Short answer
The best-supported explanation is that the body pushes back against weight loss, and stopping the drug removes what was holding that push in check. After weight loss, appetite hormones shift toward more hunger and the body burns fewer calories at rest. Both changes have been measured a year or more later. The GLP-1 withdrawal trials measured the regain, not its cause.
Appetite hormones stay shifted
A 2011 study in the New England Journal of Medicine put 50 adults with overweight or obesity on a 10-week very-low-energy diet. They lost 13.5 kg on average. Levels of leptin, peptide YY, cholecystokinin, insulin and amylin fell, ghrelin rose, and people rated their appetite higher.
The researchers measured again at 62 weeks. Leptin, peptide YY, cholecystokinin, insulin and ghrelin were still significantly different from baseline, and so was hunger. Their conclusion was that the appetite signals that encourage regain do not revert to pre-weight-loss levels within a year.
The body burns less
A 2016 study followed 14 contestants from “The Biggest Loser” for 6 years. At the end of the 30-week competition they had lost 58.3 kg on average, and their resting metabolic rate had dropped by 610 calories a day. Six years later they had regained 41.0 kg of it, yet resting metabolic rate was 704 calories a day below baseline.
After adjusting for body composition and age, the gap was still 499 calories a day. This was a small study of very large weight loss in a television competition, so treat the size of the numbers as specific to that group.
What the withdrawal trials add
Three trials took the drug away on purpose. In the STEP 1 extension, 327 people who stopped semaglutide and lifestyle support after 68 weeks regained 11.6 percentage points of a 17.3% loss over the next year, about two-thirds. In STEP 4, people switched to placebo gained 6.9% over 48 weeks while those who continued lost a further 7.9%. In SURMOUNT-4, people switched from tirzepatide to placebo gained 14.0% over 52 weeks, and those who continued lost a further 5.5%.
The STEP 1 extension authors wrote that the findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain the improvements.
What nobody has shown
The hormone and metabolism studies were done after diet or competition weight loss, not after a GLP-1. The withdrawal trial abstracts report weight and health markers, not appetite hormones or metabolic rate. So the link between the two sets of findings is a reasonable inference, not a measured result.
None of these papers tested a way to stop a GLP-1 without regain. Whether and how to stop is a decision to make with your prescriber.
Related questions
Does everyone regain the weight?
No. In SURMOUNT-4, 16.6% of people switched to placebo still held at least 80% of their weight loss a year later, compared with 89.5% of those who stayed on tirzepatide.
Does all of the weight come back?
Not within a year in the STEP 1 extension. People regained about two-thirds and were still 5.6% below their starting weight at week 120.
Does metabolism recover over time?
In the Biggest Loser follow-up it had not after 6 years. Resting metabolic rate was 704 calories a day below baseline.
Read next
Sources
- New England Journal of Medicine: Long-term persistence of hormonal adaptations to weight loss, Sumithran (2011)
- Obesity: Persistent metabolic adaptation 6 years after “The Biggest Loser” competition, Fothergill (2016)
- Diabetes, Obesity and Metabolism: Weight regain after withdrawal of semaglutide, the STEP 1 trial extension, Wilding (2022)
- JAMA: STEP 4 randomized clinical trial, Rubino (2021)
- JAMA: SURMOUNT-4 randomized clinical trial, Aronne (2024)
Published 2026-10-04 · Last checked 2026-10-04
Educational content, not medical advice. Made for the United States.