How tirzepatide works

Two gut hormones: GIP and GLP-1

After a meal, your intestine releases hormones. Two of them are GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). The European Medicines Agency summary of Mounjaro® describes both as gut hormones that bind to receptors in places such as the pancreas and the brain ^[4].

Most medicines in this family act only on the GLP-1 receptor. Tirzepatide is different: the Mounjaro® label calls it a GIP receptor and GLP-1 receptor agonist. It selectively binds to and activates both receptors, the same targets the natural hormones use ^[1].

What the molecule looks like

The description section of the label says tirzepatide is based on the GIP sequence. A few parts are deliberately changed: an unusual amino acid called aminoisobutyric acid sits at positions 2 and 13, the chain ends in an amide, and the lysine at position 20 carries a 20-carbon fatty diacid attached through a linker ^[1].

The label gives a molecular weight of 4813.53 daltons, large for a medicine. It comes as a clear, colourless to slightly yellow solution injected under the skin ^[1]. The European product information counts 39 amino acids in the chain ^[5].

In the first published description of the compound, then known by its code LY3298176, Lilly researchers presented it as a fatty acid-modified peptide built for once-weekly injection under the skin; their phase 1 data in healthy volunteers and people with type 2 diabetes supported weekly dosing ^[7].

Two receptors, not engaged equally

Acting on two receptors does not mean acting on both in the same way. The European product information compares tirzepatide with the natural hormones: at the GIP receptor its activity matches that of native GIP, whereas at the GLP-1 receptor it is weaker than the body’s own GLP-1 ^[5].

A 2020 laboratory study, by a team made up largely of Lilly employees, estimated how much of each receptor tirzepatide occupies at the doses used in clinical trials. It found more engagement of the GIP receptor than of the GLP-1 receptor, which the authors call an imbalanced profile. At the GLP-1 receptor, tirzepatide favoured one signalling route (cAMP) over another (β-arrestin recruitment) and pulled fewer receptors into the cell than GLP-1 does ^[6].

In islet cells from the pancreas, β-arrestin 1 limited the insulin response to GLP-1 but not to tirzepatide, and the authors suggest this bias may add to its effect on insulin ^[6]. These are cell and tissue experiments: they describe a mechanism, not what an individual patient will notice.

Appetite and calorie intake

The Zepbound® label says GLP-1 is a physiological regulator of appetite and calorie intake, and that non-clinical studies suggest adding GIP may further contribute to regulating food intake. Receptors for both hormones are found in brain areas involved in appetite, and animal studies showed tirzepatide reaching and activating nerve cells there ^[2].

In people, the label says tirzepatide decreases calorie intake and that the effect is likely mediated by appetite. It also says tirzepatide lowers body weight with greater loss of fat mass than lean mass. Study results are group averages from people who also followed a reduced-calorie diet with more activity ^[2].

The European text adds detail from clinical studies: tirzepatide increased feelings of satiety and fullness, reduced hunger, and lowered both the intensity of food cravings and the preference for very sugary and fatty foods ^[5]. In mice, the early Lilly work found larger falls in body weight and food intake than with a GLP-1 receptor agonist alone ^[7].

Insulin, glucagon and blood sugar

According to the Mounjaro® label, tirzepatide enhances both the first and second phase of insulin secretion and reduces glucagon, in a glucose-dependent manner. Put simply, the push on insulin is strongest when blood sugar is high. A clamp study after 28 weeks also showed improved insulin sensitivity ^[1].

The label reports that, after 28 weeks, the 15 mg dose reduced fasting glucagon by 28% and glucagon after a mixed meal by 43%, while placebo showed no change. The labels still warn that using tirzepatide with insulin or with medicines such as sulfonylureas can raise the risk of low blood sugar, and your prescriber may adjust those medicines ^[1][2].

What the labels measured

The table collects the measured effects in one place, with the section where each number appears. They come from studies in groups of people, most of them with type 2 diabetes for the insulin and glucagon results.

Slower stomach emptying, mostly at the start

Tirzepatide delays gastric emptying. Both labels add a detail worth knowing: the delay is largest after the first dose and becomes smaller over time ^[1][2]. In a study described in the Mounjaro® label, a first 5 mg dose cut the peak level of paracetamol (acetaminophen) taken by mouth by half, while by week 4 there was no meaningful effect; the Zepbound® label reports a 55% cut and no meaningful effect at week 6 on 15 mg ^[1][2].

This is why the labels mention oral birth control pills. Because slower emptying may make them less effective, the labels point pill users to a contraceptive that is not swallowed, or to a condom alongside the pill, during the first four weeks of treatment and again for four weeks after every step up ^[1][2]. In the label study, a single 5 mg dose lowered the peak levels of the pill’s hormones by 55% to 66% and their total exposure by about a fifth ^[1].

The same timing matters for other tablets. For medicines that only work above a certain blood level, or that have a narrow safe range such as warfarin, the labels ask prescribers to monitor more closely while tirzepatide is being used ^[1][2].

Why it is injected once a week

The 20-carbon fatty diacid lets tirzepatide bind to albumin, the main protein in blood; the label says about 99% is bound and that this prolongs the half-life. The Mounjaro® label gives an elimination half-life of about 5 days, and the Zepbound® label gives about 5 to 6 days in people with overweight or obesity ^[1][2].

After an injection, the highest level in the blood is reached within 8 to 72 hours, with a median of 24 hours in the Zepbound® label, and on weekly use the level settles into a steady pattern after about 4 weeks. Injections in the abdomen, thigh or upper arm gave similar exposure ^[1][2].

The body breaks tirzepatide down by cutting the peptide chain, shortening the fatty acid and splitting off the amide group, and no intact drug was found in urine or faeces ^[1]. Kidney or liver impairment, including end-stage kidney disease, did not change how it is handled, and neither label gives a dose adjustment for them; the labels do ask for kidney checks in people whose stomach side effects could dehydrate them ^[1][2].

A long half-life also means the medicine is still present for some time after the last injection. The European text advises stopping it at least one month before a planned pregnancy for that reason, and the US label takes the roughly five-day half-life into account when describing how long to watch someone after an overdose ^[1][5].

One molecule, two US labels

• Mounjaro® is approved, alongside diet and exercise, to improve blood sugar control in type 2 diabetes for adults and for children from age 10, and to reduce the risk of major cardiovascular events in adults with type 2 diabetes who are at high risk ^[1].
• Zepbound® is approved, with a reduced-calorie diet and more activity, for weight reduction and long-term maintenance in adults with obesity, or overweight with at least one weight-related condition, and to treat moderate to severe obstructive sleep apnoea in adults with obesity ^[2].
• The Zepbound® label says using it together with other tirzepatide products or any GLP-1 receptor agonist is not recommended ^[2].
• In the European Union, the EMA summary shows a single Mounjaro® authorisation covering both type 2 diabetes and weight management. Approved uses differ by country ^[4].

Keeping notes that help your clinician

Because the stomach effect is strongest early on, many people notice the most change in the first weeks and after each dose step. Writing down appetite, meals, stomach symptoms and weight next to each weekly dose turns vague memories into something your clinician can read.

Mounjaro® and Zepbound® are registered trademarks of Eli Lilly and Company. PepLabo is not affiliated with or endorsed by Eli Lilly and Company.

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