Readers will recall, that once-weekly injections of the novel long-acting GLP-1 analogue semaglutide was recently shown (in patients with type 2 diabetes) to result in a rather impressive weight loss.
Now, a phase II dose-finding study comparing various oral doses of semaglutide to subcutaneous injections in patients with type 2 diabetes was just published in JAMA.
The 26-week trial with 5-week follow-up included around 600 patients with type 2 diabetes and insufficient glycemic control using diet and exercise alone or a stable dose of metformin were randomized to once-daily oral semaglutide of 2.5 mg (n = 70), 5 mg (n = 70), 10 mg (n = 70), 20 mg (n = 70), 40-mg 4-week dose escalation (standard escalation; n = 71), 40-mg 8-week dose escalation (slow escalation; n = 70), 40-mg 2-week dose escalation (fast escalation, n = 70), oral placebo (n = 71; double-blind) or once-weekly subcutaneous semaglutide of 1.0 mg (n = 70) for 26 weeks.
Mean change in HbA1c level from baseline to week 26 decreased with oral semaglutide (dosage-dependent range, −0.7% to −1.9%) and subcutaneous semaglutide (−1.9%) and placebo (−0.3%);
Significant reductions were also seen in body weight with both oral (dosage-dependent range, −2.1 kg to −6.9 kg) and subcutaneous semaglutide (−6.4 kg) vs placebo (−1.2 kg)>
Adverse events (largely consisting of mild to moderate gastrointestinal events) were as expected and relatively comparable between the treatment arms.
Although this was a diabetes study, these findings clearly hold promise for the further development of an oral formulation of semaglutide for the obesity indication.
Disclaimer: I have served as a consultant for Novo Nordisk, the maker of semaglutide.
The following is a guest post from my Australian colleague Dr. Georgia Rigas, who reports on the recent recognition of obesity as a disease by the Royal Australian College of General Practice (RACGP).
Last week, the Royal Australian College of General Practice (RACGP) President, Dr Seidel recognised obesity as a disease. The RACGP is the first medical college in Australia to do so.
This was exciting news given that we have just observed World Obesity Day a few days ago.
According to the Australian Bureau of Statistics1, over 60% of Australian adults are classified as having overweight or obesity, and more than 25% of these have obesity [defined as a Body Mass Index (BMI) ≥30] (ABS2012). Similarly in 2007, around 25% of children aged 2–16 were identified as having overweight or obesity, with 6% classified as having obesity (DoHA 2008). These are alarming statistics.
The recent published BEACH data for 2015-162, showed that the proportion of Australian adults aged 45-64yo presenting to GPs has almost doubled in the last 15+ years. Worryingly the numbers are predicted to continue rising, with 70% of Australians predicted to have overweight or obesity by 2025. Embarrassingly, the BEACH data also indicated that <1% of GP consultations centred around obesity management.
So obviously what we, as GPs have been doing..,or rather not doing…isn’t working!
The RACGP’s General Practice: Health of the Nation 2017 3report found Australian GPs identified obesity and complications from obesity as one of the most significant health problems Australia faces today and will continue to face in coming years as the incidence of obesity continues to rise.
But what are we doing about it?…. I think the answer is evident… clearly not enough!
Thus, we can only hope that this announcement by the RACGP will have a ripple effect, with other medical colleges in Australia and then the Australian Medical Association following suit.
So what does this mean in practical terms?
For those individuals with obesity (BMI ≥30) with no “apparent” comorbidities or complications from their excess weight…[though you could argue they will develop (if not already) premature osteoarthritis of the weight bearing joints…..] would be eligible for a chronic care plan [government subsidized access to a limited number of consultations with allied health services] given the chronic and progressive nature of the disease.
It also highlights the need for GPs to start screening ALL patients in their practice-young and old;
- for children their parameters need to be plotted on a BMI-for-age chart;
- for adults BMI & waist circumference, taking into account their ethnicity (as different cut- offs for different ethnic groups) and physical activity levels (if they are muscular or not) are important
This powerful statement should help clear any ambivalence.
Why is there a therapeutic inertia when it comes to treating people with obesity?
People with obesity suffer significant degrees of stigma, discrimination and weight bias and as a result may be reluctant to access healthcare. Today, we are giving these patients a voice.
As health care professionals, let’s not forget that the health message needs to change from “lose weight” to “gain health” in recognition that obesity is about more than body weight.
In closing, to effectively and equitably work towards reducing obesity in our communities, we need a balanced combination of both individual and public health measures. This media release by the RACGP shows their commitment to both the primary prevention and the treatment of this life- threatening disease, to ensure better health outcomes and quality of life for all Australians.
Dr Georgia Rigas, MBBS FRACGP
SCOPE certified obesity doctor
Bariatric Medical Practitioner
Why do doctors weigh people? Because, very early in medical school, we are taught that body weight is an important indicator of health.
While one may certainly argue about the value of a single weight measurement at any point in time (especially in adults), there is simply no denying that weight trajectories (changes in body weight – up or down) can provide important (often vital) clinical information.
Let’s begin with the easiest (and least arguable) situations of all – unintentional weight loss.
Among all clinical parameters one could possibly measure, perhaps non should be as alarming as someone losing weight without actively trying. In almost every single instance of “unintentional” weight loss, the underlying problem needs to be found, and more often than not, the diagnosis is probably serious (cancer is just one possibility).
As with any serious condition, the earlier you detect it, the sooner you can do something about it, therefore, the more often you weight someone, the more likely you will detect early “non-intentional” weight loss.
The contrary situation (un-intentional weight gain) is as important. When someone is gaining weight for no good reason, one needs to look for the underlying cause, which can include everything from an endocrine problem to heart failure.
On the other hand, weight stability, is generally a sign that things are probably “under control”, as they should be when energy homeostasis works fine and people are in energy balance.
Perhaps my own obsession with weighing people comes from my work in nephrology, where we obsess about people’s “dry weight” and use weight as a general means to monitor fluid status. The same is true for working with patients who have heart failure.
Note for all of the above, that while a single (random) weight measurement tells you very little (almost nothing) about anybody’s health status, unexplained changes in body weight are one of the most useful and important clinical signs in all of medicine. Obviously, to plot a trajectory, one has to start somewhere, which means that every patient needs to have a “baseline” body weight recorded somewhere in their chart. While this value may not provide any valuable information, the next one may.
This is why every single patient needs to be weighed at least once in a clinical setting.
As you will imagine, both the context and interpretation of serial weight measurements becomes most challenging in the setting of obesity management.
For one, there is no greater challenge than to suspect underlying “un-intentional” weight loss in someone who is actively trying to lose weight. When “suddenly” a weight loss strategy that was providing modest results “starts working” – all alarm bells should go off. Also, if weight loss is much better than “predicted” it is time to take a serious second look at what’s happening. Furthermore, you need to watch out for patients who are doing far better than expected (even after bariatric surgery) – it takes a keen clinical mind to watch out for weight loss that appears “too good to be true” (even if the patient is delighted to see the pounds drop off).
Also, in the obesity management setting, weight stability is an important clinical indicator. In someone at their maximum weight, it tells me that the patient is not actively gaining weight, which by definition means that the patient is in caloric balance – remember, the first sign of “success” in obesity management is when the patient stops gaining weight.
In someone, who has already lost weight (in the context of obesity management), weight stability means that the patient’s efforts are continuing (here weight stability is a means to monitor “control”) – weight regain means that the patient may have to re-engage in weight control efforts or (more often) that something has come up in that person’s life that is “sabotaging” their efforts and may need to be identified and addressed (e.g. lost a job, change in medication, depression, etc.). Again, the earlier you identify a “relapse”, the earlier you can intervene.
Finally, in someone attending an obesity clinic, who continues gaining weight, you can be sure that the underlying cause of weight gain has not yet been fully identified or addressed. In other words, the disease is not “controlled” and continues to “progress”.
Thus, patients must be aware, that asking not to be weighed (usually out of shame or embarrassment) derives their clinician of important and possibly “vital” information about their health status.
Again, while a single weight (or BMI) says very little about a patient’s health, changes in body weight (up or down) is a vital sign that should prompt further clinical investigation and possibly intervention.
None of this has anything to do with the fact that people can very well be healthy over a wide range of body shapes and sizes.
It also does not mean that we should take a “weight-centric” approach to obesity management – all of the usual HAES arguments remain valid, even when you regularly ask your patient to step on the scale.
Recording a weight trajectory should be no more “judgemental” than recording a fever chart in a patient with an infection – everything lies in the context and interpretation of the data.
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]
“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.
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.