I have been practicing medicine long enough to remember treating hypertension before there were ACE inhibitors or ARBs. I vividly remember training in a lipid clinic before the introduction of statins. Many will recall managing type 2 diabetes before we had TZDs, DPP4 inhibitors, SGLT2 blockers, or GLP-1 analogues.
In all of these disease areas, prior to the introduction of the currently available effective medications, the focus was on dietary and other behavioural interventions. Thus, I recall giving talks on sodium restriction, physical activity, or the DASH diet for managing hypertension or on the AHA Step I/II diets to manage dyslipidemia. While dietary and other behavioural interventions remain important pillars for managing these conditions, it would be quite uncommon today to see clinicians manage any of these entities with “lifestyle” interventions alone.
However, the latter is still the case for treating obesity, which in itself remains the exception rather than the rule as far as clinical management is concerned.
This may be about to change.
Thus, according to a paper by Timo Müller and colleagues, published in Nature Reviews Drug Discovery, there is much reason for hope that we will soon have a plethora of anti-obesity medications that may well drastically change obesity management.
The paper extensively reviews the rather sketchy past history of anti-obesity medication and provides a brief primer on the complex neuroendocrine systems that govern the energy homeostasis.
The authors also highlight the important challenges in developing effective anti-obesity medications including heterogeneity of the disorder, the complexity of the neuroendocrine system, translating findings from animals to humans, and of course safety aspects.
The authors then go on to discuss the various existing and potential targets with an update on the rather wide range of molecules currently under investigation. Broadly, these can be classified as incretin-based (mono-, dual- and even triple-agonists), leptin, leptin-sensitisers and MC4 receptor agonists, mitochondrial uncouplers, GDF15, amylin, PYY, and a few others.
While no one expects all or even most of these molecules to ultimately meet the rather high bar of efficacy and safety, one would have to be rather pessimistic to think that none of these molecules will make it.
Rather, as we are currently witnessing with the recent regulatory approval of semaglutide for obesity (in the US, UK, EU and Canada), which is promising to deliver weight-loss in the 15-20% range, and the emerging data for the dual agonist tirzepatide or the early data for the combination of semaglutide with the amylin analogue cagrilinitide, it is foreseeable that medical treatment of obesity will one-day routinely involve the use of anti-obesity medications, in the same way that medications are routinely used to manage hypertension, dyslipidemia or type 2 diabetes.
Obviously, much needs to happen before this becomes a reality. Not only do we need long-term outcome studies (some of which are already underway) but we also need payors to help make these medications accessible to those who need them. Finally, we need education of both health care providers and patients to fully understand why these medications are necessary in the first place and how they can be best used to reduce the burden of obesity related complications and impairments in quality of life in people living with obesity.
Obesity is a complex and heterogeneous condition that can occur at any age throughout the lifespan for a myriad of reasons. Furthermore, once established, obesity generally becomes a lifelong problem requiring long-term (often lifelong) management.
Thus, given that almost anyone can be affected (no matter how healthy your lifestyle in the past) and early intervention in high-risk individuals would seem prudent, it would clearly be of great interest to identify those at highest risk of weight gain.
The researchers analysed longitudinal data from 400 primary care practices and included over two million individuals aged 18–74 years who had BMI and weight measurements recorded between Jan 1, 1998, and June 30, 2016, with at least 1 year of follow-up.
Of all the potential factors that one might imagine would predict weight gain, including socioeconomic factors, comorbidities, medications, etc., the only significant predictor of future weight gain turned out to be young age!
Thus, being a young adult between 18-24 years of age carried the highest risk (4 to 5 fold higher than for older adults) of developing obesity or transitioning to a more severe obesity stage (based on BMI).
Other socio-demographic factors including sex and race were only marginally significant.
Not only are these findings surprising but also pose an important challenge to clinicians trying to identify individuals at risk. After all, young age is not much information to go on.
This of course does not mean that predicting obesity is hopeless. It just shows that there are probably myriads of risk factors for future obesity (e.g. adverse life events, comorbidities, medications, etc.) that act throughout the lifespan and can be significant for individuals but not for entire populations.
My advice to clinicians would be to keep a close eye on changes in body weight (especially in younger adults) and try to identify drivers of excess weight gain as early as possible, remembering that an upward weight trajectory can occur in pretty much anyone at any point in life.
Humans are social beings and supporting each other in challenging endeavours is often the best path to success.
Thus, one would imagine that peer support would be one of the key elements that can help nudge, motivate, encourage and ultimately steer someone towards their goals.
Not surprisingly, peer support groups are often mentioned and recommended in the context of weight management and lifestyle change.
But how effective are such groups in actually helping people change their lifestyles and support relevant outcomes (e.g. weight loss)?
This is the topic of a systematic review and meta-analysis by Lim Siew and colleagues from Monash University, Victoria, Australia, published in Obesity Reviews.
The researchers examined data from 65 studies, including over 15,000 participants, looking at the effectiveness of peer intervention in changing body weight, energy intake, and physical activity in adults.
While statistically significant, the overall effects on these parameters were rather minimal – about 1 kg decrease in body weight, an 0.75 cm reduction in waist circumference, and a minute effect on physical activity with no change in energy intake.
Interestingly, adding a health professional to the group appears to have little influence on the outcomes.
As one may expect, there was considerable heterogeneity between studies and given the nature of peer-support groups, it was virtually impossible to pinpoint the source of variations in outcomes.
Thus, while peer-support groups may well provide other benefits to participants, as in social contact and support, they are hardly a reliable means of promoting lifestyle change.
This should not discourage anyone from participating in such groups if they happen to find them helpful – however, there does not appear to be any pressing argument to join such a group if peer-groups are not your thing. .
Bariatric/metabolic surgery has been shown to promote improvements and even remission of type 2 diabetes.
Now, as paper by Lena Oppenländer and her German colleagues, in a paper published in Molecular Metabolism, shows that vertical sleeve gastrectomy (VSG), in contrast to a low-energy diet results in fast ß-cell recovery in diabetic db/db mice, a model of severe obesity and type 2 diabetes.
Using single-cell profiling of islets of Langerhans, the researchers showed that VSG induced distinct, intrinsic changes in the β-cell transcriptome, but not in that of α-, δ-, and PP-cells.
Furthermore, within two weeks of interventions, VSG triggered fast β-cell redifferentiation and functional improvement.
Expansion of β-cell area was attributed to both redifferentiation and by creating a proliferation competent β-cell state.
In addition, the paper presents substantial information on changes in molecular pathways that would in part explain these observations.
Although evidence from animal studies should always be taken with a grain of salt, these studies should lead to further exploration of similar mechanisms resulting in the restoration of ß-cell function in humans following metabolic surgery.
People living with obesity are all too aware of being the butt of “fat-jokes” – indeed, there remains a shockingly widespread societal acceptance of weight-related humour – not least, manifested in the recent spate of COVID-19 “jokes”. Moreover, there appears to be a widely held belief that “fat” individuals are funnier, more entertaining, and merrier, and thus, perhaps fair game – after all we’re just having a harmless laugh.
This impression may well be strengthened by the observation that people living with excess weight often seem to make jokes about and laugh about themselves. This has been interpreted as being “better if they laugh with me, than at me”.
Now an interesting paper by Natalia Maazurkiewicz and colleagues from the University of Gdansk, Poland, published in the International Journal of Environmental Research in Public Health, reveals self-deprecating humor to be a strategy often used by women, who perceive weight stigma.
Their research was conducted in 127 young adult women both with and without excess body fat, who were administered the Humor Styles Questionnaire, Perceived Stigmatization Questionnaire, and the Brief COPE.
As their study reveals,
“…women with overfat (sic) more often use humor to reduce stress, especially in situations where they feel stigmatized. Interestingly, this humor is often aimed at themselves, as self-depreciation. At the same time, obese individuals (sic) are often the objects of jokes and are used as a source of humor in entertainment media; they are thus an object of ridicule, and references to one’s own weight are typically met with laughter.”
Indeed, it should not be surprising that these women use humour as a coping strategy, but rather that this can in fact be harmful.
“The originators of the concept of humor styles indicate that humor may have an adaptive character, but that it can also be harmful and maladaptive. Thus, it is not the sense of humor in itself but rather the ways one uses it and the goals one has when using it that are important for understanding its role in everyday functioning. Maladaptive styles of humor are associated with aggression and being snide. Aggressive humor is directed outwardly; it is associated with raising one’s status and mood by demeaning and ridiculing other people, making fun of them.”
In the context of the issue at hand, the authors remind us that,
“Self-defeating humor is based on the need for approval through paying the price of ridiculing oneself. It is expressed through attempts to make people laugh by telling self-ridiculing stories . Oftentimes, an individual who uses this kind of humor can be perceived as funny or witty (e.g., “the class clown”). At the same time, they often hide their emotional needs and have low self-esteem, and the humor is used as a form of defensive denial or for ridiculing one’s shortcomings. According to this view, as also shown by our study, when women with overfat (sic) face threatening situations where they perceive behaviors that are hostile toward them, using humor to cope with stress, they select maladaptive styles of humor.”
But we must not forget that obesity is no laughing matter nor is humour a helpful way to deal with stigma. As the authors note,
“Stigmatization does not help people “to not be fat”; instead, it fosters a sense of blame and lack of agency about one’s appearance, potentially leading to increased unhealthy eating behaviors and thus to weight gain in some individuals.”
Clearly, this topic is not much to laugh about.
Over the past several years we have seen a spate of large randomised controlled trials (RCTs) designed to test the efficacy of various anti-obesity medications. All of these trials included a control group, in which patients were offered some form of dietary counseling aimed at reducing caloric intake and instructions on increasing physical activity.
Perhaps, even more importantly, these studies were conducted in volunteers, run at centres with at least some expertise in obesity management, and included regular visits and contact with study personnel, all factors that would be expected to promote weight loss.
Taken together, most of these features would by far exceed what would normally be offered in terms of obesity management in routine clinical practice.
Thus, it would be fair to say that the control groups in these studies are not only a reflection of what may be expected in ‘usual care’ with lifestyle interventions but most likely represent best outcomes.
Although I have not conducted a formal meta-analysis of these trials, it is quite evident that the average weight loss in the control groups ranges somewhere between 3-6% of initial weight.
This, interestingly enough, is exactly the range of weight loss seen in RCTs that are specifically designed to test various dietary and other non-pharmacological treatments for obesity.
In light of these findings, it would only be fair to conclude that based on the vast body of evidence from RCTs on various obesity treatments – the best we can expect in terms of weight loss from behavioural interventions (even in volunteers, seen at regular intervals by experts in the field), is in the ball-park of 3-6%.
While this degree of weight loss may well have some health benefits, these outcomes should be rather sobering, to anyone who believes that they can “conquer” their obesity with “lifestyle-change”.
In practical terms, if all you are aiming for is a 3-6% weight loss, it would be fine to just see a dietitian and perhaps increase your physical activity – for anything more, you should clearly be looking at adding medication or perhaps considering surgery (where indicated).
Anyone following the literature should by now have noticed the steady stream of evidence consistently showing reductions in morbidity and mortality following metabolic surgery.
Now, yet another study, this one by Anita Courcoulas and colleagues, published in the Annals of Surgery, provides further evidence for this.
Their retrospective analyses included a cohort of patients who underwent sleeve gastrectomy (SG, n=13,900) or Roux-en-Y gastric bypass (RYGB, n=17,258) from January 2005 to September 2015 in three integrated health systems in the US, that were matched to 87,965 nonsurgical patients on site, age, sex, body mass index, diabetes status, insulin use, race/ethnicity, combined Charlson/Elixhauser comorbidity score, and prior health care utilization, with follow-up through September 2015.
RYGB and SG were each associated with a significantly lower risk of all-cause mortality compared to nonsurgical patients at 5-years of follow-up (RYGB: HR = 0.43; SG: HR = 0.28). Similarly, RYGB was associated with a significantly lower 5-year risk of cardiovascular- (HR = 0.27), cancer- (HR = 0.54), and diabetes-related mortality (HR = 0.23).
For patients with SG, there was not enough follow-up time to assess 5-year cause-specific mortality, but at 3-years follow-up, there was significantly lower risk of cardiovascular- (HR = 0.33), cancer- (HR = 0.26), and diabetes-related (HR = 0.15) mortality.
These findings are clearly consistent with the growing body of evidence that metabolic surgery, despite involving rather complex surgery, can very significantly reduce morbidity and mortality in individuals with severe obesity.
Not that I expect these data to convince the nay-sayers and sceptics – but for those of us who regularly counsel patients considering metabolic surgery, they do continue to raise our level of confidence in the substantial benefits of these procedures.
To anyone involved in adult obesity management, harrowing stories of adverse life events that may have significantly contributed to weight gain, are neither uncommon nor surprising.
While retrospective data in adults often implicates adverse events during childhood, longitudinal studies on the role of such events on body weight during childhood are less common.
This is now the topic of a study by Miriam Schiff and colleagues published in Public Health Nutrition.
The researchers looked at the relationship between adverse childhood events (ACEs) and excess weight in longitudinal data from three waves of the second cohort of the US National Survey of Child and Adolescent Well-Being (NSCAW II), which sampled cases from US Child Protective Services investigations that were closed between February 2008 and April 2009 nationwide. The sample included 3170 kids ranging in age between infancy and 14 at baseline.
Abusive and neglectful events were measured using the Conflict Tactics Scale – Parent-Child version at each wave, whereby hitting with a fist or kicking, beating, choking, burning and threatening with or using a knife or gun were coded as physical abuse; leaving a child alone when an adult should be present, not being able to provide food, being too drunk or high, or not being able to get to a doctor when a child needed it were coded as neglect; any forced sexual contact was coded as sexual abuse; so caught up with problems that parent did not tell child (s)he were not loved were coded as emotional neglect and shout/yell/scream, swear or curse, called dumb or lazy or threaten to send away were coded as psychological abuse.
While supporting the hypothesis that ACEs play a role in the development of childhood obesity, both the number and nature of events as well as the sex of the child appear to matter.
Thus, for e.g., while for all youth, neglect as a single event was associated with about 2.5 greater odds of obesity, for girls who experienced neglect, the odds ratio was closer to 5.
Not all ACEs were positively associated with obesity. Thus, girls, experiencing physical abuse or having a parent with mental health problems had decreased odds of obesity (OR = 0.4), while boys who experienced sexual abuse were likewise less likely to develop obesity (OR =0.06).
As the authors point out, several limitations to these data must be considered. For one, the assessment of ACEs was entirely based on parental reports. Furthermore, it is not clear that these data are fully representative of the population at risk due to the way that individuals were ascertained.
If anything, the data highlight the need for more research (including qualitative assessments) into understanding the role of ACEs in childhood obesity.