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Liraglutide 3 mg For Obesity: The SCALE Trial

saxendaThis week, the New England Journal of Medicine publishes the results of the SCALE Trial, a 56-week randomised controlled trial of liraglutide 3.0 mg vs. placebo (both groups got advice on diet and exercise), on weight loss and other metabolic variables.

The study, that enrolled about 3,700 subjects (70% of who completed the trial), showed greater clinically relevant weight loss in participants treated with liraglutide than with placebo.

Overall, at 56 weeks,

– 2 in 3 individuals on liraglutide achieved a 5% weight loss (compared to 1 in 4 on placebo).

– 1 in 3 individuals on liraglutide achieved a 10% weight loss (compared to 1 in 10 on placebo).

– 1 in 6 individuals on liraglutide achieved a 15% weight loss (compared to fewer than 1 in 20 on placebo).

The adverse effect profile was as expected from a GLP-1 analogue (mainly gastrointestinal and gall bladder related issues).

While liraglutide 3.o mg has now been approved as an anti-obesity agent in the US, Canada and Europe, its key downsides will likely be cost and the fact that it consists of a once-daily injection.

Obviously, as with any obesity treatment, discontinuation will likely result in weight regain (which is not unexpected, given that obesity, once established, becomes a chronic disease).

While in the US, where there are now 4 novel prescription medications for obesity, liraglutide 3.o mg will be the only novel anti-obesity drug available in Canada – a rather sorry state of affairs for those who need medical treatment for this condition.

Where exactly liraglutide will establish itself in the treatment of obesity in clinical practice remains to be seen (time will tell) – but for some patients at least (especially the high-responders), it will hopefully offer a useful adjunct to behavioural treatments.

@DrSharma
Edmonton, AB

Disclaimer: I have received honoraria for consulting and speaking from Novo Nordisk, the makers of liraglutide

 

 

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Do Preferences In Diet Matter For Weight Loss

sharma-obesity-fat-dietingAs regular readers are well aware, obesity is a chronic disease which simply means that any treatment you decide to pursue needs to be one you can stick with in the long-term (this applies as much to your diet as it does to taking an anti-obesity drug or, for that matter having surgery – when the treatment stops the weight comes back!).

That said, it would be easy to assume that if you chose (or otherwise have a say) in the kind of diet you think will help you manage your weight, you’d a) lose more weight and b) be more likely to keep it off.

As a randomised controlled study by William Yancy Jr. and colleagues from Duke University Medical Center, Durham, North Carolina, published in the Annals of Internal Medicine, neither of these assumptions may be true.

The researchers randomised 207 participants to two groups – a choice group in which participants had the choice of going either on a low-carbohydrate (less than 20 g/day) or low-fat diet (less than 30% energy from fat).

The non-choice group was not given this choice but were randomly assigned to either of these diets. Both groups were provided with group and telephone counseling for 48 weeks.

Of the 105 choice participants, 58% chose low-carb and 44% chose low-fat – 83% completed the study – and lost on average 5.7Kg.

Of the 102 non-choice participants, 52 % were assigned to low-carb and 48% to low-fat – 86% completed the study – and lost on average 6.7 Kg.

Of note, the actual reported intake of carb in the low-carb groups ranged between 45-80 g of carbs per day (down from about 200 g/day) while fat intake in this group increased from about 40 to 55% of total energy); In the low-fat group, actual fat intake, fell from about 40% at baseline to about 35% on the diet.

There were no difference in dietary adherence, physical activity or quality of life.

This study illustrates that whether or not you get to chose your preferred diet or not doesn’t matter – what does is that you stick with it.

Or as the authors put it,

“The double-randomized preference design of our study allowed us to determine that preference did not meaningfully affect weight loss. Moreover, the range of estimated weight differences between groups in the 95% CIs does not contain a clinically meaningful difference in favor of the choice group.”

Both findings may not be exactly what one may have predicted – which is exactly why we need these types of studies.

@DrSharma
Edmonton, AB

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How Your Gut Tastes What You Eat

sharma-obesity-guthormones2If you thought that the only senses that determine the palatability of food are your sense of taste and smell, you may be wrong.

It turns out that we have a rather sophisticated sensing mechanism in our gut that senses the composition of our diet and interacts with the brain to regulate our appetite and food intake.

Just how exactly this gut “nutrient-sensing” system works, is reviewed by Sophie Hamr and colleagues from the University of Toronto in a paper published in Current Diabetes Reports.

As the authors point out,

“…the gastrointestinal (GI) tract is anatomically positioned to provide initial feedback following a meal via detection of incoming nutrients and relaying signals to the brain and peripheral tissues to prevent excess energy intake and circulating nutrients…..This, coupled with the vast neural and humoral connectivity of the gut to other important sites of energy regulation, such as the brain, allows the gut to effectively relay information to the rest of the body about the size and composition of an incoming meal.”

Each nutrient (fats, carbohydrates, protein) interacts with specific sensory and signal transduction mechanisms in the gut.

Animal studies show that exposing the gut to certain nutrients (for e.g. by tube feeding) can stimulate or suppress feeding behaviour making animals chose or avoid certain foods. Often these effects can persist for days or even weeks, well beyond the time course of a single meal.

Furthermore, these effects appear to be largely dependent on the presence of specific nutrients rather than on the actual nutritional or energy state of the animal.

“…these evidences lend notion for the intestine to sense specific nutrients (i.e., lipid and carbohydrate) at specific concentrations, rather than calories, in an effort to drive further food consumption.”

The authors point out that changes in how the gut senses nutrients may well explain how bariatric surgery works to reduce appetite and change food preferences.

No doubt, a better understanding these mechanisms and the molecular mechanisms involved could lead to novel dietary or pharmacological interventions to prevent or treat obesity.

@DrSharma
Edmonton, AB

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Post-Weight Loss Fat Gain in US Rangers

army-rangersAnd finally, to conclude this week’s discussion of evidence to support the notion that weight cycling predicts weight (fat) gain especially in normal weight individuals, I turn back to the paper by Dulloo and colleagues published in Obesity Reviews, which quotes these interesting findings in US Rangers:

“…U.S. Army Ranger School where about 12% of weight loss was observed following 8–9 weeks of training in a multi-stressor environment that includes energy deficit. Nindl et al. reported that at week 5 in the post-training recovery phase, body weight had overshot by 5 kg, reflected primarily in large gains in fat mass, and that all the 10 subjects in that study had higher fat mass than before weight lost. Similarly, in another 8 weeks of U.S. Army Ranger training course that consisted of four repeated cycles of restricted energy intake and refeeding, Friedl et al. showed that more weight was regained than was lost after 5 weeks of recovery following training cessation, with substantial fat overshooting (∼4 kg on average) representing an absolute increase of 40% in body fat compared with pre-training levels. From the data obtained in a parallel group of subjects, they showed that hyperphagia peaked at ∼4 weeks post-training, thereby suggesting that hyperphagia was likely persisting over the last week of refeeding, during which body fat had already exceeded baseline levels.”

Obviously, association (even in a prospective cohort) does not prove causality or, for that matter, provide insights into the physiological mechanisms underlying this observation.

All we can conclude, is that these observations in US Rangers (and the other studies cited in Dulloo’s article) are consistent with the notion that weight loss in normal weight individuals can be followed by significant weight gain, often overshooting initial weight.

Incidentally, these findings are also consistent with observational studies in women recovering from anorexia nervosa, famine, cancer survivors and other situations resulting in significant weight loss in normal weight individuals.

Certainly enough evidence to consider a work of caution against “recreational” weight loss, especially in individuals of normal weight.

@DrSharma
Edmonton, AB

ResearchBlogging.orgDulloo AG, Jacquet J, Montani JP, & Schutz Y (2015). How dieting makes the lean fatter: from a perspective of body composition autoregulation through adipostats and proteinstats awaiting discovery. Obesity reviews : an official journal of the International Association for the Study of Obesity, 16 Suppl 1, 25-35 PMID: 25614201

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Did Dieting Make You Fat? Blame Your ‘Proteinstat’

Skeletal muscle

Skeletal muscle

Yesterday, I posted on the intriguing finding (now documented in 15 prospective studies) that dieting can make you fat – especially if you start out with a normal weight.

In the paper by Dulloo and colleagues published in Obesity Reviews, the authors attribute part of this effect to the so far elusive “proteinstat” – a system, similar but different from the “adipostat” – that is designed to protect your lean body mass.

As the paper nicely delineates, the problem with post-dieting weight regain is that the fat comes back first but that the drive to eat does not cease till you have also regained the lost lean body mass (muscle).

It appears as though there are two complimentary biological systems that regulate weight regain.

The better known system is the “adipostat” that worries about protecting and restoring fat mass – the neuroendocrine players include leptin and perhaps other signals derived from fat tissue that signal fat stores to the brain. This system works (primarily through dropping metabolic rate but also through effects on appetite) to very quickly and effectively restore the depleted fat mass after dieting.

The less known system is the “proteinstat”, that apparenty worries about restoring lean body mass. The system works slower than the “adipostat” but continues its activity (often reaching its peak) even after all the lost fat has been regained and you are back to your original weight. In fact, it continuous working (primarily through appetite and cravings) till lean body mass is restored, even if this means gaining even more fat in the process.

In their careful reanalysis of starvation studies, Dulloo and colleagues also come up with an explanation why this process of “weight overshoot” results in more gain the skinnier the individual is to begin with.

“…the lower the initial adiposity, the greater the proportion of energy mobilized as body protein (referred to as P-ratio) during weight loss. The steep part of the negative exponential curve lies between 8–20% body fat, and a shift from the upper to the lower values in this range, generally considered to reflect a ‘normal’range of adiposity for men living in affluent societies, results in 2.5- to 3-fold increase in the P-ratio; the latter constitutes a proxy of the fraction of weight that is lost as FFM since protein belongs to the FFM compartment. This extremely high sensitivity of the P-ratio with regard to the initial body composition emphasizes the critical importance of even small differences in the initial percentage body fat in dictating the individual’s energy-partitioning characteristic and, hence, the pattern of lean and fat tissue deposition during weight loss and subsequent
weight regain, in turn, determining the extent of fat overshooting.”

In other words, lean dieters are far more susceptible to mobilising energy (and thus losing mass) from their muscle than from their fat stores, resulting in a much greater likelihood of overshooting their original weight.

Eventually, as these dieters get fatter with every diet cycle, they get less and less susceptible to this effect, which matches well with the finding that dieting is a far better predictor of long-term weight gain in people with lower fat percentages than in those who already have overweight or obesity).

As for exactly how the “proteinstat” works, much remains unclear. Early work focussed on the notion that certain amino acids may serve as signals of protein stores, however, now work is focussing on the far more plausible theory that some of the over 100 molecules now known to be secreted by skeletal muscle (myokines) may play a role in this system.

Certainly a topic that will be interesting to watch develop over the coming years.

@DrSharma
Calgary, AB

ResearchBlogging.orgDulloo AG, Jacquet J, Montani JP, & Schutz Y (2015). How dieting makes the lean fatter: from a perspective of body composition autoregulation through adipostats and proteinstats awaiting discovery. Obesity reviews : an official journal of the International Association for the Study of Obesity, 16 Suppl 1, 25-35 PMID: 25614201

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