Why is tirzepatide the comparator in so many trials?

It won the direct comparison against semaglutide in SURMOUNT-5, after which beating semaglutide alone stopped being a meaningful claim.

Can I rank these compounds from the three trials?

No. Different durations, populations and estimands. Tirzepatide's own reported figure differs between them for those reasons alone.

Why do sponsors risk head-to-heads?

Prescribers and payers increasingly expect direct evidence, and running one signals confidence — though REDEFINE 4 shows the risk is real.

GLP-1 & Incretin Science

Three Head-to-Heads, One Common Comparator

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-234 cited sources

Tirzepatide appears as the comparator in SURMOUNT-5 against semaglutide, in REDEFINE 4 against CagriSema, and in TRIUMPH-5 against retatrutide. It has become the standard a new obesity compound is expected to be tested against.

Key facts

SURMOUNT-5: Tirzepatide 20.2% vs semaglutide 13.7%
REDEFINE 4: Tirzepatide 25.5% vs CagriSema 23.0%
TRIUMPH-5: vs retatrutide — completes Nov 2026
REDEFINE 4 registration: NCT06131437, n=809, completed
TRIUMPH-5 registration: NCT06662383, n=800, active
Common feature: Tirzepatide is the reference arm

How a benchmark forms

A compound becomes the comparator when beating it is what the field considers meaningful. Tirzepatide reached that position by winning the one direct comparison against semaglutide that mattered — SURMOUNT-5 randomised 751 adults over 72 weeks and reported 20.2% against 13.7%. After that, showing superiority to semaglutide stopped being sufficient.

Why sponsors run these trials at all

They are risky. A head-to-head against a strong comparator can produce a result the sponsor did not want, publicly and irreversibly — which is exactly what happened to Novo Nordisk in REDEFINE 4. Running one signals confidence, and prescribers and payers increasingly expect the evidence rather than accepting cross-trial comparison.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

What the three trials are not

Comparable with each other. SURMOUNT-5 ran 72 weeks, REDEFINE 4 ran 84, TRIUMPH-5 is a different population again. Tirzepatide's reported figure differs between them — 20.2% in one, 25.5% in another — and that difference reflects trial design, duration and population rather than the drug changing. Reading across them as a league table is exactly the error head-to-heads exist to prevent.

Why tirzepatide's own number moves

Different durations, different populations, different estimands. In REDEFINE 4 the efficacy estimand gave 25.5% and the treatment-policy estimand 23.6% — a 1.9 point gap within one trial, from the same participants, reflecting only how discontinuation is handled. A figure quoted without its estimand cannot be compared with anything.

What TRIUMPH-5 will and will not settle

Registered as NCT06662383, active and not recruiting, 800 participants, primary completion November 2026. Because retatrutide and tirzepatide are both Lilly molecules built on modified GIP scaffolds, the comparison isolates the glucagon receptor arm about as cleanly as a trial can. It will not tell you how retatrutide compares with CagriSema, because nobody has run that trial.

The regulatory point that gets lost

Tirzepatide and semaglutide are licensed medicines. CagriSema is filed and unapproved. Retatrutide is investigational. A table of weight-loss percentages flattens a group of compounds at completely different regulatory stages into apparent equivalents, and none of them has any relationship to research material.

Quick reference

Trial	Comparison	Duration	Status
SURMOUNT-5	Tirzepatide vs semaglutide	72 weeks	Reported
REDEFINE 4	CagriSema vs tirzepatide	84 weeks	Completed Jan 2026
TRIUMPH-5	Retatrutide vs tirzepatide	—	Completes Nov 2026

Extended research context

The GLP-1 & Incretin Science deep dive

Deep dive: the two routes to a bigger effect

Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.

Deep dive: why a percentage is not a result

The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.

Deep dive: what happens after the trial stops

Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.

Research applications

▸Comparing incretin and amylin compounds on a like-for-like basis
▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
▸Tracking the obesity pipeline across sponsors and jurisdictions
▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
▸Distinguishing licensed medicines from investigational compounds

Handling checklist

✓Identify which estimand a quoted percentage comes from before citing it
✓Check the trial population and baseline BMI against the comparison you are making
✓Confirm the duration and whether the reduction curve had plateaued
✓Read discontinuation rates alongside efficacy figures
✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Comparing headline percentages across different trials

Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.

✗ Quoting the larger of two figures from the same trial

Fix: Name the estimand. Efficacy and treatment-policy answer different questions.

✗ Treating peak reduction as a durable outcome

Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.

✗ Assuming an oral route means a weaker mechanism

Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.

✗ Reading investigational compounds as available treatments

Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

Why is tirzepatide the comparator in so many trials?: It won the direct comparison against semaglutide in SURMOUNT-5, after which beating semaglutide alone stopped being a meaningful claim.
Can I rank these compounds from the three trials?: No. Different durations, populations and estimands. Tirzepatide's own reported figure differs between them for those reasons alone.
Why do sponsors risk head-to-heads?: Prescribers and payers increasingly expect direct evidence, and running one signals confidence — though REDEFINE 4 shows the risk is real.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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