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
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.
Dietitians play an often critical role in helping patients with obesity better manage their weight.
However, I also know that dietitians are the first to agree that obesity management is not just about diet (and exercise) but rather, that diet is just one aspect of an interdisciplinary management approach.
The two-day retreat (October 7-8, Toronto), which follows a highly intense interactive workshop format, covers all aspects of interdisciplinary obesity management including behavioural, medical and surgical treatments. There will also be a special focus on the nutritional management of bariatric patients as well as weight-sensitive behavioural modification.
Speakers at the event include Michael Vallis, Eric Doucet, Jennifer Brown-Vowles, Sean Wharton, and myself.
The course is open to all registered dietitians and anyone else interested in (not-just) nutritional aspects of obesity management.
For advanced registration (early bird registration ends Sept 15) and more information click here.
There is no doubt that for the vast majority of patients with type 2 diabetes, bariatric (or, as some surgeons prefer to call it, “metabolic”) surgery, can lead to marked improvement and even remission of diabetes.
A paper published in The Lancet by Geltrude Mingrone and colleagues, shows that even five years following surgery, about 50% of patients who had a biliopancreatic diversion (a rather uncommon and somewhat drastic form of bariatric surgery) and about 40% of patients who had a roux-n-y gastric bypass will still be in remission.
No doubt (as the study shows), such results are unthinkable with conventional treatments.
Although numbers are small, the fact that 25% of the non-surgical patients in this study experienced major complications from their diabetes, compared to none in the surgical groups, suggests that this is not simply glucose cosmetics but rather, that the metabolic benefits of surgery do turn into tangible benefits.
So what does this mean for the diabetes epidemic – not much, I’m afraid.
Not because surgery is not effective – it surely is.
Unfortunately, however, surgery is not scalable the way medical treatments are.
Even if we magically saw a three-fold increase in bariatric surgery (to worldwide about 1 million surgeries a year), this would hardly make a noticeable dent in the prevalence (or for that matter complications) of over 400 million people living with diabetes.
Even a five or ten-fold increase in metabolic surgery would hardly be noticeable at a global level.
Bariatric surgery (as most surgeries), is simply not a scalable procedure for a disease that affects 15% or more of the population.
Thus, aside from helping the lucky few, who do somehow manage to get surgery, the real lesson here is that we urgently need to understand exactly why surgery works (it is not just weight loss, although this does contribute to the benefit).
There are many things that happen after surgery – changes in hormonal responses to food intake (e.g. higher levels of GLP-1), changes in gut microbiota, changes in bile acid metabolism). We need to understand these factors and find non-surgical ways to mimic these changes in a manner that allows scalability to millions of people around the world.
This does not mean we need to stop doing surgery – rather, the more patients can benefit from this treatment now, the better (for them).
But let us not kid ourselves that surgery will one day solve the problem – till we can package the metabolic benefits of surgery into a tablet or a pen (or both), these findings will have little impact on the global problem of diabesity.
Yesterday, the Health Quality Council of Alberta, released a report called Overweight and obesity in adult Albertans: a role for primary healthcare, which provides an in-depth analysis of the prevalence, burden, and rates of use of a number of key healthcare services for overweight and obese individuals in Alberta. The report also provides a strong rationale for the role of primary healthcare in weight management for adult Albertans living with overweight and obesity.
In 2014, the HQCA conducted a survey of adult Albertans about their use and satisfaction with healthcare services. As part of this survey, self-reported height and weight were collected from individuals in order to calculate their body mass index. According to these findings, nearly six out of 10 Albertans over the age of 18 were either overweight or obese. The estimated provincial prevalence of adults with overweight and obesity was 35.2 per cent and 23.9 per cent, respectively. In addition, obesity was associated with an increased risk of multiple comorbidities, greater use of healthcare system services, and a lower self-rated individual quality of life.
Managing overweight and obese populations, as well as comorbid conditions, falls predominantly on primary healthcare providers. Evidence shows that diverse strategies for the management of overweight and obesity within primary healthcare are associated with benefits in weight management; however, the most effective mix of providers, interventions, and duration requires further evaluation. Moving forward, Alberta may benefit from working towards a more unified strategy for weight management that includes opportunities to engage Albertans in discussions about weight management, and to increase the use of team-based care across all weight categories.
The full report is available here.
A fact sheet is available here.