Why your heart attack may just be collateral damage in big pharma's turf wars.

When a pharmaceutical company tells you that its drug is safer than it really is, it probably plays with your health. And possibly with your life. That's not a very nice thing to do. But it's also very profitable. Which is why it happens more often that you care to know. 

 These days Takeda Pharmaceuticals has gotten some bad press from a whistle blower suit which claims that TP deliberately withheld trial data for Actos, a drug which treats diabetes. The active ingredient is Pioglitazone, which improves the body's sensitivity to insulin and therefore your ability to metabolize glucose.

You remember one of my earlier blogs, in which I introduced you to the concept of "cherchez l'argent". The simple strategy of finding motives behind actions. Particularly within the health care environment. Which is why I want you to keep a few facts in mind before I tell you a little suspense story which plays out more often in the universe of medicine, than you and I would like to.

The Villains

TP's Actos generates annually 2.6 Billion Dollars for TP. 

It's patent expires in 2016.

GlaxoSmithKline's Avandia is, or was, Actos' competitor. Its active ingredient is Rosiglitazone, whose patent expires this year. Until 2005, Avandia saw yearly sales of 2.5 Billion dollars.

A few years back, the FDA became concerned with the entire class of drugs, the so called thiazolidinediones, because of serious side effects, such as an increased risk of heart disease, stroke and heart failure. Within it's 'adverse events reporting system', the FDA collects data on serious adverse events of drugs, which enables it to compare drugs based on benefits AND risk.

The Beginning

In 2007 the New England Journal of Medicine published the results of Dr. Nissen's meta-analysis of publicly available trial data on the cardiovascular effects of Avandia [1]. In his analysis of 42 published studies he came to the conclusion that there was a significant increase in the risk of heart attacks in patients taking Avandia. Interestingly, Dr. Nissen also pointed out that he did not have access to the source data of these trials, which prevented him from conducting a "more statistically powerful time-to-event analysis". So his conclusion was, correctly, that "more comprehensive evaluations are required" to address these cardiovascular risks. Not an unreasonable demand, given that two thirds of diabetics die of such events. Which is why they are prescribed drugs like Avandia and Actos in the first place. Dr. Nissen expressed his hopes for the yet to be published results of the RECORD trial, which was under way at that time. Financed by GSK, mind you.

The Assassination

In a highly unethical move, one journal reviewer leaked the draft of the Nissen paper to GSK a few days after its submission. The source of the leak was no lesser than a professor of medicine at the University of Texas Health Sciences Center, Dr. Steve Haffner. Why would he do such a thing? Maybe, because he also happened to be a consultant to GSK? Your guess is as good as mine. Cherchez l'argent. 

GSK's own scientists found Nissen's statistical methods beyond reproach. Not so GSK's marketing goons. They promptly showed up at Nissen's Cleveland Clinics in Ohio. But Nissen was prepared for the worst, as he expected GSK to apply some pressure tactics, as it had done in the past with Dr. John Buse, a professor of medicine at the University of North Carolina.

Buse had been at the receiving end of GSK's intimidation tactics for the same reason: openly voicing concerns about the cardiovascular risks associated with Avandia. The issue had gone to head, with the U.S. Senate Committee on Finance investigating the case and coming to the conclusion that "Had Dr. Buse been able to continue voicing his concerns, without being characterized as a “renegade” and without the need to sign a “retraction letter,” it appears that the public good would have been better served".

Buse had warned Nissen in a private email about GSK's corporate persuasion program. With this in mind Nissen secretly taped the entire conversation with the GSK representatives.

Anyway, Nissen was no push-over, and so his meta-analysis was published. Again, ethical considerations took a leave, this time from the RECORD trial, whose investigators were made to prematurely milk it for whatever results could be used to counter the Nissen paper. The manuscript submitted to the New England Journal of Medicine (NEJM) interpreted the results of the trial as contradicting the Nissen meta-analysis. Only the journal editors didn't think so. They simply couldn't reconcile the data with the authors' interpretation. That's why NEJM's reviewers and editors told GSK that "an explanation for the continued use of Avandia is needed in this manuscript".  The paper was finally published on 5th July 2007 concluding that "The data do not allow a conclusion as to whether treatment with rosiglitazone results in a higher rate of myocardial infarction..." [2].

The FDA had somewhat different data. On July 30th 2007 their scientists concluded that Avandia had caused 83,000 excess heart attacks (in the U.S. only) since it had entered the market. But preventing heart attacks in diabetics is what these drugs are all about! So, what's the point of a drug, which controls your blood sugar but  INCREASES your chance of a heart attack? The FDA wondered, too, and subsequently required the drug to be sold only under very strict conditions. Sales dwindled to a fraction of the 2.5 Billion US$ of 2006. But it continues to rake in over a Billion US$ worldwide.

Two years later the same authors who had glossed over Avandia's performance data conceded that those patients who took Avandia had a more than 2-fold risk of developing heart failure compared to those who didn't take that drug [3]. Again the U.S. Senate Committee on Finance had to investigate the matter and came to the conclusion of misconduct on the part of GSK. 

The Payback

 

Guess who followed the GSK drama with delight? Correct, Takeda Pharmaceuticals. With Actos being beautified as the safer drug, and Avandia being seriously clobbered by stiff FDA restrictions and the senate committee's investigations, Actos had cornered the market. But the party mood is over.

Because now Takeda suddenly finds itself in the same hot seat which GSK has kept warm all the while. Dr. Ge's suit alleges that TP deliberately did not report heart failure cases, which, by right, should have been registered in the FDA's database.  Dr. Ge claims that TP terminated her employment after she had complained to 3 superiors about the underreporting of events. Without the whistle blower suit Takeda would have stood another 4 years of market dominance (until its patent expires).

The Surprise Finale

Now here comes the twist: While Dr Ge does not name Dr. Nissen or Cleveland Clinics as a defendant, she insists that investigators of her claims should consider the financial connections between Takeda and Dr. Nissen's Cleveland Clinics.

And all the while you thought only John Grisham novels delivered suspense.

So, what else will we see and hear from the next senate committee report? Whatever it is, you'll see again that playing around with your health is big business. It wasn't if the old rule of the Hippocratic Oath would find its way back into the business of medicine: "Never do harm to anyone!"

Armed with our knowledge about these business ethics, we should suspect the degree of deception to correlate closely with the potential for profits. So, am I right with my 'cherchez l'argent' method? Before you answer, just keep one thing in mind: If successful with her suit, Dr Ge stands to get a sizeable chunk of the settlement. Enough for you AND me to comfortably retire for life. Very comfortably. So let's stay tuned to this unfolding opera. 

In my next post I want to give you a glimpse at how deeply entrenched the ballgame with your health really is. And how you can safeguard yourself against being the unfortunate avoidable heart attack, also known as collateral damage.   

1.           Nissen, S.E. and K. Wolski, Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine, 2007. 356(24): p. 2457-71.

2.           Home, P.D., et al., Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis. New England Journal of Medicine, 2007. 357(1): p. 28-38.

3.           Home, P.D., et al., Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet, 2009. 373(9681): p. 2125-35.

Nissen, S.E. (2007). Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes New England Journal of Medicine, 357 (1), 100-100 DOI: 10.1056/NEJMx070038

Home, P., Pocock, S., Beck-Nielsen, H., Gomis, R., Hanefeld, M., Jones, N., Komajda, M., & McMurray, J. (2007). Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis New England Journal of Medicine, 357 (1), 28-38 DOI: 10.1056/NEJMoa073394

Home, P., Pocock, S., Beck-Nielsen, H., Curtis, P., Gomis, R., Hanefeld, M., Jones, N., Komajda, M., & McMurray, J. (2009). Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial The Lancet, 373 (9681), 2125-2135 DOI: 10.1016/S0140-6736(09)60953-3

It's not your genes, stupid.

Imagine traveling back in time and meeting your caveman ancestor of 10,000 years ago. Imagine telling him about what life is like today: that, with the tap of a finger you turn darkness into light, a cold room into a warm one and a tube in the wall of your cave into a spring of hot and cold water. You tell him...

you can fly from one place to another, and watch any place on this Earth without ever leaving your cave. You tell him you never have to run after your food, or fear that you run out of it. Your ancestor will have a hard time believing you. In his world only his gods can do all that.

Then you tell him how some of your friends think his way of life is preferable for health, which is why you are visiting him because you want to see for yourself. Before I get to your ancestor's most likely answer, let's get on the same page with those friends of ours first.

You have probably heard them talk about the past 10,000 years having done nothing to our genetic make-up. In other words, your ancestor's DNA blueprint was the same as yours. Today this blueprint collides  with a space age environment in which we don't expend any energy to get our food, and the food we acquire delivers far more energy and far less nutrients than what had been the case during 99.9% of human evolution. 

According to this view, today's epidemics of obesity, diabetes, cardiovascular diseases and cancer are simply the collateral damage of this collision. This explanation is so persuasive that it is being parroted by every media type and talking head who can spell the word  'genetics'. I'm afraid it is not that simple. Here is why:

Remember when the 3 billion letters, or base-pairs, of the human genome had first been decoded at the beginning of this century. This decryption had been delivered with the promise of revolutionizing medicine. Aside from new therapies, the hottest items were prognostic and diagnostic tools, which, we were made to believe, would lay in front of each individual his biomedical future. And with this ability to predict would come the ability to prevent, specifically all those diseases which result from an unfavorable interaction between genes and environment.

Almost ten years later we are nowhere near this goal. OK, we have identified some associations between some genetic variants and the propensity to become obese or get a heart attack or diabetes. But these associations are far from strong and they hardly help us to improve risk prediction. Just this year, Vaarhorst and colleagues had investigated the ability of a genetic risk score to improve the risk prediction of conventional risk scores which are based on biomarkers, such as the ones used in the Framingham score. Less than 3% of the study participants would have been reclassified based on the genetic risk score [1].

In a study which was released just yesterday, genetic markers for the development of diabetes in asymptomatic people at high risk, did not improve conventional biomarker risk scoring at all [2]. 

Obviously we are not simply our genes. This is because genes do not make us sick or healthy. Genes make proteins. And on the way from gene to protein a lot of things happen on which genes do not have any influence. To express a gene, as biologists call it, that gene must first be transcribed on RNA and then translated from RNA into the final protein. Whether a gene is transcribed in the first place depends on whether it is being made accessible for this transcription process. Today we know at least two processes which can "silence" the expression of a gene, even though it is present in your DNA. These processes are called DNA methylation and histone modification. Simply imagine them as Mother Nature's way of keeping a gene under wraps.

That's a good thing if the protein product of the silenced gene would be detrimental to your health. It could well be the other way round, too. Anyway, these happenings have been called epigenetics. Epigenetic mechanisms enable cells to quickly match their protein production with changing environmental conditions. No need to wait for modifications of the genetic blueprint which takes many generations and a fair element of chance to materialize. The most astonishing discovery is that these epigenetic changes may become heritable, too. Which means, there is really no need to change the genetic code. 

I believe you get the picture now. While it is true that your ancestor's genetic code is indistinguishable from yours 10,000 years later, the way your body expresses this code in the form of proteins and hormones can differ in many ways. Which is why researchers are now as much excited about epigenetics as they used to be about genetics 10 years ago.

I don't want to be the party pooper, but whenever I see such excitement I'm reminded of how it has often evaporated after some further discoveries. Here I'm skeptical because of the picture, which we are beginning to see. Insulin, for example, is known to regulate the expression of many genes. At least in rats it has been shown that insulin's suppressive effect on gene expression in the liver, can be altered by short term fasting [3]. That means, relatively minor behavioral changes may affect the way our organism expresses its genetic code.   

Observations like these support the idea that we are not our genes, but what we make of them. In plain words: let's not hide behind the "it's-our-stone-age-genes" excuse, to explain why we are fat and lazy and ultimately chronically sick.

Now, back to your ancestor and his response to your friends' suggestions that his way of life is preferable for health. When you also tell him you live a lot longer than the 40 years he has on average, he'll tell you: You have got some nutcase friends over there. Let me live like a god first and then I'll worry about health later.

Maybe, we are not so different from our stone age ancestors after all. 

1.           Lu, Y., et al., Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study. Atherosclerosis, 2010. 213(1): p. 200-205.

2.           Schmid, R., et al., Current Genetic Data Do Not Improve the Prediction of Type 2 Diabetes Mellitus: The CoLaus Study.Journal of Clinical Endocrinology and Metabolism, 2012.

3.           Zhang, Y., et al., Insulin-Regulated Srebp-1c and Pck1 mRNA Expression in Primary Hepatocytes from Zucker Fatty but Not Lean Rats Is Affected by Feeding Conditions. PLoS ONE, 2011. 6(6): p. e21342.

Lu, Y., Feskens, E., Boer, J., Imholz, S., Verschuren, W., Wijmenga, C., Vaarhorst, A., Slagboom, E., Müller, M., & Dollé, M. (2010). Exploring genetic determinants of plasma total cholesterol levels and their predictive value in a longitudinal study Atherosclerosis, 213 (1), 200-205 DOI: 10.1016/j.atherosclerosis.2010.08.053 

Zhang Y, Chen W, Li R, Li Y, Ge Y, & Chen G (2011). Insulin-regulated Srebp-1c and Pck1 mRNA expression in primary hepatocytes from zucker fatty but not lean rats is affected by feeding conditions. PloS one, 6 (6) PMID: 21731709

To hell with exercise

Who says that exercise is medicine? For one, the American College of Sports Medicine (ACSM) of which I'm a professional member. Then, how can I say it isn't?

Let's look first at the conventional view of the benefits of exercise. There is a large and increasing amount of evidence which clearly tells us that exercise prevents today's number 1 killer: cardiovascular disease. That is, heart attack, stroke and peripheral vascular disease. Mind you, what is common knowledge today emerged only some 50 years ago when Morris and colleagues discovered that UK bus conductors, the guys climbing up and down the double-decker London buses, had better fitness and fewer heart attacks than their all-day-seated driver colleagues [1].

In the years since then our knowledge about the effects of physical activity on cardiovascular, metabolic and mental health has virtually exploded. From this evidence the U.S. Dept. of Health and Human Services (HHS) concluded in 2008 that the most active people of the population have a 35% reduced risk of dying from cardiovascular disease compared to the least active people [2]. The WHO lists insufficient physical activity (PA) as the 4th leading cause of death world wide after high blood pressure, tobacco use and high blood glucose. What's wrong with this picture? High blood pressure and high blood glucose are known consequences of a sedentary lifestyle. So is obesity, which ranks 5th place on the WHO killer list. Which is why physical inactivity deserves top spot on that list.

What most people don't know is the way lack of physical activity causes all those diseases, from insulin resistance and diabetes to arterial dysfunction and atherosclerosis, and from there to heart attack, stroke, kidney failure. The mechanisms are extremely complex, and, while we have untangled quite some of them, there are probably a lot more to discover. I'll try to make this the subject of one of the next blog posts. 

Now you are probably asking yourself, how the hell, with all this evidence, will I ever be able to make my point that physical activity is not a medicine. Ok, here it comes: it's a matter of viewpoint. The one I'm taking is the one of evolutionary biology. Let me play its advocate and present as evidence a couple of insights.

First, our human ancestors, who had roamed this Earth as hunter/gatherers for the most part of human existence, had, by necessity, a much more physically active lifestyle. A lifestyle which required at least 1.7 to 2 times the normal resting energy expenditure [3]. [To get an idea about resting energy expenditure and physical activity levels and how they are calculated, simply follow the links to the videos.] Those ancestors' genes are what we have inherited. And these genes are exposed to a lifestyle which is vastly different from the ones under which these genes evolved. Specifically with a view to physical activity, which brings me to evidence no 2:

What we typically observe today are physical activity levels with factors of somewhere between 1.2 and 1.4 of our resting energy expenditure. That's true for most people.

Even if you were to follow the ACSM's recommendation of 30 minutes of moderate to vigorous exercise on at least 5 days per week, would you NOT reach the level of 1.7 if you are working in a typical office job or doing house work. Which means, the physical activity levels which we recommend today, do not add a behavioral type of medicine into our lives, they merely reduce the extent of a "poisonous" behavior called sedentism. It's like cutting down from 2 packs of cigarettes per day to 1 pack. Would you call this a "medicine"? Would the ACSM call that a medicine? With respect to exercise they do.

So, OK, if you had been attracted to this post in the hope of finding some excuse for not doing exercise, or some argument to get those exercise evangelists, like myself, off your back, I'm sorry to have disappointed you. No, actually, I'm not sorry. And neither will you be, if you get your physical activity level above those 1.7. Then you may just start calling exercise a medicine. Until then, chances are you will still go to hell with exercise, because you get too little of it. Certainly too little to stay out of that hell of heart disease, stroke, diabetes and many cancers.

1.           Morris, J.N. and P.A. Raffle, Coronary heart disease in transport workers; a progress report. Br J Ind Med, 1954. 11(4): p. 260-4.

2.           Physical Activity Guidelines Advisory Committee, Physical Activity Guidelines Advisory Committee Report, 2008, U.S. Department of Health and Human Services: Washington, D.C.

3.           Eaton, S.B. and S.B. Eaton, An evolutionary perspective on human physical activity: implications for health. Comp Biochem Physiol A Mol Integr Physiol, 2003. 136(1): p. 153-9.

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MORRIS JN, & RAFFLE PA (1954). Coronary heart disease in transport workers; a progress report. British journal of industrial medicine, 11 (4), 260-4 PMID: 13208943
Eaton, S., & Eaton, S. (2003). An evolutionary perspective on human physical activity: implications for health Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology, 136 (1), 153-159 DOI: 10.1016/S1095-6433(03)00208-3

Screw Your Health?!

So, what's your excuse for not exercising enough, for smoking, for not watching your diet, for getting fatter every year, and therefore having high blood pressure, and too much glucose and cholesterol in your blood?

 That's what the American Heart Association has been telling you for so many years NOT to do. How can I be sure that you, dear reader, are one of those people who only pay lip service to health? I can't, but as a numbers guy I go with the statistics. 

And when health is concerned the statistics tell me that there are obviously only two types of people. Those who do enough for their health, and those who merely think they do. The latter make up 98.8% of the population [1]. That is, only one in a hundred meets all 7 health metrics: not smoking, eating a healthy diet, no overweight, sufficiently physically active, normal blood pressure, normal levels of glucose and cholesterol. Four out of every 5 Americans meet 4 or less of those metrics. Actually, only one in four meets 4 metrics. How can that be when having at least 6 of those metrics will cut your risk of dying from cardiovascular disease by 75% compared to those who meet one criterion or none? How much more incentive do you want?

That's the frustrating question I'm asking myself every day. Because whether it is in the US, in Germany or anywhere else in this world, maintaining health and preventing disease is a frustrating service to provide. I used to think this is so, because when you don't feel it, it is health. And what you don't feel, you don't appreciate. But if that was true, the first diagnosis of a chronic condition, such as heart disease or diabetes, should surely be a wake-up call. But it isn't. Only 40% of smokers quit when  being told that they have such a chronic disease, and that smoking will make it worse [2]. That's still a lot compared to the behavior change in exercise: Nil, no change at all.  And for every American who quit smoking in 2011 another American became obese. 

If you have read my earlier blog posts, you'll remember that I'm a strong advocate of recognizing the autonomic neurohormonal mechanisms which certainly drive our eating and exercising behaviors. But we are not exclusively controlled by those. We still have a few brain centers which give us the abilities and skills that make us human: volition, reasoning, intelligence. Of course you can use them to find the most elaborate excuses for your health behaviors, or rather for the lack thereof. But he who is good for making excuses is seldom good for anything else. That's what Benjamin Franklin said. Are you good for something else? Make that something your health. And start today. Here!

1.           Yang, Q., et al., Trends in Cardiovascular Health Metrics and Associations With All-Cause and CVD Mortality Among US Adults. JAMA: The Journal of the American Medical Association, 2012.

2.           Newsom, J.T., et al., Health Behavior Change Following Chronic Illness in Middle and Later Life. The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 2011.

Yang, Q., Cogswell, M., Flanders, W., Hong, Y., Zhang, Z., Loustalot, F., Gillespie, C., Merritt, R., & Hu, F. (2012). Trends in Cardiovascular Health Metrics and Associations With All-Cause and CVD Mortality Among US Adults JAMA: The Journal of the American Medical Association, 307 (12), 1273-1283 DOI: 10.1001/jama.2012.339 

 Newsom, J., Huguet, N., McCarthy, M., Ramage-Morin, P., Kaplan, M., Bernier, J., McFarland, B., & Oderkirk, J. (2011). Health Behavior Change Following Chronic Illness in Middle and Later Life The Journals of Gerontology Series B: Psychological Sciences and Social Sciences, 67B (3), 279-288 DOI: 10.1093/geronb/gbr103

When risk scores for heart attack really suck!

When risk scores really suck.

If you are a man aged 55 or younger, or a woman aged 65 or younger and have had your risk for heart attack and stroke profiled recently, chances are your doctor told you that you have a low risk. So you probably walked out of her clinic, seeing no reason to change your lifestyle. Now here I am, the party pooper, who is going to rain on your parade. How so?

Well, first off, those risk scores, like the Framingham score used in the US and the PROCAM score used here in Germany, typically look at things like cholesterol, blood pressure, blood sugar, smoking status, age and gender. From these values the scores determine your 10-year forward risk. Conventionally, if your chances of suffering a heart attack, stroke or any other of the cardiovascular diseases endpoints is less than 10% for that 10-year period, yours is categorized as low-risk. If it was in excess of 20%, you would be considered a high-risk person, and anything in between is called moderate risk. Now here is the problem: of the women who are hospitalized for their first heart attack at an age younger than 65, typically none would have scored as high-risk even a day before the event [1].  In fact, 95% of these women would have flown under the risk radar in the low-risk altitude.

How come, you may ask. To understand the reason you need to know how heart attacks and strokes happen. Most of them are the result of a blood clot being formed at the site of a ruptured plaque (those fatty streaks) in one of your arteries. Traveling downstream these clots may be dissolved or they may be not. If they get stuck some place downstream, blocking the supply of blood, and thereby of oxygen, to your heart or brain tissue, a heart attack or stroke occurs. But most plaque ruptures do not cause a heart attack or stroke. There is a large element of chance involved. Fact of the matter is, we can't really predict which plaques will cause a heart attack or stroke. We can't even say whether a stable or a so-called vulnerable plaque will still be stable or vulnerable in a few months down the line. They can change their status. Which means, even if your doctor was able to map all the plaques in all the arteries throughout your body, he still wouldn't be able to tell you exactly your risk. How much less accurate will his risk prediction be when he uses risk factors which just correlate somewhat with plaque burden, such as cholesterol? There you go.  

Which is why you should not look at 10-year risk, but at lifetime risk. For a woman that risk stands at roughly 40% once she has reached the age of 50 [2]. Men, by the way have a 52% risk at that age. But here is the kicker: being free of any of the risk factors (those of the Framingham or PROCAM variety) at that age, means a dramatically lower lifetime risk of 8% and 5% for women and men respectively.

So here you are. Your doctor has just sent you off with a low-risk assurance for the next 10 years, even though 2 of your risk factors are elevated. You walk out of his clinic with a strong sense of invulnerability and no real motivation to change your lifestyle and to get those two risk factors back into the green zone. That's why risk scores really suck. When they rain on your parade later on it's a lot worse than if I, the party pooper, do it right now. Don't you think?

1.           Akosah, K.O., et al., Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? Journal of the American College of Cardiology, 2003. 41(9): p. 1475-9.

2.           Lloyd-Jones, D.M., et al., Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.Circulation, 2006. 113(6): p. 791-8.