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Resetting The Setpoint: Is There Something To Learn From Bariatric Surgery?

Yo-Yo Rubber Band Feb 2014I am currently in Rio de Janeiro, speaking at the 21st World Congress of the International Federation for the Surgery of Obesity & Metabolic Disorders – IFSO 2016.

As Lee Kaplan from Harvard University reminded the audience, obesity is a disease of energy homeostasis, where everything seems to be working just fine, except that the “setpoint” of the system is set too high.

Kaplan used the analogy of the temperature in a room, where the thermostat is set too high – say to 30 Centigrade.

Everything else in the room works just fine: nothing wrong with the heater, or the air-conditioning, or the ventilation system, or the isolation. In fact, even the thermostat is working just fine doing its job – except that it is set too high!

Dieting would be like tearing open a window to lower the temperature in the room. Yes, if you open the window, things may cool down, but the thermostat will only make the heating work extra hard trying to heat the room and, once you close the window, the thermostat will rapidly bring the temperature back to 30 Centigrade (or come off your diet).

So how do we reset the set point?

Well, that appears to be exactly what bariatric surgery does to the system – it somehow manages to lower the set point, allowing the body to regulate its weight at a lower level than before (something that does not happen when you lose weight simply with diet and exercise).

How exactly surgery does this, remains unclear, but there is no doubt that this happens and there are a lot of experiments showing that after sugery, the body actively regulates body weight at a lower “setpoint”.

Unfortunately, this “resetting” is not permanent.

If you reverse the surgery, the body goes right back to regulating its weight at the higher level, resulting in the rapid weight regain, which is why I consider obesity surgery a “treatment” rather than a “cure”.

Kaplan went on to talk about the role of the bacteriome and bile acid metabolism (both dramatically changes with bariatric surgery – but very little with diet and exercise).

Figuring out how bariatric surgery changes the setpoint (even temporarily) will hopefully lead to new medical treatments for obesity.

Till then, anyone losing weight (no matter what diet, exercise, or medication) needs to remember that they stand to regain the weight, the minute they stop the “treatment”.

@DrSharma
Rio de Janiero

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MetAP2 Inhibitors For Obesity – Take Two

Regular readers may recall that Zafgen, a Boston-based biopharmaceutical company, recently abandoned its development program for belanorib, a MetAP2 inhibitor. The program had to be abandoned, despite substantial weight loss in indiviuals with Prader-Wili syndrome, hypothalamic obesity, as well as “garden-variety” obesity, due to serious thrombotic adverse events.

Now, Zafgen reports that they have initiated a new round of Phase 1 studies of their 2nd generation MetAP2 inhibitor (ZGN-1061), which despite similar MetAP2 inhibition, appears to have much more favourable effects on coagulation.

The Phase 1 trial, designed to evaluate safety, tolerability, and weight loss efficacy over four weeks will enroll up to 48 healthy subjects across up to six cohorts of single escalating doses of ZGN-1061. The clinical trial also includes a multiple-ascending dose portion, which is evaluating twice-weekly ZGN-1061 over four weeks in up to 24 obese subjects.

The Company expects that top-line data from this clinical trial will be available by the end of the first quarter of 2017.

Given the rather spectacular weight loss seen with belanorib, this 2nd generation MetAP2 inhibitor study certainly warrants our attention.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting honoraria from Zafgen

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GLP-1 Analogue and SGLT-2 Inhibitor Combination Provides Additive Weight Loss

1-plus-1Yesterday, I posted about the significant weight loss seen with the glucagon-like peptide 1 (GLP-1) analogue semaglutide in patients with type 2 diabetes, a finding that holds promise for the use of this agent for obesity treatment.

Now, Juan Frias and colleagues, in a paper published in Lancet Diabetes & Endocrinology, present data showing an additive weight-loss effect of combining the GLP-1 analogue exanatide with the SGLT2 inhibitor dapagliflozin in patients with type 2 diabetes.

The DURATION-8 trial randomised 695 patients with type 2 diabetes to a combination of once-weekly GLP-1 agonist exenatide (Bydureon(R)) and the SGLT-2 inhibitor dapagliflozin (Farxiga(R)) vs. either drug as monotherapy for 28 weeks.

While the combination was superior in all diabetes-related end-points to monotherapy with either substance, I was particularly interested in also seeing superior weight loss with the combination.

Thus, overall patients on dual therapy with exenatide and dapagliflozin lost 3.41 kg vs. 1.54 kg and 2.19 kg on monotherapy, respectively.

However, participants with a baseline A1c between 8% and 9% appeared to experience a greater, more additive weight loss, with participants treated with both dapagliflozin and exenatide experiencing a mean weight loss of 4.5 kg weight reduction, compared to 1.9 kg with exenatide and 2.2 kg with dapagliflozin.

Importantly perhaps, adverse events occurred with approximately equal frequency in each group, suggesting that the combination was as well tolerated as either substance alone.

Again, it is important to note that this was a diabetes study in patients with diabetes and not a study designed to test the efficacy of this drug combination for weight loss, a study design that would have also included diet and exercise recommendations to maximise the effect of this combination.

As I have argued before, given the complexity of the body’s defence mechanisms against weight-loss, the future probably lies in the use of combination treatments for obesity (not unlike the widespread use of combination therapies for diabetes or hypertension).

Thus, it is certainly of interest to see that combining two drugs with different modes of action does indeed produce additive effects on body weight.

@DrSharma
Edmonton, AB

Disclaimer: I have received speaking honoraria from Astra Zeneca, the maker of dapagliflozin

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How Far Are We From Once-Weekly Medications For Obesity?

Anyone who follows these pages is aware of the fact that we desperately lack better medical treatments for obesity.

Last year, Health Canada approved the glucagon-like peptide 1 (GLP-1) analogue liraglutide (Saxenda(R)) for obesity treatment, which although effective and generally well-tolerated, has to be administered by daily injections.

Now, the results of the SUSTAIN-6 trial, published in the New England Journal of Medicine, show that the once weekly injection of the GLP-1 analogue semaglutide, not only decreases cardiovascular events, but also significantly lowers body weight, a promising finding for future obesity treatment with this drug.

The SUSTAIN 6 trial randomised 3297 patients with type 2 diabetes to once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks.

At baseline, 2735 of the patients (83.0%) had established cardiovascular disease, chronic kidney disease, or both.

The primary outcome (MACE) occurred in 108 of 1648 patients (6.6%) in the semaglutide group and in 146 of 1649 patients (8.9%) in the placebo group (hazard ratio, 0.74).

Nonfatal myocardial infarction occurred in 2.9% of the patients receiving semaglutide and in 3.9% of those receiving placebo (hazard ratio, 0.74); nonfatal stroke occurred in 1.6% and 2.7%, (hazard ratio, 0.61).

While average body weight at week 104 remained stable in the placebo group, it decreased by 3.6 kg in the semaglutide 0.5 mg group and and 4.9 kg in the semaglutide 1.0 mg group.

While this may not seem spectacular, it is important to remember that weight loss is notoriously difficult in patients with type 2 diabetes and that this was a diabetes and not an obesity trial, in which case participants would have also been counselled to change their diet and activity levels to achieve weight loss.

Thus, one can only speculate on what the differences in body weight would have been had the participants been actually trying to lose weight.

That said, it was perhaps surprising to note that fewer serious adverse events occurred in the semaglutide group, although more patients discontinued treatment because of adverse events, mainly gastrointestinal.

It will be interesting to see how well semaglutide fares in studies in which this treatment is assessed for the obesity indication, which will hopefully bring us closer to a once-weekly medication for obesity.

In the meantime, once-daily liraglutide 3.0 mg is certainly a welcome addition to medical management of obesity, but clearly there is more to come in terms of harnessing GLP-1 for obesity management.

@DrSharma
Edmonton, AB

Disclaimer: I have received consulting and speaking honoraria from Novo Nordisk, the makers of liraglutide and semaglutide

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5th Canadian Obesity Summit – Call For Abstracts And Workshops Now Open

banff-springs-hotelEvery two years the Canadian Obesity Network holds its National Obesity Summit – the only national obesity meeting in Canada covering all aspects of obesity – from basic and population science to prevention and health promotion to clinical management and health policy.

Anyone who has been to one of the past four Summits has experienced the cross-disciplinary networking and breaking down of silos (the Network takes networking very seriously).

Of all the scientific meetings I go to around the world, none has quite the informal and personal feel of the Canadian Obesity Summit – despite all differences in interests and backgrounds, everyone who attends is part of the same community – working on different pieces of the puzzle that only makes sense when it all fits together in the end.

The 5th Canadian Obesity Summit will be held at the Banff Springs Hotel in Banff National Park, a UNESCO World Heritage Site, located in the heart of the Canadian Rockies (which in itself should make it worth attending the summit), April 25-29, 2017.

Yesterday, the call went out for abstracts and workshops – the latter an opportunity for a wide range of special interest groups to meet and discuss their findings (the last Summit featured over 20 separate workshops – perhaps a tad too many, which is why the program committee will be far more selective this time around).

So here is what the program committee is looking for:

  • Basic science – cellular, molecular, physiological or neuronal related aspects of obesity
  • Epidemiology – epidemiological techniques/methods to address obesity related questions in populations studies
  • Prevention of obesity and health promotion interventions – research targeting different populations, settings, and intervention levels (e.g. community-based, school, workplace, health systems, and policy)
  • Weight bias and weight-based discrimination – including prevalence studies as well as interventions to reduce weight bias and weight-based discrimination; both qualitative and quantitative studies
  • Pregnancy and maternal health – studies across clinical, health services and population health themes
  • Childhood and adolescent obesity – research conducted with children and or adolescents and reports on the correlates, causes and consequences of pediatric obesity as well as interventions for treatment and prevention.
  • Obesity in adults and older adults – prevalence studies and interventions to address obesity in these populations
  • Health services and policy research – reaserch addressing issues related to obesity management services which idenitfy the most effective ways to organize, manage, finance, and deliver high quality are, reduce medical errors or improve patient safety
  • Bariatric surgery – issues that are relevant to metabolic or weight loss surgery
  • Clinical management – clinical management of overweight and obesity across the life span (infants through to older adults) including interventions for prevention and treatment of obesity and weight-related comorbidities
  • Rehabilitation –  investigations that explore opportunities for engagement in meaningful and health-building occupations for people with obesity
  • Diversity – studies that are relevant to diverse or underrepresented populations
  • eHealth/mHealth – research that incorporates social media, internet and/or mobile devices in prevention and treatment
  • Cancer – research relevant to obesity and cancer

…..and of course anything else related to obesity.

Deadline for submission is October 24, 2016

To submit an abstract or workshop – click here

For more information on the 5th Canadian Obesity Summit – click here

For sponsorship opportunities – click here

Looking forward to seeing you in Banff next year!

@DrSharma
Edmonton, AB

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