Tirzepatide does not act like a simple stronger version of a glucagon-like peptide-1 (GLP-1) drug. A 2020 JCI Insight study showed that the molecule activates both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the GLP-1 receptor, but not equally: its pharmacology is weighted toward GIP-receptor engagement while producing a distinct signaling pattern at the GLP-1 receptor. That dual design helps explain why GIP has become central to the next generation of metabolic medicines.
GIP and GLP-1 are both incretins, but they are not interchangeable
GIP and GLP-1 are released from specialized enteroendocrine cells in the gut after food intake. GIP is produced mainly by K cells in the upper small intestine, while GLP-1 is produced by L cells that are found throughout the intestine and become more abundant distally. Both hormones amplify glucose-stimulated insulin secretion from pancreatic beta cells, which is why they are called incretins.
The overlap ends there. GLP-1 also slows gastric emptying, suppresses glucagon when glucose is elevated, and reduces appetite and calorie intake. Those effects help explain the established clinical role of selective GLP-1 receptor agonists such as semaglutide, which we review in our GLP-1 drugs explainer.
GIP biology is more complicated. Native GIP strongly supports meal-stimulated insulin release, but it can also promote glucagon secretion under some glucose conditions and has signaling roles in adipose tissue. For years, that made GIP seem like a less obvious weight-loss target than GLP-1.
Tirzepatide changed the question from GIP versus GLP-1 to what happens when both receptors are activated
The drug now known as tirzepatide was originally developed as LY3298176, a long-acting peptide designed to activate both GIP and GLP-1 receptors. In a 2018 Molecular Metabolism paper, Coskun and colleagues showed that the molecule activated both receptors in preclinical systems and lowered glucose and body weight in early human studies.
A later mechanistic study by Willard and colleagues showed that tirzepatide is not a balanced 50:50 agonist. In cell-based assays, it had activity similar to native GIP at the GIP receptor, while showing lower affinity and lower potency than native GLP-1 at the GLP-1 receptor. Modeling in that study predicted greater engagement of the GIP receptor than the GLP-1 receptor at clinically relevant exposure.
The researchers also found signaling bias at the GLP-1 receptor. Tirzepatide favored cyclic adenosine monophosphate signaling relative to beta-arrestin recruitment and drove less receptor internalization than native GLP-1. That matters because receptor signaling is not determined only by whether a receptor turns on. The pattern, intensity, and duration of signaling can also change the biological response.
Willard and colleagues described the result as “a unique pharmacological profile tailored for improving broad metabolic control.” That is a mechanistic interpretation, not proof that any one signaling feature explains tirzepatide’s clinical efficacy.
Dual agonism produced larger metabolic effects than an older selective GLP-1 agonist in early clinical testing
A 26-week phase 2 trial published in The Lancet randomized 318 adults with type 2 diabetes to four tirzepatide doses, dulaglutide 1.5 mg, or placebo. The modified intention-to-treat population included 316 participants.
Hemoglobin A1c fell in a dose-dependent manner with tirzepatide, from 1.06 percentage points at 1 mg to 1.94 percentage points at 15 mg, compared with 0.06 percentage points with placebo and 1.21 percentage points with dulaglutide. Mean body-weight changes ranged from 0.9 to 11.3 kg of loss across tirzepatide doses, compared with 0.4 kg with placebo and 2.7 kg with dulaglutide.
Those early results helped move tirzepatide into larger phase 3 programs. In SURMOUNT-1, a later 72-week obesity trial, tirzepatide produced mean body-weight reductions of 15.0%, 19.5%, and 20.9% at the 5 mg, 10 mg, and 15 mg doses, respectively, versus 3.1% with placebo. Tirzepatide is now also approved for obstructive sleep apnea in adults with obesity.
The clinical success of tirzepatide does not prove that GIP alone causes the extra effect
It is tempting to look at tirzepatide’s results and conclude that adding GIP signaling is the reason it can outperform a selective GLP-1 agonist in some trials. That conclusion goes further than the evidence allows.
Tirzepatide is one engineered molecule with its own receptor potency, pharmacokinetics, signaling bias, dose-response relationship, and exposure profile. Its effects cannot be reproduced conceptually by taking the known effects of a GIP agonist and adding them to the known effects of a GLP-1 agonist. The exact contribution of each receptor to appetite, insulin secretion, glucagon regulation, adipose biology, and weight loss remains an active research question.
This is also why cross-trial comparisons between semaglutide and tirzepatide need care. Different doses, patient populations, trial durations, and estimands can create apparent differences that are not a clean test of receptor biology. Our GLP-1 side-effects review makes the same point when comparing adverse-event percentages across studies.
GIP may be especially important because its effects depend on metabolic context
One reason GIP remained controversial for so long is that its physiology changes with glucose levels, nutritional state, and tissue context. In healthy physiology it is a major contributor to meal-stimulated insulin secretion, but its insulinotropic effect is impaired in poorly controlled type 2 diabetes. Meanwhile, GIP-receptor signaling outside the pancreas can influence adipose tissue and central nervous system pathways.
Tirzepatide shows that this complexity does not make GIP therapeutically useless. Instead, it suggests that the effect of GIP-receptor activation depends on the molecule delivering the signal, the simultaneous activation of GLP-1 receptors, and the metabolic environment in which both receptors are engaged.
What the evidence cannot yet answer
Current studies do not provide a simple percentage showing how much of tirzepatide’s benefit comes from GIP versus GLP-1. Mechanistic experiments can measure receptor affinity, signaling, insulin secretion, or animal phenotypes, but those findings do not directly partition weight loss or glycemic improvement in humans.
Most of the foundational tirzepatide pharmacology was also generated by teams that included Eli Lilly scientists, and the early phase 2 and later SURMOUNT programs were industry funded. That does not invalidate the findings, but it makes independent replication and mechanistic work especially important.
The most defensible conclusion is narrower: GIP and GLP-1 are distinct incretin systems with overlapping control of insulin secretion, and tirzepatide demonstrates that activating both in one engineered drug can produce powerful metabolic effects. The precise reason the combination works as well as it does is still being resolved.
References
- Willard FS, Douros JD, Gabe MBN, et al. Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist. JCI Insight. 2020;5(17):e140532. DOI: 10.1172/jci.insight.140532.
- Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes. Lancet. 2018;392:2180-2193. DOI: 10.1016/S0140-6736(18)32260-8.