One of the topics that I have often thought about (especially in light of our seeming inability to develop zero-risk obesity drugs) is the problem of averages. Our entire medical philosophy of “evidence-based” medicine seems built on the “Gaussian” assumption that averages can reflect the true benefit (or risk) of a drug, when in real life (or medical practice) there is no such thing as the truly average patient.

Clearly, a drug that works in most cases may be entirely ineffective (or have rare but serious adverse effects) in a given patient. Similarly, a drug that is ineffective for most patients can potentially work miracles in a small set of individuals.

For those of you who like analogies, imagine wanting to treat every case of fever with penicillin. Yes, if you run your study during an epidemic of streptococcal infections, more people with fevers may respond than during other times. But even then you will need large numbers to cut through the “noise”, as many fevers will spontaneously resolve or continue unabated unto death (which is why we need a “control” group). Chances are, we may well find that treating all fevers with penicillin is not much better that placebo and we will likely nicely demonstrate that simply taking penicillin for fever has unacceptable individual risks (including deaths from anaphylactic shock). Clearly, penicillin should not be on the market given its potential for “abuse” by anyone who has a fever.

But as we take a closer look at the data we may find that while penicillin is not a great drug for everyone who comes down with a fever, there may be a subset of patients (strangely those who appear to have bacterial infections), in which penicillin does seem to sometimes work. Yes, some of these patients may also have severe anaphylactic responses, but on “average”, people with fever due to bacterial infections do seem to get better faster than people with other causes of fever.

As we look even more closely at the data it seems that even among those with bacterial infections not everyone is “average” – fever patients affected with a certain type of bacteria (interestingly those who stain positively with a certain dye) seem to respond well (albeit still with occasional anaphylactic responses), while those infected by non-staining bacteria (and even some of those that stain positive) seem entirely unresponsive.

You can see where I am going with this – as long as we treat fever as a uniform entity, our chances of finding a “cure” in a large randomized trial of patients presenting with fever is virtually zero unless we are dealing with a very common etiological cause of fever (as in a rare epidemic when most fevers in a population may just happen to be due to a penicillin-sensitive bug), or in a massive study that allows drilling down to meaningful subgroups in post-hoc analyses (purists will likely object to this no matter the size of the study).

In fact, our large randomized fever study will likely tell us that the risk/benefit of using penicillin to treat fever is entirely unacceptable (given that penicillin has the potential to kill) – clearly no regulator would ever consider allowing penicillin on the market, especially for a condition as common as fever. Imagine all the people “misusing” penicillin to treat their fevers – no benefit (on average) – huge risks (for individuals).

No doubt, a company hoping to develop penicillin as a new treatment for fever, better invest heavily into identifying the group of fever patients for whom penicillin does in fact work. Patients in whom penicillin is so effective that even with the occasional death from anaphylactic shock, the “average” benefit remains indisputable. Clearly, simply taking 10,000 cases of fever off the street and treating them all with penicillin is unlikely to convince any regulator on the planet that this drug belongs on the market.

For readers, who may perhaps argue that using penicillin for fever is a long stretch, I’d be happy to offer other analogies: try methotrexate for patients with malignancies, try allopurinol for patients with an inflamed joint, or try vitamin B12 injections for patients with anemia. While all of these treatments may well be highly effective in a subset of patients with these disorders, for the “average” patient with cancer, joint pain, or anemia, these treatments will harbor nothing but side effects.

So what about obesity? The notion that we can take the next best 10,000 people with excess weight off the street and treat them all with a given compound that will result in clinically meaningful weight loss with virtually no side effects is not only overly optimistic but also contrary to any current understanding of the complex nature of obesity.

From where do the companies developing these compounds get the notion that a compound that is indeed powerful enough to override one of nature’s most intricate and essential survival instincts, will be both safe and effective for the “average” person who happens to find himself in a state of positive energy balance?

What is the biological rationale for hoping to find a drug that is as effective in reducing emotional (hedonic) eating as it is in overeating due to true hunger (homeostatic overeating), or perhaps overeating in social settings (as in peer pressure)? And how should this compound work in the person where clearly the problem is not overeating but undermoving (perhaps from that back injury, asthma, or lack of time). Indeed, it would truly have to be a miracle drug if it could also override the hyperphagic response to a hypoglycemic agent or to an atypical antipsychotic drug.

If scientific rationale does not convince us, that obesity is a remarkably heterogeneous condition, let us simply look at the results of our clinical trials with antiobesity drugs. Yes, the average response is modest (indeed some people even gain weight in obesity trials), but that should hardly be a surprise. The real surprise (or is this expected?) is that there is often a subset of patients (perhaps as few as 15% of the entire study population), who do remarkably well, losing not twice, but three-times the amount of weight seen in the control group. Not only do these patients reap clear benefits, but strangely, they may even appear to tolerate the drug better than the rest. Are these patients “random” outliers or are these the very patients for whom this drug would truly be nothing short of a Godsend?

Regulators may well agree that such subgroups exist but would want to see data to support this. They may not care about the biological reason why these “super responders” respond so well, but would certainly want to know if there is a way that these patients can be identified (so as to reasonably limit the license to this population).

But predicting responders (as any prediction) can be a tricky business. Once we know that penicillin is only likely to control fever in people with gram-positive infections, we can certainly limit the use of penicillin to patients with evidence for such infections (or even better use actual resistance testing) – but when we have no such “rationale”, can we somehow still screen for responders?

What easier way to screen than to actually try the drug – albeit in a limited and controlled setting. If a drug is meant to produce weight loss but fails to do so, clearly it is not working and should be discontinued. Even the safest weight loss drug is unlikely to have any benefits in someone who does not lose or even continues to gain weight – in such a setting even the smallest risk will have an infinitely high risk/benefit ratio.

Fortunately, response to weight loss medications can be easily measured (on a simple office scale). All we need to ask are the following questions:

1) How long would it take to be reasonably sure that we are dealing with a “responder”?

2) What is the risk of exposing “non-responders” to this drug long enough to determine if they are indeed “non-responders”?

3) How likely will “non-responders” continue using the drug (despite not losing weight) thereby exposing themselves to unacceptable risk?

Most obesity experts will agree that the answer to the first question is probably 6-12 weeks. The answer to the second question will of course depend on the nature of the drug and its potential for serious (irreversible?) side effects with short-term treatment. The answer to the third question is, probably very few.

Interestingly, this is exactly the way most drugs are actually used in the real world, i.e. outside of the highly artificial construct of randomized double-blind clinical trials.

In my clinical practice I routinely start patients on drugs for any number of complaints and conditions and judging on my patient’s response (with regard to both efficacy and tolerability), I adjust the dose, or discontinue the drug altogether (often only to switch to the next available agent or running additional tests to confirm my diagnosis). Never in clinical practice would I (or my patients) consider continuing patients on drugs that have no demonstrable effect or precipitate unacceptable side effects (cost alone would prove a remarkable deterrent).

Denying approval for compounds that have the potential to deliver important benefits to even a subgroup of patients, simply with the argument that the “average” patient may not benefit and would therefore have an unacceptable risk/benefit ratio cannot be an ethical rationale for denying patients who could well benefit from such compounds.

Obesity has high risks – killing an estimated 300,000 Americans every year. For those with medically relevant obesity the only evidence-based option today is bariatric surgery (surprisingly safe but definitely not without risk). If only a subset of obese patients (15%?) could be effectively and safely treated with existing or emerging anti-obesity compounds, is the potential for misuse by those who should not be taking these compounds enough of an ethical argument to deny this treatment to those who do benefit?

For those who chose to misuse or abuse these compounds, where is the role of personal responsibility, which we so readily call upon to justify ridiculously lax gun or gambling laws? (Inability to enforce these laws has certainly not convinced courts or legislatures of the need to reverse their decisions)

On what legal precedents do regulators (and their advisors) base their recommendations to deny potentially safe and effective treatments to a few (for whom these treatments may well be safe and effective) in order to protect those who should clearly not be using these compounds in the first place?

If such compounds do exist, all I can say is, “restrictions, yes – denial, no”!

I firmly believe that as long as companies (and regulators) continue treating obesity as a homogeneous condition for which we can potentially find a drug that is both safe and effective for anyone with excess weight (irrespective of the cause), we will be unlikely to have safe and effective pharmacological treatments for ANY patients with obesity in the foreseeable future.

AMS
Ucluelet, BCYou can now also follow me and post your comments on FaceBook

As an enthusiastic supporter and user of public transit, I have long suggested that promoting the availability and use of public transportation could go a long way in promoting physical activity and fitness, especially among those who have little time, interest or energy to invest in recreational physical activity.

Simply put, if public transportation is the most efficient way to get from A to B, then more people will spend more time on their feet irrespective of any interest in or motivation for physical activity.

But can the use of public transportation really have a measurable impact on body weight?

This question was addressed by J MacDonald and colleagues from the University of Pennsylvania, who, in a paper just published in the American Journal of Prventive Medicine, examined the impact of light rail transit (LRT) use on BMI and physical activity.

Data were collected on individuals before (July 2006-February 2007) and after (March 2008-July 2008) completion of an LRT system in Charlotte, North Carolina and BMI, obesity, and physical activity levels were calculated for a comparison of these factors before and after LRT construction.

Data were adjusted for differences in baseline characteristics among LRT and non-LRT users.

Over the course of the study, the use of LRT to commute to work was associated with an average 1.18 reduction in BMI and an 81% reduced risk of becoming obese over time.

Obviously, body weight is only one possible benefit of being more active. It remains to be seen if the use of LRT (or other efficient modes of public transportation) may also help improve or prevent other conditions known to be positively associated with decreased physical activity including hypertension, dyslipidemia, diabetes, arthritis, depression, and perhaps even certain cancers.

Nevertheless, as the authors note, “The results of this study suggest that improving neighborhood environments and increasing the public’s use of LRT systems could provide improvements in health outcomes for millions of individuals.”

Thus costs for the construction and promotion of efficient public transit can potentially translate into very significant savings in health care costs (not to mention carbon footprint).

I, for one, can certainly attest to the fact that the recent expansion of the Edmonton LRT system to my neighborhood has markedly increased my number of daily steps (while actually saving time (and money) on my daily commute).

AMS
Edmonton, Alberta

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MacDonald JM, Stokes RJ, Cohen DA, Kofner A, & Ridgeway GK (2010). The effect of light rail transit on body mass index and physical activity. American journal of preventive medicine, 39 (2), 105-12 PMID: 20621257

Her Excellency Alexandra Volkoff, Canada's Ambassador to Sweden and Arya Sharma, Scientific Director of the Canadian Obesity Network

Since its inception in 2006, the Canadian Obesity Network has grown into an organisation that brings together over 4000 Canadian obesity researchers, health professionals, decision makers and other stakeholders interested in reducing the mental, medical and economic burden of obesity on Canadians.

As many of the problems faced by Canada are not unlike those faced by other countries and much of the Canadian research and experience in obesity prevention and management may well be applicable to tackling obesity in other countries, the Canadian Obesity Network has always sought to promote Canadian research beyond our borders.

This why, at the ongoing XI International Congress on Obesity in Stockholm, the Obesity Network partnered with the Canadian Embassy to Sweden to host a “Meet the Canadians” reception. This networking event, attended by well over 150 participants, provided a perfect opportunities for Canadians attending the conference to meet each other but also to interact with friends and collaborators from other countries.

In her welcome address, her Excellency Alexandra Volkoff, Canada’s Ambassador to Sweden (picture), highlighted the importance of the work that the Canadian Obesity Network is doing to address the obesity epidemic and emphasized the commitment of the Canadian Government to help build international partnerships and collaborations to reduce the global burden of obesity through excellence in obesity research and practice.

Judging by the many Obesity Network members attending and presenting at this World Conference, there is no doubt that Canadian obesity research is highly competitive, well respected and certainly relevant to the many issues related to the prevention, management and control of obesity.

AMS
Stockholm, Sweden

Anyone working in academia is well familiar with the slogan, “publish or perish”.

Indeed, the quantity and quality of scientific publication continues to be a major measure of academic achievement. But how relevant are these publications really? Research shows that the vast majority of publications appearing even in top journals often have little if any measurable impact on decision makers or policy.

Is this because the science is truly irrelevant or is the science largely ignored because it faces a world of non-scientists who do not understand its significance and simply couldn’t be bothered?

This is the topic of a most interesting book that I just finished reading.

Unscientific America: How Scientific Illiteracy Threatens Our Future, is a short text written by Chris Mooney and Sheril Kirshenbaum, which explores the roots and consequences of the increasing divide between what science reveals and a population that largely ignores these revelations.

As Mooney and Kirschenbaum point out,

“For every five hours of cable news, less than a minute is devoted to science; 46 percent of Americans reject evolution and think the Earth is less than 10,000 years old; the number of newspapers with weekly science sections has shrunken by two-thirds over the past several decades. Meanwhile, only 18 percent of Americans have even met a scientist to begin with; more than half can’t name a living scientist role model.”

But rather than simply blaming schools or parents or politicians or the media or an increasingly anti-intellectual public, the authors point a finger directly at the scientific community itself - a community that is clearly failing to make itself relevant or interesting to policy makers or the general public (who will ultimately determine what policy makers care about).

Not only do Mooney and Kirshenbaum deplore the fact that very few scientists have communication skills that allow them to effectively convey the relevance and importance of their work to “outsiders” but that “there are too few collaborations between scientists and journalists, screenwriters, politicians, and religious leaders”.

They quote Preston Manning, who argued that scientists need to “establish a relationship with the political community on grounds other than the milk cow - milking machine relationship” and not only reach out to politicians when they want research funding. Rather, they should establish long-term mulitdirectional relationships, where they are helping as much as they are being helped.

In terms of communicating science, Mooney and Kirshenbaum are also not very happy with science bloggers (to which I dare count myself). They point out that the vast majority of science blogs serve rather specialised audiences - often preaching to the converted and can hardly be considered part of mainstream discourse.

Indeed, the fact that today anyone can find any information supporting any view is exactly one of the main problems with the new media. Like-minded readers congregate to whatever media best represents their opinions or beliefs, thereby essentially eliminating the need for serious discourse, the key to true understanding of any issue.

The authors have several pieces of advise on how to address this scientific illiteracy. One solution may be to train a small army of ambassadors who can translate science’s message and make it relevant to the media, to politicians, and to the public in the broadest sense. Another may be to stoke a cultural change at academic institutions that will specifically reward scientists for their public outreach and communication endeavours - efforts that will hopefully make all of society more scientifically engaged.

Certainly a book all scientists should read.

AMS
Stockholm, Sweden

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As most smokers are well aware, smoking cessation is often accompanied by a variable amount of weight gain, and there is some evidence that some people (particularly young women) primarily smoke to control their appetite and weight.

Indeed, as blogged previously, the progress on fighting tobacco in the US may be eroded by the gains in obesity rates, as over the past 15 years, smoking rates in the US have declined by 20%, whereas obesity rates have increased by 48%..

So do policies that address tobacco consumption increase the prevalence of obesity?

This question was addressed by Anindya Sen and colleagues from the University of Waterloo, Ontrario, in a paper just published online in the journal Health Policy.

In this study, the researchers used the the substantial cross-province differences that exist between Eastern and Western Canada to estimate the effects of higher cigarette taxes on aggregate health region and individual level data from the 2003 and 2005 waves of the Canadian Community Health Surveys (CCHS).

According to their estimates, a 10% higher cigarette tax is correlated with a 4% lower rate of smoking but also a 4-5% higher prevalence of obesity. These findings were robust across several models that took into account various demographic variables and potential confounders.

The researchers conclude that health benefits from higher cigarette taxes and lower smoking rates may be partially offset by a corresponding increase in obesity levels.

However, given the tremendous negative impact of smoking on health, one would need to gain quite a considerable amount of weight to fully negate the many potential benefits (less heart disease, COPD, cancers, amputations) of smoking cessation.

Smoking cessation programs and anti-tobacco policies should probably actively promote measures to prevent excessive weight gain.

As blogged before, this may be easier said than done.

AMS
Edmonton, Alberta

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Sen A, Entezarkheir M, & Wilson A (2010). Obesity, smoking, and cigarette taxes: Evidence from the Canadian Community Health Surveys. Health policy (Amsterdam, Netherlands) PMID: 20570008