GLP-1 plus GIP: what the tirzepatide trials show

Why one drug activates both incretin receptors, what the tirzepatide trials show against semaglutide, and which explanations are still uncertain.

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ARTICLE · METABOLIC & MITOCHONDRIAL · BASICS

A molecule that activates both the GLP-1 and the GIP receptor lowers weight and glucose in trials more than a GLP-1 agonist alone. Why that is so is less settled.

MVMichel van der Veen — Registered Nurse · Science Editor, Peptalis Sources checked via PubMed · 14 referencesReviewed September 2026 · 10 MIN READ

Illustration after the structure PDB 7RGP (Sun et al., PNAS 2022): tirzepatide bound to the GLP-1 receptor. The fatty-acid side chain is drawn in; it is absent from the deposited model.

A molecule that activates both the GLP-1 and the GIP receptor lowers weight and blood glucose in clinical trials more than a drug that activates the GLP-1 receptor alone. That has been shown with tirzepatide in a direct comparison against semaglutide. Why it is so is less settled. The explanations range from an extra appetite signal in the brain to more insulin-sensitive fat tissue and a different way of binding to the GLP-1 receptor, and each of them rests mainly on mice.

Why two receptors

The idea comes from DiMarchi's chemistry and Tschöp's physiology. In 2013, Finan and colleagues described a peptide that binds both incretin receptors with equal potency, built from an intermixed amino acid sequence of GLP-1 and GIP. In diabetic mice and obese rats this dual incretin lowered glucose and fat mass more than a selective GLP-1 agonist, while a selective GIP agonist on its own did almost nothing. In cynomolgus monkeys and in a first human study the glucose lowering was also greater than with a comparably modified GLP-1 agonist. The authors named a second advantage: because a smaller share of the effect depended on GLP-1, the gastrointestinal complaints that characterise GLP-1 agonists were avoided (Finan 2013).

The reasoning behind the combination is therefore twofold. GIP adds, in animals, an effect of its own on fat tissue and insulin sensitivity, as described in part 2. And a molecule working through two receptors might be dosed lower at each, with fewer adverse events per unit of effect.

Tirzepatide: from design to phase 3

Tirzepatide, developed by Eli Lilly under the code LY3298176, is a 39-amino-acid peptide with a fatty acid chain that binds it to albumin, suited to weekly injection. Coskun and colleagues described the path from cell to human in 2018: in cell lines it activated both receptors, in mice the glucose lowering ran through both, and in a phase 1 programme with 142 participants in total, patients with type 2 diabetes on 10 mg saw fasting glucose fall by 49 mg/dl relative to placebo after four weeks and weight by 2.6 kg (Coskun 2018).

The molecule is not a balanced agonist. Willard and colleagues calculated in 2020 what fraction of each receptor is occupied at clinical doses and found a stronger occupancy of the GIP receptor than of the GLP-1 receptor. At the GIP receptor, tirzepatide behaves like the natural hormone. At the GLP-1 receptor it does not: it favours the cAMP route over the recruitment of β-arrestin and internalises the receptor more slowly than GLP-1 itself. In isolated islets of Langerhans, β-arrestin turned out to limit the insulin response to GLP-1 but not to GIP or tirzepatide (Willard 2020). This so-called biased agonism is a third candidate explanation, next to the GIP component itself.

What the studies in people show

The first direct comparison was SURPASS-2. In this open-label phase 3 trial, 1879 patients with type 2 diabetes and a mean HbA1c of 8.28 percent received 40 weeks of weekly tirzepatide 5, 10 or 15 mg, or semaglutide 1 mg. HbA1c fell by 2.01, 2.24 and 2.30 percentage points against 1.86 with semaglutide; the difference at the highest dose was 0.45 percentage points with a confidence interval of 0.32 to 0.57. Weight fell 1.9, 3.6 and 5.5 kg more than with semaglutide. Nausea occurred in 17 to 22 percent on tirzepatide and 18 percent on semaglutide, vomiting in 6 to 10 against 8 percent. Serious events: 5 to 7 percent against 3 percent (Frías 2021). One caveat the authors themselves make: semaglutide was given here at the diabetes dose of 1 mg, not the 2.4 mg studied for obesity.

SURMOUNT-1 looked at obesity without diabetes. 2539 adults received 72 weeks of tirzepatide 5, 10 or 15 mg or placebo. Weight fell by 15.0, 19.5 and 20.9 percent against 3.1 percent on placebo. In the 15 mg group, 57 percent reached a weight loss of 20 percent or more, against 3 percent on placebo. Adverse events led to discontinuation in 4.3, 7.1 and 6.2 percent, against 2.6 percent on placebo (Jastreboff 2022).

Whether this is more than a strong GLP-1 agonist was answered only in SURMOUNT-5. There, 751 adults with obesity and no diabetes received 72 weeks of the maximum tolerated dose of tirzepatide (10 or 15 mg) or the maximum tolerated dose of semaglutide (1.7 or 2.4 mg). Weight fell by 20.2 percent against 13.7 percent, with confidence intervals of 19.1 to 21.4 and 12.6 to 14.9. Waist circumference decreased by 18.4 against 13.0 cm. Gastrointestinal complaints were the most reported adverse events in both groups, mainly during escalation (Aronne 2025). This is an open-label trial, which weighs less heavily for an outcome like weight than for a subjective one, but it remains a limitation. The direct head-to-head comparison therefore exists, and it comes out in favour of the combination.

On the mechanism in people, the study by Heise and colleagues is the most informative. 117 patients with type 2 diabetes received 28 weeks of tirzepatide 15 mg, semaglutide 1 mg or placebo, with clamp measurements of insulin secretion and insulin sensitivity. The disposition index, a measure combining both, improved 0.84 units more with tirzepatide than with semaglutide (interval 0.46 to 1.21). Insulin secretion rose more, insulin sensitivity improved more, and after a meal both the glucose and the glucagon response were lower (Heise 2022). That insulin sensitivity improves more in people fits what Samms found in mice. It does not prove the GIP receptor is responsible, because the study cannot separate the weight loss from the receptor route.

What the animal studies add

The mouse studies supply the explanations the human studies cannot, and they partly contradict each other.

Samms and colleagues showed in 2021 that tirzepatide, in obese mice without a GLP-1 receptor where the weight loss dropped away, still improved insulin sensitivity through higher glucose uptake in white fat tissue. A selective long-acting GIP agonist did the same, and both lowered branched-chain amino acids in the blood (Samms 2021). This is the fat tissue explanation.

Zhang and colleagues showed in the same year that the advantage of GLP-1/GIP co-agonism over GLP-1 alone disappeared in mice without a GIP receptor in the central nervous system (Zhang 2021). This is the brain explanation: GIP adds an appetite signal of its own.

Bergmann's study in seventeen men with overweight, discussed in part 2, points the other way: an acute GIP infusion alongside GLP-1 did not amplify the effect on energy intake and even raised it slightly (Bergmann 2019). An acute infusion of the hormone is not the same as weekly exposure to a long-acting agonist, but it is the only direct human test of the brain explanation, and it came out negative.

The uncertain explanations, side by side

There are four explanations for the difference between tirzepatide and semaglutide, and none of them is proven in people.

The first is that the GIP component makes a contribution of its own to appetite or fat tissue. The evidence is preclinical; the human infusion study contradicts it for appetite.

The second is the biased binding at the GLP-1 receptor, which winds the receptor down more slowly and raises insulin release in islets. This has been measured in cells and isolated tissue, not in people.

The third is that tirzepatide simply delivers more GLP-1 receptor activation than the dose of semaglutide it was compared with. SURMOUNT-5 has made this explanation less likely, because there the maximum tolerated doses stood against each other, but without a tirzepatide variant lacking GIP activity it is not excluded.

The fourth is that the GIP component reduces gastrointestinal complaints, so that a higher effective GLP-1 dose is tolerated. Finan proposed this in 2013 on the basis of animals. In SURPASS-2 and SURMOUNT-5 the rates of nausea and vomiting were comparable to those of semaglutide, which neither supports nor refutes this explanation, because the doses were not matched on tolerability.

That the GIP receptor adds something is meanwhile also supported from the other side: a drug that blocks the GIP receptor alongside GLP-1 activation, maridebart cafraglutide, produced substantial weight loss in a phase 2 trial as well (Jastreboff 2025). If activating and blocking both work, an appetite signal of GIP's own does not explain that well, and Killion's desensitisation hypothesis does (Killion 2020). The review by Nauck and D'Alessio from 2022 reaches the same conclusion: the clinical advantage of tirzepatide is established, the mechanistic contribution of GIP is not (Nauck 2022).

Adverse events and limitations

The adverse events of the combination are the same in kind as those of GLP-1 agonists: nausea, vomiting, diarrhoea, constipation, dose-dependent and mainly during escalation. Hypoglycaemia below 54 mg/dl occurred in SURPASS-2 in 0.6 to 1.7 percent on tirzepatide and 0.4 percent on semaglutide, in a population partly using sulfonylureas (Frías 2021).

The cardiovascular outcome trial has since arrived. SURPASS-CVOT randomised 13,299 patients with type 2 diabetes and established atherosclerotic disease to weekly tirzepatide up to 15 mg or dulaglutide 1.5 mg, a GLP-1 agonist already shown to reduce cardiovascular events. The composite endpoint occurred in 801 patients (12.2 percent) on tirzepatide and 862 (13.1 percent) on dulaglutide, a hazard ratio of 0.92 with an interval of 0.83 to 1.01. Tirzepatide was thereby non-inferior to dulaglutide; superiority was not reached (Nicholls 2025). It is a comparison against an active drug, not placebo, so it says nothing about the absolute cardiovascular benefit, and it shows that the larger weight loss did not translate in this population into a measurably smaller number of cardiac events than with a GLP-1 agonist alone.

The limitations of the evidence are the open-label design of the two direct comparisons, the diabetes dose of semaglutide in SURPASS-2, and the absence of a GIP-free control variant of tirzepatide. What the mechanistic studies need is a human test that isolates the GIP contribution: for instance a long-acting selective GIP agonist alongside a GLP-1 agonist, in a study with energy intake, energy expenditure and body composition as endpoints. Until that exists, the combination is better supported clinically than it is understood mechanistically. Part 4 of this series turns to the third hormone added to this combination: glucagon.

About the authorMVMichel van der VeenRegistered Nurse · Science Editor, Peptalis

Registered nurse with eleven years in psychiatry and founder of Peptalis. Writes the platform's knowledge layer: compound profiles, evidence reviews and the quality methodology. Works from primary literature (PubChem for chemistry, PubMed for studies) and states where evidence is absent.

Sources checked via PubMed · 14 references

Compound profilesEvidence reviewsQualityIN THIS ARTICLE
  • Why two receptors
  • Tirzepatide: from design to phase 3
  • What the studies in people show
  • What the animal studies add
  • The uncertain explanations, side by side
  • Adverse events and limitations
SCIENTIFIC REFERENCESView all references →RELATED COMPOUNDTirzepatide →RELATED ARTICLES

Compounds in this article

For laboratory research use only. Not for human use.

SCIENTIFIC REFERENCES

These references are provided for informational and research purposes only. They do not constitute medical advice.

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  3. 03Preclinical · in vitroTirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.Willard FS, et al. JCI Insight. 2020.View on PubMed →DOI →
  4. 04Human RCTTirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes.Frías JP, et al. N Engl J Med. 2021.View on PubMed →DOI →
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  9. 09Preclinical · animalThe glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling.Zhang Q, et al. Cell Metab. 2021.View on PubMed →DOI →
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