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Are Overly Enthusiastic Interpretations of Lifestyle Studies Harming People Living With Obesity?

As for many chronic diseases, there is certainly a role for dietary and other behavioural measures in the management of obesity.  But let us not kid ourselves. According to all of the available evidence, diet and exercise (often described as “lifestyle” interventions) simply do not come close to measuring up with medication or surgical treatments for obesity. Nevertheless, we continue to see overly enthusiastic reports on the efficacy (not effectiveness!) of lifestyle interventions, which not only tend to oversell the benefits but also ignore the reality that most of these interventions that may work more or less in clinical trials, would be almost impossible to implement with any degree of fidelity in routine clinical practice.  Case in point, the Look AHEAD study. This was certainly one of the most ambitious and best-resourced randomized controlled trials of intensive lifestyle intervention, designed and run by the leading experts in the field with the aim of once and for all demonstrating the benefit of weight loss on cardiovascular morbidity and mortality (albeit in elderly patients with type 2 diabetes).  Indeed, not only was running the trial (till its abandonment for futility) a major logistical feat, but there were certainly several indicators of benefit, even if not in the primary endpoint of the study.  These benefits are now nicely summarized and highlighted in a paper by Rena Wing on behalf of the Look AHEAD Research Group in a recent issue of OBESITY.  While the paper highlights a number of secondary outcomes that were apparently improved in the intensive lifestyle intervention (ILI) group, the article also notes that, “…several important outcomes (cardiovascular morbidity and mortality, cancer, and cognition) did not show significant differences between ILI and control, and frailty fractures occurred more often in ILI than in control.”  As much as the many post-hoc analyses discussed in this paper suggest health improvements in various aspects in the ILI group, the authors also state that, “There were also some subgroups that appeared to have poorer outcomes in ILI relative to DSE, most notably those who had the highest BMI at the start of the trial and those with poorer initial health, including a history of CVD and more health deficits at baseline.” Based on these findings, the authors conclude that,  “it would seem best to recommend ILI early in the course of diabetes, when individuals are younger, hopefully have less obesity, and before they have developed… Read More »

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What Do People (Want to) Eat After Bariatric Surgery?

The reason that medications and surgery work so much better for managing obesity than behavioural interventions alone, is because they change the underlying biology that drives weight gain and defends against weight loss. Thus, rather than relying on willpower, these treatments change ingestive behaviour by modifying the complex neuroendocrine pathways that regulate food intake.  So what exactly do people who undergo bariatric surgery experience in terms of wanting and liking foods and how does their dietary intake change following surgery? This is the topic of a systematic review and meta-analyses of food preference modifications after bariatric surgery by Erika Guyot and colleagues from the University Laval, Quebec, Canada, published in Obesity Reviews.  Apart from the homeostatic control of energy intake, the authors remind us that, “Food intake is partly under the control of the reward system (tonsil, ventral tegmental area, hypothalamus, limbic system, and prefrontal cortex). This system assigns a hedonic value to food and generates motivation for food intake. Food reward has been shown to have two distinct components. The first component is “liking” and is related to the pleasure and the sensory properties of foods. The second component is “wanting”, which is related to the motivation and is defined as an implicit drive to eat.”   Both of these components of food intake have been reported to be altered in patients post-surgery and imaging studies have shown a decrease in the potential of palatable foods’ ability to activate the relevant areas of the brain in post-surgical patients.  The authors included 57 studies in their review (47 studies were prospective, 8 were cross-sectional, and 2 were longitudinal retrospective) that included 2,271 patients with RYGB and 903 patients with SG. As expected, there was significant heterogeneity amongst the studies, which used a total of 16 different methods to assess food intake and preferences, with the majority being based on food records (N = 24), Food Frequency Questionnaires (FFQ) (N = 12), and food recalls (N = 11). Likewise, time points for assessment ranged from days to months post-surgery all the way up to 10 years later.  Despite these methodological differences, a couple of important themes emerged. Overall, despite a marked reduction in caloric intake, there was a significant increase in protein intake (from baseline), with a reduced intake of calories from fat. Carbohydrate intake, as a proportion of overall caloric intake, was largely unaltered.  Perhaps more interestingly, several studies also described differences in food preferences. Thus,… Read More »

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Does Neuromodulation Modulate Obesity?

Over the past decades, numerous neuromodulation therapies have been proposed to alter several of the physiological processes underpinning obesity, ranging from the brain control of food intake, satiety, and compulsive eating, to gastrointestinal responses.  These neuromodulation approaches include deep brain stimulation [DBS], transcranial magnetic stimulation [TMS], transcranial direct current stimulation [tDCS], percutaneous neurostimulation [PENS], vagus nerve stimulation [VNS], and gastric electrical stimulation [GES].  So far, none of these treatments have made it into routine practice, and according to a review by Flavia Gouveia and colleagues, published in Obesity Reviews, there are probably good reasons for this, the principle one being lack of effectiveness.  Thus, their review of 60 trials that had weight loss as an outcome,  including 7 DBS, 5 TMS, 7 tDCS, 17 PENS and VNS, and 24 GES in over 3,000 participants, yielded a seemingly consistent pattern. Initial promising results in open label studies and case reports, followed by double-blinded randomized clinical trials that generally failed to reach their primary endpoints, with no technique inducing a striking long-term reduction in body weight. As the authors note, both the case reports and randomised trials were fraught with important sources of bias or lacked details of important confounders.  While the authors remain cautiously enthusiastic about the future of neuromodulation, it is fair to say that at this time these approaches must be considered experimental and should probably not be used outside of well-controlled clinical trials.  @DrSharmaBerlin, D

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Should Youth With Type 2 Diabetes Be Prioritized for Metabolic Surgery?

One alarming and direct consequence of the obesity epidemic, is the marked increase in the incidence of type 2 diabetes in children and youth.  According to a recent paper by the TODAY study group, published in the New England Journal of Medicine, these youth face disastrous outcomes with regard to diabetic microvascular complications.  Thus, amongst the 500 individuals observed over 5 years in the study (average age 26, average duration of diabetes 13 years), the cumulative incidence of hypertension was 68%, the incidence of dyslipidemia was 52%, the incidence of diabetic kidney disease was 55%, the incidence of nerve disease was 33%, and the incidence of retinal disease was 51%.  Notably, the average BMI of this group was 35 kg/m2! These disastrous outcome were seen despite the fact that all participant were treated with metformin with or without insulin to maintain glycemic control during the first 2 years of the study, which the authors note, is probably more than the average youth with type 2 diabetes receives in the real world.   While several factors including minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia were associated with increased risk, the authors also point out that, “…youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved medical therapies, which is compounded by major challenges in adherence and management because of age and characteristic socioeconomic factors.” Moreover, “The only medications approved by the Food and Drug Aministration (FDA) for youth-onset type 2 diabetes are metformin and insulin, with the recent addition of a glucagon-like peptide-1 (GLP-1) receptor agonist. Sodium–glucose cotransporter 2 (SGLT2) inhibitors, which impede progression of cardiovascular and kidney disease in patients with adult-onset type 2 diabetes, are not yet approved by the FDA for youth-onset type 2 diabetes.” These challenges aside, the authors also discuss whether more consideration should be given to metabolic surgery in this group. Not only does metabolic surgery result in durable weight loss and improvement in glycemic control in the majority of patients, but data from the Teen–Longitudinal Assessment of Bariatric Surgery (Teen-LABS) showed a greater effect of bariatric surgery than medical therapy on both glycemic and nonglycemic outcomes . Furthermore, Teen-LABS showed greater regression and earlier attenuation of kidney disease in youth with type 2 diabetes than in adults with type 2 diabetes.” While metabolic surgery in adolescents comes with its own challenges, it seems that the alternative of trying to… Read More »

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No One Is Obese – End Of Story!

This morning I was reading an article in my favourite news magazine The Economist and came across a passage that reads as follows: “About two out of five American adults are obese, according to the CDC…..Almost half of Americans have high blood pressure, and 12% have high cholesterol. About one in ten has type 2 diabetes.” Perhaps I am overly sensitive, but I could not help notice how the authors talk about Americans BEING obese, vs. Americans HAVING high blood pressure, high cholesterol, or type 2 diabetes.  Of course the authors could have chosen to talk about Americans being obese, hypertensive, dyslipidemic, and diabetic, but they did not.  Perhaps “chose” is too strong a word, because it implies intention and making a conscious decision. Rather, I think the authors probably gave no thought to this at all. In fact, they may be surprised that this is even a “thing”.  However, this “thoughtlessness” about the use of the word “obese” remains common place, even amongst colleagues working in the field of obesity, who should by now know better. While the major obesity journals now at least pay attention to people-first language, copy editors of most medical and scientific journals appear blissfully ignorant that this is even an issue.  Thus, we continue to see the term “obese” used freely in manuscripts, lectures, and conversations. How much of this should we continue to tolerate and does it even matter? Well, if it doesn’t matter, we would probably not even be talking about it. But we are, so I guess it does.  Do I now sit down and write a letter to The Economist pointing out the problem – or do I just roll my eyes and shrug it off to thoughtless ignorance? I guess I’ll find out. DrSharmaBerlin, D

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Here’s Why You Need To Eat Your Sauerkraut!

In most cultures, fermented foods (yoghurt, kim-chi, sauerkraut, etc.) have long been a staple component of traditional diets.  Now, according to Hannah Wastyk and colleagues from Stanford University, in a paper published in Cell, these foods may not just be a convenient method of preservation, but also an important modulator of immune function.  The authors studied the effects of a diet containing high amounts of fibre (e.g. fruits, vegetables, legumes, grains, nuts and seeds) compared to a diet rich in fermented foods (e.g. yogurt, kefir, fermented cottage cheese, fermented vegetables, vegetable brine drinks, kombucha, etc.) on the microbiome and immune status of healthy volunteers.  Over the 10-week randomised dietary intervention, the high-fibre diet increased levels of microbiome-encoded glycan-degrading carbohydrate active enzymes (CAZymes) without altering the intestinal flora, whereas the high-fermented-food diet incrementally increased microbiota diversity while decreasing inflammatory markers.  As the authors discuss, “Given that fermented foods have historically been part of many diets around the world, consuming fermented foods may offer an effective way to reintroduce evolutionarily important interactions. They may also provide compensatory exposure to safe environmental and foodborne microbes that have been lost over the course of sanitizing the industrialized environment.” Thus, Fermented foods may be valuable in countering the decreased microbiome diversity and increased inflammation pervasive in industrialized society. Although not examined in this study, in my personal experience sauerkraut goes well with another fermented German staple, i.e. Beer! Don’t tell me that’s just a co-incidence! Prost! @DrSharmaBerlin, D

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Can Gastrointestinal Effects Alter Mental Health After Bariatric Surgery?

Although the overall impact of bariatric surgery on mental health is overwhelmingly positive, there remains a subset of individuals in whom mental health issues like self-harm or addictions may appear after surgery.  Now a paper by Robyn Brown and colleagues, published in Nature Reviews Endocrinology, presents an intriguing hypothesis, that alterations in the gut-axis may play a role in these problems.  As readers are well aware, bariatric surgery (with some variations depending on the type of procedure) results in profound changes in gut function including alterations in incretin release, intestinal flora, bile acid disposition, and vagal signaling. As discussed in the paper, all of these factors may potentially affect mental health. However, the evidence is sparse and often contradictory. As the authors point out, despite a strong potential for some of these alterations induced by surgery to alter mental health, few mechanistic studies appear in the animal or clinical literature that could potentially lead to better mechanistic insights and hopefully effective preventive and treatment measures.   Be the role of the gut in adverse mental health outcomes after bariatric surgery as it may, it’s perhaps important to recall that there are plenty of other probable contributing factors to adverse mental health in bariatric patients.  These include high rates of pre-existing depression, unmet expectations regarding the life-changing effects of weight loss, post-surgical alterations in the absorption of antidepressant and anxiolytic medications, and changes in alcohol metabolism, which might increase disinhibition and impulsivity, leading to self-harm.  In addition weight regain and recurrence of weight-related comorbidities, body dissatisfaction (perhaps heightened by excess skin after weight loss), as well as the reduced capacity to eat or enjoy highly-palatable foods as an emotional coping strategy may play a role in individual patients. Thus, although fear of mental health issues post surgery should probably not deter anyone from undergoing surgery if they really need it, clinicians should be aware of the possibility of adverse mental health outcomes and counsel and monitor patients accordingly.  DrSharma,Berlin, D

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How Common Are Monogenic Forms of Obesity And What Can We Do About Them?

Most of obesity is clearly polygenic, meaning that many (perhaps hundreds) of gene variants may cumulatively or synergistically increase genetic predisposition in a given individual. In contrast, monogenic forms of obesity, where a single gene variant (e.g. loss-of-function leptin deficiency) may have a profound effect on body mass, are thought to be exceedingly rare.  However, a recent paper by Kaitlin H Wade, published in Nature Medicine, suggests that some monogenic forms of obesity may be a lot more frequent than we think.  In this study, the researchers examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children and found that heterozygous loss-of-function (LoF) mutations in MC4R affected around 1 in 337 (0.3%) individuals with profound effects on body weight.  At age 18 years, carriers of LoF mutations were almost 18 kg heavier with a BMI almost 5 points higher than non-carriers.  Extrapolating this to a country like Germany with almost 20 million people living with obesity, LoF mutations in the MC4R gene could be the key culprit in almost 6,000 individuals. Clearly, genetic screening for both children and adults who experience significant weight gain in early childhood appears prudent to identify such individuals. For them, the good news is not only that they can stop blaming themselves for their excess weight, but also that there may be promising treatments on the horizon.  Thus, the MC4R-agonist setmalonitide, recently approved by the FDA for treatment of derangements of the melanocortin pathway caused by pro-opiomelanocortin (POMC) deficiency, proprotein subtilisin/kexin type 1 (PCSK1) deficiency, or leptin receptor (LEPR) deficiency, may turn out to also be effective in people with MC4R mutations.  This may be attributable to the fact that setmelanotide appears to be significantly more potent at the MC4R than the endogenous ligand alpha-melanocyte stimulating hormone (α-MSH) and (at least in vitro) can disproportionally rescue signaling by a subset of severely impaired MC4R mutants.  Specific clinical trials with setmelanotide in individuals with MC4R mutations are currently underway.  DrSharmaBerlin, D

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