How GLP-1 drugs work: semaglutide switches on one hormone receptor, tirzepatide two

One receptor or two

Both semaglutide labels open their mechanism section with the same two sentences: “Semaglutide is a GLP-1 analogue with 94% sequence homology to human GLP-1. Semaglutide acts as a GLP-1 receptor agonist that selectively binds to and activates the GLP-1 receptor, the target for native GLP-1.”

Put plainly, semaglutide is a near-copy of a hormone your body already makes, and it acts on the same receptor that hormone does. And it lasts: the labels put its half-life at about a week.

Tirzepatide is one molecule that acts on two receptors. The Mounjaro and Zepbound labels both call it “a GIP receptor and GLP-1 receptor agonist” that “selectively binds to and activates both the GIP and GLP-1 receptors, the targets for native GIP and GLP-1”. GIP stands for glucose-dependent insulinotropic polypeptide, as both labels spell it out. How the four products compare on approvals and doses is on semaglutide vs tirzepatide.

Appetite and calorie intake

The weight-loss labels explain weight loss through appetite. Wegovy’s reads: “GLP-1 is a physiological regulator of appetite and caloric intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.” Animal studies, it adds, show semaglutide reaching and activating neurons in brain regions that regulate food intake.

Zepbound says the same of GLP-1 and adds one line on the second hormone: “Nonclinical studies suggest the addition of GIP may further contribute to the regulation of food intake.” The verbs are the label’s own, and they’re careful: nonclinical studies, suggest, may.

Both weight labels then make the same two claims in their pharmacodynamics section. The drug “lowers body weight with greater fat mass loss than lean mass loss”, and it “decreases calorie intake. The effects are likely mediated by affecting appetite.”

The diabetes labels tell it differently, even for the same molecule. The Ozempic label never mentions appetite; its mechanism section is about blood sugar, and its pharmacodynamics section says only that semaglutide “reduces body weight”. Mounjaro says tirzepatide “decreases food intake, and reduces body weight in patients with type 2 diabetes mellitus”. Same molecules, each described in terms of what its label treats.

Blood sugar: insulin and glucagon

All four labels say the drugs increase insulin release and lower glucagon, and that the insulin effect is glucose-dependent. Ozempic spells out what that means: “when blood glucose is high, insulin secretion is stimulated, and glucagon secretion is inhibited.”

It also reports what happened when blood sugar was deliberately driven low in a study: semaglutide “did not alter the counter regulatory responses of increased glucagon compared to placebo”. In other words, the body’s own glucagon response to a low still worked.

The tirzepatide labels claim one effect the semaglutide labels don’t. Tirzepatide “increases insulin sensitivity”, shown in a clamp study in patients with type 2 diabetes after 28 weeks of treatment. Neither semaglutide label says that of semaglutide.

The labels’ warnings about low blood sugar center on combining these drugs with insulin or a sulfonylurea.

The stomach empties more slowly

All four slow the stomach, and each words it differently. Ozempic calls it “a minor delay in gastric emptying in the early postprandial phase”, the stretch just after a meal. Wegovy’s whole statement is: “Semaglutide delays gastric emptying.”

One Ozempic detail sits oddly beside that. Its label reports a separate study in which “no apparent effect on the rate of gastric emptying was observed with semaglutide 2.4 mg”, which is Wegovy’s dose. The Wegovy label itself doesn’t carry that sentence.

The tirzepatide labels give a time course: “The delay is largest after the first dose and this effect diminishes over time.” Zepbound puts a number on it with a test drug. After a first 5 mg dose, peak levels of acetaminophen fell 55% and arrived an hour later; by week 6 on 15 mg there was “no meaningful impact”.

The labels tie the slower stomach to two practical warnings. It “may influence the absorption” of oral medicines taken at the same time, and the insulin and sulfonylurea rules sit beside that on drug interactions. And Ozempic’s counseling section says it “may lead to complications with anesthesia or deep sedation” during planned procedures, one of the warnings on who should not take a GLP-1.

Why one dose lasts a week

Both molecules bind to albumin in the blood, and that’s what stretches a dose to a week. The Ozempic label calls albumin binding “the principal mechanism of protraction resulting in the long half-life of semaglutide”: it slows clearance by the kidneys and protects the drug from being broken down. Semaglutide is also “stabilized against degradation by the DPP-4 enzyme”.

The result is a half-life of about a week. Ozempic’s label says semaglutide “will be present in the circulation for about 5 weeks after the last dose”; Wegovy’s says 5 to 7 weeks after the last 2.4 mg or 7.2 mg injection or 25 mg tablet.

Tirzepatide works on the same principle. It “contains a C20 fatty diacid that enables albumin binding and prolongs the half-life”, and 99% of it is bound to albumin. Mounjaro puts its half-life at about 5 days, “enabling once-weekly dosing”. Zepbound puts it at about 5 to 6 days.

The Wegovy tablet is co-formulated with SNAC, which “facilitates the absorption of semaglutide”, and it’s absorbed mainly in the stomach. Even so, the label puts its absolute bioavailability at about 1% to 2%, against 89% for the injection.

Wegovy turns that long half-life into a pregnancy rule: stop at least 2 months before planning a pregnancy, “to account for the long half-life of semaglutide”.

Where the labels’ explanation stops

The two semaglutide labels say outright where their explanation runs out. Ozempic: “The mechanism of kidney-related risk reduction has not been established.” Wegovy: “The exact mechanism of semaglutide in CV risk reduction in adults has not been established.” For liver disease (MASH), Wegovy adds that the mechanism “is not fully understood and may involve multiple pathways mediated by weight loss and other factors”.

Elsewhere the labels are simply silent. Ozempic and Mounjaro both carry an indication to lower the risk of major heart events, and neither label’s mechanism section says how that works. Zepbound is approved for obstructive sleep apnea in adults with obesity, and its mechanism section doesn’t mention sleep apnea.

Sources

See the providers

If you’ve settled on a molecule, the boards list the providers who sell it and what each one publishes.

• Semaglutide providersprovider board

  Readers who have settled on semaglutide and are choosing who to buy it from.

• Tirzepatide providersprovider board

  Readers who have settled on tirzepatide and are choosing who to buy it from.

More, read from the same labels

• Semaglutide vs tirzepatidereading the label

  What the four FDA-approved labels say each molecule is, what each is approved to treat, and where the two differ.

• Dose escalation schedulesreading the label

  The starting dose, the escalation interval and the maximum dose each label sets, and why they are not interchangeable.

• Side effect ratesreading the label

  What each label reports for nausea, vomiting, diarrhea and constipation — and the sentence every label prints above those numbers.

• Hair lossreading the label

  Which labels report hair loss, the rate against placebo where a trial measured it, and why two of them put no number on it.

• Fatigue and tirednessreading the label

  Which labels list fatigue, the rate against placebo where a trial measured it, and what each label counts as fatigue.

• Missed dose rulesreading the label

  The window each label gives for a late dose, and the minimum gap it requires when the injection day changes.

• Drug interactionsreading the label

  Insulin and sulfonylureas, oral medications, and the oral-contraceptive precaution that appears on two of these four labels and not the other two.

• Buying one onlinereading the label

  The agency's own warning signs for a telehealth GLP-1 seller, its 28-day vial rule, and what it says about drugs that arrive warm.

• Refrigeration and storagereading the label

  How cold each pen is kept, how many days it can spend at room temperature, and what the labels say about heat and freezing.

• Who should not take onereading the label

  The boxed warning every one of these labels carries, the two contraindications, and which warnings appear on which product.