Thursday, July 1, 2010

The Trouble with Medications

One recent set of headlines noted that an experimental, cutting-edge drug for the difficult-to-treat disease hepatitis C isn't looking good for FDA approval because there's evidence it can harm patients without much helping them. That's terrible news for hepatitis C sufferers, of course, but most of us might just shrug, figuring that's exactly the sort of outcome we might well expect from many and perhaps most unproven, high-tech treatments that are undergoing trials. What the public is much less aware of is that the same dubious benefit-to-risk situation applies to many of the drugs that are already widely prescribed. In just the past few days we've read headlines about how the diabetes drug Avandia, which has been taken by more than a million people, has now been strongly linked by big studies to potentially fatal heart disorders and strokes. And also making the news is a smaller study that suggests testosterone gel--increasingly commonly prescribed to older men to counter some of the debilitating effects of aging, including loss of bone density, muscle mass, mobility, energy and libido--may be strongly linked to heart disorders, at least in much older men with low mobility.

This isn't just some small run of bad luck for the drug world. These sorts of problems are inherent to the very nature of drugs. Our bodies function via chemical "pathways" in which a vast number of proteins made by our genes interact with each other in ways so staggeringly complex that scientists struggle mightily to identify small pieces of the picture. When you take a drug, the hope is that it will go in and interrupt or boost some isolated part of a pathway that's contributing whatever disorder you may be suffering from. But disorders can rarely be neatly pinned down to a simple pathway, which means there isn't a clean target for the drug, which means the drug isn't likely to hit the problem head on. What's more, everyone has different genes, and even when we have the same relevant genes they may be turned "on" or "off" in different ways in different people, so that our pathways our different, which means that even when a drug is somewhat effective in one person it might not be so in another. Even worse, the drug is almost certainly affecting other pathways that are important to our health, with the effects rippling through the body in ways that may well cause harm. These basic problems are why we've seen a stream of much-hyped, widely used drugs yanked from the market after years, leaving behind a trail of people who weren't much helped, or of people who suffered or even died from the drugs. Vioxx is probably the best-known example from the past several years, but recent headlines have listed many others.

Indeed, it would be miraculous if a drug could go in, completely solve a problem, and do nothing else--virtually no drugs have ever been found that pull that trick off. Instead, the vast majority of our drugs have much messier effects on us: they sort of help some people, hurt others, and don't do much of anything for yet others. Even established, major drugs don't work on 40% to 75% of people, according to a 2005 review paper in The New England Journal of Medicine, and the variation in effectiveness and risk of side-effects tends to be much greater for newer, less-proven drugs. The picture gets even worse when you're talking about patients who are on multiple drugs, which can react with each other in any number of ways that are rarely well understood and often altogether unstudied. We don't get all this from the findings of most studies, because they tend to report averages, and are often presented in a way that make it sound as if a drug can do a lot for you, with only some chance of causing you problems. That may be sort of true, but there's really no way of getting around the fact that for most drugs you're rolling the dice to some extent as to whether the drug is going to help or hurt, if it does anything at all. There's hope genetic tests will eventually boost the odds further in your favor, but right now the claims you hear in the news that this is happening today is mostly hype, with just a few exceptions.

I want to make it clear I am in no way advocating pressuring your doctor to take you off any of your drugs--doctors admit in surveys to often succumbing to patient pressure on some drug decisions even if they don't think the decision is medically best for the patient--and I most certainly don't want anyone stopping drugs on their own. But there's no reason why you shouldn't ask your doctor to explain in more detail how likely a drug is to help, how likely it is to hurt, and why he thinks it's worth it. By the same token, you might want to know what applicable drugs she's decided aren't right for you, and why. Why shouldn't you be involved in a decision that essentially involves placing a bet on risks and benefits to your health? I always bow to my doctor's judgment, but she's willing to explain how she's arrived at it, and she's interested in getting my input when it's a matter of weighing the odds, as is usually the case with medications.

Sunday, June 27, 2010

Breakthrough School Anti-Obesity Study Proves...Little?

If you want a wonderful illustration of the paucity of clear information with which many and possibly most health studies provide us, and in particular how hard it is to wring any sort of credible insight out of weight-loss studies, look no further than the study currently making headlines by claiming that it proved the effectiveness of school programs designed to reduce obesity.

The USA Today report on the study kept it really simple: "The health interventions significantly lowered body mass index (BMI) in children in the 85th percentile or more. Overweight or obese kids in intervention schools were 21% less likely of being obese by the end of 8th grade. The program also lowered average levels of fasting insulin and the number of students with a waist at or over the 90th percentile in intervention schools."

But the HealthDay report provided some additional information: "....The program failed to reduce the overall numbers of overweight and obese schoolchildren--those numbers fell by 4 percent over three years whether the 42 middle schools in the study had such initiatives or not, the researchers report.... [and] children from both types of schools had the same average blood sugar levels and the same percentage of students with elevated blood sugar."

OK, so let's review: The interventions made a big difference with overweight kids--but didn't make the kids much less overweight. And the interventions reduced the risk of diabetes--but didn't prevent the high blood sugar levels that are the main indicator of diabetes or pre-diabetic conditions. Got that?

Here's what apparently happened. The schools that had the interventions saw their initially overweight kids become on average very slightly less overweight over the course of the study--just enough of a drop, it seems, to push many of them from being just heavy enough to be classified as overweight to just missing being heavy enough to be classified as overweight. Voila! Not much reduction in weight (compared to height) for the overweight kids, but a significant drop in the number of them that were "officially" overweight. The interventions did little or nothing to keep kids who weren't initially overweight from becoming overweight. And there was almost no difference between what happened in the schools that had the interventions and the schools that didn't--in both schools, there was a very slight drop over the course of the study in the kids' weight (compared to height).

As for the diabetes risk, the kids in the intervention schools saw slightly lower levels of insulin in their blood, which is generally associated with a lower diabetes risk. But it's a less important indicator than blood sugar levels, which weren't improved in the intervention schools. That's a great example of how scientific findings get muddled and often outright derailed by the choice of what gets measured in a study. (It's a problem I discuss at more length in an article in the July/August 2010 issue of Discover Magazine.)

Aside from the confusing and somewhat misleading way these results were presented in the press release, and made worse in some media accounts--it seems to me an honest presentation would have simply stated up front that the interventions didn't seem to offer any clear evidence that the interventions worked--there were complicating issues in the way the study was conducted. For one thing, the intervention schools not only made changes to the food available to the kids, but it also required longer and more intense physical activity. Yes, most of us (including me) believe these two factors go hand in hand when it comes to reducing obesity. But it may be that one of these factors has a much bigger effect than the other, and it is probably the case that some schools will find it much easier to implement only one, and not the other. So studies need to try to tease these two apart. But the bigger problem, I think, is that the schools that didn't get the official interventions were given money to make whatever changes they felt like making to their nutrition and fitness programs. Who knows what these schools did with the money? We don't even know what we're comparing here.

I certainly believe we have to come up with school-based approaches to reducing the astonishingly high child obesity rates, and I applaud any effort to study how that might be done. Unfortunately, this study's results seem to join the long train of obesity study findings that cast little light on the subject. Presenting the findings in a way that makes it sound as if a marvelous breakthrough was achieved only makes things worse.

Monday, June 21, 2010

Why We Keep Questioning Exercise and 'Healthy' Eating

Newsflash: Exercise is good for your health. So is cutting down on high-fat meats, and on sugar and refined carbs such as white flour and white rice. Are you surprised? I'm not, personally, but it sounds as if a lot of people out there are finding these notions hard to believe, because we keep seeing health headlines that announce the latest study to discover that following these straightforward and generally well-accepted suggestions lowers the risks of various diseases, and of obesity.

Why do studies keep pounding these points home, when most people who actually care what studies have to say on these questions (as most people in America probably do not) have long since come to believe they've heard enough to make up their minds? Well, for one thing, that's how science is supposed to work--you keep validating theories with new tests, because the new tests may be better than the old ones, and might turn up different answers or at least new twists on them. And the accumulated results from many studies give scientists a much better handle on what's really going on. (The far bigger problem in science is that the vast majority of published research isn't validated at all, but that's a different story.)

Not only that, but the fact of the matter is that every so often an at least fairly credible study turns up evidence that suggests these standard healthy habits may not do as much for us as we'd like to think, and may even hurt. Thus there was the recent scientific review that suggested there is little solid evidence that any of the recommended lifestyle and nutritional habits lower the risk of Alzheimer's, even though we've been hearing that they do for years. There are studies that, in violation of what virtually everyone who has lost weight and kept it off knows, have found that exercise doesn't make any difference in controlling weight, a claim transmitted without doubt or qualification by former U.S. FDA commissioner David Kessler in his best-selling book on obesity. There are studies that find that eating a lot of saturated fat is just fine (these are pushed by the Atkins diet fanatics, of course), and others that conclude people would be thinner and healthier if they loaded up every morning on a high-carb breakfast. More than one study has found that being overweight may help you live longer.

So what's up with all that? Probably several things. First of all, bear in mind that scientists themselves have recognized (as I've documented at length elsewhere) that even most prestigiously published medical research is refuted within a few years. Research is hard enough when done impeccably, but it is in fact plagued with surprising levels of sloppiness, bias, fudging and other distorting shenanigans. So no results should be surprising--someone, somewhere will manage to screw a study up and get exciting but false results that some perfectly good journal will be thrilled to publish. In addition, different researchers who are supposed to be studying the same thing often end up measuring very different things in very different ways, and in very different sorts of people. Thus one study might conclude that a certain diet lowers the risk of, say, diabetes while another concludes it does not--simply because one of the studies measured blood-sugar levels in healthy patients while the other measured deaths from diabetes-related complications in very ill patients. (These measurement mismatches may be part of the problem with the studies that find obesity can be protective--it seems to prove so only for older patients and those with extensive heart disease, perhaps because old or sick people who are thin face greater risks from nutritional shortages than from the slower-acting ravages of obesity, or so it has been speculated.)

But there's an even more basic reason why we shouldn't be surprised that studies conflict on the healthfulness of nutrition and habits. There are thousands of factors that come into play when it comes to the ways various nutrients, habits and other environmental factors affect us, and they interact in a complex web that science may not yet have barely begun to unravel. Scientists try to tease the roles of individual factors out in their studies, but rarely can they honestly claim to have succeeded. (And let's not even get started here on the fact that they often base their claims on animal studies.)

All of these challenges conspire to distort study results and further confuse an already confusing picture. At least with exercise, satured fat and refined carbs there's a reasonably strong consensus of evidence, if not an unblemished one. That's why I'm going to keep exercising, and limiting saturated fat and refined carbs. I'm not fully confident any of that will do much for me, but at least I know I'm playing the odds.

Sunday, June 13, 2010

Do Blood-Pressure Pills Cause Cancer?

Blood-pressure pills appear to be linked to higher risks of cancer, according to a big review study making headlines. Should these results be at least a little worrisome to you if you're on one of these medications? In my opinion, yes--it's worth discussing with your doctor. (Please don't stop taking your pills on your own.) This study has many of the earmarks of more trustworthy research. It's a meta-study, which means it looked at the results from several previous studies, so that if some of the studies were troubled there's still some hope the results from the better studies will partly compensate for those problems. The studies were randomized, controlled trials, which means the people in them were randomly assigned to either take the medication in question or not take it, which can eliminate a lot of the problems studies run into. (I'm oversimplifying, but that's the basic idea.) And the studies were large, totaling some 60,000 patients, so there shouldn't be as big a chance for statistical flukes as there would be in small studies. None of these characteristics guarantee reliable findings, but they can all help.

It's worth noting that some articles describing this new study report that the study found that people on the drugs have a one percent higher risk of getting cancer. But other articles say the findings indicate risks go up on average about 10 percent, and for lung cancer a whopping 25 percent. The seeming contradiction here is due to the media's ongoing, near-complete and deeply problematic failure to specify and make clear the difference between absolute risk and relative risk. When your absolute risk of contracting a disease goes up by, say, ten percent, it means that, for example, if your risk of the disease was 14 percent, it is now 24 percent (14 plus 10), a big difference. When your relative risk goes up by ten percent, then if it was 14 percent, it is now around 15 percent (14 plus ten percent of 14)--not such a big difference. So in this example, an increase in relative risk of about 10 percent translates to an increase in absolute risk of a mere 1 percent. Research institutions typically want the public to be impressed with the importance of their results, so they often emphasize to the press relative risk, which is a generally misleadingly high number. But in this case--perhaps because there is concern that people on blood-pressure pills will overreact and stop taking them--there seems to be more interest than usual in reporting the change in absolute risk, which tends to be a very low number. Assuming you don't carry any special risk factors for lung cancer (such as smoking), you only have a tiny chance of getting it, and if you add on the apparent increased risk from blood-pressure pills, you now have a slightly less-tiny chance of getting lung cancer. Still, your chances of getting cancer of any type aren't so tiny, and a one percent increased absolute risk is nothing to sneer at. A percentage here, a percentage there, and pretty soon you're taking years off your life.

If you read about the study, you might note that even though the study found an increased risk for blood-pressure-pill takers of getting cancer, it didn't find an increased risk of them dying from it. Unfortunately, you shouldn't take this as reassuring. Most cancer studies fail to convincingly link increased risk factors to mortality, usually simply because it tends to take people many years to die of cancer (if they do die from it, that is), and studies usually don't go on long enough to follow people to their graves. (That's another reason, by the way, that researchers love running studies on mice instead of people--they're conveniently short-lived. We humans can be annoyingly enduring, from a medical-research point of view.)

Talk to your doctor about it. It may be that if you were just on the borderline of high blood pressure but have special risks for cancer, she may want you off the pills. But if your doctor feels your risks from uncontrolled high blood pressure outweigh the possible slightly increased risks of cancer turned up by this study, I'd trust him. In the unlikely chance your doctor doesn't know what you're talking about when you ask about this study, I myself would tell him that I'd be happy to sit there and wait while he looked the study up.

Tuesday, June 8, 2010

WHO Knew If Flu Was True?

Two recently released European reports have raised the possibility that scientists who helped fuel world fear of an H1N1 flu crisis were motivated by ties to drug companies enriched by the ensuing rush to stockpile medications. The reports, which were from credible parties, including a Council of Europe committee and the British Medical Journal, noted that several of the World Health Organization scientists behind that agency's pressuring of governments to take dramatic action in response to the flu had received consulting or other fees from the drug companies, but that WHO hadn't bothered to identify these potential conflicts of interest. (Though the scientists in question had previously identified these ties in research-journal papers). With H1N1 turning out to fall far short of the devastating pandemic WHO and others predicted, many of the world's governments have ended up with vast unused stores of antiviral and other medications snatched up at WHO's urging.

There's no evidence that the scientists ginned up the warnings in order to channel sales to drug companies that had been good to them, and it seems unlikely that's the case. Scientists widely agreed there was plenty of reason to fear that H1N1 could become widespread and deadly. And we surely want our scientists, institutions and governments to err on the side of caution in these matters. It may even be that the rapid action taken by governments at WHO scientists' prodding was at least partly why H1N1 appears to have been something of a dud, so that the wasted drugs are in a way a sign of WHO's competence rather than its failure. (WHO actually continues to warn there's still a real danger of H1N1 getting out of hand.)

Still, science is supposed to be tough on biases, and especially blatant conflicts of interest. It has long been standard to insist that scientists openly and clearly state any ties they have to any corporations when there is any chance that their work could be seen as benefiting those corporations. But there's little question that conflict of interest remains a big problem in medical research. A 2003 Journal of the American Medical Association review of conflict-of-interest meta-studies involving some 67 conflict-of-interest studies and 398 other research reports confirmed a strong correlation between industry sponsorship and positive findings. (I provide sources in Wrong for that last and the following points).  And the problem may be worse than it looks, because companies often disguise that they are behind certain findings by paying university researchers to put their names to studies actually conducted and written up by the companies--so-called "ghost authorship," a problem that infects about three-quarters of industry-backed drug trials, one study found According to another study, at least 30 percent of published medical researchers have been in a potential conflict-of-interest situation, and as few as 2 percent of researchers fully disclosed that fact. Every single one of the 170 psychiatric experts contributing to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) used to diagnose psychiatric disorders had financial ties to manufacturers of psychiatric drugs.

Remember this situation every time you hear of research that concludes a drug works well, or a new type of test is effective, or, yes, an infectious disease is about to wreak havoc on the world unless governments buy up all the treatments they can get their hands on. That's not to say the specific research is likely to be wrong--but it's another reason why we need to be wary consumers of research conclusions.