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.
A version of this article first appeared on Medscape.com.