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How it works

How GLP-1 works

GLP-1 drugs act on receptors in the gut, stomach, pancreas and brain. The oral drugs act on appetite and reward centers in the brain.

Drugs

Gut to brain

Where the drugs act

1. Gut: where GLP-1 comes from

GLP-1 is released from enteroendocrine cells of the gut. In 1987 Holst's group isolated it from pig intestine and showed it raised insulin release. Native GLP-1 lasts 1.5 to 2 minutes in blood before the enzymes DPP-4 and NEP break it down. Liraglutide lasts 13 hours, tirzepatide about 5 days and semaglutide about one week.[1][2][3]

2. Stomach: slower emptying

GLP-1 slows gastric emptying. The Wegovy, Saxenda and Zepbound labels state the drug delays gastric emptying and may change how other oral drugs are absorbed. For tirzepatide the delay is largest after the first dose and lessens over time.[1][2][3]

3. Pancreas: insulin and glucagon

Semaglutide raises insulin release and lowers glucagon release in a glucose-dependent manner. This lowers blood sugar, and the same drugs are labeled for type 2 diabetes as Ozempic and Mounjaro.[1][2][3]

4. Brain: appetite centers

The GLP-1 receptor is present in several brain areas that regulate appetite. In animal studies, injected liraglutide reached the hypothalamus, and semaglutide activated neurons in regions that control food intake.[1][2]

5. GIP receptor: tirzepatide's second target

Tirzepatide activates the GIP receptor as well as the GLP-1 receptor. Nonclinical studies suggest GIP adds to the control of food intake. The Zepbound label states it lowers weight with more fat mass loss than lean mass loss.[1][2]

6. Hypothalamus and reward system: oral drugs

Phentermine likely releases catecholamines in the hypothalamus, which reduces appetite. Naltrexone-bupropion acts on the hypothalamus and the mesolimbic dopamine reward circuit, and increased firing of POMC appetite neurons in lab studies.[1][2]