GLP-1 vs. GIP vs. Glucagon: What’s the Difference?

The three hormones at a glance

GLP-1: the appetite and insulin hormone

GLP-1 is released from the lining of the gut within minutes of a meal. Its jobs:

• Insulin. It tells the pancreas to release more insulin, but only when blood sugar is high. That glucose dependence is why GLP-1 drugs rarely cause low blood sugar on their own.
• Glucagon. It suppresses glucagon release, which reduces the liver’s glucose output after meals.
• Stomach emptying. It slows how fast food leaves the stomach, which smooths the rise in blood sugar and makes you feel full longer.
• Appetite. It acts on the brain, particularly the hypothalamus and brainstem, to reduce hunger and food intake.

Natural GLP-1 is broken down in about two minutes by an enzyme called DPP-4. Drugs like semaglutide are modified to resist that enzyme and bind to blood proteins, which stretches their action to about a week.

GIP: the other incretin

GIP was actually discovered first, and in healthy people it accounts for most of the incretin effect, the extra insulin release you get from eating glucose rather than injecting it. Its jobs:

• Insulin. Like GLP-1, it boosts insulin release when blood sugar is high.
• Glucagon. Unlike GLP-1, it can raise glucagon when blood sugar is low, which may help protect against hypoglycemia.
• Fat tissue. GIP receptors are found on fat cells, where the hormone influences how fat is stored and how blood flow to fat tissue responds to meals.
• Appetite. On its own GIP has a modest effect. Combined with GLP-1, animal and human data suggest it adds to weight loss and may reduce nausea.

For years GIP was considered a poor drug target because its insulin effect is blunted in type 2 diabetes. Tirzepatide changed that view. It activates both GIP and GLP-1 receptors and produced more weight loss and A1c reduction than semaglutide in head-to-head trials. Researchers are still working out exactly how much of that comes from GIP.

Glucagon: the counter-hormone

Glucagon is the mirror image of insulin. When blood sugar falls, the pancreas releases glucagon, which tells the liver to release stored glucose and make new glucose. That is why glucagon is used as an emergency treatment for severe low blood sugar.

Glucagon has other effects that matter for obesity drugs:

• Energy expenditure. It increases the body’s calorie burn and fat oxidation.
• Appetite. It reduces food intake.
• Liver fat. It promotes fat breakdown in the liver.

The problem is obvious: a drug that raises blood sugar is not an obvious diabetes treatment. The solution in retatrutide and similar drugs is to pair glucagon activity with GLP-1 and GIP activity, so the insulin-boosting effects offset the glucose-raising effect while the calorie-burning effect remains. Whether that balance holds in everyone is one reason these drugs are studied closely.

Why combine them

Each hormone works through a different pathway. These figures come from separate trials with different participants, lengths, and analysis methods, so they cannot show what effect adding pathways has.

TRIUMPH-1 is published in NEJM; Lilly’s press release also reported 28.3%, an estimate of the effect if everyone had stayed on the drug. Retatrutide is investigational. Retatrutide trials have reported skin sensation changes. In the phase 2 trial, heart rate rose with higher doses, peaked around 24 weeks, then declined.

Mono, dual, and triple agonists

An agonist is a molecule that activates a receptor. The naming is simple:

• Mono-agonist: one receptor. Semaglutide, liraglutide, dulaglutide (GLP-1).
• Dual agonist: two receptors. Tirzepatide (GIP + GLP-1). Survodutide is in phase 3 trials and is not approved; it targets glucagon + GLP-1.
• Triple agonist: three receptors. Retatrutide (GIP + GLP-1 + glucagon).

The receptor list tells you the mechanism. It does not tell you the dose, the trial results, or the approval status, which differ for every drug.