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Kidney Outcomes

John Montgomery3 min read

Kidney Outcomes

Evidence for tirzepatide’s effects on kidney function comes from post-hoc analyses of the SURPASS programme and secondary outcomes of the SURMOUNT obesity trials — not from a dedicated, powered kidney outcome trial. The most important data source is a post-hoc analysis of SURPASS-4 (Heerspink et al., Lancet Diabetes Endocrinol 2022), which compared tirzepatide against insulin glargine over a median 85 weeks in T2D patients with high cardiovascular risk.

The SURPASS-4 post-hoc analysis found that tirzepatide slowed eGFR decline (−1.4 vs −3.6 mL/min/1.73m²/year), reduced urinary albumin-to-creatinine ratio (−6.8% vs +36.9%), and nearly halved the composite kidney endpoint compared with insulin glargine (HR 0.58, 95% CI 0.43–0.80). These are clinically meaningful differences. The protective effect was more pronounced in patients with baseline eGFR <60 mL/min/1.73m².

A pooled post-hoc analysis of SURPASS-1 through SURPASS-5 (Ludvik et al., Diabetes Care 2025) confirmed UACR reductions of −19.3% to −26.3% with tirzepatide versus pooled comparators. Mediation analysis suggested approximately half of this albuminuria reduction was attributable to weight loss, meaning weight-independent mechanisms (reduced intrarenal pressure, improved metabolic environment) may also contribute — but are not definitively established.

Important limitations: All kidney evidence from tirzepatide is post-hoc or secondary. The comparator in the most important analysis (SURPASS-4) is insulin glargine — a comparator that was associated with a 36.9% increase in UACR, potentially making tirzepatide appear more renoprotective than it is relative to other active treatments. A dedicated randomised kidney outcomes trial (SURPASS-RENAL or equivalent) had not been reported as of late 2024.

Ontology Kidney Outcomes [measured_by] SURPASS-4 Kidney Outcomes [associated_with] Tirzepatide Kidney Outcomes [relates] Type 2 Diabetes Kidney Outcomes [relates] Albuminuria Kidney Outcomes [compared_against] Insulin Glargine Kidney Outcomes [evidence_gap_for] Dedicated CKD Outcome Trial

Evidence Summary

Best-supported finding: Tirzepatide reduces UACR and slows eGFR decline vs insulin glargine in T2D with high CV risk

Absolute numbers (SURPASS-4 post-hoc, Heerspink et al., 2022, PMID 36152639):

  • eGFR decline rate: −1.4 SE 0.2 (tirzepatide) vs −3.6 SE 0.2 (glargine) mL/min/1.73m²/year
  • Between-group difference: 2.2 mL/min/1.73m²/year (95% CI 1.6–2.8)
  • In eGFR <60: between-group difference 3.7 (95% CI 2.4–5.1)
  • UACR change: −6.8% (95% CI −14.1 to +1.1) vs +36.9% (95% CI 26.0–48.7) with glargine
  • Composite kidney endpoint HR: 0.58 (95% CI 0.43–0.80)
  • Baseline: mean eGFR 81.3 mL/min/1.73m², median UACR 15.0 mg/g

Pooled SURPASS-1-5 UACR analysis (Diabetes Care 2025, PMID 39746157):

  • UACR change vs pooled comparators: −19.3% (5mg), −22.0% (10mg), −26.3% (15mg)
  • Mediation: ~50% of UACR reduction attributable to weight loss

Time period: 40–104 weeks (primarily 85-week median in SURPASS-4)

Confidence level: Moderate — consistent direction of effect across multiple analyses, but all are post-hoc; no primary powered kidney outcome trial

Main caveats:

  • All kidney evidence is post-hoc, not pre-specified as primary endpoint
  • Comparator in SURPASS-4 post-hoc is insulin glargine (which worsened UACR) — not placebo or SGLT2i (proven renal protectors)
  • Weight loss mediates ~50% of UACR effect — patients who do not lose weight may see attenuated benefit
  • No data in patients with eGFR <25 or severe albuminuria (macroalbuminuria >300 mg/g)
  • Funding by Eli Lilly for all analyses

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