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Semaglutide probably works in the brain
How it works
Appetite suppression may be a large part of how the drug works, and taken to an extreme it produces nausea, which some patients cannot tolerate.
Muscle and regain
The drugs are catabolic across the board, so patients lose muscle as well as fat. Weight comes back after stopping semaglutide, though newer versions seem to preserve the weight loss even off the drug.
Calories and unknowns
Calories can get around the drug: patients who keep drinking a lot of caloric drinks, alcohol especially, seem to find it easier to get around its benefits, an anecdotal observation. It is still unclear whether people will cycle on and off or stay on indefinitely, and whether resistance will develop.
How does semaglutide act on the brain?
GLP-1 receptors are found in the hypothalamus and brainstem, areas that regulate hunger and fullness. In a 2020 study in JCI Insight led by Sanne Gabery in rodents, semaglutide reached the hypothalamus through regions where the blood-brain barrier is more permeable and activated neurons that suppress appetite. GLP-1 receptors have also been found in brain areas linked to reward.
How did a lizard lead to semaglutide?
In the early 1990s, the endocrinologist John Eng at the Bronx Veterans Affairs Medical Center isolated a peptide called exendin-4 from the saliva of the Gila monster. It resembles human GLP-1 and resists breakdown, and it became the basis for the first GLP-1 drug, exenatide, approved in 2005. Semaglutide is instead built on the human hormone, with changes that let it bind albumin in the blood and last about a week.
How much of weight lost is muscle?
In a DEXA substudy of 140 participants in the STEP 1 trial, published in the New England Journal of Medicine in 2021 by John Wilding and colleagues, about 39 percent of the weight lost on semaglutide was lean mass. Lean mass includes muscle but also organs and water.
How much weight returns after stopping?
A STEP 1 extension study published by John Wilding and colleagues in 2022 followed participants for a year after they stopped semaglutide. They regained about two-thirds of the weight they had lost. Improvements in blood pressure and cardiometabolic markers also reverted toward baseline.
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