Obesity Therapies: What Will the Future Bring?

“Obesity only recently caught the public’s attention as a disease,” Matthias Blüher, MD, professor of medicine at the Leipzig University and director of the Helmholtz Institute for Metabolism, Obesity and Vascular Research, Leipzig, Germany, told attendees in a thought-provoking presentation at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.
Even though the attitudes around how obesity is perceived may be relatively new, Blüher believes they are nonetheless significant. As a sign of how the cultural headwinds have shifted, he noted the 2022 film The Whale, which focuses on a character struggling with obesity. As Blüher pointed out, not only did the film’s star, Brendan Fraser, receive an Academy Award for his portrayalbut he also theorized that the majority of celebrities in the audience were likely taking new weight loss medications.
“I strongly believe that in the future, obesity treatment will carry less stigma. It will be considered not as a cosmetic problem, but as a progressive disease.”
He sees several changes in the management of obesity likely to occur on the near horizon, beginning with when interventions directed at treating it will begin.
Obesity treatment should start at a young age, he said, because if you have overweight at ages 3-6 years, the likelihood of becoming an adult with obesity is approximately 90%. “Looking ahead, shouldn’t we put more emphasis on this age group?”
Furthermore, he hopes that clinical trials will move beyond body weight and body mass index (BMI) as their main outcome parameters. Instead, “we should talk about fat distribution, fat or adipose tissue function, muscle loss, body composition, and severity of disease.”
Blüher pointed to the recently published framework for the diagnosis, staging, and management of obesity in adults put forward by the European Association for the Study of Obesity. It states that obesity should be staged not based on BMI or body weight alone but also on an individual’s medical, functional, and psychological (eg, mental health and eating behavior) status.
“The causes of obesity are too complex to be individually targeted,” he continued, unlike examples such as hypercholesterolemia or smoking cessation, where clinicians may have one target to address.
“But overeating, slow metabolism, and low physical activity involve socio-cultural factors, global food marketing, and many other factors. Therefore, clinicians should be setting health targets, such as improving sleep apnea and improving physical functioning, rather than a kilogram number.”
Three Pillars of Treatment
Right now, clinicians have three pillars of treatments available, Blüher said. The first is behavioral intervention, including strategies such as counseling, diet, exercise, self-monitoring, stress management, and sleep management.
“We know that these behavioral aspects typically lack adherence and effect size, but they’re important, and for a certain group of people, they may be the best and safest treatment.”
The second pillar is pharmacotherapy, and the third is surgery.
Each pillar poses questions for future research, he explained.
“First, do we really need more evidence that behavioral interventions typically fail in the long run and are prone to rebound of body weight and health issues? No. Or which diet is best? We have hundreds of diet interventions, all of which basically show very similar outcomes. They lead to an average weight loss of 3% to 5% and do improve health conditions associated with obesity.”
When it comes to pharmacotherapies, Blüher does believe clinicians need more options.
Depending on affordability and access, glucagon-like peptide 1 (GLP-1) semaglutide will likely become the first-line therapy for most people living with obesity who want to take medications, he suggested. The dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 tirzepatide will be reserved for those with more severe conditions.
“But this is not the end of the story,” he said. “The pipelines for obesity pharmacotherapies are full, and they have different categories. We are optimistic that we will have more therapies not only for type 2 diabetes (T2D) but also for obesity. Combinations such as CagriSema (cagrilintide + semaglutide, currently indicated for T2D) may outperform the monotherapies. We have to see if they’re as safe, and we have to wait for phase 3 trials and long-term outcomes.”
“The field is open for many combinations, ideas and interactions among the incretin-based signaling systems, but personally, I think that the triple agonists have a very bright future,” Blüher said.
For example, retatrutide, an agonist of the GIP, GLP-1, and glucagon receptors, showed promise in a phase 2 trial. Although that was not a comparative study, “the average changes in body weight suggest that in a dose-dependent manner, you can expect even more weight loss than with tirzepatide.”
Treating the Causes
The future of obesity therapy might also be directed at the originating factors that cause it, Blüher suggested, adding that “treating the causes is a dream of mine.”
One example of treating the cause is leptin therapy, as shown in a 1999 study of recombinant leptin in a child with congenital leptin deficiency. A more recent example is setmelanotide treatment for proopiomelanocortin deficiency.
“We are at the beginning for these causative treatments of obesity, and I hope that the future will hold much more of these insights and targets, as in cancer therapy.”
“Finally,” he said, “We eat with our brain. And so in the future, we also will be better able to use our knowledge about the complex neural circuits that are obesogenic, and how to target them. In doing so, we can learn from surgeons because obesity surgery is very effective in changing the anatomy, and we also observe hormonal changes. We see that ghrelin, GLP-1, peptide YY, and many others are affected when the anatomy changes. Why can’t we use that knowledge to design drugs that resemble or mimic the effect size of bariatric surgery?”
And that goes to the third pillar of treatment and the question of whether the new weight loss drugs may replace surgery, which also was the topic of another EASD session.
Blüher doesn’t see that happening for at least a decade, given that there is still an effect-size gap between tirzepatide and surgery, especially for individuals with T2D. In addition, he noted, there will still be nonresponders to drugs, and clinicians are not treating to target yet. Looking ahead, he foresees a combination of surgery and multi-receptor agonists.
“I believe that obesity won’t be cured in the future, but we will have increasingly better lifelong management with a multidisciplinary approach, although behavioral interventions still will not be as successful as pharmacotherapy and bariatric surgery,” he concluded.
Q&A
During the question-and-answer session following his lecture, several attendees asked Blüher for his thoughts around other emerging areas in this field. One wanted to know whether microbiome changes might be a future target for obesity treatment.
“So far, we don’t really understand which bacteria, which composition, at which age, and at which part of the intestine need to be targeted,” Blüher responded. “Before we know that mechanistically, I think it would be difficult, but it could be an avenue to go for, though I’m a little less optimistic about it compared to other approaches.”
Given that obesity is not one disease, are there cluster subtypes, as for T2D — eg, the hungry brain, the hungry gut, low metabolism — that might benefit from individualized treatment, another attendee asked.
“We do try to subcluster people living with obesity,” Blüher said. “We did that based on adipose tissue expression signatures, and indeed there is large heterogeneity. But we are far from addressing the root causes and all subtypes of the disease, and that would be a requirement before we could personalize treatment in that way.”
Next, an attendee asked what is responsible for the differential weight loss in people with diabetes and people without? Blüher responded that although he doesn’t have the answer, he does have hypotheses.
“One could be that the disease process — eg, deterioration of beta cell function, of the balance of hormones such as insulin and leptin, of inflammatory parameters, of insulin resistance — is much more advanced in diseases such as T2D and sleep apnea. Maybe it then takes more to address comorbid conditions such as inflammation and insulin resistance. Therefore, combining current therapies with insulin sensitizers, for example, could produce better results.”
What about using continuous glucose monitoring to help people stick to their diet? 
“That’s an important question that speaks to personalized treatment,” he said. “It applies not only to continuous glucose monitoring but also to nutrition and other modes of self-monitoring, which seem to be among the most successful tools for long-term weight maintenance.”
Blüher finished by saying, “As we look into the future, I hope that there will be better approaches for all aspects of personalized medicine, whether it is nutrition, exercise, pharmacotherapy, or even surgical procedures.”
Blüher received honoraria for lectures and/or served as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novo Nordisk, Novartis, Pfizer, and Sanofi.
Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lancet (where she was a contributing editor), and Reuters Health.
 
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