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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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1st International Diabetes Expert Conclave (IDEC) 2017

Last week I was an invited plenary speaker at the 1st International Diabetes Expert Conclave (IDEC2017) held in Pune, India. This 3-day event, organised by Drs. Neeta Deshpande (Belgaum), Sanjay Agrawal (Pune) and colleagues, brought together well over 900 physicians from across India for a jam-packed program that covered everything from diabetic food disease and neuropathy to the latest in insulin pumps and devices – all in a uniquely Indian context. I, of course, was there to speak on obesity, which featured prominently in the program. Topics on obesity ranged from the potential role of gut bugs to bariatric surgery. While Dr. Allison Goldfine, former Director of Clinical Research at the Joslin Diabetes Center in Boston spoke on the latest developments in anti-obesity pharmacotherapy (delivering her talk via Skype), I spoke about obesity as a chronic disease and the need to redefine obesity based on actual indicators of health rather than BMI. During my visit in Pune, I also had the opportunity to visit with my friend and colleague Dr. Shashank Shah, whose bariatric surgical center in Pune alone performs about 75 to 100 bariatric operations per month – a remarkable number by any standards. Of course, the overwhelming number of talks were given by Indian faculty (there being only a handful of select invited international faculty at the meeting), and I did come away most impressed by the breadth and depth of knowledge presented by the local speakers. Diabetes care certainly appears to be in good hands although the sheer number of patients with diabetes (estimated at about 70 million, which I assume to be a rather conservative assessment), would provide a challenge to any health care system. On the obesity front, things are a lot less rosy, given that (as everywhere else) obesity has yet to receive the same level of professional attention and expertise afforded to diabetes or other chronic diseases. Thanks again to the organisers for inviting me to this exciting meeting and congratulations on an excellent event that bodes well for the 2nd Conclave planned for 2018. @DrSharma Edmonton, AB

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Zona Incerta Stimulation Provokes Instant Binge Eating in Mice

The neuronal control of appetite and food intake is among the most complex and fascinating systems. Now, in a paper published in Science, Xiaobing Zhang and Anthony van den Pol from Yale University, New Haven, report the identification of a novel role of the zona incerta in inducing profound binge eating behaviour in mice. The zona incerta, is a little know part of the central nervous system within the subthalamus with extensive projections all the way from the cerebral cortex into the spinal cord. It is thought to play an important role in limbic-motor integration as well as synchronizing brain rhythms. The researchers showed that optogenetic stimulation of zona incerta GABA neurons or their axonal projections to paraventricular thalamus excitatory neurons rsults in an immediate (in 2 to 3 seconds) binge-like eating behaviour – the animals ate up to 35% of their total energy requirements in just 10 mins. Furthermore, while intermittent stimulation of these neurons led to body weight gain, ablation reduced weight. The authors suggest that the identification of this novel orexigenic system may lead to better treatments not just for binge-eating disorder. @DrSharma Edmonton, AB  

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Balancing Benefits And Harms From Redefining Obesity

The final and eight item on the disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  deals with issue of determining the benefit/harm ratio of the proposed new definition. With terms to redefining obesity as the presence of abnormal or excess body fat that impairs health, I have discussed the potential benefits and harms in previous posts. The question is, whether or not the overall balance comes down on the benefit or harm side of the equation. Here, the authors of the checklist have the following to offer, “Modifying a disease definition should be guided by a balanced assessment of the anticipated benefits and harms, using the best evidence available. The definition should reflect the values and preferences of patients and the wider community and include the impact on resource usage….In general, we recommend that panels consider both an individual and societal approach to assessing the overall benefits and harms of changing disease definitions. We recommend introducing a new disease definition where there is an expected positive balance of harms and benefit for individuals, and in aggregate at the societal level.” In addition, the authors note, “Different definitions may be required for research purposes, for example more stringent standardization, than for clinical purposes where more stringent definitions may deny access to care for patients who would benefit.” Thus, as we have seen, changing disease definitions is not just a matter of opinion but rather, the pros and cons must be considered both at an individual and societal (resource) level. That said, disease definitions are in constant flux as new knowledge and treatments emerge – obesity, should be no exception. Indeed, guidelines would be amiss in not reconsidering the validity of current definitions and exploring potential changes as part of the guidelines process. The published checklist can certainly serve as a guide for this process. @DrSharma Edmonton, AB

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Are There Any Harms Of Redefining Obesity?

The seventh item on the disease definition modification checklist developed by the Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group published in JAMA Internal Medicine,  deals with issue of potential harms to patients. Given the obvious benefits of redefining obesity as the presence of abnormal or excess body fat that impairs health outlined in the previous post, it is nevertheless prudent to explore the possibility of unintentional harms. Obviously, expanding the term obesity to include millions of people, who currently fall under the BMI threshold but may well have health impairments attributable to their body fat, may not sit well with these folks. In fact, they may find themselves shocked to learn that they would now be considered to have obesity (more a reflection of the stigma attached to this term, than its non-judgemental medical meaning). Thus, the authors of checklist remind us that, “The potential harms from diagnosis include the physical harms of diagnosis and treatment; psychological effects, such as anxiety; social effects, such as stigma and discrimination; and financial consequences, such as effects on employment….Potential harms also include the misapplication and misinterpretation of the disease definition when taken from a confined research application to more widespread clinical use.” A, perhaps more concerning issue, is the impact that redefining obesity may have on limited resources for obesity management in the healthcare system. “Changes in resource usage can result in harm by reducing access to care for some patients and by diversion and distraction of clinical care. This can happen at both the societal level, with resources taken from areas more important to health, and at the individual level, by distracting individuals from activities more important to their well-being. Modifications of disease definitions can have considerable impacts on costs, including the costs of testing, and the resources needed for treatment and follow-up for those diagnosed using the new criteria. There may also be resources needed for training and implementation regarding the change, and to minimise misdiagnosis. Costs are particularly important in low- and middle-income countries where inappropriate disease definitions can result in considerable diversion of limited health care resources.” These concerns are far from trivial. Not only are current resources for managing obesity in our healthcare systems limited (to non-existant), but one of the main reasons that employers and payers balk at providing access to obesity treatments, is the sheer number of individuals that already qualify for such treatments. Significantly expanding the pool of eligible patients, is therefore. unlikely to be met with much enthusiasm from these stakeholders. Not only would one need to demonstrate… Read More »

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