SGLT2 Inhibitors Associated with Lower Risk of Sight-Threatening Retinopathy

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Sodium-glucose cotransporter 2 (SLGT2) inhibitor use was associated with a significantly lower risk of sight-threatening retinopathy than dipeptidyl peptidase-4 inhibitors, pioglitazone, and sulfonylureas among patients with type 2 diabetes (T2D), according to new research.¹

Across the nationwide cohort in Taiwan, the potential protective role of SGLT2 inhibitors for sight-threatening retinopathy was observed across various subgroups of patients, including by age, sex, comorbidities, and medication use.

As chronic kidney disease (CKD) and diabetic retinopathy share similarities in pathophysiological processes, the SGLT2 inhibitor class is presumed to play a role in reducing the risk of diabetic retinopathy. Since the first approval in 2023, SGLT2 inhibitors have transformed into one of the most prominent therapies based on management and clinical recommendations for patients both with and without T2D, as well as heart failure and CKD.²

“This finding suggests that SGLT2 inhibitors may play a role not only in reduced risk of diabetic nephropathy but also in the slow progression of diabetic retinopathy in patients with T2D,” wrote the investigative team, led by Chii-Min Hwu, MD, section of endocrinology and metabolism, department of medicine, at Taipei Veterans General Hospital.¹

Major medical organizations across specialties have helped solidify its role in the management of cardiometabolic health. Many suggest SGLT2 inhibitor use may expand beyond diabetes, CKD, and heart failure, and these indications have only just begun to scratch the surface of the true potential of the therapy class. Hwu and colleagues conducted a nationwide cohort study to compare the risk of severe diabetic retinopathy and macular edema associated with SGLT2s and other second-line glucose-lowering medications among a population with T2D.

The study recruited patients with newly diagnosed T2D from January 2009 to December 2019, with follow-up until December 2020, using data from the National Health Insurance Research Database. Investigators applied a new-user and active-comparator design for the cohort study. Propensity score matching identified pairs of patients treated with SGLT2 inhibitors versus DPP-4 inhibitors, SGLT2 inhibitors versus pioglitazone, and SGLT2 inhibitors versus sulfonylurea, from January 2016 to December 2019.

The main outcome of the study was identified as sight-threatening retinopathy in individuals with ≥2 outpatient visits or 1 hospitalization for diabetic retinopathy and requiring surgery, laser photocoagulation, or anti-VEGF injections within 90 days of retinopathy diagnosis of vision loss. Participants were followed until the occurrence of sight-threatening retinopathy or until the study ended.

Investigators identified 3,544,383 patients with newly diagnosed T2D for analysis. After exclusions, the team identified 159,965 patients treated with SGLT2 inhibitors, 304,383 treated with DPP-4 inhibitors, 108,420 treated with pioglitazone, and 189,618 treated with sulfonylurea during the study period.

Then, 1:1 propensity score matching left 65,930 pairs of patients treated with SGLT2 inhibitors versus DPP-4 inhibitors, 93,760 pairs treated with SGLT2 inhibitors versus pioglitazone, and 42,121 pairs treated with SGLT2 inhibitors versus sulfonylurea. Of the matched patients, 167,048 were female (41.4%) and 326,574 were male (58.6%), with a mean age of 56.9 years.

Among the matched populations, investigators found SGLT2 inhibitors were associated with a significantly lower risk of sight-threatening retinopathy versus DPP-4 inhibitors (adjusted hazard ratio [aHR], 0.57; 95% CI, 0.51 - 0.63), pioglitazone (aHR, 0.75; 95% CI, 0.69 - 0.81), and sulfonylureas (aHR, 0.62; 95% CI, 0.53 - 0.71).

Meanwhile, Kaplan-Meier curves revealed that the SGLT2 inhibitor cohort experienced a significantly lower cumulative incidence of sight-threatening retinopathy, compared with DPP-4 inhibitors (3.52 versus 6.13; P <.001), pioglitazone (4.32 vs. 5.76; P <.001), and sulfonylureas (2.94 versus 4.67; P <.001).

In their summary, Hwu and colleagues indicated previous analyses additionally support the association between SGLT2 inhibitor treatment and a lower risk of diabetic retinopathy. They described the potential mechanisms by which SGLT2 inhibitors were associated with the decreased risk of retinopathy.

“In brief, SGLT2i has been associated with improved metabolism and microcirculation of the retinal neurovascular coupling and decreased apoptosis of retinal and microvascular endothelial cells to lower the risk of sight-threatening retinopathy,” investigators wrote.

References

Campbell P. 10 years of SGLT2 inhibitors: A Decade of Redefining Cardiometabolic Care. HCP Live. March 29, 2023. Accessed December 20, 2023. https://www.hcplive.com/view/10-years-of-sglt2-inhibitors-a-decade-of-redefining-cardiometabolic-care.