What did SURPASS-4 compare?

Tirzepatide against insulin glargine in 2,002 randomised participants with type 2 diabetes and increased cardiovascular risk, over 52 weeks.

Why is the sulfonylurea subgroup important?

Without a sulfonylurea, tirzepatide hypoglycaemia was 1–3% against glargine's 16% — isolating the glucose-independent agent as the source of most of the residual risk.

Did it show cardiovascular benefit?

No. The MACE-4 hazard ratio was 0.74 with an interval from 0.51 to 1.08, which crosses one — establishing no excess risk rather than benefit.

Research & Regulatory News

The Trial Where Glucose-Dependence Shows Up in Numbers

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-233 cited sources

SURPASS-4 randomised 2,002 participants with type 2 diabetes and increased cardiovascular risk to tirzepatide or insulin glargine over 52 weeks. Del Prato and colleagues published it in the Lancet in November 2021, and its sulfonylurea subgroup isolates the glucose-dependence effect.

Key facts

Published: Lancet, 13 November 2021 (PMID 34672967)
Randomised: 2,002
Dosed: 1,995 — glargine n=1,000
Design: Randomised, open-label, parallel-group
HbA1c at 52 weeks: −2.43% (10 mg), −2.58% (15 mg) vs −1.44%
Hypoglycaemia overall: 6–9% vs 19%
Without sulfonylurea: 1–3% vs 16%
MACE-4: HR 0.74 (95% CI 0.51–1.08)

Why comparing against insulin is the informative design

Insulin lowers glucose regardless of what glucose is doing — it is the archetype of a glucose-independent agent. Setting an incretin against it puts the two mechanisms side by side in one population, which is where a difference in hypoglycaemia should appear if glucose-dependence means anything.

The headline glycaemic result

At 52 weeks, mean HbA1c fell 2.43% on tirzepatide 10 mg and 2.58% on 15 mg, against 1.44% with glargine. So the incretin lowered glucose substantially more than insulin titrated in a trial setting — which makes the hypoglycaemia comparison more striking rather than less.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

The subgroup that carries the mechanism

Hypoglycaemia, defined as glucose below 54 mg/dL or clinically severe, occurred in 6 to 9% on tirzepatide against 19% on glargine. Among participants not taking a sulfonylurea the figures were 1 to 3% against 16%. That split isolates the effect: remove the glucose-independent oral agent and the incretin's rate falls to near-negligible while insulin's barely moves.

What the sulfonylurea contribution demonstrates

That the residual hypoglycaemia seen with the incretin was largely attributable to something else in the regimen. A compound showing 1 to 3% alone and 6 to 9% in combination has not become more dangerous — the combination has. This is as clean a natural demonstration of glucose-dependence as trial data offers.

The cardiovascular finding

Adjudicated MACE-4 events — cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina — occurred in 109 participants, with a hazard ratio of 0.74 and a confidence interval from 0.51 to 1.08. The interval crosses one, so this establishes no excess risk rather than demonstrating benefit. Sixty deaths occurred, 25 on tirzepatide and 35 on glargine.

The design limitation

Open-label. Blinding an injectable titrated against glucose readings is impractical, and participants and investigators knew their assignment. That is a real limitation for subjectively reported outcomes, though less consequential for a laboratory-defined endpoint like glucose below a threshold.

What this does not concern

Research material. Both compounds are licensed medicines administered in a registered trial under clinical supervision, in people with type 2 diabetes and elevated cardiovascular risk. Nothing supplied on this site affects blood glucose or is an alternative to any diabetes treatment.

Quick reference

	Tirzepatide	Glargine
HbA1c change, 15 mg	−2.58%	−1.44%
Hypoglycaemia, overall	6–9%	19%
Hypoglycaemia, no sulfonylurea	1–3%	16%
Deaths	25 (3%)	35 (4%)

Extended research context

The Research & Regulatory News deep dive

Deep dive: why 2026 was the year the incretin field split in two

For a decade every meaningful GLP-1 medicine was a peptide, and every one of them was injected. 2026 broke that pattern in both directions at once. In August the MHRA authorised orforglipron, a small molecule with no peptide bonds that works as an ordinary daily tablet. Three months earlier, retatrutide's TRIUMPH-1 reported a 28.3% mean weight reduction — the largest figure yet from a single molecule, and achievable only with a peptide capable of engaging three receptors at once. The field is not converging on one answer; it is separating into a convenience track and a magnitude track, and those tracks have different chemistry.

Deep dive: what a marketing authorisation actually means

An authorisation is granted to a specific product, in a specific formulation, for a specific indication, by a specific regulator. It is not a statement about a compound class and it does not transfer. Orforglipron being licensed in the UK tells you nothing about the legal or regulatory status of any other incretin, and nothing at all about compounds that remain investigational. Authorisation is also separate from funding: a licensed medicine is not automatically available on the NHS, which requires a further NICE appraisal.

Deep dive: reading trial results without being misled

Headline percentages are the least transferable part of a trial. A figure is only meaningful alongside its population, its duration, its comparator and its dropout rate. TRIUMPH-1's 28.3% came from an 80-week study in a relatively uncomplicated obesity population; TRIUMPH-3's 22.6% came from adults with severe obesity and established cardiovascular disease, and the gap between those two numbers is mostly population, not potency. Discontinuation rates deserve the same attention as efficacy: 11.3% of the TRIUMPH-1 12 mg arm stopped due to adverse events against 4.9% on placebo, and that figure is routinely dropped from summaries.

Research applications

▸Tracking regulatory status of investigational incretin compounds
▸Understanding the difference between authorisation, NICE appraisal and NHS availability
▸Comparing peptide and non-peptide receptor agonist pharmacology
▸Interpreting Phase 3 topline releases before peer-reviewed publication
▸Verifying trial identity against ClinicalTrials.gov registrations

Handling checklist

✓Check the compound named in a trial registration matches the compound being discussed
✓Confirm the NCT identifier resolves to the acronym being cited
✓Read topline press releases as preliminary until peer-reviewed publication
✓Separate the trial population from the headline percentage before comparing studies
✓Treat authorisation in one jurisdiction as saying nothing about status in another

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Treating a positive Phase 3 as approval

Fix: Filing begins a review that commonly takes a year or more and can end in a request for more data.

✗ Comparing weight-reduction percentages across different trials

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

✗ Assuming one incretin's approval legitimises another compound

Fix: Authorisations are product-specific and do not transfer between compounds.

✗ Citing a TRIUMPH number without checking the NCT identifier

Fix: Verify against ClinicalTrials.gov — the numbering has been widely misreported.

✗ Reading research material as an alternative to a licensed medicine

Fix: Research material is supplied for laboratory use only and is not a substitute for anything prescribed.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

What did SURPASS-4 compare?: Tirzepatide against insulin glargine in 2,002 randomised participants with type 2 diabetes and increased cardiovascular risk, over 52 weeks.
Why is the sulfonylurea subgroup important?: Without a sulfonylurea, tirzepatide hypoglycaemia was 1–3% against glargine's 16% — isolating the glucose-independent agent as the source of most of the residual risk.
Did it show cardiovascular benefit?: No. The MACE-4 hazard ratio was 0.74 with an interval from 0.51 to 1.08, which crosses one — establishing no excess risk rather than benefit.

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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