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The Key To Obesity Management Lies In The Science Of Energy Homeostasis

If there is one thing we know for sure about obesity management, it is the sad fact, that no diet, exercise, medication, not even bariatric surgery, will permanently reset the body’s tendency to defend and regain its body weight to its set point – this generally being the highest weight that has been achieved and maintained for a notable length of time.

Thus, any effective long-term treatment has to offset the complex neurobiology that will eventually doom every weight-loss attempt to “failure” (no, anecdotes don’t count!).

Just how complex and overpowering this biological system that regulates body weight is, is described in a comprehensive review by the undisputed leaders in this field (Michael Schwartz, Randy Seeley, Eric Ravussin, Rudolph Leibel and colleagues) published in Endocrine Reviews. Indeed the paper is nothing less than a “Scientific Statement” from the venerable Endocrine Society, or, in other words, these folks know what they’re talking about when it comes to the science of energy balance.

As the authors remind us,

“In its third year of existence, the Endocrine Society elected Sir Harvey Cushing as President. In his presidential address, he advocated strongly in favor of adopting the scientific method and abandoning empiricism to better inform the diagnosis and treatment of endocrine disease. In doing so, Cushing helped to usher in the modern era of endocrinology and with it, the end of organo-therapy. (In an interesting historical footnote, Cushing’s Energy Homeostasis and the Physiological Control of Body-Fat Stores presidential address was given in , the same year that insulin was discovered.)”

Over 30 pages, backed by almost 350 scientific citations, the authors outline in excruciating detail just how complex the biological system that regulates, defends, and restores body weight actually is. Moreover, this system is not static but rather, is strongly influenced and modulated by environmental and societal factors.

Indeed, after reading this article, it seems that the very notion, that average Jane or Joe could somehow learn to permanently overcome this intricately fine-tuned system (or the societal drivers) with will power alone is almost laughable (hats off to the very few brave and determined individuals, who can actually do this – you have climbed to the top of Mount Everest and decided to camp out there for the foreseeable future – I wish you all the best!).

Thus, the authors are confident that,

“The identification of neuromolecular mechanisms that integrate short-term and long-term control of feeding behavior, such that calorie intake precisely matches energy expenditure over long time intervals, will almost certainly enable better preventive and therapeutic approaches to obesity.”

Sadly, despite all we have learnt about this system, we are still far from fully understanding it. Thus, the canonical molecular/ cellular signaling pathway: LEP → LEPR → POMC, AgRP → PC → MC4R is just one pathway in a complex network of multiple interacting and sometimes redundant pathways that involve virtually every part of the brain.

Also, the effect of environmental factors appears to be far more complex than most people think. Thus,

“During sensitive periods of development, ontogenic processes in both brain and peripheral organs can be modified so as to match anticipated environmental conditions. Although many exposures during development could potentially predispose to obesity in adulthood, we focus here on two that some researchers think contribute to the secular trends in obesity: parental obesity and exposure to endocrine disrupting chemicals (EDCs).”

Throw in the role of gut bugs, infections, and societal factors, and it is easy to see why no simple solution to the obesity epidemic are in sight (let alone a range of effective long-term treatments like we have for most other common chronic diseases).

As for solutions,

“To be viable, theories of obesity pathogenesis must account not only for how excess body fat is acquired, but also for how excess body fat comes to be biologically defended. To date, the preponderance of research has focused on the former. However, we must consider the possibility that some (perhaps even most) mechanisms underlying weight gain are distinct from those responsible for the biological defense of excess fat mass. A key question, therefore, is how the energy homeostasis system comes to defend an elevated level of fat mass (analogous to the defense of elevated blood pressure in patients with hypertension). Answering this question requires an improved understanding of the neuro-molecular elements that underlie a “defended” level of body fat. What are the molecular/neuroanatomic predicates that help establish and defend a “set point” for adiposity? How do these elements regulate feeding behavior and/or energy expenditure, so as to achieve long-term energy balance? By what mechanisms is an apparently higher set point established and defended in individuals who are obese?” [sic]

Clearly,

“Given that recovery of lost weight (the normal, physiological response to weight loss irrespective of one’s starting weight) is the largest single obstacle to effective long-term weight loss, we cannot overstate the importance of a coherent understanding of obesity-associated alterations of the energy homeostasis system.”

There is much work to be done. Whether or not, in this climate of anti- and pseudo-science, funding for such fundamental work will actually be made available, is anyone’s guess.

@DrSharma
Edmonton, AB

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Alternate Day Fasting Is No Better Than Any Other Fad Diet

It seems that every year someone else comes up with a diet that can supposedly conquer obesity and all others health problems of civilization.

In almost every case, the diet is based on some “new” insight into how our bodies function, or how our ancestors (read – hunters gatherers (never mind that they only lived to be 35) ate, or how modern foods are killing us (never mind that the average person has never lived longer than ever before), or how (insert remote population here) lives today with no chronic disease.

Throw in some scientific terms like “ketogenic”, “guten”, “anti-oxidant”, “fructose”, or “insulin”, add some level of restriction and unusual foods, and (most importantly) get celebrity endorsement and “testemonials” and you have a best-seller (and a successful speaking career) ready to go.

The problem is that, no matter what the “scientific” (sounding) theories suggest, there is little evidence that the enthusiastic promises of any of these hold up under the cold light of scientific study.

Therefore, I am not the least surprised that the same holds true for the much hyped “alternative-day fasting diet”, which supposedly is best for us, because it mimics how our pre-historic ancestors apparently made it to the ripe age of 35 without obesity and heart attacks.

Thus, a year-long randomised controlled study by John Trepanowski and colleagues, published in JAMA Internal Medicine, shows that alternate day fasting is evidently no better in producing superior adherence, weight loss, weight maintenance, or cardioprotection compared to good old daily calorie restriction (which also produces modest long-term results at best).

In fact, the alternate day fasting group had significantly more dropouts than both the daily calorie restriction and control group (38% vs. 29% and 26% respectively). Mean weight loss was virtually identical between both intervention groups (~6 Kg).

Purists of course will instantly critisize that the study did not actually test alternative-day fasting, as more people dropped out and most of the participants who stayed in that group actually ate more than prescribed on fast days, and less than prescribed on feast days – but that is exactly the point of this kind of study – to test whether the proposed diet works in “real life”, because no one in “real life” can ever be expected to be perfectly compliant with any diet. In fact, again, as this study shows, the more “restrictive” the diet (and, yes, starving yourself every other day is “restrictive”), the greater the dropout rate.

Unfortunately, what counts in real life is not what people should be doing, but what people actually do. The question really is not whether or not alternate-day fasting is better for someone trying to lose weight but rather, whether or not “recommending” someone follows an alternate-day fasting plan (and them trying to follow it the best they can) is better for them. The clear answer from this study is “no”.

So why are all diets the same (in that virtually all of them provide a rather modest degree of long-term weight loss)?

My guess is that no diet (or behaviour for that matter) has the capability of fundamentally changing the body’s biology that acts to protect and restore body fat in the long-term. Irrespective of whether a diet leads to weight loss in the short term and irrespective of how it does so (or how slow or fast), ultimately no diet manages to “reset” the body-weight set point to a lower level, that would biologically “stabilize” weight loss in the long-term.

Thus, the amount of long-term weight loss that can be achieved by dieting is always in the same (rather modest) ballpark and it is often only a matter of time before the biology wins out and put all the weight back on.

Clearly, I am not holding my breath for the next diet that comes along that promises to be better than everything we’ve had before.

My advice to patients is, do what works for you, but do not expect miracles – just find the diet you can happily live on and stick to it.

@DrSharma
Edmonton, AB

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Use of Low Calorie Diets in Type 2 Diabetes

Managing weight in patients with type 2 diabetes (most of who have significant overweight or obesity) is always challenging, not least because many medications used to treat diabetes can also promote weight gain.

Now, a paper by Judy Shiau and colleagues from the University of Ottawa, in a paper published in the Canadian Journal of Diabetes, present the results of a retrospective cohort study (1992 to 2009) of weight, glycemic control and diabetes medications changes in 317 patients with obesity and type 2 diabetes at 6 months on a low-calorie diet program.

The program (week 1 to week 26) included mandatory weekly group sessions led by a dietitian, behaviour therapist or exercise therapist. All patients received OPTIFAST ®900 as full meal replacements (MR) starting at week 2. Patients consume 4 MR shakes per day for a total of 900 kcal per day, a regimen that is high in proteins (90g/day) and moderate in carbohydrates (67 g/day). Patients with initial body mass indexes (BMIs) of 33 kg/m2 or higher commited to 12 weeks of full MRs, while patients with initial BMIs below 33 started with 6 weeks of full MRs and the option to increase to up to 12 weeks of full MRs. Once patients completed their full MR regimen, there was a 5-week transition period to regular food, typically followed by a maintenance diet, as determined in a one-on- one dietitian counselling session.

As glycemic control improved with weight loss, anti-diabetes medications were adjusted or discontinued, thereby stopping any weight-gain-promoting medications first.

As the authors note,

“At 6 months, both groups had lost 16% of their weight, and the decreases or discontinuations of medications were 92% sulfonureas, 87% insulins, 79% thiazolidinediones, 78% alpha-glucosidase inhibitors, 50% meglitinides, 33% dipeptidyl peptidase-4 (DPP-4) inhibitors and 33% metformin. At 6 months, compared with baseline, A1C levels improved significantly and at 6 months, 30% of patients were no longer taking diabetes medications and had significantly better percentages of weight loss compared with those taking medications (18.6% vs. 16%; p=0.002).”

Thus, this paper shows that, a low-calorie meal replacement program can substantially improve glycemic control and reduce the need for anti-diabetes medications.

Unfortunately, as participants were transitioned to community care at 6 months, little is know about how long these effects last.

Nevertheless, with the increasing availability and use of weight-neutral or even weight-reducing anti-diabetes medications, one may expect that some of these effects can be sustained for relevant periods of time.

@DrSharma
Edmonton, AB

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What Do Health Professionals Need To Know About Obesity?

Achieving and maintaining competencies is an ongoing challenge for all health professionals. But in an area like obesity, where most will have received rather rudimentary training (if any), most health professionals will likely be starting from scratch.

So what exactly must you expect of a health professional involved in the care of individuals living with obesity.

This is the subject of a white paper on “Provider Competencies for the Prevention and Management of Obesity“, developed with support from the Robert Wood Johnson Foundation.

The panel of authors led by Don Bradley (Duke) and William Dietz (George Washington) included representatives from over 20 national (US) professional organisations.

The competencies expected cover the following 10 topics:

Competencies for Core Obesity Knowledge
1.0 Demonstrate a working knowledge of obesity as a disease

2.0 Demonstrate a working knowledge of the epidemiology of the obesity epidemic

3.0 Describe the disparate burden of obesity and approaches to mitigate it

Competencies for Interprofessional Obesity Care
4.0 Describe the benefits of working interprofessionally to address obesity to achieve results that cannot be achieved by a single health professional

5.0 Apply the skills necessary for effective interprofessional collaboration and integration of clinical and community care for obesity

Competencies for Patient Interactions Related to Obesity
6.0 Use patient-centered communication when working with individuals with obesity and others

7.0 Employ strategies to minimize bias towards and discrimination against people with obesity, including weight, body habitus, and the causes of obesity

8.0 Implement a range of accommodations and safety measures specific to people with obesity

9.0 Utilize evidence-based care/services for people with obesity or at risk for obesity

10.0 Provide evidence-based care/services for people with obesity comorbidities

Some of the topics include further subtopics that are deemed especially relevant.

Thus, for e.g., topic 6.o, regarding communication, includes the following sub-competencies:

6.1 Discuss obesity in a non-judgmental manner using person-first language in all communications

6.2 Incorporate the environmental, social, emotional, and cultural context of obesity into conversations with people with obesity

6.3 Use person- and family-centered communication (e.g., using active listening, empathy, autonomy support/shared decision making) to engage the patient and others

Similarly, topic 7.0, regarding the issue of weight bias and discrimination, includes the following sub-competencies:

7.1 Describe the ways in which weight bias and stigma impact health and wellbeing

7.2 Recognize and mitigate personal biases

7.3 Recognize and mitigate the weight biases of others

This is clearly a forward-thinking outline of competencies that we will hopefully come to expect of most health professionals, given that virtually every health professional, no matter their specialty or scope of practice, will likely be called upon to care for people living with obesity.

The full document can be downloaded here.

@DrSharma
Edmonton, AB

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GLP-1 Analogue Semaglutide Appears Promising in Phase 2 Study

Readers may by now be familiar with the GLP-1 analogue liraglutide, which has now been approved at the 3 mg dose (Saxenda(R)) for long-term obesity treatment in a growing number of countries.

Now, Novo Nordisk, the maker of liraglutide, announced preliminary results from their long-acting GLP-1 analogue semaglutide, suggesting a rather remarkable ~14% weight loss in a one-year double-blind placebo controlled dose-finding study.

According to the company’s press release,

In the trial, 957 people with obesity were randomised to treatment with doses of semaglutide between 0.05 to 0.4 mg/day or placebo. Liraglutide 3.0 mg/day was included for comparison. Approximately 100 people were included in each active treatment arm in combination with diet and exercise. All people in the trial were treated for 52 weeks followed by a 7-week follow-up period.

Furthermore,

From a mean baseline weight of around 111 kg and a body mass index of approximately 39 kg/m2, a weight loss up to 17.8 kg was observed after 52 weeks of treatment with semaglutide. This corresponded to an estimated 13.8% weight loss compared to the weight loss of 2.3% achieved by diet, exercise and placebo alone, with all treatment arms adjusted for people discontinuing treatment in the study. The results from the liraglutide 3.0 mg treatment arm were broadly in line with previously reported data.

Side effects were mainly reported as gastro-intestinal, as expected from this class of hormone analogues.

Clearly, if borne out by the final publication and confirmed in larger and longer studies, semaglutide may well prove to be even more effective than liraglutide.

It may be worth noting, that the ~14% weight loss reported in this trial comes very close to the mean ~15% weight loss seen with adjustable gastric banding, a bariatric surgical technique that is now increasingly seen as obsolete due to long-term complications and loss of effectiveness.

I’m guessing it’s now on to Phase 3 for this promising anti-obesity drug.

@DrSharma
Edmonton, AB

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

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