SGLT2 inhibitors potentially protective against dry eye disease

Type 2 diabetes (T2D) patients on sodium-glucose cotransporter 2 (SGLT2) inhibitors appear to be at lower risk of dry eye disease (DED) compared with their counterparts who are receiving glucagonlike peptide-1 receptor agonists (GLP-1 RAs), as shown in a study.

In a cohort of 10,038 and 1,077 T2D patients who had recently initiated treatment with SGLT2 inhibitors or GLP-1 RAs, respectively, DED occurred less frequently among those on SGLT2 inhibitors (9.0 vs 11.5 events per 1,000 person-years). [JAMA Netw Open 2022;5:e2232584]

Compared with GLP-1 RAs, SGLT2 inhibitors cut the risk of DED by 22 percent (hazard ratio [HR], 0.78, 95 percent confidence interval [CI], 0.68–0.89).

“Given that DED 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 events per 1,000 person-years) between SGLT2 inhibitors and GLP-1 RAs may provide an important reference for clinical decisions about prescribing different antidiabetic medications to delay or prevent DED in patients with T2D,” according to the investigators. [Curr Ophthalmol Rep 2013;1:51-57; J Ophthalmol 2016;2016:8201053]

Sex, renal function factor in DED risk

Subgroup analyses revealed that the seemingly protective effect of SGLT2 inhibitor use on DED risk in T2D patients was somewhat greater for men (HR, 0.62, 95 percent CI, 0.51–0.75), those with estimated glomerular filtration rate (eGFR) level ≥90 mL/min/1.73 m² (HR, 0.62, 95 percent CI, 0.51–0.77), and those with urine albumin-creatinine ratio (UACR) <30 mg/g (HR, 0.65, 95 percent CI, 0.54–0.78 mg/g).

Explaining the results of the subgroup analyses, the investigators pointed out that sex and renal function might be a crucial risk factor for DED. This was supported by observations of 1.5-fold and 1.2-fold higher incidence rates of DED among women vs men with T2D as well as in patients with both eGFR <90 mL/min/1.73 m² and UACR ≥30 mg/g vs those with better kidney function, respectively.

“Women may be more likely to develop DED due to other systemic factors, such as lower androgen levels, a higher prevalence of autoimmune diseases, and higher sensitivity to pain. Similarly, patients with renal impairment or proteinuria have been shown to be at increased risk of DED due to tear hyperosmolarity and increased ocular surface inflammation,” the investigators said. [Ocul Surf 2017;15:284-333; Clin Ophthalmol 2021;15:4327-4332; Cornea 2001;20:695-702]

“Because there were no significant differences in DED risks between SGLT2 inhibitor and GLP-1 RA 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,” they added.

Optimizing glucose-lowering benefits

For most patients with T2D, DED is managed with topical treatments and adequate glycaemic control. SGLT2 inhibitors, meanwhile, have anti-inflammatory benefits that may extend to the ocular surface. Since most types of DED result in tear film hyperosmolarity and promote ocular surface inflammation in T2D patients, SGLT2 inhibitors may hinder the inflammatory process, according to the investigators. [JAMA 2022;327:478-479; Clin Exp Ophthalmol 2018;46:608-615; EBioMedicine 2017;20:137-149; Diabetes Obes Metab 2018;20:2515-2522]

“Another reason why SGLT2 inhibitors may have anti-inflammatory effects on the ocular surface could be that DED has been shown to be associated with proinflammatory M1-polarized macrophages and an elevation of inflammatory cytokine levels. SGLT2 inhibitors have been reported to reduce M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages and to lower inflammatory cytokines. This action could explain the greater DED risk reduction with SGLT2 inhibitors compared with GLP-1 RAs,” they explained. [Ocul Surf 2017;15:438-510; Nat Commun 2020;11:2127; EBioMedicine 2017;20:137-149]

Taken together, the data underscores the potential for evaluating the risks of ophthalmologic conditions when selecting glucose-lowering medications as intensification therapy to optimize the treatment benefits in patients with T2D, the investigators said.