Contributing authors: Lars Johansson, CSO & Danielle Sjogren, Science Communication Manager
Earlier this month we heard the latest diabetes and obesity research at the American Diabetes Associaton (ADA)’s Scientific Sessions in New Orleans, LA. It was a very eventful few days, with top-line data, insightful symposia and plentiful presentations all contributing to the overall feeling that the field is rapidly progressing amid a therapeutic landscape that continues to expand.
Lars spoke about body composition changes during weight loss in a breakfast symposium, a topic which resurfaced several times throughout the meeting. In this blog post, we discuss a couple of highlights from the congress and reflect on what could be next in the field of obesity research.
Highlight 1: The nature of the link between adipose tissue insulin resistance and systemic metabolic dysfunction
A recurring question in metabolic disease pathogenesis was sought to be answered during the ‘Insulin Resistance: A Cause or Consequence of Metabolic Dysfunction?’ session. An important part of this is the role of adipose tissue insulin resistance and the contribution of adipocytes to its development. Philipp Scherer, in his talk ‘Adipose Insulin Resistance as a Driver of Metabolic Dysfunction’”, addressed this and provided some insights that made it one of the highlights of the conference.
His talk focused on insulin sensitivity at the level of the adipocyte. When there is excessive lipid accumulation in the adipocytes, the adipose tissue becomes inflamed and infiltrated with immune cells, fibrotic, and resistant to insulin signaling, which impairs glucose uptake and dysregulates adipokine production. This can lead to ectopic fat accumulation subsequent insulin resistance in other tissues like the liver and skeletal muscle, and the alterations in adipokine signaling can cause dysregulation of systemic metabolism.
This emphasized the role of adipose tissue insulin resistance as a driver of metabolic dysfunction, but also its potential as a solution. One example presented was research that demonstrated improved systemic metabolic effects with the elimination of phosphatase and tensin homolog (PTEN) from subcutaneous adipocytes, which normally functions to negatively regulate insulin signaling. The findings warrant further research in this area and speak more broadly to the importance of future research looking specifically into adipose tissue changes during weight loss and with therapeutic intervention.
Highlight 2: Comparing apples to apples when interpreting weight loss data
Another highlight was the ‘Obesity Year in Review: Major Advances and Discoveries’ symposium, and particularly the ‘Clinical’ overview given by Louis Aronne. What made this a highlight was not only that it gave an informative overview of some the most impactful trials that were published throughout the year, though that is always very interesting to hear, but rather the time that was spent explaining some of the things that need to be kept in mind when interpreting weight loss data.
Lars mentioned during his talk the reasons why body composition as measured by DXA cannot be compared to those done with MRI, and that in addition to these measurement differences, trial duration and patient characteristics like sex and race can have an impact on results. But this part of the symposium also touched upon other considerations like treatment vs. efficacy estimands, baseline BMI, adherence and comparator strategies.
This last point on adherence and comparator strategies was brought up by others throughout the congress, mostly as a reflection of the difficulties in maintaining adherence in control placebo groups who can be disappointed by early lack of weight loss efficacy. With approved therapies now available for the treatment of obesity, or overweight with comorbidities, there could be less motivation for participants to sign up for clinical trials in which they might receive placebo. It seems likely the field will need to move towards comparator strategies that involve standard of care, which will have implications for how we interpret weight loss data and other efficacy measures as well.
Reflection: What’s next in the ever-expanding therapeutic landscape for obesity?
A key question mused during the congress was whether current therapies in development have approached maximal efficacy in terms of weight loss, and if so, what this could mean for future drug development. Therapies in development are based on a wide range of different targets and mechanisms of action, which opens up the possibilities for combinations. However, it also underscores the need for deeper, more comprehensive understanding of mechanism of action, to help guide targeted and complementary combinations.
Importantly, the field is really moving beyond weight loss in and of itself. During this congress there was a big focus on ‘health benefits’, such as organ protection in the liver, kidney and heart. There was also data presented on changes in downstream conditions such as knee osteoarthritis and obstructive sleep apnoea. It seems this will continue, as treatment with weight loss-inducing therapeutics continues to expand into other health conditions, and even into extending the healthy lifespan itself.
Closing thoughts
There was so much science at this year’s ADA conference that it would be impossible to delve into it all, so in this blog post we chose a couple of highlights and some overall reflections to discuss:
- The nature of the link between adipose tissue insulin resistance and systemic metabolic dysfunction: insights into adipocyte insulin resistance and its effects systemically underlined the relevance of looking specifically into changes in the adipose tissue during weight loss and with therapeutic intervention.
- Comparing apples to apples when interpreting weight loss data: trial duration, efficacy estimands, adherence, comparator strategies and patient characteristics like sex, race and baseline BMI can all influence weight loss data. These things need to be kept in mind when interpreting data or drawing conclusions from comparisons.
- What’s next in obesity: deep understanding of mechanisms of action will enable targeted and complementary combinations, as well as expansion into more organ protection and other health benefits.
We are looking forward to seeing how the field has advanced again at next year’s ADA Scientific Sessions in Washington, D.C.
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The views and opinions expressed in this article are solely those of the contributing author/s. These views and opinions do not necessarily represent those of Antaros Medical.
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