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A potential benefit of SGLT2 inhibitors in patients with type 2 diabetes (T2D) may be reduced incidence of dry eye disease, said authors of a large retrospective study.

In more than 10,000 patients followed for approximately 4 years, the incidence of dry eye disease was lower in those receiving SGLT2 inhibitors compared with GLP-1 receptor agonists (9.0 vs 11.5 events per 1,000 person-years), said Jia-Horung Hung, MD, of National Cheng Kung University Hospital in Taiwan, and colleagues.

As they reported in the study in , the 22% risk reduction (HR 0.78, 95% CI 0.68-0.89) was generally maintained across subgroups, although there were greater risk reductions in men (HR 0.62, 95% CI 0.51-0.75) and in patients with better kidney function (HR 0.62, 95% CI 0.51-0.77).

"Given that DED [dry eye disease] affects about one-fifth of patients with T2D and reduces the patients' quality of life, our findings with the small absolute risk difference (2.5 per 1,000 person-years) between SGLT2 inhibitors and GLP-1 RAs [receptor agonists] may provide an important reference for clinical decisions about prescribing different antidiabetic medications to delay or prevent DED in patients with T2D," the researchers wrote.

"In addition, similar changes in glycemic control and kidney function for SGLT2 inhibitors and GLP-1 RAs implied that possible mechanisms underlying the lower incidence of DED from SGLT2 inhibitor use are independent of these factors," the investigators said.

They explained that chronic inflammation plays a major role in dry eye disease and SGLT2 inhibitors may have anti-inflammatory effects on the ocular surface.

In addition, DED has been associated with proinflammatory M1-polarized macrophages and elevated inflammatory cytokine levels. But SGLT2 inhibitors have been reported to reduce the accumulation of M1-polarized macrophages while inducing the anti-inflammatory M2 macrophage phenotype. SGLT2 inhibitors have also been shown to lower inflammatory cytokine levels by inducing low-grade ketonemia, the researchers noted.

"This action could explain the greater DED risk reduction with SGLT2 inhibitors compared with GLP-1 RAs," Hung's group said. Previous studies reported that SGLT2 inhibitors reduce the risk of other ocular inflammatory diseases, such as diabetic retinopathy, diabetic macular edema, and glaucoma.

Therefore, "clinicians may also evaluate the risks for ophthalmologic conditions when selecting antidiabetic medications as intensification therapy to optimize the treatment benefits," Hung and co-authors suggested.

They retrospectively analyzed information from the largest multi-institutional database in Taiwan, which had information on 10,038 patients with T2D who received SGLT2 inhibitors and 5,608 who received GLP-1 receptor agonists. Nearly half were women, and mean age was approximately 59. Clinical factors, such as glucose control and kidney function, were similar in the two groups.

The primary outcome was incidence of dry eye disease as determined by International Classification of Diseases codes and prescriptions of medications used to treat the condition. The researchers used Cox proportional hazards regression models to examine associations between the primary outcome and the type of diabetes medication as well as various clinical factors.

Discussing the greater risk reductions for dry eye disease observed in men and in patients with better kidney function, the researchers noted that the incidence of dry eye disease was 1.5 times higher in women compared with men and twice as high in patients with reduced kidney function (estimated glomerular filtration rate less than 90 mL/min/1.73 m²) compared with those with better function. This could have obscured the risk reduction in these groups and emphasized it in their counterparts, the investigators explained.

They noted that women may be more likely to develop dry eye disease due to systemic factors, such as lower androgen levels and a higher prevalence of autoimmune diseases. Similarly, patients with renal impairment or proteinuria may be at increased risk of the condition due to tear hyperosmolarity and increased ocular surface inflammation.

"Because there were no significant differences in DED risks between SGLT2 inhibitor and GLP-1 receptor agonist use in women with T2D or patients with worse kidney function, the prescription of SGLT2 inhibitors for these populations at high risk of DED should be based on other clinical considerations," Hung and co-authors advised.

A notable limitation of the study, they said, was the much larger size of the SGLT2 inhibitor group, which may have obscured greater heterogeneity in this group compared with the GLP-1 group.

"In addition, owing to the nature of retrospective study design, we did not evaluate clinical types in patients developing DED," the team wrote. "Additional studies with prespecified clinical and instrumental diagnostic assessment are suggested to investigate the role of SGLT2 inhibitors in DED incidence."

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