In the meantime, Novo Nordisk, the maker of liraglutide, is continuing its development of a new GLP-1 analogue semaglutide as a once-weekly injection for the treatment of diabetes and obesity.
Last week the company released topline data from its SUSTAIN 3 study, a phase 3a trial in around 800 patients with type 2 diabetes randomized (open-label) to once-weekly semaglutide 1.0 mg vs. exenatide 2.0 mg (another once weekly GLP-1 analogue) over 56 weeks.
Participants on semaglutide achieved a greater reduction in A1c (1.5% vs. 0.9%; baseline = 8.4%) and weight loss (5.6 kg vs. 1.8 kg; baseline = 96 kg) compared to exenatide.
In general, adverse events (mainly GI-symptoms) were as expected for GLP-1 analogues with a rate of nausea twice as high with semaglutide compared to eventide (22% vs. 11%).
The overall discontinuation rate due to adverse events was slightly higher with semaglutide than eventide but fairly low overall (9.4% vs. 7.2%).
It should be noted that this was a diabetes and not an obesity study – so the almost 6% weight loss is indeed quite impressive (weight loss in studies designed to test drugs for obesity tends to be higher as patients are also advises to change their diet and physical activity).
According to Novo Nordisk, phase 2 dose-ranging trials of semaglutide in obesity could begin as early as next year – certainly an interesting development to watch.
Disclaimer: I have received honoraria as a consultant and speaker from Novo Nordisk
Yesterday, I attended the inaugural networking event of the Canadian Obesity Network’s Toronto Chapter. Judging by the enthusiasm of the almost 100 folks who came out to this event, this chapter appears off to a great start.
As expected for any CON event, the participants came from virtually every walk of interest in obesity – from professional to personal – research, prevention, clinic, policy, industry, NGOs.
Hopefully, we will see similar activities and chapters starting across Canada in the coming months – the success off this event shows that there is a dire need for local networking to address local issues related to obesity prevention and management.
For more information on the Toronto Chapter (CON-YYZ) click here.
For more information on how to start a CON chapter in your city click here.
Anyone who has closely followed my writings on this topic will know by now that health for a given individual cannot be measured by simply stepping on a scale (or for that matter using a measuring tape).
There are indeed individuals who appear rather healthy even at BMI levels considered to be well into the obesity range (just how many depends on your definition of “healthy”).
In an article and commentary that appears in the American Journal of Epidemiology, Juan Pablo Rey-López and colleagues from the School for Policy Studies, University of Bristol,UK, argue that the notion of “metabolically healthy obesity” (MHO), if anything is distracting and even counterproductive to public health efforts to prevent obesity.
They argue that,
“the MHO phenotype is not benign and as such has very limited relevance as a public health target.”
Throughout the article, the authors indeed make the oft-heard arguments for a population wide approach based on the notion that even a small left-shift in the weight distribution curve (as popularized by Geoffrey Rose) can have a potentially large influence on the population burden of excess weight.
This is not something anyone would argue with – at least at a population level and when the issue is prevention.
Unfortunately, Rey-López and colleagues then fall into the trap of pooh-poohing the research efforts around better trying to understand exactly why there is such a variation in how excess weight may (or may not) affect an individual’s health.
“More efforts must be allocated to reducing the distal and actual causal agents that lead to weight gain, instead of the current disproportionate scientific interest in the biological processes that explain the heterogeneity of obesity.”
Furthermore, they argue against further investments into obesity treatments:
“Nevertheless, it should be openly recognized that further investments in this predominantly individual approach will not reverse the obesity epidemic, because 1) medical therapies or dramatic lifestyle changes do not modify the distal causes of obesity (i.e., modern processed food and the built environment) and 2) individualized lifestyle modifications are commonly unsuccessful and inaccessible.“
The two facts that are largely ignored in this discussion are 1) that efforts at prevention (no matter how effective) are not helping the millions of people already living with this problem and 2) trying to find better treatments by learning more about the biology of this condition is exactly how we have found treatments for a host of other conditions ranging from diabetes to hypercholesterolemia and that these treatments have indeed allowed millions of people with these conditions to live productive and meaningful lives.
Personally, I find that the line of argument presented by the authors reeks of discrimination against people living with this problem. Thus, I cannot help but think that the authors consider people with obesity a “lost cause” not worthy of the investment into finding or providing better treatments.
Whether or not the discussions about MHO will help advance the field or not is certainly debatable.
Wether pitching prevention against treatment has the potential to actually harm people living with this problem is not.
Thus, a study by Asheley Skinner and colleagues, published in the New England Journal of Medicine, shows that increased cardiometabolic risk is tightly linked with severe obesity both in children and young adults.
The study looks at cross-sectional data from overweight or obese children and young adults (3-19 yrs) who were included in the US National Health and Nutrition Examination Survey (NHANES) from 1999 through 2012.
Among 8579 children and young adults with a body-mass index at the 85th percentile or higher (according to the Centers for Disease Control and Prevention growth charts), 46.9% were overweight, 36.4% had class I obesity, 11.9% had class II obesity, and 4.8% had class III obesity.
Overall, for a given weight, males tended to have higher cardiometabolic risk than females.
Even after controlling for age, race or ethnic group, more severe obesity maps more likely to be associated with low HDL cholesterol level, high systolic and diastolic blood pressures, and high triglyceride and glycated hemoglobin levels.
Importantly, while this relationship was constantly present in males, the there were fewer significant differences in these variables according to weight category among female participants, suggesting that for a given body weight, girls were less likely to be at cardiometabolic risk compared to boys.
Thus, while body weight (or body fat) may not be a precise measure of individual health, the risk for having one or more cardiometabolic risk factor increases substantially with increasing severity of obesity.
However, it is also important to note that even in kids and youth with class III obesity, 70% of participants had normal lipids and about 90% of participants did not have elevated blood pressure or glycated hemoglobin.
This points to the fact that for a given body weight there is indeed wide variability in whether or not someone actually has cardiometabolic risk factors.
Thus, whether or not it makes sense to target every kid that presents with an elevated BMI for intervention, remains to be shown – most likely such an approach would probably not be cost-effective.
As in adults, it seems that interventions in kids are probably best targeted by global risk rather than simply by numbers on a scale.
Next week, the newly formed Toronto Chapter of the Canadian Obesity Network (CON-YYZ) will be hosting its inaugural networking event at the MaRS Discovery District in Toronto.
The event titled Roadblocks & Detours will explore the barriers and challenges to improving obesity prevention and management in Toronto and beyond.
The panel and speakers will include Dr. Sean Wharton (Internist and Chapter President), Sandra Elia (Life Coach and host of Your Daily Diet – A Spiritual Guide to Healthy Body Size), Dr. Cynthia Maxwell (Associate Professor, Maternal-Fetal Medicine, Mount Sinai Hospital) and yours truly as the key-note speaker.
The event will be moderated by Deborah Schwartz (Senior Analyst on the Health System Research team at the Canadian Institute for Health Information and PhD candidate in psychology at the University of Toronto).
I look forward to a most interesting discussion and the opportunity to meet and network with all of CON’s members in Toronto.
The event takes place
Tuesday October 6, 2015 from 6:00pm – 9:00pm
MaRS Discovery District
101 College Street, Room CR-2
Toronto, ON M5G 1L7 Canada
To learn more about the CON Chapter in Toronto, click here
To register for CON-YYZ’s inaugural event, click here.
Nevertheless, for what it is worth, a publication by Ruth Brown and colleagues from York University, Toronto, published in Obesity Research and Clinical Practice, suggests that people today may be more susceptible to obesity than just a few decades ago.
The study looks at self-reported dietary from 36,377 U.S. adults from the National Health and Nutrition Survey (NHANES) between 1971 and 2008 and physical activity frequency data from 14,419 adults between 1988 and 2006 (no activity data was available from earlier years).
Between 1971 and 2008, BMI, total caloric intake and carbohydrate intake increased 10-14%, and fat and protein intake decreased 5-9%.
Between 1988 and 2006, frequency of leisure time physical activity increased 47-120%.
However, for a given amount of caloric intake, macronutrient intake or leisure time physical activity, the predicted BMI was up to 2.3kg/m2 higher in 2006 that in 1988.
So unless there was some major systematic shift in what people were reporting (which seems somewhat unlikely) it is clear that factors other than diet and physical activity may be contributing to the increase in BMI over time – or in other words, it appears that people today, for the same caloric intake and physical activity, are more likely to have a higher BMI than people living a few decades ago.
There are of course several plausible biological explanations for these findings including epigenetics, obesogenic environmental toxins, alterations in gut microbiota to name a few.
If nothing else, these data support the notion that there is more to the obesity epidemic than just eating too much and not moving enough.
Apart from its important role in appetite regulation, leptin has a number of other central and peripheral actions – one of which is to increase activity of the sympathetic nervous system.
A paper by Wenwen Zeng and colleagues published in Cell, now provides conclusive evidence that leptin can mediate fat breakdown from fat cells and does so via stimulation of the sympathetic nervous system.
Using sophisticated nerve imaging techniques, the researchers show that fat cells are often densely surrounded by sympathetic nerve endings, which, when stimulated, lead to the mobilization of stored fat and a reduction in fat mass.
Genetic ablation of these nerve endings or removal of the key enzyme involved in catecholamine synthesis completely blocks the lipolytic effect of leptin showing that the fat mobilizing effect of leptin is entirely dependent on intact sympathetic innervation and signalling in fat tissue.
Overall the finding that sympathetic nerve activity stimulates lipid release in adipose tissue is not new – but the clear demonstration that his mechanism is harnessed by leptin is.
How this finding could possibly be harnessed for obesity treatment is difficult to say – while stimulating sympathetic nerve activity may well result in lipid mobilisation, it also comes with the feared adverse effects of stimulating heart rate and increasing blood pressure, which would likely limit the clinical use of any such approach.
Any form of rapid weight loss is well known to promote the formation of gall stones. Thus, given the rapid rate of weight loss post bariatric surgery, patients are at particularly high risk of developing gall stones (and related complications).
Now, a study by Lindsay Adams and colleagues, published in Obesity Surgery reports on a trial that examined whether or not administration of ursodeoxycholic acid (UDCA) could reduce the incidence of galls stones following sleeve gastrectomy.
75 eligible patients (57 of who completed the study) were randomized to receiving 300 mg UDCA twice daily for 6 months post-surgery or no treatment. Gallbladder ultrasounds were performed preoperatively and at 6 and 12 months postoperatively.
At 6 months, 2 of the 19 treated patients who had ultrasounds had gall stones compared to 10 of 25 patients in the control group.
However, at 12 months (6 months after discontinuation of therapy), 2 of 22 treated patients had galls stones compared to 3 out of 14 in the control group.
Of the 17 patients who developed gallstones, 7 patients underwent cholecystectomy.
Whether or not patients developed sludge or stones with treatment was highly dependent on compliance to treatment. Thus, from those patients who completed the 6-month ultrasounds, neither gallstones nor sludge were reported in any of 11 patients who reported good compliance. Two out of three patients who reported moderate compliance developed gallstones or sludge, and two out of five who reported poor compliance developed gallstones or sludge.
Overall, the authors note that the incidence of gallstones with about 30% was as high as has been reported for patients with gastric bypass surgery.
Clearly this study (as acknowledged by the authors) has important limitations due to the considerable number of participants that were lost to follow-up.
Nevertheless, for what it’s worth, the study certainly suggests that USCA treatment can markedly reduced the incidence of sludge and gallstones at 6 months in patients undergoing sleeve gastrectomy.
As to whether or not this would justify the routine use of USCA in all patients following bariatric surgery is certainly debatable.