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    What Does Tirzepatide Really Mean For Obesity Medicine?

    The last few weeks have been abuzz about the remarkable weight loss seen with the dual GIP/GLP-1 agonist tirzepatide in the SURMOUNT-1 study. While this degree of weight loss surpasses that of the GLP-1 analogue semaglutide by several percentage points, this is not the most important implication of these findings.?

    Rather, the real implication of the SURMOUNT-1 data is, that we will soon see another major global pharmaceutical player, namely Eli Lilly, enter the obesity space.?

    Over the past decade or so, the only major international player in this field has been Novo Nordisk. With the introduction of liraglutide, recently followed by the approval of semaglutide for the obesity indication, Novo Nordisk has not only played a flagship role in developing the field of obesity medicine, it has also had to bear the considerable costs associated with raising obesity awareness, medical education, engaging payers, supporting obesity NGOs, and generally promoting the notion of obesity needing to be managed as a chronic disease. 

    While Novo Nordisk must be commended for their remarkable efforts in promoting a better understanding of obesity as a chronic disease, much more remains to be done in this regard. Thus, having another major company enter the field of obesity medicine should considerably increase the resources that can be put towards professional and public education and supporting the work of the various NGOs working on this issue.?

    For those, who are are perhaps sceptical about industry involvement in physician education or support for NGOs, it is important to remind ourselves of the fact that industry actually provides much of the evidence from large randomised controlled trials on which we base our guidelines and treatment algorithms.

    Moreover – like it or not – industry also supports substantial academic research, investigator-initiated trials, training of new professionals, and a host of other activities that ultimately benefit our patients. In fact, I cannot think of a single disease area in which most significant therapeutic advances are not largely attributable to industry efforts.?

    We perhaps also need to remind ourselves that the pharmaceutical industry, in contrast to the free-for-all-anything-goes predatory billion-dollar “weight-loss industry”, underlies strict regulatory oversight and is held to ethical codes and standards that provides a transparent and effective framework for their promotional activities.?

    Thus, my expectation is that with the entrance of another major global player like Eli Lilly into the obesity area, we will not only see much-needed competition but also a major expansion of funding and support for activities that will ultimately benefit those living with obesity. 

    Finally, I can only hope that with the successful development of novel medications like semaglutide and tirzepatide, other major pharmaceutical companies will now take heart at the success of Novo Nordisk and Eli Lilly and finally venture into this space.?

    Despite the fact that these companies have clearly raised the bar for what is now possible with effective anti-obesity medication, hopefully, more major companies will make the necessary investments into this area of medicine – which has been underfunded and largely ignored to the detriment of the vast number of people living with obesity who have had to wait far too long for advances in this important therapeutic area.?

    @DrSharma,?
    Berlin, D

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    Guest Post: Why Gynecologists Should Learn About Obesity Medicine

    Today’s guest post comes from Emilia Huvinen, MD, PhD, Gynecologist, Helsinki, Finland

    My first step into the world of obesity research and care began with my PhD studies on gestational diabetes.?

    For a young gynecologist, it was all new in the beginning but soon I found myself immersed in the world of behavioural medicine, adiposity and glucose metabolism. As years went by, and I learned more and more about different aspects of healthy behaviours and the complex biology of weight regulation, I finally got involved in actually treating women with obesity for their obesity.

    As a gynecologist, it is not difficult to see how obesity can play a crucial role in several periods of a woman’s life; starting from having early puberty and continuing to heavy menstrual bleeding, infertility, pregnancy complications, and stronger menopausal symptoms. Treating obesity can also be beneficial when treating women with polycystic ovaries syndrome (PCOS), infertility and endometrial hyperplasia, a pre-stage of uterine cancer. As obesity is associated with several pregnancy complications, helping our patients better manage their weight preconceptionally can improve pregnancy outcomes and hopefully even influence the health of the next generation.

    As a gynecologist, being the trusted long-term doctor for women, we have the privilege of being really close to our patients’ lives. We are also very used to discussing intimate and even very delicate issues in our everyday practice. However, it is apparently still a million-dollar-question how to get more gynecologists involved in obesity care. 

    Unfortunately, the general advice currently given to women living with obesity is still to just “eat less and exercise more”. Many of us are still unaware that obesity is a chronic disease, and that people need care and treatment, not guilt and accusations. 

    I suspect that the most common obstacle preventing more gynecologists getting involved in obesity medicine, is simply lack of information. Starting a conversation on obesity feels uncomfortable and delicate, and there’s a general assumption that specific skills are needed that are best left to obesity specialists. Often it is also a question of time, and many feel that it might not be worth the effort. For gynecologists, medications for obesity treatment are also unfamiliar and different from the ones we typically use.

    My wish is to develop a sustainable and practical protocol for treating and supporting my patients living with obesity. Developing multi-professional networks together with skilled dietitians and psychologists is crucial. I also believe that by using electronic technologies like video consultations, we can offer better access to obesity care even to women living in remote areas – which in Finland is not uncommon! 

    Even if most gynecologists currently may not feel comfortable treating obesity, I hope we can at least all talk to our patients in a sensitive way and support and guide our patients with obesity to places where care is offered. We should also acknowledge that as doctors we often play a major role in creating obesity stigma. 

    As new and highly effective treatments for obesity are now becoming available, I clearly see a golden opportunity for us as gynecologists to become more involved in obesity medicine as part of our practice. Our patients certainly deserve comprehensive care, which includes helping them better manage their obesity.

    Dr Emilia Huvinen,
    Helsinki, Finland

    About the author: Dr Emilia Huvinen, MD PhD, is a specialist in Obstetrics and Gynecology and currently works as an OBGYN in Aava clinic and treats women with obesity in weightclinic.online. She’s also a postdoctoral researcher at University of Helsinki. Her PhD studies focused on heterogeneity of GDM and long-term health of GDM women, but in recent years her research has expanded from lifestyle and pregnancy to metabolomics and genetics and their interplay in the health of women and their children.

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    Do We Need Billing Codes For Stopping Insulin?

    Starting patients on insulin is not easy. Patients have to be counseled, educated, introduced to self-monitoring, and need to be seen more frequently till they are comfortable and have achieved their treatment goals.?

    For this, in many countries, there are dedicated billing codes – some of which can be rather attractive. As a case in point, in Germany, billing codes for starting patients with type 2 diabetes on insulin, have resulted in Germany perhaps being the world leader in the use of insulin in patients with T2D. 

    As we now enter the era of increasingly effective anti-obesity medications, resulting in two-digit weight loss, there will be a growing number of T2D patients, who will eventually need to be taken off their insulin.?

    This again, is not as simple as it sounds. Many T2D patients are on rather high doses of various types of insulin and will need to be gradually tapered off. During the time of active weight loss, insulin doses will need to be adjusted, both to avoid hypoglycemic episodes but also to ensure that the HbA1c targets are maintained.?

    This is extra work for doctors (and their staff) and will need to be accounted for. 

    Thus, it may be reasonable to ask whether it is time to introduce billing codes for stopping insulin, given the large number of patients who are currently on it but will need to come off as they experience significant weight loss.?

    We have already seen such situations in patients undergoing bariatric surgery, but there, due to the rather rapid improvement in glycemic control, we can often simply hold the insulin following surgery.?

    With the more gradual weight loss seen with anti-obesity medications, this process will take longer and needs to be closely monitored.

    In jurisdiction where there are no special billing codes for starting insulin, this may not be an issue.

    However, in jurisdictions, where such billings provide an incentive to doctors to start patients on insulin, we may need to create new billing codes to incentivise docs to take their patients off insulin as effective anti-obesity medications become more widely available.?

    DrSharma

    Berlin, D

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    Guest Post: Racism and Health Disparities in Black Americans

    Today’s guest post comes from Sean Wharton, my friend and colleague from Toronto, well known to all of us working in obesity medicine.

    Since the George Floyd incident in the United States, the entire world has taken greater account of instances of racism and discrimination in all walks of life.  Medicine is no different and it is therefore no surprise that much of medicine is steeped in racism.  Many people refer to this as the social determinants of health, but the structure and underlying reasons for those determinants, in many countries, is racism.  

    In America, the remnant of slavery also lives on in the social determinants that drive the obesity epidemics in African Americans.? African American women have an incidence of obesity of 57%, compared to white women at 40%. This is 42% higher!?

    This is a staggering difference. What accounts for this? 

    We now have a greater understanding that most disparities in health, including hypertension, diabetes and obesity, are due to racial and ethnic inequities, many of which are a legacy of their past history.  

    For obesity in African Americans, we can start by looking at the nutrition during slavery.? A slave’s diet was primarily made up of inexpensive foods that were high in sugar and fat, designed to provide fuel that would be burned off during the day.?

    As reported historically slave rations could include:

    10 quarts rice or peas

    1 bushel sweet potatoes

    2-3 mullet or mackerel salt fish

    1 pint mollasses

    2 pounds pork

    Thus, African Americans became accustomed to this diet and continue to have a palate for such as evidenced by the menu in many Southern African American restaurants and homes.   

    Today food choices for African American follow a similar pattern as in the times of slavery.? Foods – high starch, fat, sodium, cholesterol, and caloric content, and are inexpensive and often low-quality nature of the ingredients such as salted pork and cornmeal.?

    This gives us some explanations regarding the disparity in the incidence of obesity between the races, and now we deal with the fact that there is are difference in success of obesity treatment between the races. Again this is likely due to the very same social determinants.  

    Our own research has documented that women of colour lost less weight at weight management clinic, but when adjusted for the number of visits, the weight loss was the same.??

    It was clear that the system was not built for women of colour to access the care. There was no biological difference, just a difference in access.

    There is a lot of discussion regarding whether the reason for health disparities is biological or due to societal differences between races.  There is now considerable research that points to the fact that race is a social construct and determinants of health are based on racism and discrimination and not biology.  

    Interestingly, as a recent example, the equation for adjustment in eGFR for renal failure, for Black people, has been removed by most labs as it has no scientific validity and does nothing apart from fueling racism.? Remember also, the check box for the adjustment for renal function was Black or White, so what box would Barack Obama, or Beyonce check?

    My hope is that the social determinants that define this dramatic differences in rates of obesity and success of obesity treatment will improve as we work to break down the walls of racism around the world.

    Sean Wharton,
    Toronto, Canada

    About Sean Wharton:

    Dr. Wharton has a doctorate in Pharmacy and Medicine from the University of Toronto and is the medical director of the Wharton Medical Clinic, a community based internal medicine weight management and diabetes clinic. He is an adjunct professor at McMaster University in Hamilton and York University in Toronto. He also academic staff at Women’s College Hospital, and clinical staff the Hamilton Health Sciences. Dr. Wharton’s research focuses on bariatric medicine and type 2 diabetes. He is the co-lead authour of the Canadian Obesity Guidelines. Apart from his interest in obesity medicine, Dr. Wharton is enthusiastically involved in activism to achieve health equity in Canada. In 2000, he founded the BMSA (Black Medical Students Association) at the University of Toronto, now recognized as a leading mentorship organization across Canada.

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    Why Calories Still Matter

    Over the past decade or so, alternative explanations for the rise in obesity rates, that de-emphasize the role of caloric intake vs. the role of specific nutrients, have had a field day.??

    Leading amongst these, no doubt, is the Carbohydrate-Insulin-Model (CIM) of obesity, whereby, carbs stimulate insulin release, which in turn stimulates expansion of adipose tissue, which in turn leads to insulin resistance, resulting in even higher insulin levels, ultimately resulting in a vicious cycle that can only be interrupted by religious adherence to a low-carb diet.?

    Although this model has had broad populistic appeal, spawning a whole industry of best-sellers, low-carb products, and even treatment programs built around this paradigm, as pointed out in rather comprehensive article by Kevin Hall and a host of notable obesity experts, published in the American Journal of Nutrition, CIM (which has undergone several modifications since its inception), does not quite concur with all of the pre-clinical and clinical evidence.?

    In this paper, the authors make a rather compelling argument in favor of the Energy-Balance-Model (EBM), which pretty much aligns with virtually everything we know about the science of body weight regulation. 

    According to the authors,

    “The EBM proposes that the brain is the primary organ responsible for body weight regulation via integration of external signals from the food environment along with internal signals from peripheral organs to control food intake. Specific brain regions, such as the hypothalamus, basal ganglia, and the brainstem modulate food intake below our conscious awareness via complex endocrine, metabolic, and nervous system signals acting in response to the body’s dynamic energy needs as well as environmental influences…..whereas day-to-day energy intake and energy balance of an individual can be highly variable, neural regulation of energy balance is generally achieved over prolonged time scales.”  

    The key term in all of this is “positive energy balance”, without which there can be no accumulation of excess weight. Ergo, as calories are  the currency of energy balance, there can be no excess energy balance without excess calories. 

    As the authors go on to explain, the physiological processes that determine caloric intake are subject to a host of biological and environmental perturbations, explaining both the differences in individual susceptibility as well as the wide variability in shape and size evident even in populations with similar environmental exposure. Furthermore, this model also explains the wide variation in response  to dietary, pharmacological, or even surgical manipulations that modify the functioning of the system. 

    Importantly, while the EBM model of obesity fully accommodates a role for high-glycemic foods and a role for insulin, it also allows for a number of alternative mechanisms that ultimately drive positive energy balance.?

    Recognizing the central role of caloric intake, does not mean that we all need to go back to calorie counting or restrictive caloric dieting – rather, it is clear that such approaches tend not to be very effective in the long-term and may in fact be counterproductive in terms of obesity management. 

    However, turning to simplistic alternative notions that disregard the fundamental importance of caloric balance is neither helpful nor in line with the basic laws of physics that govern conservation of energy. 

    Or, as the authors highlight,

    …the CIM sets forth a single exposure as the primary determinant of common obesity and proposes a single “practical strategy” to treat obesity by prescribing low-glycemic-load diets despite evidence that such interventions are no more effective than prescribing higher-glycemic-load alternatives.“

    As a general rule, when faced with simple explanations or solutions to a complex problem, a certain level of skepticism is generally in order.

    @DrSharma,
    Berlin, D

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    Will the Weight-Loss Results for Tirzepatide Shrink the Field for Future Anti-Obesity Treatments?

    At the 2022 European Congress on Obesity, which I attended over the last few days, there was much buzz about the rather spectacular 22% average weight loss achieved with the dual GIP-GLP-1 agonist tirzepatide – a degree of weight loss that is not far from matching the weight-loss outcomes of patients undergoing metabolic surgery.

    Clearly these results  are shifting the benchmark for what we can expect from future anti-obesity medications. 

    While we await the full publication of these results and the outcomes of the other trials in the SURMOUNT program, it may be prudent to speculate what these results mean for compounds and treatment options for obesity currently in the pipeline. 

    At last count, there were over twenty different anti-obesity compounds across a range of modes of action at various stages of clinical development. 

    Some may well have the capacity to match the degree of weight loss seen with tirzepatide, but matching or even exceeding the 20% mark is likely to be a tall order for most. 

    Thus, no doubt many anti-obesity medication development programs may now be seriously reconsidering or even abandoning current candidates.  

    This would be unfortunate! 

    For one, given the heterogeneity of pharmacodynamics responses, there will always be individuals for whom tirzepatide may either not work or not be well tolerated, leaving ample room for less effective medications that may do the job for these patients. 

    More importantly, it may well be that, although these compounds may not be effective enough when used alone, they may be ideal candidates for add-on or combination treatments. 

    An example that comes to mind would be the combination of the long-acting amylin analogue cagrilinitide with the long-acting GLP-1 analogue semaglutide, for which we have early data suggesting that it may well match or even exceed the weight loss seen with tirzepatide. 

    Given that combination treatment is now the most common approach to treating a host of chronic diseases including hypertension, diabetes, heart or kidney disease, there is no reason why this would not be the case for obesity.  

    While each component of these combinations may only be moderately effective on their own, they may well have synergistic effects that more than add up (as seen for buproprion plus naltrexone) or allow the use of lower doses, thus improving safety and tolerability (as with the combination of low-dose phentermine and low-dose topiramate). 

    Thus, rather than abandoning compounds currently in the pipelines just because they promise less than 20% weight loss on their own, it may be time to consider developing these compounds as add-on or as combination therapies. 

    Indeed, given that we now already have several effective medications for obesity, it will only be a matter of time before ethic committees decide that it is no longer ethical to test new anti-obesity compounds against a placebo. 

    As in trials of medications for type 2 diabetes, hypertension, or dyslipidemia, the control arm (and likely even the intervention arm) of future studies would need to include baseline or standard medications. 

    Although, at this time, none of the available anti-obesity medications would be considered “standard care”, this is largely because anti-obesity medications are currently not widely used in clinical practice, not because they lack efficacy. Thus, in the setting of a clinical trial, this argument as justification for having a placebo arm may no longer satisfy an ethics committee.  

    Also, knowing that effective medications for obesity are already approved and available may make individuals seeking obesity treatments less likely to participate in lengthy trials that have placebo arms. 

    The finding of “surgery-strength” weight-loss with tirzepatide may also be the benchmark against which future devices or surgical techniques would have to measure up. 

    In fact, we may well reach the point where any novel obesity treatment will have to establish its superiority (or at a minimum non-inferiority) to approved anti-obesity medications. 

    I certainly look forward to seeing how this plays out in the future. 

    It would certainly be a shame if the rather spectacular results reported for tirzapetide leads to the premature abandoning of compounds that may well be perfect candidates for combination or add-on treatments for obesity. 

    @DrSharma
    Berlin, D

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    Zooming Forward to New Connections

    This week I am attending the joint meeting of the European Association for the Study of Obesity (EASO) and the International Federation for the Surgery of Obesity and Metabolic Disorders – European Chapter (IFSO-EC) in Maastricht, held under the timely title ZoomForward2022.

    Indeed, after two years of virtual meetings on Zoom and other platforms, it is finally time to meet friends and colleagues again in-person. 

    Given the hiatus, for many young students, postdocs, residents, and other trainees, this may be their first opportunity to meet and connect with their peers in-person.?

    I therefore thought it would be appropriate to remind everyone of a previous post on how to get the most out of scientific meetings – a guide for early career participants

    The key messages, that I think will be most useful to anyone starting out their careers (and perhaps for some older folks) are summarized in this video on YouTube.

    Hopefully, these tips, based on my own strategies and tactics, that have helped me throughout my career, will help you get the most out of the next few days (or any other scientific meeting you may attend in the future).

    See you in Maastricht.
    DrSharma,
    Berlin, D

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    Deep Dive Into Obesity Phenotypes

    Last week, in my capacity as a Strategic Advisor, I had the pleasure of attending the SOPHIA general assembly in Favrholm, just outside of Copenhagen.

    SOPHIA stands for the Stratification of Obesity Phenotypes to Optimise Future Therapies, and consists of a large research consortium that includes thirty-one international members from academia, industry, and NGOs.

    With funding support of around € 16 million from the Innovative Medicines Initiative (IMI), a joint undertaking of the European Commission and the European Federation of Pharmaceutical Industries and Associations (EFPIA), T1D Exchange, JDRF, International Diabetes Federation (IDF), and Obesity Action Coalition, the SOPHIA research consortium aims to find better solutions to address obesity and reduce its consequences.?

    The eight work packages range over a variety of issues ranging from technical challenges like creating a confederation of large harmonised databases to allow sophisticated analyses of phenotypes, trajectories and outcomes, specific projects on the relationship between obesity and diabetes (both type 1 and 2), exploration of surgical outcomes, to important work on better understanding the patient voice and incorporating their views and needs throughout the various projects.?

    Now in its 3rd year, the progress in all work packages has been remarkable (despite the complications due to COVID) and one of our strategic recommendations has been to perhaps explore opportunities to identify and incorporate additional data sets, particularly in the areas of mental, cardiovascular, and reproductive health.?Researchers working in these areas, who may be interested in contributing datasets to this initiative can contact the SOPHIA office via the project website.

    Overall, this joint effort, guided by the patient voice, is certainly exciting and innovative and I look forward to several of the work packages presenting their findings during the 28th European Congress on Obesity in Maastricht later this week.?

    @DrSharma
    Berlin, D

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