Treatment with tirzepatide, compared with lifestyle intervention alone, helps prevent the incidence of new or progressive diabetic retinopathy (DR) and its complications among patients with diabetes and overweight or obesity, suggests a study.
“The present analysis suggests that tirzepatide is unlikely to exacerbate DR or related complications during the first year of therapy and may confer protection in this population,” the researchers said.
A total of 173,846 patients with diabetes and overweight or obesity who initiated tirzepatide were included in this population-based, retrospective cohort study using the TriNetX US Collaborative Network. Each patient was propensity-score matched to a similar individual who received lifestyle intervention alone and was not exposed to any weight-loss medication.
Each cohort consisted of 86,923 patients (mean age 56.9 years, 52.0 percent women). [Ophthalmology 2026;133:728-732]
Compared with lifestyle intervention alone, tirzepatide use correlated with a reduced 12-month risk of DR incidence and worsening events, including incident mild non-proliferative DR (risk ratio [RR], 0.864, 95 percent confidence interval [CI], 0.758‒0.985), proliferative DR (RR, 0.705, 95 percent CI, 0.564‒0.882), and DR with macular oedema (RR, 0.624, 95 percent CI, 0.536‒0.727).
Furthermore, treatment with tirzepatide was associated with a lower incidence of vitreous haemorrhage (RR, 0.607, 95 percent CI, 0.429‒0.860), tractional retinal detachment (RR, 0.370, 95 percent CI, 0.179‒0.765), intravitreal anti-VEGF injection (RR, 0.479, 95 percent CI, 0.368‒0.625), and pan-retinal photocoagulation (RR, 0.610, 95 percent CI, 0.403‒0.924).
Mixed results
“Studies assessing risk of DR with tirzepatide have presented mixed results,” the researchers said. “The SURPASS trial compared tirzepatide with semaglutide, excluded participants with moderate or severe DR, and did not mandate additional retinal imaging, limiting trial safety conclusions.” [N Engl J Med 2021;385:503-515]
In a pooled analysis of nine phase 3 trials, no significant difference was found in DR risk between tirzepatide and comparators. [Diabetes Obes Metab 2024;26:2497-2500]
On the other hand, a retrospective cohort study observed a higher likelihood of early DR worsening among tirzepatide users with moderate to severe DR. However, the study also reported that tirzepatide was associated with fewer new-onset retinopathy events among those without baseline DR. [Diabetologia 2025;68:2069-2076]
“Our findings align closely with the pooled analysis because both populations had relatively low baseline DR severity,” the researchers said.
“Because our propensity-matched design balanced baseline DR severity and glycaemic status, and the median follow-up captured the first year of therapy when early worsening effects would typically manifest, our results mirror the neutral safety profile seen in pooled trial data,” they added.
Mechanism
Tirzepatide differs from semaglutide through its coactivation of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors (R). This dual agonism leads to improved insulin sensitivity and energy expenditure beyond GLP-1 monotherapy, according to the researchers.
“Experimental data suggest that GIP-R signalling complements GLP-1–mediated pathways by further suppressing oxidative stress, inflammation, and vascular leakage in retinal tissues, potentially counteracting risks linked to abrupt glycaemic change,” the researchers said. [Front Endocrinol (Lausanne) 2023;14:1234925]
“This dual mechanism may explain the absence of early worsening effects and the apparent protective association observed in our retrospective cohort,” they added.