Role of systemic hypoxia in the progression of diabetic retinopathy: a propensity-matched retrospective cohort study.

OBJECTIVE

This study aims to assess the association between systemic hypoxia and progression from non-proliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and vision-threatening outcomes.

METHODS AND ANALYSIS: This retrospective cohort study used the TriNetX Network to identify adults with NPDR with no prior PDR. Systemic hypoxia was defined using International Classification of Diseases 10th revision (ICD-10) codes for anaemia, obstructive sleep apnoea, chronic respiratory failure, chronic obstructive pulmonary disease, pulmonary hypertension or interstitial lung disease. Both cohorts were propensity score-matched. The primary outcome was progression to PDR. Secondary outcomes included vitreous haemorrhage, tractional retinal detachment, legal blindness, diabetic macular oedema and therapeutic interventions. Time-to-event analyses were performed using Cox proportional hazards models, and 5-year cumulative incidence was assessed using Kaplan-Meier analysis.

RESULTS

After matching, 92 454 patients were included in each cohort with well-balanced baseline characteristics (all standardised mean differences <0.1). Systemic hypoxia was associated with increased risk of PDR progression (HR 1.24; 95% CI 1.18 to 1.31; p<0.001). 5-year cumulative PDR incidence was higher in the hypoxia cohort (4.2% vs 2.6%; risk ratio 1.63). Patients with systemic hypoxia also had higher risks of vitreous haemorrhage, tractional retinal detachment, blindness and increased utilisation of panretinal photocoagulation and pars plana vitrectomy. Subgroup analyses identified anaemia as the primary driver of PDR progression, whereas respiratory aetiologies were not independently associated after matching.

CONCLUSIONS

Systemic hypoxia, a diagnosis-code-based composite in which anaemia-associated phenotypes showed the strongest association, is associated with accelerated PDR progression and near-doubled legal blindness risk. Anaemia screening may offer an opportunity to reduce vision-threatening complications in diabetic patients. These findings are hypothesis-generating and warrant prospective validation before informing screening pathways, given the retrospective design and absence of measured oxygen saturation, haemoglobin and glycaemic data.