Exercise in a Pill

Physical activity has numerous beneficial effects on mental and physical health. With the reduced need for physical activity to ensure our basic needs (utilitarian activity), it is increasingly up to the individual to compensate by consciously engaging in recreational (non-utilitarian) activity, generally referred to as exercise.

Numerous barriers exist to engaging in exercise, including time limitations, lack of motivation, and pain or injury. Researchers have therefore pursued the idea of being able to mimic the beneficial effects of exercise with the help of drugs that induce the same gene-expression patterns and metabolic changes seen with exercise.

In yesterday's issue of CELL, Vihang Narkar and colleagues from the Salk Institute, La Jolla, CA report on their findings that the combination of an orally active AMPK agonist with a PPARβ/δ agonist can induce metabolic genes and dramatically enhance running endurance in sedentary mice. Furthermore, the PPARβ/δ agonist in combination with exercise synergistically induced fatigue-resistant type I fibers and mitochondrial biogenesis, ultimately enhancing physical performance

These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

Obviously, treatments that work in mice may not be as effective or safe in humans. Furthermore, the researchers did not actually demonstrate that the induction of metabolic genes and increased endurance actually improves the health of the mice.

But the results are promising and certainly a major step towards developing a pharmacological alternative to exercise.

In the meantime, however, there is no alternative to being as physically as you can. As Angelo Tremblay, presenting today to the students at the CON Obesity Boot Camp emphasized, increased participation in physical activity is a key characteristic of individuals who lose weight and manage to keep it off.

AMS
Duschesnay, Quebec

Clip art licensed from the Clip Art Gallery on DiscoverySchool.com

Addiction Drug for Obesity?

This week, Orexigen, a biopharmaceutical company in La Jolla, CA, announced that it won a patent covering its obesity drug Contrave.

Contrave actually consists of a sustained-release version of two older drugs: bupropion, which is currently used as an antidepressant and smoking cessation aid, and naltrexone, which is used for opioid addiction and alcoholism. Contrave is currently undergoing Phase III trials for obesity and the company hopes to file for FDA approval in late 2009.

Why is Contrave, a combination of two drugs that have been around for a while, novel?

Firstly, there is no doubt that depression is a common problem in treatment-seeking obese individuals, many of whom are "self-medicating" with food - i.e. eating highly palatable foods that increase serotonin levels in the brain to improve their mood (albeit temporarily). There is indeed evidence that buproprion may help some people lose weight.

Secondly, many patients with obesity will be the first to admit that for them eating is akin to an addiction - a statement that is not surprising given that opioid-mediated reward mechanisms may play an important role in the hedonic aspects of ingestive behaviour and that this behaviour may well involve exactly the same neurocircuitary that plays a role in other addictions.

So the idea of combining two drugs that address depression and addiction, respectively, is certainly one with merit and may well prove to be highly effective in obese patients in whom depression and hedonic eating are significantly contributing to hyperphagia.

I have not seen data from these trials and have no relationship with Orexigen. I do however, like the concept of this drug and can't wait to try it on some of my patients, who I can well imagine would benefit.

Obviously, we need to await the results of the Phase III program and certainly need to very carefully look at the side effect profile of the two drugs used in combination.

But I do think that this could indeed be a useful drug for some patients battling obesity - although it is unlikely to be the "magic bullet" for everyone.

Remember, obesity is a highly complex and heterogeneous disorder and there is absolutely no reason why any one treatment should work for all.

AMS
Edmonton, Alberta

Recognising Barriers Key to Obesity Management?

Most people fail to keep off any weight they lose.

This may in part be attributable to the substantial barriers that undermine long-term obesity management strategies.

In a paper I wrote with my colleagues Marina Mauro, Valerie Taylor and Sean Whartan just out in the European Journal of Internal Medicine, we highlight the importance of recognizing and addressing these barriers before embarking on obesity treatments.

Common barriers include lack of recognition of obesity as a chronic condition, low socioeconomic status, time constraints, intimate saboteurs, and a wide range of comorbidities including mental health, sleep, chronic pain, musculoskeletal, cardiovascular, respiratory, digestive and endocrine disorders.

Furthermore, medications used to treat some of these disorders may further undermine weight-loss efforts and promote weight regain.

Unfortunately, lack of specific obesity training of health professionals, attitudes and beliefs as well as coverage and availability of obesity treatments can likewise pose important barriers.

Health professionals need to take care to identify, acknowledge and, if possible, address these barriers in order to increase patient success as well as compliance and adherence with treatments.

Failure to do so may further promote the sense of failure, low self esteem and low self efficacy already common among individuals struggling with excess weight.

I have little doubt that addressing treatment barriers can save resources and increase the prospect of long-term success.

Identifying and discussing barriers with patients has to be a routine part of obesity care.

AMS
Edmonton, Alberta

Rimonabant for CAD - it's Not Just About the Heart

The heart is an important organ. Heart disease kills millions every year. Abdominal obesity is an important risk factor for heart disease. Medical treatments for obesity should help reduce cardiovascular risk.

Not surprisingly, several large studies are examining the effect of anti-obesity drugs, both old (e.g. sibutramine) and new (e.g. rimonabant), on cardiovascular morbidity and mortality.

This week, one such study reported on its results. STRADIVARIUS, a double-blind randomized controlled trial with over 800 patients conducted at 112 centres in North America, Europe and Australia was designed to determine whether treatment with 20 mg of the CB-1 antagonist rimonabant (an anti-obesity drug now available in many countries but not in Canada or the US) would reduce progression of coronary artery disease (CAD) in patients with abdominal obesity and the metabolic syndrome. Progression of CAD was measured by intravascular ultrasound (IVUS) before and after 12 to 18 months of treatment.

On average, patients on rimonabant lost 4.5 Kg and as many cms off their waistlines. HDL cholesterol, triglycerides and HbA1c levels (in patients with diabetes) improved as expected. Although the primary endpoint (change in percent atheroma volume) was not different between rimonabant and placebo, other measures of atherosclerosis appeared to change favourably. Rimonabant was well tolerated although (as expected) there were more psychiatric and gastrointestinal side effects and discontinuations in the rimonabant group.

So why, with the significant reduction in weight and risk factors were the results not more positive? The authors speculate that this may have been because patients were already receiving effective treatment for CAD (e.g. 80% of patients were on statins). Therefore showing incremental benefits of adding rimonabant would have been difficult.

The real question to ask, however, is whether or not influencing heart disease is indeed the best and most important use of an anti-obesity drug. We already have a multitude of effective medications to reduce the progression of heart disease. When used according to current guidelines, these agents can indeed markedly reduce the risk of cardiovascular disease (obviously, this risk will never be zero, no matter how good the treatment).

So is reduction in heart disease really the great "unmet need" when it comes to obesity treatment? As a bariatrician, I would say NO!

Yes, while preventing heart disease (or its progression) is perhaps one benefit of treating obesity, I can think of many other benefits that are relevant to patients battling obesity-related comorbidities for which we currently have no effective medical treatments.

My short list would include sleep apnea, osteoarthritis, hepatic steatosis, polycystic ovary syndrome, infertility, pseudo tumor cerebri and many more. Sure, these conditions may not sound as dramatic as heart disease and may be less likely to kill you, but for the people who have these problems, these conditions are very real, distressing and affecting their quality of life. If obesity treatments can help alleviate these conditions, perhaps even just limit exacerbation by helping curb further weight gain, a lot would be won.

Remember, obesity is a chronic disease with virtually 100% rezidivism. It significantly affects many aspects of mental, physical and socioeconomic health. Effective treatments for obesity are required irrespective of whether or not they also help reduce heart disease.

Unfortunately, pharma companies, regulators and payors appear obsessed with the cardiometabolic consequences of obesity and fail to see the urgent need for treating obesity-related comorbidities beyond heart disease.

So, while the results of STRADIVARIUS are nice, I'd be far more interested in whether or not rimonabant reduces obesity-related comorbidities for which we have no alternative treatments - at least that's where I'd put my research money if I had any say in the matter.

AMS
Edmonton, Alberta

Alberta: No Country for (Fat) Old Men

Last Saturday, apart from participating in the Super Size Me event, I also spoke at the 2nd Annual Endocrine Day for Family Physicians, organized by our division of endocrinology.

At this meeting Donald Morrish from our division presented a neat little update on Androgen Deficiency in the Aging Male (ADAM). This is what happens when guys' testosterone levels drop to below 10 mmol/L with age.

Typical symptoms include sexual dysfunction (decreased libido and erection problems), osteoporosis, gynecomastia and infertility often accompanied by fatigue and low-energy levels.

What makes this issue interesting to the bariatrician is the fact that male hypogonadism is also associated with loss of lean body mass and accumulation of abdominal fat.

Indeed, there is ample evidence to support the idea that testosterone substitution in hypogonadic men will increase muscle strength and decrease visceral fat. Without substitution, trying to lose weight, build muscle or finding the energy to exercise may be impossible.

Importantly, while these benefits have been shown for replacement doses, there is no proven benefit of using supra-physiological or "pharmacological" doses of testosterone.

Similarly, while replacing low levels of testosterone is probably without risk, the use of testosterone in males with normal testosterone levels is potentially problematic.

Unfortunately, the diagnosis of male hypogonadism is not straightforward. The most commonly used assay for testorsterone measures total testosterone, i.e. both free (active) testosterone and that bound to sex homone-binding globulin (SHBG). The latter, however, is commonly decreased in obesity, resulting in a falsely low level of total testosterone.

So to really know if someone with obesity who also has low total testosterone levels truly has hypogonadism, one has to order the more expensive bioavailable or free testosterone.

This test, at least in Alberta, is not covered by the public health system and will cost the poor fellow around $45 - by no means a trivial sum.

Furthermore, once you decide to substitute testosterone (of which the most convenient gel form is also not covered by Alberta Blue Cross), you again have to monitor the free-testosterone levels at regular intervals - overall a venture that may cost around $1500 a year - definitely not cheap.

I guess Alberta is no Country for Fat Old Men.

AMS

Opening Eyes to Obesity Management

Yesterday I had the privilege of speaking to around 400 dietitians (and other health professionals) at Capital Health's 12th Annual Regional Nutrition and Food Services symposium.

After my presentation, many of the attendees came up to personally thank me for such an "eye opening" take on obesity.

This of course is surprising, given that you'd think that, if anyone, dietitians would be the ones with the greatest knowledge and understanding of the issues around obesity management.

So I asked the folks who came up to me about what exactly they found so "eye opening".

The answers were pretty much the issues that I have so often blogged about:

- The problems with clinically defining exactly what obesity is and who really needs treatment (no, BMI is not the best criterium!).

- The fact that obesity is a chronic disease that requires life-long treatment - a condition for which we have no cure (with a few rare exceptions).

- The rather limited long-term success of lifestyle (3-5% sustained weight loss), pharmacological (5-15% sustained weight loss) and even surgical (20-30% sustained weight loss) treatments (and even these results only if you continue the treatments!).

- The fact that while maintaining energy balance appears simple (energy in must equal energy out), energy regulation is highly complex.

- The concept that pharmacotherapy and surgery are not a "substitute" for lifestyle change but in fact only work when patients really do make substantial changes to their lifestyle (click here for a previous entry on this topic).

So, to readers of my blog, nothing really new or enlightening - yet, "eye opening" to many in the audience.

I guess we have a long way to go before all health professionals (especially physcians!) understand these basic concepts of obesity management.

If only I could speak to 400 health professionals everyday!

AMS

Antipsychotics and Weight Gain

It is no secret that medications commonly used to treat psychosis can lead to remarkable weight gain. This is particularly true of the second generation antipsychotics clozapine (Leponex, Clozaril) and olanzapine (Zyprexa), but the mechanisms leading to weight gain are poorly understood.

In a recent study Kluge and colleagues from the Max Planck Institute of Psychiatry in Munich, ramdomised 30 patients with schizophrenia, schizophreniform, or schizoaffective disorder in a double-blind, parallel study comparing abnormal eating behavior using a standardized scale to clozapine and olanzapine.

In both treatment groups, there was a significant increase in cravings and in binge eating, whereby the rate of these effects was somewhat higher with olanzepine. Clinical improvements in psychiatric symptoms was comparable.

What the study does not disclose is what one could possibly do to help patients avoid weight gain. The evidence that "lifestyle" interventions are effective in preventing this weight gain is marginal at best. A recent randomized study published in JAMA showed some benefit of prescribing metformin alone or in combination with lifestyle advice.

An earlier double-blind placebo-controlled study in 37 patients on olanzepine showed greater weight loss with sibutramine (Meridia, Reductil) over 12 weeks than on lifestyle alone.

Amantadine, in an even smaller randomised placebo-controlled study in 21 patients, was at least somewhat effective in limiting olanzapine-induced weight gain.

Clearly, addressing weight gain in patients, who need effective antipsychotic medications remains challenging at best.

AMS