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All obesity interventions eventually lead to a plateau in weight, where further loss ceases despite ongoing efforts. But the duration of continuous weight loss before hitting a plateau is longer with both glucagon-like peptide 1 (GLP-1) receptor agonist drugs and gastric bypass surgery than with dietary restriction, primarily because they alter how weight loss affects appetite, not energy expenditure.

That's the conclusion from a new mathematical modeling study based on published data. The study showed that both GLP-1 agonists and Roux-en-Y gastric bypass (RYGB) surgery act to weaken the increase in appetite that normally occurs with time after weight loss attained through dietary restriction alone.

The average time to weight loss plateau occurred within 12 months with dietary restriction vs 24 months in studies of tirzepatide (a dual glucose-dependent insulinotropic polypeptide/GLP-1 agonist), semaglutide, and RYGB, according to Kevin D. Hall, PhD, chief of the integrative physiology section at the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

The findings were published in Obesity.

Both RYGB and tirzepatide resulted in greater weight loss than semaglutide, but plateau timing of the three was roughly the same at 24 months. "The timing of the plateau is a different question than how much weight they lost," Hall told Medscape Medical News.

The modeling data came from studies of people who underwent RYGB, had continuous dietary intervention, or took semaglutide or tirzepatide on a weekly basis for the entire study until reaching a weight loss plateau.

"The plateau is not primarily due to reduction in calorie expenditure, which I think many physicians still believe. It's mostly about how quickly your appetite is going up as weight is lost as you persist in this constant intervention," Hall said.

Clinically, this means "you expect a plateau to be reached. That doesn't mean that the intervention has stopped working. It's just now that has been matched by the body's pushback with equal strength to the intervention magnitude. And this is primarily due to an increase in appetite, more so than the calorie expenditure, although that plays a smaller role," he explained.

Asked to comment, Giles Yeo, MBE, professor of molecular neuroendocrinology at the University of Cambridge, Cambridge, England, told Medscape Medical News "as a concept, this makes sense."

Yeo said it fits with his conceptualization of "appetite" as having three aspects that form a triangle: Hunger, fullness, and reward. "If you tug at one, you change the shape of the triangle. If you just go on a diet, you become hungrier. Your brain is trying to drag you back up. Therefore, you change the triangle in a specific way."

But, with surgery and the GLP-1 drugs, both of which act on the gut hormones, "you make the person feel fuller. As a result, you're not only pulling on the hunger bit, you're also tugging pretty strongly on the fullness bit. You feel fuller longer, so the appetite takes longer to come back."

However, Yeo noted that the study is not empirical. "What he's done is taken open access data that has been published in the clinical trials and fit it into his model to ask the question about the rate at which we finally get to a plateau, and to work out the role of appetite vs the role of energy expenditure."

And, Yeo pointed out, the model doesn't consider interindividual variability, noting, "he's taking an average."

Appetite Feedback Control Is Key

Hall used a validated mathematical model to simulate body weight trajectories, body composition, and energy balance dynamics for each of the four weight loss interventions: Diet restriction, semaglutide 2.4 mg, tirzepatide 10 mg, and RYGB. The model quantified the effect of the intervention within a system that dynamically adapts both energy expenditure and proportional feedback control of appetite.

In one of the two diet-alone studies, participants cut an average of 1200 kcal/d from their baseline diets at the beginning of the intervention, but at about 12 months, their appetites began to increase by about 100 kcal/d for every kilogram of weight loss, resulting in a progressive increase in calorie intake over time. In the other diet study, those values were 830 kcal/d and 82 kcal/d/kg, respectively.

Tirzepatide, on the other hand, resulted in a maximum cut of 1560 kcal/d after the initial dose titration period, with appetite reduced to only a 48 kcal/d increase in caloric intake per kilogram of weight lost, reaching a plateau at 24 months. For semaglutide, those numbers were 1300 fewer kcal/d, increasing by 49 kcal/d/kg, respectively.

And RYGB surgery resulted in a 3600 kcal/d cut, weight loss through 24 months, and approximately a 58 kcal/d increase in energy intake per kilogram of weight loss after that.

"So, the drugs and the surgery are weakening, not eliminating, the appetite's natural response to weight loss," Hall said.

According to Yeo, the main message of this paper is, simply, that the medications and surgery add a boost to diet restriction to make weight loss easier. "This model explains why because your hunger triggers just drag you back up a heck of a lot quicker if you aren't on a drug."

Hall's model is now incorporated into a prototype "personalized body weight management system" for use by healthcare professionals in the context of comprehensive healthcare or wellness programs.

This work was supported by the Intramural Research Program of the National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases. Hall had no further disclosures. Yeo consults for Novo Nordisk and Eli Lilly and received grant funding from Novo Nordisk to understand the mechanisms of GLP-1 action in the human brain.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape Medical News, with other work appearing in the Washington Post, NPR's Shots blog, and Diatribe. She is on X: @MiriamETucker.