Thiazolidinediones During nAMD Therapy May Raise Odds for Intraretinal Fluid

3D ocular coherence tomography (OCT) after ranibizumab injection, showing age-related macular degeneration (AMD).
Analysis of CATT data reveals more patients who took thiazolidinediones developed intraretinal fluid, but subretinal fluid thickness improved.

Thiazolidinediones (TZDs) are often prescribed for patients with diabetes to help manage insulin sensitivity and steady glucose levels, although there has been evidence this drug class may expand permeability of vascular endothelial cells. Prior research has offered conflicting results for whether these medications are associated with increased risk for neovascular conditions and diabetic macular edema.

Research  into TZDs’ potential effects on age-related macular degeneration (AMD) have been relegated to in situ and in vitro studies. However, an investigation published in the British Journal of Ophthalmology now explores the effect of TZDs on retinal anatomy and visual acuity in patients with both diabetes and neovascular AMD (nAMD) who underwent anti-vascular endothelial growth factor (anti-VEGF) therapy.

The study was based on a secondary analysis of data reported in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT) ( Identifier: NCT00593450). It reviewed 207 patients from the trial who had diabetes at baseline, 30 who were taking TZDs, and 177 who were not. The TZD-treated patients began the study with average visual acuity of 55.2±2.4 ETDRS letters, compared with participants not taking this medication, 61.4±1.0 letters (P =.02). But after 1 year, participants using the drug caught up, reaching 65.3±3.3 letters, compared with those not taking TZDs who also improved to 68.0±1.3 letters (P =.46). At the 2-year mark, the drug-treated cohort maintained 62.5±3.6 letters, compared with the not taking group at 66.6±1.5 letters (P =.27).

Those who were not prescribed TZDs had relatively the same amount of injections in the first year of the study (P =.36) and in the second (P =.30). Notably, more participants taking the drug developed intraretinal fluid (IRF) after 1 year (P =.10) and 2 years (P =.04).

At baseline, both groups displayed comparable subretinal fluid (SRF) at foveal center and subretinal tissue complex thickness (P =.34) but the TZD cohort experienced larger improvements in SRF and sub-RPE fluid thickness after starting anti-VEGF treatment with bevacizumab or ranibizumab. Those taking TZDs showed more sizable decreases from baseline in SRF thickness at the 1-year and 2-year visits (both P =.001).

Previous research has demonstrated rosiglitazone may raise VEGF levels and permeability in some types of cells. Thus, continuing or repeated neovascular membrane could possibly cause leakage and IRF, as seen in CATT, the investigators speculate. Yet, additional studies have reported TZDs inhibit VEGF expression in other cells. It is not yet known what impact this drug class has on retinal cells of those with neovascular disease, but decreased fluid thickness in the present study may indicate the nAMD lesions respond well to anti-VEGFs, and the greater IRF resulted from cystic deterioration. In a number of prior analyses, pioglitazone and rosiglitazone have been associated with the contrasting effect of reduced pro-inflammatory cytokines such as TNF-α, suggesting that TZDs may suppress the inflammatory environment.

The analysis is limited in that it is post hoc, and therefore does not include randomization and cannot determine causative relationships. Also, limitations include a somewhat small cohort, and low resolution imaging. 

 “[TZDs] could prove either beneficial or detrimental to the retina of people affected by diabetes or other types of neovascular disease,” study authors report.

Disclosures: Several study authors have disclosed affiliations with the biotech, and/or pharmaceutical industries. Please see the original reference for a full list of authors’ disclosures. 


Core JQ, Hua P, Daniel E, et al. Thiazolidinedione use and retinal fluid in the comparison of age-related macular degeneration treatment trials. Br J Ophthalmol. Published online April 15, 2022. doi:10.1136/bjophthalmol-2021-320665