Diabetic retinopathy (DR) has several well-established risk factors, including poor glycemic control, longer diabetes duration and hypertension. But growing evidence suggests another metabolic factor may deserve attention: elevated uric acid.
A new study published in Graefe's Archive for Clinical and Experimental Ophthalmology examined whether patients with type 2 diabetes (T2D) and gout faced greater risks of developing DR, vision-threatening complications and the need for ocular interventions.
Researchers also explored whether urate-lowering therapy (ULT) was associated with better outcomes among patients who already had severe DR.
Give me some background first.
Gout is a chronic inflammatory condition associated with hyperuricemia, or elevated levels of uric acid in the blood—which may be relevant to the retina.
Previous research has linked hyperuricemia with inflammatory cytokines, oxidative stress and endothelial dysfunction, processes that also contribute to the microvascular injury seen in DR.
Plus: Studies have also suggested that uric acid may increase inflammatory mediators and vascular endothelial growth factor (VEGF), potentially promoting DR development and progression.
And the clinical evidence into this?
That’s been building as well: A 2022 systematic review and meta-analysis of 21 studies found significantly higher serum uric acid levels among patients with DR than among controls with diabetes.
That being said, however: Large-scale evidence examining clinically diagnosed gout—rather than uric acid levels alone—and subsequent DR outcomes has remained limited.
Now, talk about the study.
Researchers conducted a retrospective cohort study using the U.S. Collaborative Network within TriNetX, a federated health network containing deidentified data from 67 U.S. healthcare organizations and more than 135 million patients.
The primary analysis identified T2M patients and divided them according to whether they also had a diagnosis of gout.
- To note: Patients with pre-existing DR, less than 1 year of follow-up, or certain ocular conditions that could confound the results were excluded.
And what was evaluated?
Outcomes were assessed at 1, 3, and 5 years and included nonproliferative DR (NPDR), proliferative DR (PDR), vitreous hemorrhage (VH), diabetic macular edema (DME), tractional retinal detachment (TRD) and neovascular glaucoma (NVG).
Researchers also examined the need for intravitreal (IVT) injections, panretinal photocoagulation (PRP), and pars plana vitrectomy (PPV).
They then conducted a secondary analysis to determine whether ULT was associated with different outcomes among patients with gout and severe NPDR or PDR.
Who was included in the analysis?
Before propensity score matching, the primary analysis included 31,734 patients with gout and 376,705 without gout.
After matching for factors including age, sex, race, hypertension, ischemic heart disease, hyperlipidemia, chronic kidney disease, obesity, BMI, hemoglobin A1c and medication use, researchers analyzed 21,707 patients in each group.
The secondary ULT analysis included 3,425 matched patients in each cohort.
Patients were considered part of the treatment group if they had at least two recorded instances of a urate-lowering medication (allopurinol, febuxostat, lesinurad, rasburicase, pegloticase, or probenecid).
Next up: the findings
The differences were substantial: At 5 years, compared with matched patients without gout, those with gout had higher risks of:
- NPDR: risk ratio (RR) 8.31
- PDR: RR 1.75
- VH: RR 5.83
- DME: RR 6.94
- NVG: RR 3.90
The increased risks of NPDR, PDR, VH, DME and NVG were already significant at 1 year and remained significant at 3 and 5 years. However, researchers found no significant difference in the risk of tractional retinal detachment.
Were these differences limited just to diagnoses?
They were not. Patients with gout were also more likely to require treatment.
At 5 years, these patients had a:
- 2.88-times higher risk of receiving IVT injections
- 7.60-times higher risk of PRP
- Four-fold higher risk of PPV
Notably: There was no significant difference in subtenon injections.
Did urate-lowering therapy make a difference?
Potentially. Among patients with gout and severe NPDR or PDR, those receiving ULT had significantly lower 5-year risks of several outcomes than those who weren't receiving ULT.
ULT was associated with:
- 41% lower relative risk of VH (RR: 0.59)
- 19% lower relative risk of DME (RR: 0.81)
- 22% lower relative risk of IVI (RR: 0.78)
- 56% lower relative risk of PPV (RR: 0.44)
There were no significant differences in TRD, NVG, PRP or subtenon injections.
What else?
Importantly: A multivariable Cox regression sensitivity analysis produced a similar pattern.
After additional adjustment for demographic and clinical factors, ULT remained independently associated with reduced hazards of VH, DME, IVI and PPV.
Any limitations to keep in mind?
As a retrospective database study, the analysis relied on ICD-10 coding, creating the possibility of inaccurate diagnoses or disease staging.
TriNetX also didn't provide serum uric acid measurements—meaning the investigators had to use a gout diagnosis as a proxy for hyperuricemia.
- They couldn't determine gout severity, either, despite previous evidence suggesting that the degree of hyperuricemia may influence DR risk.
Did patients’ medications pose any issues?
Adherence to their mediation did.
- The researchers could identify ULT prescriptions but couldn't determine whether patients consistently took the medication
- They also couldn't evaluate how different ULT doses affected outcomes
Tell me more.
Also worth noting: The CPT code used for IVT injections doesn't distinguish among anti-VEGF agents, IVT steroids, or other pharmacologic treatments.
In the end: The study's observational design meant that the findings demonstrated associations—not proof—that gout caused the worse retinal outcomes or that ULT itself prevented them.
So what do the researchers think this could mean clinically?
The authors suggested that gout could represent a potentially modifiable factor worth considering when assessing DR risk.
Their reasoning: Because uric acid can be measured through relatively simple blood or urine testing, the findings raise the possibility that identifying gout or hyperuricemia could eventually help refine risk assessment in patients with diabetes.
The association between ULT and fewer complications also raises the possibility that gout management could have ophthalmic benefits.
I’m sensing a “but” …
But that's still a possibility, not a treatment recommendation.
The researchers emphasized the need for randomized controlled trials (RCTs) to determine whether actively lowering uric acid can reduce DR progression or vision-threatening complications.
And now for the take home.
For now, the findings support closer monitoring of patients with both diabetes and gout while raising a larger question for future prospective trials:
Could treating hyperuricemia eventually become another way to reduce vision-threatening DR complications?