Dipeptidyl peptidase-4 inhibitors and diabetic retinopathy in type 2 diabetes: A network meta-analysis of randomized clinical trials

Amparo Ortiz-Seller; José Tomás Real; Esteban Morcillo; José Luis Ortiz

doi:10.1016/j.jdiacomp.2025.109234

Dipeptidyl peptidase-4 inhibitors and diabetic retinopathy in type 2 diabetes: A network meta-analysis of randomized clinical trials

J Diabetes Complications. 2026 Jan;40(1):109234. doi: 10.1016/j.jdiacomp.2025.109234. Epub 2025 Nov 26.

Authors

Amparo Ortiz-Seller¹, José Tomás Real², Esteban Morcillo³, José Luis Ortiz⁴

Affiliations

¹ Ophthalmology Service, La Fe University and Polytechnic Hospital, Valencia, Spain.
² Endocrinology and Nutrition Service of the Clinic University Hospital, Spain; CIBERDEM and Medicine Department, University of Valencia, Spain; INCLIVA Biomedical Research Institute, Valencia, Spain.
³ INCLIVA Biomedical Research Institute, Valencia, Spain; Pharmacology Department, University of Valencia, Valencia, Spain.
⁴ INCLIVA Biomedical Research Institute, Valencia, Spain; Pharmacology Department, University of Valencia, Valencia, Spain. Electronic address: jose.l.ortiz@uv.es.

PMID: 41314124
DOI: 10.1016/j.jdiacomp.2025.109234

Abstract

Aims: To update evidence on the relationship between dipeptidyl peptidase-4 (DPP-4) inhibitors and incident diabetic retinopathy (DR) in type 2 diabetes.

Methods: We searched Embase, PubMed, Web of Science, and ClinicalTrials.gov (to July 2025) for randomized controlled trials (RCTs) and pooled odds ratios (ORs) with 95 % credible intervals (CrIs) using a Bayesian network meta-analysis. Network meta-regression assessed estimated effect modification; a model-based network meta-analysis (MBNMAdose) evaluated dose-response. Evidence certainty was appraised with Confidence in Network Meta-Analysis (CINeMA).

Results: Forty-three trials (74,546 participants; 779 DR events) were analyzed. No DPP-4 inhibitor significantly changed the DR risk versus placebo (ORs ranged from 0.31 [omarigliptin] to 2.31 [saxagliptin]; all CrIs crossed 1.0). Rankings suggested omarigliptin as most favorable, alogliptin/linagliptin/sitagliptin intermediate, and saxagliptin/teneligliptin least favorable. Baseline DR incidence moderated treatment effects; other prespecified covariates were not significant. MBNMAdose showed no dose-response relationship for DR.

Conclusions: Current randomized evidence indicates class-level neutrality of DPP-4 inhibitors on DR incidence, with no dose-response signal. Choice among gliptins may therefore be guided primarily by glycemic efficacy, safety, and participant characteristics rather than retinal risk.

Keywords: Diabetic retinopathy; Dipeptidyl peptidase-4 inhibitors; Network meta-analysis; Network meta-regression; Systematic review; Type 2 diabetes.

Publication types

Network Meta-Analysis
Review

MeSH terms

Diabetes Mellitus, Type 2* / complications
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / epidemiology
Diabetic Retinopathy* / epidemiology
Diabetic Retinopathy* / prevention & control
Dipeptidyl-Peptidase IV Inhibitors* / adverse effects
Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use
Humans
Randomized Controlled Trials as Topic

Substances

Dipeptidyl-Peptidase IV Inhibitors