patients taking statins.
So if this is true, how can you say that statins don't cause diabetes????
1. The 9% value is a relative risk, not an absolute risk. If 1/100 patients taking placebo have a side effect, and 2/100 patients taking a statin have a side effect, the relative risk increase is a doubling or 100%, but the real or absolute risk is only 1%. Drug companies and the media (and unfortunately some authors, as was the case in this study) like to talk about relative risk instead of absolute risk, because it makes there drug/data/news story look better. In this study, the actual increase in diabetes was 0.38% or about one third of 1%. Even though the result is statistically significant (true by scientific standards), the magnitude of the increase is so small that there is a high possibility that this is not true.
2. The study is a meta-analysis, which by design can not prove causation. The only way to really find this out is to do a large, randomized controlled study to specifically look at whether or not statins cause diabetes. This will never happen because 1) given the low absolute risk, the number of patients needed in this study would be tens to hundreds of thousands, which means the study would be ridiculously expensive and 2) with Lipitor going generic, no drug company is going to fund such a study. I spoke of the dangers of meta-analysis many times, specifically in talking about Nissen's meta-analysis of Avandia (multiple posts on this). Even in Nissen's own meta-analysis showing a "40% increase in heart attacks" in patients taking Avandia (relative risk), there was really NO DIFFERENCE in the absolute risk in his study! Of course that didn't stop the press, and millions of patients stopped taking Avandia. Unlike the randomized, controlled trial for statins and diabetes we will never see, there was a randomized controlled trial on cardiac safety and Avandia called the RECORD trial which was presented at the ADA this past summer. It showed NO RISK of heart attacks with Avandia. Don't be surprised if you never hear about this, since the press does not seem to be too fond of reporting good news.
3. As above, there is no biologic reason to believe that a statin medication would cause diabetes.

In other words, what you are seeing in the headlines is statistical garbage, that really doesn't mean anything. An incredibly low absolute risk found in a meta-analysis without a biologic reason to support a connection between statins and diabetes should not be cause for concern.

More problems with insulin

I have previously blogged about my concerns with the use of insulin therapy in patients with type 2 diabetes (The Problem With Insulin and The Problem with Insulin- Part 2). Several studies show new concerns using insulin to treat type 2 diabetes. The most notable is the ACCORD study which investigated intensive diabetes treatment and was stopped early because patients in the intensive treatment group had more heart attacks and death. Many experts suspect that even though controlled blood sugar is desirable, blood sugar that is too low may cause problems. This seems to be especially true for insulin, most likely because insulin causes hypoglycemia, or blood sugar that is too low. Hypoglycemia can be dangerous and may explain the excess deaths seen in the ACCORD and other studies. One of the main reasons for my concern is that some recent recommendations from worldwide experts in diabetes suggest that we are not using insulin enough! These guidelines dismiss or leave out altogether newer and potentially safer agents, suggesting that the older (all be it cheaper) diabetes pills which are known to fail over time continued to be used with advancement to insulin once they have failed.

However, a new study from the Lancet gives further evidence to more cautious use of insulin in type 2 diabetes. This UK study looked at two groups of diabetics. One group of about

28,000 patients were already on a diabetes pill (metformin or sulfonylurea) and had their regimen adjusted by adding another pill (metformin plus sulfonylurea). In the second group of about 20,000 patients, patients on one pill that were not under control were either switched to insulin alone, or insulin was added to their diabetes pill. The chart is below, but as you can see the higher your A1c (high A1c means that diabetes is under poor control) is, the greater your chance of death (and heart attack, seen in similar graphs), EXCEPT when your A1c is too low (under 7) and you have a greater risk of death. This is known as a U shaped curve, which means that treatment works, but you need to be careful because over-treatment can cause harm. Both groups saw this effect, but the effect was much greater in the second group that got insulin. In other words, similar to what waas seen in the ACCORD study, if you are on a diabetes pill and you need to get to a goal of below 7, you should probably reserve insulin as a last resort, since it will increase the likelihood of killing you compared to a diabetes pill. In addition, one of the side effects of sulfonylureas is hypoglycemia. It would be very interesting to see how these curves look when non-sulfonylurea drugs such as the TZD's (Avandia, Actos), DPP4 inhibitors (Januvia, Onglyza) or even incretin mimetics (Byetta and just approved Victoza) that DON"T cause hypoglycemia were used. I would suspect the difference would be even greater.

Again, this study lends further evidence that insulin should be used cautiously and other agents should be considered to get diabetes under control before going to insulin. This is in stark contrast to the recently released consensus as mentioned above. I have previously speculated ( here, here, here, and here) why certain experts continue to recommend older drugs and insulin when evidence continues to point to the benefit of some of the newer drugs

Lantus and Cancer- A Closer Look Is Not Reassuring

Kevin MD brought up the issue of Lantus and cancer on his blog, linking to both my original post which stated that patients should be concerned, as well as a post from Amy Tenerich at Diabets Mine who takes a more conservative approach, like the ADA and AACE. ( I do question the motivations of these groups in my recent post on this matter: Lantus Causes Cancer! Why Doesn't Anyone Seem Care? ). Some responders to my inital post felt that I had not read the studies correctly. Therefore, below is my detailed interpretation of the four studies recently presented which caused the controversy.

The first study was a German study of 127,000 patients, which 20,000 were treated with Lantus. Most of these patients had Type 2 diabetes. Overall, this study found a correlation with all insulins and cancer, but no difference between the analogue insulins. However, because patients on combination analogue and human insulin were excluded in the study, the dose of lantus was much lower than the other analogues. The researchers then adjusted for insulin dose, and they found a dose dependent relationship of cancer and Lantus. The magnitude of this effect was such that 1 cancer might be caused for every 100 patients taking Lantus for a year. One of the limitations of the study was that it was not possible to break the analysis down by types of cancers caused. Given this and other possible limitations, the editors of the journal decided not to publish this study until these results could be replicated in other studies/countries, especially considering the importance of the findings if corroborated.


Since then 3 other studies were performed, and subsequently all four were published together.



The second study was a Swedish study matched a national cancer database and a national diabetes database looking for a connection. This study included over 120,000 patients of which about 6000 were on Lantus. They found no increase in risk for cancer with Lantus when taken with other kinds of insulin. These patients were younger, and more likely to have type 1 diabetes. However, analysis of patients who took Lantus alone, most of whom had type 2 diabetes, showed a doubling of breast cancer, which was highly statistically significant (though no increase in other types of cancers).


A third Scottish study used national database registeries similar to the Swedish study and they found exactly the same thing. The patients who took Lantus with other insulins, who were generally younger type 1 diabetics had no increased risk of cancer with Lantus compared to human insulin (actually had lower rates) but the patients on Lantus without other insulins, mostly older type 2 diabetics had a higher risk of cancer. There was also similarly an increased risk of breast cancer in women taking Lantus alone, which was about the same magnitude as the Swedish study.



The fourth study looked at cancer risks associated with a range of insulins. This retrospective UK study looked at over 62,000 adults that were started on oral agents and/or insulin. Diabetes developed in adulthood, so these were mostly type 2 diabetics. In general, the study found no difference between human insulin and analogue insulins like glargine (Lantus). However, the study did find that metformin use is associated with a lower risk of cancer, and seemed to abolish cancer risk. Also, only 10,000 patients in the study were on insulin, and only 2000 on Lantus. Plus, it was not clear who was taking meformin plus Lantus. Thus, given the very small number of patients on Lantus, some of who may have been taking metformin, this negative finding is not all that reassuring.

Taken together, in my opinion, these 4 studies strongly suggest a link between new cancers in adult type 2 diabetics who are taking Lantus alone. Now, we can't say that Lantus actually causes cancer. In fact, it is unlikely that Lantus actually causes cancer alone, because it takes years to develop most cancers. However, it is more likely that Lantus causes existing cells to grow and divide more rapidly. Usually, the body's own natural cancer fighting abilities take care of these cells. In other words, though Lantus may not cause cancer, adult type 2 diabetics taking Lantus seem to develop clinically apparent cancers at much higher rates (double for breast cancer) then those not on Lantus. Though whether or not Lantus is causative of cancer is an interesting academic discussion. However, from the patient's standpoint if taking Lantus increases the likelihood they will develop cancer, that's all they need to know.



Large observational studies are far from perfect. The can detect differences (i.e. adult type 2 diabetics taking Lantus were more likely to get cancer), but can detect the reasons for these differences. The only way to show actually causation would be a very large, randomized control trial conducted over years. However, this will take years to complete. The Europeans are suggesting meta-analysis of even larger databases to find out sooner.

Until we know for sure, given a possible risk for Lantus increasing the rate of cancer development, I would suggest it would be prudent to stop taking Lantus if you are a type 2 diabetic, especially if you are not taking other kinds of insulin. Detemir insulin (Levemir) is a reasonable alternative. Though it has not been studies as extensively, its effect on the IGF-1 receptor (the purported mechanism of the cancer association) if much, much less than Lantus.

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.

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.

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 .

Diabetes Conspiracy

I bought my Honda Civic Hybrid after watching Al Gore's An Inconvenient Truth and Who Killed the Electric Car, the latter of which tells how despite a overwhelming acceptance of consumers for an electric car, the project was killed. The documentary demonstrates that many had a role in killing the electric car including the government, car manufacturers and big oil; but never really gives an answer on who literally pulled the plug. In a similar fashion, the timeline below shows that there are many involved with various motivations and biases that have likely forever changed the way type 2 diabetes is managed. The cause for my concern is that important guidelines and public policy have been enacted and influenced by stakeholders with their own personal motivations and by using not entirely evidence based data to make these decisions; and these decisions (in my opinion) are not in the best interest of patients with type 2 diabetes.







August 22nd, 2001 -Nissen publishes Vioxx study
It is important to note that the Avandia story begins with Vioxx. Vioxx is an example of a drug that didn't have a lot of benefit over generic medications available, but was aggressively marketed by Merk and prescribed by millions of doctors. Unfortunately, it also carried some serious side effects, including heart attacks which seems to have been covered in some earlier publications. This JAMA article, whose second author was Dr. Steve Nissen, a cardiologist from the Cleveland Clinic, was the first sign of trouble. Though this study did some good by helping to pull a not very useful, quite expensive and likely dangerous drug from the market, Dr. Nissen quickly found that protecting the public from the harms of drugs garnered him lots of attention. Here is a Pharmalot post highlighting some of the conquests of Dr. Nissen. Though his intentions may be for the good, it is clear that with the publicity of this study and Vioxx, Dr. Nissen intended to make a name for himself warning the public of the dangers of some drugs.







August 26, 2004- Glaxo Agrees to Post Results Of Drug Trials on Web Site.

It is also important to note that the Avanida story also begins with Elliot Spitzer. Then attorney general Elliot Spitzer sued GlaxoSmithKline for fraud, because GSK publicized only one of five trials studying the effect of its antidepressant Paxil, in children. The other four not only failed to show a benefit, but also suggested a risk of suicide. As part of their settlement, which Spitzer claimed was "transformational", GSK agreed to post the results of ALL their trials for ALL their products on the web. Though a boxed warning was eventually added to ALL antidepressants in children, most experts believe that antidepressants still have substantial value in treating pediatric depression. Though GSK may have not been as brutally honest as possible with its data, fraud was a bit of a reach (and certainly nothing as bad as a Governor being involved with a prostitution ring). Whether Mr. Spitzer's zeal to sue GSK was due his desire to become Governor or to hide his own indiscretions, this settlement set the entire Avandia controversy into motion.

Septermber 30th, 2oo4- Vioxx Pulled from the Market

Here is a great recount of the whole Vioxx saga. That it took several years from Nissen's publication to Merk's pulling the product raised public concern. Vioxx was a game changer in that physicians, patients, policy makers, etc. are all now highly concerned about drug safety, and the FDA's ability to ensure it. The FDA is now under the gun, and thus highly sensitive to safety criticism.

November 18, 2004 - David Graham Testifies Before Congress. Enter Dr. David Graham, and FDA insider. After the Vioxx scare, he was called to congress to testify regarding what other drugs the public might be concerned about. Though Avandia wasn't named as one of Dr. Graham's five drugs to look out for, his testimony to congress against his own institution made it clear that Graham intended to be a whistle blower and would place the FDA safety folks at odds with the other branches of the agency. Here is the Washington Post Article as well as a Forbes article with more information about Graham the whistle blower. The theme here is that when you talk about drug safety after the Vioxx fiasco, a lot of people are willing to listen and give you lots of attention.

August, 2006- GlaxoSmithKline submits Avandia data to FDA

One known side effect of Avandia was fluid retention and the potential for congestive heart failure. After the product was approved in the late 90's, as part of due diligence, GSK agreed to perform a large randomized trial looking at heart benefits and risks of Avandia, as well as present the results of their planned studies, looking for any heart risks. The RECORD study was of particular interest because Avandia was also known to have potential heart benefits, including improving good cholesterol, lowering triglycerides, and reducing other markers of heart disease. The question was whether the potential heart benefits (reduced heart attacks) outweighed the potential heart risks (congestive heart failure). It is important to note that at no time did anyone predict that Avandia might cause heart attacks. If anything, it was thought that Avanida might reduce heart attacks.
In August of 2006, GSK submitted both a pooled analysis (meta-analysis) of 42 separate double-blinded, randomized, controlled clinical trials to assess the efficacy of rosiglitazone (Avandia) for treatment of type 2 diabetes as well as a population-based database of 33,363 patients looking for similar endpoints. The 42 studies showed a potential increase in myocardial ischemia in patients taking Avandia compared to placebo. There were no problems when Avandia was compared to other diabetes meds, no issues with death, heart attack, or other adverse events in the FDA's meta-analysis. In addition, the large data base showed no problems with ischemia.

The FDA also knew that two large, randomized trials (ADOPT and DREAM) were about to be published that could help shed some light on this surprising and potential safety signal. In addition, the RECORD study was a large, randomized trial designed specifically to answer the question of cardiovascular safety and Avandia. Though the results would not be available until 2009, the study had be going on for almost 2 years and an independent group which periodically looks at the study to assess safety (commonly done in safety studies) had not reported any problems. Given that GSK's data was inconsistent and that more data would soon be published, the FDA did not publicly disclose the findings of either the pooled data or population based data. This decision was made by the head of the FDA. There were some, as we will see, that probably didn't agree.

October, 2006. The results of the DREAM trial presented.

This was a study designed to see whether Avandia could prevent diabetes in patients with pre-diabetes. The study found that 8 mg daily of rosiglitazone given to 2365 patients resulted in 306 cases of diabetes or death (11.6%) compared with 686 cases of diabetes or death (26.0%) in 2634 patients given a placebo, a difference that was highly statistically significant at P < .0001. Also of note, there was no cardiovascular risk seen in these patients.

December 7th, 2006- ADOPT published

One of the largest diabetes studies ever done, the ADOPT trial showed that Avandia, a thiazolidinedione or TZD, substantially reduced loss of diabetes control compared to both metformin (Avandia 32% better) and sufonlyurea(Avandia 63% better). TZD's work by reducing insulin resistance, and also can improve beta cell dysfunction and both effects were seen in ADOPT. After 5 years of treatment, only 15% of patients failed on Avandia monotherapy. This is far better than the failures from UKPDS. the previous large study which looked at the commonly used drugs for type 2 diabetes, metformin and sufonlyurea. Though both lower blood sugar and reduced microvascular (eye and kidney problems) complications, about half of all patients taking either of these medications lost diabetes control by three years, with the vast majority losing control at 9 years. One would think these results would be exciting news; however, in his editorial to the ADOPT study, Dr. David Nathan, author of a recently published consensus statement that would soon be adopted as the American Diabetes Association's guidelines stated that "given the modest glycemic benefit of rosiglitazone and higher cost, metformin remains the logical choice when initiating pharmacotherapy for type 2 diabetes."

February 1st, 2007- Dr. David Nathan sees no need for new diabetes medicines.

However, only a few months later, despite the exciting results of DREAM and ADOPT, in response to the recent approval of Januvia, a new class of diabetes medicines called DPP4's, Dr. Nathan published this Perspective piece in the New England Journal of medicine , in which he railed against new diabetes medicines stating that newer diabetes drugs like Avandia and Januvia , "are generally no more potent, and often less effective in lowering glycemia, than the three oldest classes (insulin, the sulfonylureas, and the biguanides), all of which are more than 50 years old. Moreover, the newer classes are uniformly more expensive and are associated with adverse effects — some that are shared by the older drugs, but others that are new." In essence, Dr. Nathan is suggesting (despite the problems with insulin and the failure of the older drugs mentioned above), that we just stick with the status quo, and use caution before approving newer diabetes medicine. See my Letter to the Editor in the NEJM criticising this position. Though old medicines certainly have a place, many diabetics do not have their diabetes under control, increasing the risk of things like blindness, amputations, and heart attacks.

January 2007- ADA Guidelines published

The ADA updates it's guidelines annually, and publishes them in the January issue of Diabetes Care. In January, 2007, the ADA guidelines adopted Dr. Nathan's consensus statement. This suggested that doctors start with metformin, and if that didn't work use insulin (best agent), sulfonylurea (like glimeperide) which was cheap though it caused low blood sugar or hypoglycemia, or the TZD's which were expensive, but didn't cause hypoglycemia. Dr. Nathan and company essentially left the newer drugs like Januvia and Byetta out of the picture. This is important because with limited options, patients failing on the available pills would need to start insulin, rather than trying the other agents.

*** Sometime between 8/2006 and 3/2007-Nissen tipped off to GSK's data****

I have no actual knowledge of any communication between someone inside the FDA and Dr. Nissen. However, this must have occured in order for Nissen to perform his own meta-analysis. Avandia had known potential problems with heart failure, but no one was thinking about risk for heart attacks, and if anything possibly preventing heart attacks. Even if Nissen has combed through all of GSK's data on his own, now publicly available thanks to Eliot Spitzer, finding heart attacks with Avandia would be like finding a needle in a haystack. Though I have no knowledge or any communication, I highly suspect that it was Dr. David Graham from the FDA who tipped off Nissen. From a safety standpoint, Graham was likely at odds with FDA Commissioner Andrew C. Von Eschenbach, who made the final call not to release the GSK data to the public. From his congressional testimony back in November, 2004 (see above), Graham had established himself as an FDA whistle blower. In addition, Nissen and Graham had certainly crossed paths back in February 2005 when discussing Vioxx. Whether Graham or someone else, it is unlikely that Nissen found the Avandia data on his own.

May 2007- Nissen Meta-Analysis. This date is referred to by GSK employees in a similar way the rest of us refer to 9/11. Nissen, likely tipped off by someone inside the FDA, performed his own meta-analysis of the GSK studies. His findings were rushed to press in the New England Journal of Medicine. I have posted on this article many times (see here specifically). Most peer review articles take about a year to publish, but this one only took a matter of weeks. Congressional hearings were called the next day. as if certain members of Congress knew about the results before they were published. The media had a huge field day with this. There are many flaws and critics of the particular study, as well as an alternative analysis that found completely different results. Of all the things about the study, the one thing that stands out most to me is that though Dr. Nissen found a 43% increase in risk of for myocardial infarction, the actual event rate was lower in the Avandia group. No statistician has ever been able to explain to me how this is possible. The bottom line is that this flawed study, motivated by Dr. Nissen's desire to get yet another drug off the market, bolstered by the New England's Journal willingness to publish this without a thorough peer review, and propelled to public attention by the media's appetite for a juicy story has forever changed the way diabetes is managed, and (in my opinion) to the detriment of patient care.




May 2007- RECORD interim Analysis published.


Because of fears that the RECORD study could be jeopardized as patients might pull out of the study if Avandia were dangerous, as well as a means to vindicate their medication, GSK felt obligated to publish the partial results of the RECORD study. Though only more than half way done, the study seemed to show no signs of heart attacks, thus refuting the Nissen publication. However, the study was accompanied by not one, but three editorials discrediting the study, one of which was by written by an obviously biased Dr. Nathan.




July 2007- FDA advisory board meets



Given the publicity of the Nissen study, the FDA met to discuss the safety of rosiglitazone. The consensus was mixed. After review of all of the FDA's (not Nissen's) data, they saw something that didn't make sense. Their own meta-analysis showed a signal of myocardial ischemia, but analysis of the ADOPT, DREAM and RECORD trials, as well as analysis of large claims databases showed nothing. It is important to note that using meta-analysis to draw conclusions have potential flaws (as I discuss here). One would think that the weight of severa large, randomized clinical trials would trump one meta-analysis that didn't seem make a lot of sense. However, some, including David Graham , did not agree. Interesting to see his name pop up in the news again, especially regarding this specific issue.

Nover 14th 2007 - Boxed warning added to Avandia.

In response to the July advisory meeting, the FDA ads a boxed warning to Avandia. This is one of the most confusing warnings ever seen. The warning essentially states that there is contradictory evidence so no conclusion can be made. Nevertheless, physicians who may have been on the fence about prescribing the drug, likely stopped writing prescriptions for Avandia.

February 6th, 2008- ACCORD study stopped

I blogged about this in my post ACCORD Study: Don't stop your diabetes medicines, Please! To recap, this study shocked the diabetes community, because the thought was that aggressively treating diabetes would finally show that controlling blood sugar in type 2 diabetics would prevent heart attacks. Previous studies had failed to show this, so perhaps sugar control was not aggressive enough. Instead, the ACCORD study showed the opposite. Patients in the more aggressively treated group had more heart attacks and deaths, and the study was halted ahead of schedule. The press had a field day, and suggested that treating blood sugar in diabetics may not be the best thing to focus on. Some were worried that since many of the patients in ACCORD were taking Avandia, that it might be the culprit. However, the NIH, who ran the study, saw no signs of increased heart attacks with Avandia. What was seen was that the patients in the intense group used more insulin, and had more episodes of hypoglycemia. Could it have been the aggressive use of insulin caused the problem? Interstingly, these adverse events were not seen in a similarly designed European study called ADVANCE, where less aggressive use of insulin ocurred. I talk more about this issue in my post The Problem With Insulin and The Problem with Insulin- Part 2

June 2008- ACCORD, ADVANCE , VADT presented

The results of 3 major trials were presented at the ADA meeting in June 2008 (I blogged about this here). The main problem seen was that despite agressive measures to control blood sugar, though microvascular (eye problems, kidney problems) were improved; macrovascular problems (heart attack and stroke) were not. However, as stated, it may not be how low you go, but how you get there. Regardless, with these studies, when it comes to Avandia safety, at this point in time, we now have randomized studies where over 26,000 patients that have been studied for over 3.5 years, of which more than 15,000 patients took Avandia and showed absolutely no difference in heart attacks or myocardial ischemia.

Fall 2008- Januvia and Avandia get bashed as costly

As I pointed out in my post The Diabetes Conspiracy (Part I) , there are many that seem to be "out to get" the newer diabetes pills. In this example it is a study that points to the rising cost of diabetes care, and new medications like Januvia and Avandia as the culprits. However, two things are not mentioned. First, that the costs of the newer insulins are just as much as a contributor to costs as the newer pills, and unlike the newer pills which prescriptions have tapered off, the new insulins continue to climb in sales. Why do folks want to bash the cost of pills and not the newer insulins? The other point is that the older pills will almost always fail, whereas some newer pills (see the ADOPT study) don't. As I state in my post The Problem With Insulin, I believe certain (though not all) endocrinologists (and possibly drug makers of insulin products) do not want any new diabetes pills because they have a vested interest in keeping patients on injectible agents.

November, 2008- Nissen's name mentioned to head the FDA

Several sources (including the Wall Street Journal) name Steve Nissen as a top candidate to head the FDA. Though President Obama eventually chose another, Nissen remained at the top of the list for a while. How did Nissen garner so much attention and respect? Could aspirations to head the FDA have motivated Dr. Nissen to publish his controversial study?

December 17th, 2008- FDA makes it harder for new diabetes drugs to get approved
Here is the announcement from the FDA As this piece from the Wall Street Journal recounts, in response primarily to the Avandia issue, and despite data to the contrary, the FDA has decided to make it much tougher for ANY new diabetes products to become available. Looks like Dr. Nathan got his wish. Specifically, any new diabetes drug must now prove that it does not cause heart attacks before being approved by the FDA. All other drugs only need to show that they are relatively safe and better than placebo. Diabetes drugs now fall into a separate class of medications, needing to prove an additional level of safety. Proving that you don't cause heart attacks takes a lot of time, effort and energy and thus makes it harder for new diabetes medicines to get approved. I blog about this in more detail in my post Rough Times for New Diabetes Drugs: The Diabetes Conspiracy Part III . The bottom line is that because of one highly controversial and politically motivated study, this new policy will now delay any new diabetes products unnecessarily. This is bad news for patients.

January 2009- ADA removes Avandia, states Januvia is not recommended

Though not part of the official guidelines, Dr. Nathan once again publishes a consensus statement. This time he goes even further. He states that the more evidenced based approach to type 2 diabetes treatment is to use metformin, sulfonylurea and eventualy insulin. He states that Actos (not Avandia) and Byetta (not Januvia) are less evidenced based alternatives. I am not exactly sure where he is getting his evidence from, but Dr. Nathan seems to reluctantly keep in Actos, while leaving Januvia and Avandia as non-recommended agents. It is interesting to me why Byetta gets a better position then Januvia, since the evidence behind each is about the same. Could it be that the endocrinologists (or at least Nathan and company) gave a more favored position to an injectible agent? It is interesting that the consensus statement appears in the same January 2009 issue of Diabetes Care that updates the guidelines. Will this new algorithm take the place of Nathan's old one in the ADA's guideline? Only time will tell.

March 2009-Alloglipitn gets delayed.

Here is the first sign of the effects of the new FDA policy. Again, prior to the Nissen publication, no one thought that Avandia might cause heart attacks. Prior to and since the Nissen publication, there have been multiple studies showing that Avandia does not cause heart attacks. Yet, any new diabetes drug must now prove that it too does not cause heart attacks. Allogliptin (ironically a drug made by Takeda-makers of Actos, Avandia's competitor) is a DPP4 inhibitor similar to Januvia. In addition to some potential safety benefits, because Takeda also makes Actos, allogliptin was to be eventually combined with Actos, giving doctors and patients and entirely new combination therapy. However, as noted by Heartwire, allogliptin was severely impacted by tougher restrictions and it's approval date was delayed until it could prove cardiovascular safety.

The Diabetes Conspiracy


According to dictionary.com, a conspiracy is an evil, unlawful, treacherous, or surreptitious plan formulated in secret by two or more persons; plot. Though I doubt there has been any legal wrong doing, and it is unclear whether or not the likes of Graham, Nissen, Spitzer, Nathan or others sat together to conspire to wipe out any new treatments for diabetes (though I suspect that it was Graham who tipped off Nissen to the GSK data), it seems clear that muliple players with their own interests, which are not necessarily in the best interest of patients with type 2 diabetes have created hysteria surrounding Avandia that has not only led to decreased use of this product, but also led to decreased use of other newer products and more importantly the delayed availability of newer products to market. It might be possible that we may never see a new diabetes product again, either because proving diabetes safety is too challenging, or the pharmaceutical companies choose to invest in "friendlier" areas.



Spitzer's biases are obvious. Nissen found the path to fame, and possibly to the head of the FDA, was through "busting" drugs. Graham found that best way to get what he wanted was to become a FDA whistle blower. The reasoning behind Nathan's dislike of all new diabetes agents remains unclear, but endocrinologists (who make their living by prescribing insulin) have a vested interest in seeing insulin prescribed.



Physicians, patients, policy makers and the public should be aware that the whole Avandia issue is a house of cards. Fortunately, this house of cards may soon come down with data to be published in a few weeks. More to come on that.