How GLP-1, GIP, and Glucagon Differ

The newest generation of metabolic drugs is increasingly described not by single hormones but by combinations: single, dual, even triple agonists. To make sense of that, you need to know the three hormones being mixed and matched. GLP-1, GIP, and glucagon each have a distinct role, and the differences between them are the entire logic behind why these drugs are designed the way they are.

GLP-1: the one you have heard of

GLP-1, glucagon-like peptide-1, is released from the gut after eating. It does several useful things at once: it stimulates insulin release when blood sugar is high, slows the emptying of the stomach, and acts on the brain to reduce appetite. This combination is why GLP-1 receptor agonists became central to both diabetes and weight management.

The key feature is that its insulin-stimulating effect is glucose-dependent — it nudges insulin mainly when blood sugar is elevated, which limits the risk of driving sugar too low.

Beetroot, beets, vegetables — illustrating How GLP-1, GIP, and Glucagon Differ

GIP: the other incretin

GIP, glucose-dependent insulinotropic polypeptide, is the other major incretin hormone, also released from the gut after eating. Like GLP-1, it helps stimulate insulin in response to food. Historically GIP was a confusing character, with arguments about whether activating or blocking it would help.

What matters for the drugs is that combining GIP activity with GLP-1 activity appears, in practice, to enhance the metabolic and weight effects. Tirzepatide, a dual GIP/GLP-1 agonist, produced up to roughly 22.5% mean weight loss in the SURMOUNT-1 trial (NEJM, 2022) — more than semaglutide’s 14.9% in STEP 1 (NEJM, 2021), though the trials are not head-to-head.

The honest nuance: exactly why adding GIP helps is still an area of active discussion. The clinical results have been strong, even as the precise mechanism remains debated.

Watermelon, berry, fruit — illustrating How GLP-1, GIP, and Glucagon Differ

Glucagon: the surprising teammate

Glucagon is the one that seems out of place. It is, in many ways, insulin’s opposite: it raises blood sugar, telling the liver to release stored glucose. So why would a weight or diabetes drug want to activate it?

The answer is energy expenditure. Glucagon also increases the rate at which the body burns energy and can promote fat breakdown. The idea behind triple agonists is to pair glucagon’s energy-expending and fat-mobilizing effects with the appetite and insulin benefits of GLP-1 and GIP, carefully balanced so the blood-sugar-raising effect does not undo the metabolic gains. Retatrutide — a GLP-1/GIP/glucagon triple agonist — produced up to about 24% mean weight loss at 48 weeks in a phase 2 trial (NEJM, 2023).

Quick contrast

GLP-1: boosts insulin when needed, slows gastric emptying, reduces appetite.
GIP: an incretin that boosts insulin and, combined with GLP-1, appears to amplify benefits.
Glucagon: raises blood sugar but increases energy expenditure and fat breakdown.

Carrots, vegetables, harvest — illustrating How GLP-1, GIP, and Glucagon Differ

Why this matters for the drugs

This is the framework behind the product landscape. Single agonists target GLP-1 (semaglutide, liraglutide). Dual agonists add GIP (tirzepatide). Triple agonists add glucagon (retatrutide, still investigational). Each addition is an attempt to recruit another lever of metabolism, with the engineering challenge of balancing effects that partly pull in different directions. It also helps explain why newer agents have sometimes shown larger effects — though whether more levers always means a better risk-benefit profile is a question the long-term data is still answering.

The takeaway

GLP-1, GIP, and glucagon are three distinct hormones with three distinct jobs, and the modern metabolic drugs are essentially experiments in combining them. GLP-1 reduces appetite and helps insulin; GIP appears to amplify those gains; glucagon adds energy expenditure at the cost of raising blood sugar, requiring careful balance. Understanding these three roles is genuinely the key to reading the newest drugs.