Tirzepatide: dual GIP and GLP‑1 agonism in SURPASS and SURMOUNT
One molecule acting on two incretin receptors. We review how tirzepatide was designed, what the SURPASS diabetes trials and SURMOUNT obesity trials measured, and why comparisons across trials need care.
ATOM PHARMA Editorial Team7 min read
Evidence at a glance
- Human clinical
- Ten phase 3 randomised trials across two programmes, including two head-to-head comparisons with semaglutide.
- Mechanistic hypothesis
- Receptor pharmacology characterised in cell and islet studies, largely by the developer's scientists.
- Animal
- Mouse studies of glucose control, food intake and body weight during early development.
Tirzepatide is a single peptide designed to activate two hormone receptors: those for glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). It has been studied in two large phase 3 programmes: SURPASS in type 2 diabetes and SURMOUNT in obesity. This review summarises how the molecule was designed, what those trials measured, and how their results should and should not be compared.
This article summarises published trial evidence for scientific understanding. It is not prescribing or treatment guidance.
Two incretin hormones in one molecule
GIP and GLP-1 are incretins, gut hormones released after eating that increase insulin secretion when blood glucose is raised. Selective GLP-1 receptor agonists were already established in diabetes care. The question tirzepatide's developers set out to answer was whether adding GIP receptor activity would bring further metabolic benefit[1].
Tirzepatide, first known as LY3298176, is a fatty-acid-modified peptide designed for once-weekly injection. In cell assays it activated signalling through both receptors. In mice it improved glucose tolerance by acting at both, and with repeated dosing it reduced food intake and body weight more than a selective GLP-1 receptor agonist did[1].
An imbalanced, biased agonist
Later pharmacology work refined this picture. At clinically relevant doses, tirzepatide was estimated to engage the GIP receptor more than the GLP-1 receptor, which the authors called an "imbalanced" profile. At the GIP receptor it mimicked native GIP. At the GLP-1 receptor it showed signalling bias, favouring cAMP generation over β-arrestin recruitment and causing less receptor internalisation than native GLP-1. The authors proposed that these properties together may account for its efficacy[2]. Most of the authors were employees of the developer, Eli Lilly, and the proposal is a mechanistic interpretation rather than a demonstrated explanation of the clinical results.
Phase 2: the first signal in diabetes
A 26-week phase 2 trial in 318 randomised people with type 2 diabetes compared four tirzepatide doses with placebo and with the GLP-1 receptor agonist dulaglutide. Reductions in glycated haemoglobin (HbA1c) were dose-dependent, ranging from 1.06 to 1.94 percentage points with tirzepatide, against 0.06 with placebo and 1.21 with dulaglutide[3].
The SURPASS programme: type 2 diabetes
The SURPASS trials tested tirzepatide at 5, 10 and 15 mg once weekly against a range of comparators. Their primary endpoint was the change in HbA1c.
| Trial | Participants | Comparator and duration | Glycaemic change: tirzepatide vs comparator |
|---|---|---|---|
| SURPASS‑1[4] | 478, on diet and exercise alone | Placebo, 40 weeks | −1.87 to −2.07 vs +0.04 |
| SURPASS‑2[5] | 1,879, on metformin | Semaglutide 1 mg, 40 weeks | −2.01 to −2.30 vs −1.86 |
| SURPASS‑3[6] | 1,444, on metformin with or without an SGLT2 inhibitor | Insulin degludec, 52 weeks | −1.93 to −2.37 vs −1.34 |
| SURPASS‑4[7] | 2,002, at increased cardiovascular risk | Insulin glargine, 52 weeks | −2.43 to −2.58 (10 and 15 mg) vs −1.44 |
| SURPASS‑5[8] | 475, on insulin glargine | Placebo, 40 weeks | −2.11 to −2.40 vs −0.86 |
Glycaemic change is the change in HbA1c, in percentage points; ranges cover the tirzepatide doses tested.
Across these trials, tirzepatide also reduced body weight. In SURPASS-1, weight fell by 7.0 to 9.5 kg[4]. In SURPASS-3, tirzepatide reduced weight by 7.5 to 12.9 kg, whereas insulin degludec increased it by 2.3 kg[6].
SURPASS-2 is the most informative comparison with an established GLP-1 receptor agonist. It was open-label, and tirzepatide at all three doses was both non-inferior and superior to semaglutide 1 mg for HbA1c reduction. Weight reductions were also greater, by 1.9 to 5.5 kg depending on dose[5].
SURPASS-4 enrolled people at increased cardiovascular risk. Adjudicated major cardiovascular events were not increased with tirzepatide compared with insulin glargine (hazard ratio 0.74, 95% confidence interval 0.51 to 1.08)[7]. That is reassuring on safety, but a trial of this design was not built to show cardiovascular benefit.
The SURMOUNT programme: obesity
The SURMOUNT trials enrolled adults with obesity, or overweight with weight-related complications. Their primary endpoint was the percentage change in body weight.
| Trial | Participants | Design | Mean weight change: tirzepatide vs comparator |
|---|---|---|---|
| SURMOUNT‑1[9] | 2,539 without diabetes | 72 weeks vs placebo | −15.0% to −20.9% vs −3.1% |
| SURMOUNT‑2[10] | 938 with type 2 diabetes | 72 weeks vs placebo | −12.8% to −14.7% vs −3.2% |
| SURMOUNT‑3[11] | 579 who first lost at least 5% through intensive lifestyle intervention | 72 weeks vs placebo, after the lifestyle phase | −18.4% vs +2.5% (additional change) |
| SURMOUNT‑4[12] | 670 randomised after a 36-week open-label lead-in | 52-week withdrawal: continued vs switched to placebo | −5.5% vs +14.0% |
| SURMOUNT‑5[13] | 751 without diabetes | 72 weeks, open-label vs semaglutide | −20.2% vs −13.7% |
In SURMOUNT-1, half of participants on 10 mg and 57% on 15 mg lost at least 20% of their body weight, compared with 3% on placebo[9].
SURMOUNT-4 addressed what happens when treatment stops. After losing an average of 20.9% during the lead-in, participants switched to placebo regained 14.0% of their weight over the following year, while those who continued lost a further 5.5%[12].
SURMOUNT-5 was the programme's head-to-head comparison in obesity. At week 72, weight fell by 20.2% with tirzepatide and 13.7% with semaglutide, and waist circumference by 18.4 cm and 13.0 cm respectively[13].
Diabetes and obesity populations respond differently
The two programmes answer different questions, and their populations differ. The clearest illustration comes from within SURMOUNT. People with type 2 diabetes in SURMOUNT-2 lost 12.8% to 14.7% of body weight[10]. People without diabetes in SURMOUNT-1 lost 15.0% to 20.9% over the same 72 weeks[9]. Smaller weight loss in diabetes is a recurring pattern with weight-management medicines.
The SURPASS trials, meanwhile, were designed around glycaemic control, with weight as a secondary outcome, and their participants were generally lighter. SURPASS-1 participants had a mean body-mass index of 31.9[4], compared with 38.0 in SURMOUNT-1[9]. Weight changes from SURPASS should not be read as estimates of tirzepatide's effect in obesity.
Adverse events
Gastrointestinal effects were the most common adverse events in both programmes. They were mostly mild to moderate and occurred mainly during dose escalation. In SURPASS-1, nausea was reported by 12% to 18% of participants on tirzepatide, against 6% on placebo[4]. In SURPASS-2, serious adverse events occurred in 5% to 7% of those on tirzepatide and 3% of those on semaglutide[5].
Adverse events led to treatment discontinuation in 4.3% to 7.1% of SURMOUNT-1 participants on tirzepatide, compared with 2.6% on placebo[9]. In SURPASS-5, where participants were already using insulin, treatment was stopped early by 10% to 18% on tirzepatide and 3% on placebo[8].
Hypoglycaemia depended largely on background treatment. In SURPASS-4 it was less frequent with tirzepatide (6% to 9%) than with insulin glargine (19%), and lowest in participants not taking sulfonylureas[7].
The limits of cross-trial comparison
It is tempting to line up results from different trials, including trials of different drugs, and rank them. This is unreliable for several reasons:
- Populations differ in baseline weight, diabetes status, duration of disease and background therapy.
- Durations and designs differ, including placebo-controlled, active-controlled, open-label and randomised-withdrawal trials.
- Analyses differ. The SURMOUNT trials used a "treatment-regimen" estimand that counts outcomes regardless of discontinuation[9], and estimates depend on how discontinuation and rescue therapy are handled.
- Comparator doses matter. SURPASS-2 compared tirzepatide with semaglutide 1 mg[5], a diabetes dose, whereas SURMOUNT-5 used semaglutide at up to 2.4 mg[13].
Only direct randomised comparisons, such as SURPASS-2 and SURMOUNT-5, support conclusions about one drug relative to another, and both were open-label.
Summary
Tirzepatide combines GIP and GLP-1 receptor activity in one once-weekly peptide. In the SURPASS trials it lowered HbA1c more than placebo, insulin and semaglutide 1 mg, with accompanying weight loss. In the SURMOUNT trials it produced substantial weight reduction in adults with obesity, smaller reductions in people with type 2 diabetes, and marked weight regain when treatment was withdrawn. Gastrointestinal effects were the main tolerability issue. The strongest comparative evidence comes from the two head-to-head trials with semaglutide. Informal comparisons across different trials should be treated with caution.
References
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