Today, the New England Journal of Medicine publishes the results of the Sibutramine Cardiovascular OUTcome (SCOUT) trial - a study in over 10,000 high-risk individuals with excess weight.

Over the past eight years, I have had the privilege of being on the Executive Steering Committee of this largest ever randomised controlled trial of obesity treatment.

The SCOUT trial examined the effect of the serotonin and norepinephrine reuptake inhibitor sibutramine plus lifestyle intervention versus placebo and lifestyle intervention alone in 10,744 overweight or obese subjects, 55 years of age or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both, who successfully completed a six-week run-in phase on sibutramine.

The primary end point was the time from randomisation to the first occurrence of a primary outcome event (nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death).

Unfortunately, individuals, randomised to the sibutramine arm of the study, despite signifiicantly greater weight loss, had a 16% higher relative risk (11.4% vs. 10.0%) for a primary endpoint. This was largely accounted for by higher rates of nonfatal myocardial infarction and nonfatal stroke were 4.1% and 2.6% in the sibutramine group and 3.2% and 1.9% in the placebo group.

Fortunately, there was no increased risk of fatal events.

Given that the SCOUT participants were essentially an “off-label” high-risk population (in fact largely patients, in whom the current label specifically does not recommend the use of this agent) , one needs to be careful in extrapolating these findings to “on-label” patients, who tend to generally have much lower risk profiles.

In fact, as a colleague once aptly put it, prescribing sibutramine, may perhaps not be unlike prescribing vigorous exercise, which can potential kill someone with pre-existing heart disease, but may well be quite beneficial and well-tolerated in younger low-risk individuals.

Apart from the subjects in the SCOUT trial being an essentially “off-label” populations, it is perhaps also worth noting that in this trial, patients were advised to continue on sibutramine irrespective of wether or not they actually lost any weight.

While this was feature of the study design was meant to test for potential, non-weight loss related benefits of sibutramine, this is certainly very different from clinical practice, where it is most unlikely that anyone taking a weight-loss drug would continue taking it without at least some discernible weight loss.

Obviously, without the benefits of weight loss, simply taking a drug that can (in the same manner as other SNRIs) increase heart rate and blood pressure, certainly may ultimately cause more harm than benefit.

However, before concluding that sibutramine itself (as suggested by an accompanying editorial) is a “flawed” drug, it would be important to consider the alternatives - which for most patients in reality means continuing weight gain with the eventual prospect of facing bariatric surgery (currently widely seen as the only effective treatment for obesity).

While “hard” endpoints are clearly relevant and important in the long-term, my clinic is full of patients who desperately need help in the short term, especially given their failure, despite best efforts, to control their weight with diet and lifestyle alone. They are clearly more concerned about their back pain, their sleep apnea and their poor quality of life than they are of dying of heart disease somewhere in the remote future.

Fortunately, in clinical practice it is relatively easy to predict both weight loss response as well as any unacceptable increases in blood pressure or heart rate within the first weeks of starting treatment with sibutramine. Indeed, the SCOUT trial did not reveal any unexpected or irreversible “side effects” of this compound - both the increase in heart rate and any increase in blood pressure is quickly reversed after stopping the drug.

As blogged recently, given the heterogeneity of obesity, I neither expect to see 100% of my patients respond to any given drug, not do I expect everyone to tolerate a given substance. Even if a new treatment for obesity turns out to be safe and effective for only 15% of obese patients, we are still talking about millions who would stand to benefit from such a treatment.

Yes, there is always a potential for “misuse” in that people who should not be taking a given drug may chose to do so. Unfortunately, I doubt that there will ever be an anti-obesity drug that will be safe enough to be widely misused or abused.

As much as we may have a responsibility to prevent the wrong people from using treatments that may potentially harm them, we have a far greater responsibility of making treatments that work accessible to those for whom they may clearly have a favourable risk-benefit ratio.

Let us not forget that for many patients battling obesity, the current choices are either drowning in a mire of essentially ineffective and unregulated “weight loss” products or ultimately opting for the far riskier path of obesity surgery.

AMS
Chicago, IL

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Disclosure: I have received consulting and speaking honoraria from Abbott Laboratories, the makers of sibutramine.

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

Although, in the end I spent less than 24 hrs in the Emirates, one of the highlights of attending the 1st International Abu Dhabi Diabetes Conference, was the opportunity to once again hear David Cummings (Seattle) speak about how bariatric surgery can lead to the remission of type 2 diabetes. Cummings’ talk certainly provided plenty of food for thought on my long flight back to Canada.

As outlined in a newly released Diabetes Surgery Position Statement published in the latest issue of the Annals of Surgery, surgical approaches may well prove to be the treatment of choice in carefully selected patients with poorly controlled type 2 diabetes and a BMI greater than 30.

While the authors of the Statement emphasize the need for more clinical trials to investigate the future role of surgery in diabetes treatment, they also call for further investigations on the mechanisms of surgical control of diabetes (which are far from being fully understood).

Although weight loss itself clearly plays a significant role in the reversal of diabetes generally seen with bariatric surgery, with gastric bypass surgery, this reversal of diabetes often precedes the weight loss and there are likely neuroendocrine consequences to allowing food to bypass the duodenum that may substantially affect glucose metabolism (including regeneration of pancreatic beta-cells).

Thus, a better understanding of exactly how gastrointestinal surgery “cures” diabetes, will hopefully also open new avenues for pharmacological treatments that can mimic the effects of surgery in these patients.

Indeed, certain gut-hormones, which are known to be dramatically affected by gastric bypass surgery (e.g. GLP-1), have already been shown to have a beneficial effect both on diabetes and weight management (e.g. liraglutide).

Health professionals who want to learn more about this topic should consider attending the upcoming First Canadian Summit Metabolic Surgery for Type 2 Diabetes to be held in partnership with the Canadian Obesity Network and the Canadian Diabetes Association at the Hôtel Le Centre Sheraton, Montréal, May 6-7, 2010.

To watch a recent episode of 60 Minutes on CBS, which features interviews with Cummings and others discussing the surgical approach to type 2 diabetes, click here.

Very much appreciate hearing from my readers on their thoughts regarding whether or not diabetes surgery (vs. lifelong medications or injections) will significantly change how we treat diabetes in the future.

AMS
Edmonton, Alberta

Of course, obesity is associated with a wide range of health problems like high blood pressure, diabetes, arthritis, or reflux disease, all of which may all require pharmacological treatment. But this is not what this post is about.

Rather, this post is actually about the question whether or not larger patients need higher doses of medications to have an optimal treatment effect.

This topic was recently discussed by Matthew Falagas and Drosos Karageorgopoulos in a Lancet article that specifically addresses the issue of dose adjustments for antimicrobial agents in larger patients.

As the authors point out, body size is routinely considered in the optimization of drug therapy in oncology, anaesthetics and pediatrics. However, there remains a paucity of data on the optimal dosing of pharmacological agents for most of the drugs we use in clinical practice.

Thus, although regulatory agencies regularly demand special pharmacokinetic studies in children, elderly prople and patients with renal or hepatic impairment, no such studies are demanded for obese or even severely obese patients.

Requiring such studies would at least make theoretical sense as, conceivably, obesity can affect drug absorption, distribution, metabolism and clearance. Furthermore, it is obvious that body composition can particularly affect the disposition of lipophilic compounds. Obese patients are also likely to have comorbiditiesthat can affect these parameters (e.g. fatty liver disease) and are much more likely to be on multiple medications that can make drug-drug interactions problematic.

In short, as pointed out by Falgas and Karageorgopoulos the one-size-fits-all strategy for antimicrobial agents (and other drugs?) may well be outdated and require much more consideration than has been given to this issue in the past.

AMS
Winnipeg, Manitoba

Calories are the currency of weight management and any weight loss diet has to offer fewer calories than the body needs.

However, the means by which this caloric deficit is best achieved remains an area of continuing debate. While the proponents of ketogenic low-carb diets cite the greater ease of lowering weight, proponents of low-fat diets extol the putatively greater benefits on lipid profiles.

Nevertheless, previous studies have clearly shown that in the end both strategies lead to the same amount of weight loss, even if the low-carb approach may initially seem more effective.

This observation is once again confirmed in a new study by William Yancy Jr and colleagues from the Veterans Affairs Medical Centre, Durham, NC, published in the latest issue of the Archives of Internal Medicine.

In this study 146 overweight or obese outpatients (mean age 52 yrs) were randomized to either a ketogenic low-cab diet (initially <20 g of carbohydrate daily) or the lipase inhibitor orlistat (120 mg TID) combined with a low-fat diet (<30% energy from fat, 500-1000 kcal/d deficit) over 48 weeks.

Of the initial participants, 79% completed the low-carb arm whereas 88% completed the orlistat plus low-fat diet. Weight loss was similar between the groups, with participants losing around 9% of their initial body weight on either diet.

While the low-carb diet appeared to have a more beneficial impact on blood pressure, the orlistat low-fat combination appeared to have a greater beneficial impact on LDL-cholesterol.

However, in the end it is probably fair to say that both approaches led to more or less similar improvements in body weight and related risk measures, showing once again that this is probably not so much about which diet is more effective as it is about which diet works best for you.

Thus, in clinical practice it is likely that some patients will find it easier and preferable to severely restrict their carb intake, while others may find it easier to reduce their calories from fat by taking orlistat and reducing the fat in their diet.

The bottom line in both case is that the benefits will only persist as long as the participants stay on their respective diets or treatments. This makes it even more critical that patients chose the strategy that works best for them and that they are most likely to stay on in the long term.

Remember, neither diet is likely to “cure” obesity. As with all obesity treatments, when the interventions stop the weight comes back.

AMS
Edmonton