Satiety Pathways: How GLP-1, GIP, and Glucagon Signals Shut Off Hunger

What GLP-1 does in the body

GLP-1 is a hormone released by the intestine. It helps lower blood glucose after eating, and it acts in parts of the brain that control appetite and food intake [2]. The Wegovy label calls GLP-1 a physiological regulator of appetite and caloric intake and notes that the GLP-1 receptor is present in several areas of the brain involved in appetite regulation [1]. In animal studies, semaglutide reached and activated neurons in brain regions involved in regulation of food intake [1].

These medicines act on the same receptor as the hormone the gut releases after eating. Semaglutide remains in the body with a half-life of about one week, while orforglipron has a half-life of about 29 to 49 hours [1][7].

How a GLP-1 receptor agonist turns that signal into less eating

Every product described here starts with the same step: binding and activating the GLP-1 receptor [1][7]. What differs is the molecule and how long it stays in the body.

Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1 and a half-life of about one week. Wegovy injection is administered once weekly [1]. Orforglipron, the molecule in Foundayo, is a small molecule taken once daily with or without food, with a half-life of about 29 to 49 hours [7]. Liraglutide, sold for weight management as Saxenda, is a once-daily injection [8].

Tirzepatide is the exception in the group. Its label describes it as an agonist at both the GIP receptor and the GLP-1 receptor, a dual agonist rather than a pure GLP-1 drug, though it is commonly grouped with them [5].

The gastric emptying brake

The Wegovy label states that semaglutide causes a delay in gastric emptying, and the Zepbound and Foundayo labels say the same for tirzepatide and orforglipron [1][5][7]. Per the labels, slower emptying can change the absorption of oral medicines, and the Wegovy label advises increased clinical or laboratory monitoring for oral drugs with a narrow therapeutic index [1]. A tablet interaction study found levothyroxine exposure rose 33% with the semaglutide tablet [1]. The Foundayo label advises a non-oral contraceptive method or an added barrier method for 30 days after starting and after each dose escalation [7]; the tirzepatide label gives that advice for 4 weeks after starting and after each dose increase [5]; the semaglutide labels carry no such advice [1].

Gastrointestinal effects are the common class effect, and they are worst during dose escalation. With Wegovy 2.4 mg, nausea was reported by 44% versus 16% on placebo and vomiting by 24% versus 6% [1]; with pooled tirzepatide 15 mg, nausea was 28% versus 8% [5]; and the Foundayo label states that nausea, vomiting and diarrhea were more frequent during dose escalation and decreased over time [7]. Rates from separate trials and populations are not directly comparable [1].

What GIP adds

The tirzepatide label states that tirzepatide activates both the GIP and GLP-1 receptors, and that nonclinical studies suggest the added GIP activity may further contribute to regulation of food intake [5].

In STEP 1, 1,961 adults with obesity or overweight and no diabetes lost 14.9% of body weight on semaglutide 2.4 mg versus 2.4% on placebo over 68 weeks [3]. In SURMOUNT-1, 2,539 adults with obesity or overweight and no diabetes received tirzepatide 5, 10 or 15 mg or placebo for 72 weeks. Weight changed by -15.0%, -19.5% and -20.9% versus -3.1% [4]. In the open-label SURMOUNT-5, 751 adults with obesity and no diabetes received the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) for 72 weeks: -20.2% versus -13.7%, with waist circumference down 18.4 versus 13.0 cm [9]. In SURPASS-2, 1,879 adults with type 2 diabetes were treated for 40 weeks; weight fell 1.9, 3.6 and 5.5 kg more with tirzepatide 5, 10 and 15 mg than with semaglutide 1 mg [10].

Whether the GIP activity explains the larger weight loss is not established by these trials [5][10][9].

Where glucagon fits

None of the approved products described here is a glucagon receptor agonist. Wegovy and Foundayo are GLP-1 receptor agonists, and tirzepatide is a GIP and GLP-1 dual agonist [1][5][7].

Retatrutide, which activates the GIP, GLP-1 and glucagon receptors, has no FDA-approved product. FDA states that retatrutide cannot be used in compounding under federal law and has not been found safe and effective for any condition [6].