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LITERATURE REVIEW · HIGH CV RISK RCT

SURPASS-4

Del Prato et al., Lancet, 2021. Randomised open-label trial of once-weekly Tirzepatide vs once-daily insulin glargine (titrated) in adults with type 2 diabetes and elevated cardiovascular risk, with a pre-specified CV meta-analysis.

QUICK ANSWER
TL;DR

Quick answer

SURPASS-4 was a randomised open-label active-controlled Phase 3 trial comparing once-weekly Tirzepatide (5, 10 and 15 mg) with once-daily titrated insulin glargine in 2,002 adults with type 2 diabetes and elevated cardiovascular risk on ≥1 oral glucose-lowering agent. All three Tirzepatide doses produced greater HbA1c and body-weight reduction than insulin glargine, with a pre-specified CV meta-analysis showing no excess of MACE.
EXTENDED ANSWER
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Extended answer

What was the SURPASS-4 trial?

SURPASS-4 was a randomised, open-label, active-controlled Phase 3 trial comparing once-weekly subcutaneous Tirzepatide (5, 10 and 15 mg) with once-daily titrated insulin glargine as add-on therapy in adults with type 2 diabetes and elevated cardiovascular risk on one to three oral glucose-lowering agents. Published by Del Prato and colleagues in the Lancet in 2021, the trial randomised 2,002 participants for 52 weeks of primary analysis with up to 104 weeks of exposure and a pre-specified cardiovascular meta-analysis pooling SURPASS trials. All three Tirzepatide doses produced greater HbA1c and body-weight reduction than insulin glargine. The pre-specified cardiovascular meta-analysis showed no increased risk of major adverse cardiovascular events with Tirzepatide relative to controls.
KEY FACTS

Key facts

Compounds
Tirzepatide 5/10/15 mg SC weekly vs insulin glargine SC daily (titrated)
Design
Randomised, open-label, active-controlled, Phase 3 with pre-specified CV meta-analysis
N
2,002
Population
Adults with T2D + elevated CV risk on 1–3 oral agents
Duration
52-week primary; up to 104-week exposure
Primary outcome
Change in HbA1c from baseline
Journal
Lancet (2021)
DOI
10.1016/S0140-6736(21)02188-7
PMID
34600607

Background

Cardiovascular safety is central to type 2 diabetes therapeutic development. SURPASS-4 was designed to evaluate Tirzepatide against titrated insulin glargine as add-on therapy in adults with type 2 diabetes and elevated cardiovascular risk, and to contribute to a pre-specified cardiovascular meta-analysis across SURPASS trials. [1]

Study design

Randomised, open-label, active-controlled, four-arm parallel-group Phase 3 trial. Participants were randomised 1:1:1:3 (Tirzepatide 5, 10, 15 mg vs insulin glargine, weighted toward glargine for CV endpoint accrual). The primary analysis is at week 52; exposure extended to week 104.

Population

2,002 adults with type 2 diabetes, HbA1c 7.5–10.5%, elevated cardiovascular risk (established atherosclerotic CVD or multiple risk factors), on one to three oral glucose-lowering agents.

Intervention

Once-weekly subcutaneous Tirzepatide titrated to 5, 10 or 15 mg.

Comparator

Once-daily subcutaneous insulin glargine titrated by protocol.

Primary endpoints

Mean change in HbA1c from baseline to week 52 for each Tirzepatide dose versus insulin glargine.

Secondary endpoints

Change in body weight, hypoglycaemia rates, and the pre-specified cardiovascular meta-analysis across SURPASS trials.

Key findings

  • All three Tirzepatide doses produced greater HbA1c reduction than insulin glargine at week 52.
  • Body-weight reduction with Tirzepatide contrasted with weight gain with insulin glargine.
  • Rates of clinically significant hypoglycaemia were lower with Tirzepatide than with insulin glargine.
  • The pre-specified cardiovascular meta-analysis showed no excess of major adverse cardiovascular events with Tirzepatide versus controls.

Mechanistic significance

  • Contributes to the emerging cardiovascular safety profile of dual GIP/GLP-1 receptor agonists ahead of dedicated cardiovascular outcomes trials (SURPASS-CVOT).
  • Reinforces the glucose-dependent, weight-neutral-to-favourable pharmacology of dual incretin agonism relative to basal insulin.

Limitations

Research limitations

  • Open-label design.
  • The trial was not powered as a definitive cardiovascular outcomes trial; the CV read-out relies on a pre-specified meta-analysis.
  • Long-term (>2-year) outcomes require SURPASS-CVOT.

Research context

SURPASS-4 is the SURPASS trial specifically enriched for cardiovascular risk and contributes the largest single-trial contribution to the pooled SURPASS CV meta-analysis, complementing SURPASS-3 and SURPASS-5.

Research-use framing

This is an educational literature summary of a published clinical trial. Oxford Research Peptides supplies Tirzepatide as a lyophilised reference standard for in-vitro laboratory research only. Nothing on this page is medical advice.
Related studies
Compound reference: Tirzepatide monograph. Related guides: what is tirzepatide, tirzepatide mechanism of action, tirzepatide faq.

References1

  1. 1.

    Del Prato S, Kahn SE, Pavo I, et al.. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4).. Lancet. 2021;398(10313):1811-1824.

    DOI: 10.1016/S0140-6736(21)02188-7PMID: 34600607
EVIDENCE SUMMARY
Evidence

Evidence summary

Strong evidence
Research confidenceHigh confidence
Peer-reviewed Phase 3 randomised active-controlled trial with pre-specified CV meta-analysis, published in the Lancet (Del Prato et al. 2021).
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EDITORIAL NOTICE

Research use only

All materials referenced are supplied strictly for in-vitro laboratory research. Not for human or animal consumption, diagnosis, or therapeutic use.
VERSION HISTORY
Editorial Team
Oxford Research Peptides Editorial Team
In-house editorial staff
Oxford Research Peptides
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Scientific Review Panel
Independent scientific review
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Publication information

Published
2026-11-01
Updated
2026-11-01
Reviewed
2026-11-01
Version
1.0

Revision history

  1. v1.02026-11-01· Editorial Team

    Research Literature Programme 1 — initial publication of dedicated STEP, SURPASS and Retatrutide Phase 2 trial summaries.

Editorial standards

Content is reviewed against our editorial process for scientific accuracy, sourcing, and clarity. Read our editorial standards.

Conflict of interest

Oxford Research Peptides supplies research-grade reference peptides commercially. Editorial pages are drafted and reviewed to describe published scientific literature accurately and do not recommend, promote or endorse any specific commercial product. Product mentions on educational pages are strictly for cross-referencing catalogue entries.

Next scheduled review: 2028-05-01. Our research methodology describes how the review is conducted.

Research use only

All materials referenced are supplied strictly for in-vitro laboratory research. Not for human or animal consumption, diagnosis, or therapeutic use.
Published: 2026-11-01Updated: 2026-11-01