SURPASS-4
SURPASS-4 compared tirzepatide (5, 10, 15 mg once weekly) against titrated once-daily insulin glargine in T2D patients with high cardiovascular risk or established CVD, inadequately controlled on oral glucose-lowering medications. It was the only SURPASS trial that extended treatment to 104 weeks (for cardiovascular event adjudication) and the trial from which the most important kidney outcomes data were derived via post-hoc analysis.
Ontology SURPASS-4 [part-of] SURPASS Clinical Trial Programme SURPASS-4 [studied_in] Tirzepatide SURPASS-4 [measured_by] HbA1c Reduction SURPASS-4 [measured_by] Insulin-Use Reduction SURPASS-4 [measured_by] Kidney Outcomes SURPASS-4 [compared_against] Insulin Glargine SURPASS-4 [relates] Cardiovascular Risk
Key Results
- HbA1c change at 52 weeks: −2.43% (10mg, SD 0.05), −2.58% (15mg, SD 0.05) vs −1.44% (glargine, SD 0.03)
- Treatment difference vs glargine: −0.99% (10mg), −1.14% (15mg) — non-inferiority met and statistical superiority achieved
- Hypoglycaemia: 6–9% tirzepatide vs 19% glargine; without SU: 1–3% vs 16%
- MACE-4: HR 0.74 (95% CI 0.51–1.08) — not increased; but trial not powered for CV outcomes as primary endpoint
- Deaths: 25 (3%) tirzepatide vs 35 (4%) glargine
- GI events: Nausea 12–23%, diarrhoea 13–22%, decreased appetite 9–11%, vomiting 5–9% — mostly mild-moderate during dose escalation
Post-hoc kidney outcomes (Heerspink et al., Lancet Diabetes Endocrinol 2022):
- eGFR decline: −1.4/year (tirzepatide) vs −3.6/year (glargine) — difference 2.2 (95% CI 1.6–2.8)
- UACR: −6.8% (tirzepatide) vs +36.9% (glargine)
- Composite kidney endpoint HR: 0.58 (95% CI 0.43–0.80) — nearly halved
Limitations
- Trial design: Open-label; glargine comparator was titrated to target, ensuring fair comparison but not blinded
- Duration: Primary endpoint 52 weeks; MACE collected to 104 weeks but not powered as primary CV outcome trial
- Sponsorship: Entirely Eli Lilly-funded
- Kidney data: Post-hoc — not pre-specified; glargine was associated with UACR increase (+36.9%), making tirzepatide appear more renoprotective relative to this comparator than it might be vs other agents
Connections
- Tirzepatide — studied_in, [2021–2022], source: PMID 34672967
- HbA1c Reduction — measured_by, [2021], source: PMID 34672967
- Kidney Outcomes — measured_by (post-hoc), [2022], source: PMID 36152639
- Insulin Glargine — comparator_in, [2021–2022]
- Cardiovascular Risk — relates, [2021–2022]
- SURPASS Clinical Trial Programme — part-of