PMID-38456523 — Popovic: Tirzepatide Diabetic Retinopathy Risk (SURPASS Meta-Analysis)

[DRAFT — authored 2026-04-19. Citation web-verified 2026-04-19 against PubMed and Diabetes Obes Metab journal-of-record.]

Citation

Popovic DS, Patoulias D, Karakasis P, Koufakis T, Papanas N. Effect of tirzepatide on the risk of diabetic retinopathy in type 2 diabetes. Diabetes, Obesity and Metabolism. 2024;26(6):2497-2500. doi: 10.1111/dom.15535. PMID: 38456523.

External URL: DOI resolver

Phase 2b note: This DOI was flagged in the Table Audit report as inline in Tirzepatide profile prose without a standalone research note. This note now exists; Tirzepatide profile Evidence Base table row converts from inline DOI to wiki-link format in Sub-Section 5a integration step.

Study Design

Design: Meta-analysis of pooled data from the SURPASS clinical trial programme (Phase 3 tirzepatide in type 2 diabetes)
Comparison: Early worsening of diabetic retinopathy (EWDR) risk with tirzepatide vs pooled comparators
Methodology: Systematic synthesis of SURPASS-1 through SURPASS-5 data

Key Findings

No increased risk of EWDR (early worsening of diabetic retinopathy) identified with tirzepatide treatment across the pooled SURPASS programme
Important methodological caveat: No additional retinal surveillance was undertaken during the SURPASS studies beyond routine ophthalmologic safety monitoring. Patients with proliferative retinopathy, severe pre-proliferative retinopathy, or maculopathy were excluded at baseline.
Interpretation: This is a pre-specified trial-population analysis. It does not address the safety signal in patients with pre-existing moderate-to-severe non-proliferative retinopathy or maculopathy, which requires real-world data (see Buckley 2025 Diabetologia real-world cohort for that population).

Clinical Relevance

Popovic 2024 is the trial-population-level evidence base for the statement that tirzepatide does not appear to cause early worsening of diabetic retinopathy in the SURPASS-trial-eligible population. Appropriate clinical use of this evidence:

Supports tirzepatide use in T2D without pre-existing significant retinopathy — the EWDR signal seen historically with intensive glycemic control does not appear amplified with tirzepatide in this population
Does NOT exclude risk in patients with baseline R1M1 (mild NPDR + maculopathy) or R2+ (moderate-severe NPDR) — Popovic analyzed a trial population that excluded those patients
Real-world extension: Buckley AJ et al., Diabetologia 2025 (real-world cohort n=6,869 matched, OR 2.15 for new-onset proliferative DR in patients with baseline R1M1 or R2/R3; OR 0.73 in patients without baseline retinopathy) — both findings can be true simultaneously because the analyses address different sub-populations
Clinical implication: Baseline ophthalmic evaluation before tirzepatide initiation is reasonable in all T2D patients; patients with existing retinopathy warrant co-management with ophthalmology and closer surveillance during rapid glycemic improvement

Limitations (Author-acknowledged)

Trial-population exclusions (proliferative DR, severe pre-proliferative DR, maculopathy) limit generalizability to real-world T2D
Retinal surveillance was not intensified — spontaneous AE reporting only
Short-to-medium duration for retinopathy outcomes (SURPASS trials extend to 52-72 weeks; retinopathy progression is a longer-horizon event)
Heterogeneity across SURPASS trials in baseline retinopathy prevalence

Evidence Level

Level II (Oxford CEBM) — meta-analysis of Phase 3 RCT trial-reported adverse events.

Linked Peptides

Tirzepatide

Related Studies

PMID-35658024 – SURMOUNT-1 Tirzepatide for Obesity — SURMOUNT program (obesity companion)
Buckley AJ et al., Diabetologia 2025, PMID: 40637847 — real-world tirzepatide retinopathy cohort (distinguishes baseline-retinopathy subgroups); note: no research-note file in vault for this PMID as of audit
PMID-38958939 – Hathaway NAION Cohort — separate optic-neuropathy signal (different from diabetic retinopathy)

Orchestrator Notes

Citation web-verified 2026-04-19 via PubMed.
Popovic DS is the first author, affiliated Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, Novi Sad, Serbia.
Primary research-note anchor for the Tirzepatide profile "Diabetic retinopathy — nuanced evidence" prose section.

PMID-38456523 – Popovic Tirzepatide SURPASS Retinopathy Meta-Analysis