Tirzepatide: how it works in the body

Tirsepatide is the first drug to combine the effects of two gut hormones, GIP and GLP-1, and in clinical studies it outperformed its predecessors in effects on body weight and glucose. The editors explain how its molecule is arranged and what happens in the body after the injection.

What is tirzepatide

Tirzepatide is the first registered drug that simultaneously activates two incretin hormone receptors: the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. Because of this, it is often called a "twincretin" or dual agonist.

The molecule is a linear peptide of 39 amino acids, the sequence of which is built on the basis of natural GIP with embedded fragments that ensure activation of the GLP-1 receptor. A fatty acid chain (C20 diacid) is attached to the peptide, which binds to blood albumin. This protects the molecule from rapid breakdown and excretion by the kidneys.

Due to this modification, the half-life of tirzepatide is about five days, which makes it possible to administer the drug subcutaneously once a week. The drug was developed by Eli Lilly under the working name LY3298176 (Coskun et al., 2018).

In the US, tirzepatide is registered under the name Mounjaro for the treatment of type 2 diabetes (2022) and Zepbound for the treatment of obesity (2023). In the EU, the name Mounjaro is used for both indications.

Incretins: a brief introduction

To understand the mechanism of tirzepatide, it is worth recalling the "incretin effect". When a person receives glucose by mouth, insulin secretion is much higher than when the same amount of glucose is given intravenously. The difference is provided by intestinal hormones - incretins, which signal the pancreas about the arrival of food.

There are two main incretins. GIP is secreted by K-cells of the upper parts of the small intestine, and GLP-1 is secreted by L-cells mainly of the lower parts of the intestine. In a healthy person, it is GIP that provides most of the incretin effect.

In type 2 diabetes, the response to GIP is significantly reduced, while sensitivity to GLP-1 is partially preserved. That is why the first incretin drugs were agonists of the GLP-1 receptor, and GIP agonism was rejected as unpromising for a long time.

Tirzepatide changed this perception: it appeared that in combination with GLP-1 receptor activation, stimulation of the GIP receptor could provide additional metabolic benefits. The exact contribution of each component to humans is still being actively studied.

Unbalanced and "shifted" agonism

Tirzepatide is not an “equivalent” agonist of the two receptors. In vitro studies have shown that it has an affinity for the GIP receptor comparable to native GIP, while the GLP-1 receptor activates significantly less than native GLP-1. Therefore, the drug is described as an unbalanced agonist with a preference for the GIP component (Willard et al., 2020).

The second important nuance is the so-called biased agonism on the GLP-1 receptor. Tirsepatide mainly triggers an intracellular signal through cAMP and involves the β-arrestin protein much less. As a result, the receptor is internalized less, that is, it remains on the cell surface longer.

The researchers hypothesize that it is this feature that helps preserve the response of beta cells to long-term stimulation. However, the extent to which laboratory data on shifted agonism explain clinical results has not been definitively established.

Another hypothesis concerns portability. There is evidence that activation of the GIP receptor in the brainstem may have an antiemetic effect, partially mitigating the nausea characteristic of GLP-1 agonists. However, in clinical practice, gastrointestinal reactions to tirzepatide remain the most frequent side effects.

Effect on the body: glucose, weight, lipids

The main effect on glucose metabolism is to increase glucose-dependent insulin secretion, suppress excess glucagon, and improve tissue sensitivity to insulin. In the SURPASS-2 study, tirzepatide reduced glycated hemoglobin more than semaglutide 1 mg at all doses tested (Frías et al., 2021).

The effect on body weight is due mainly to a decrease in appetite and food consumption. In the SURMOUNT-1 program, in non-diabetic obese subjects, mean weight loss at 72 weeks was dose-dependent and exceeded 20% at the highest dose (Jastreboff et al., 2022).

Losing weight is accompanied by an improvement in many cardiometabolic indicators: blood pressure, triglycerides, fasting insulin levels decrease, and fat content in the liver decreases. At the same time, the drug slightly increases the heart rate, an effect characteristic of the entire class.

As with other methods of losing weight, part of the lost mass falls on fat-free mass. Therefore, doctors emphasize strength training and sufficient protein intake during therapy.

Briefly about the key effects:

• reduction of glucose level without a high risk of hypoglycemia in monotherapy;
• decrease in appetite and calorie content of the diet;
• slowing of gastric emptying, especially at the beginning of therapy;
• improvement of lipid profile and reduction of fat in the liver.

Limitations of the mechanism and open questions

Despite the impressive results, the mechanism of tirzepatide has its "backside". Delayed gastric emptying accounts for the nausea, feeling of fullness, and risk of aspiration during anesthesia. It also affects the absorption of oral medications, in particular oral contraceptives.

The effect of the drug is reversed: after withdrawal, appetite gradually returns, and with it, body weight. This was shown by the SURMOUNT-4 study, in which switching to placebo after the treatment phase was accompanied by significant weight gain (Aronne et al., 2024).

It remains an open question why both agonism and antagonism of the GIP receptor in preclinical models reduce body weight. One explanation is that prolonged stimulation can functionally "desensitize" the receptor. This discussion determines the direction of development of the next generation of drugs.

Tirzepatide does not affect strength or endurance directly and is not an anabolic agent. Its action is focused on the regulation of appetite and glucose metabolism.

Editorial conclusions

Tirzepatide is a dual agonist of GIP and GLP-1 receptors with preference for the GIP component and shifted signaling at the GLP-1 receptor. This pharmacology provides a distinct reduction in glucose and body weight.

The main effects are reduction of appetite, improvement of insulin secretion and action, slowing of gastric emptying. They explain typical side reactions.

The result is maintained only during therapy, so the drug is considered as a means of long-term treatment of chronic conditions.

We also recommend reading "Tirzepatide Medical Uses", "Tirzepatide Side Effects" and "Semaglutide vs. Tirsepatide: What's the Difference".

List of used literature

1. Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab. 2018;18:3–14.
2. Willard FS, Douros JD, Gabe MB, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532.
3. Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes (SURPASS-2). N Engl J Med. 2021;385(6):503–515.
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205–216.
5. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38–48.
6. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab. 2021;46:101102.
7. U.S. Food and Drug Administration. Mounjaro (tirzepatide) injection: prescribing information. Silver Spring (MD): FDA.