SGLT2 Inhibitor, Metformin Therapy May Delay Diabetic Retinopathy Progression


SGLT2 inhibitors added to metformin were associated with a significantly higher risk of diabetic retinopathy progression in the short term but significantly lower risk in the long term.

Dr. Chun-Ju Lin | Image Credit: China University Medical Hospital

Dr. Chun-Ju Lin

Credit: China University Medical Hospital

The co-administration of metformin and sodium-glucose co-transporter 2 (SGLT2) inhibitors may reduce the risk of diabetic retinopathy progression in patients with type 2 diabetes (T2D), according to new findings.1

Conducted in Taiwan, a nationwide population-based study suggested the short-term use of SGLT2 inhibitors may markedly increase retinopathy risk, while prolonged use of SGLT2s may significantly decrease that risk over the long term.

“For diabetic retinopathy patients, the continued SGLT2 inhibitor add-on therapy may yield benefits beyond glycemic control” wrote the investigative team, led by Dr. Chun-Ju Lin of the department of ophthalmology at China Medical University Hospital.

Although a common complication of diabetes, the underlying mechanisms of diabetic retinopathy are not fully understood, particuarly due to its complex pathophysiology. SGLT2 inhibitors, including empagliflozin, dapagliflozin, and canagliflozin, are widely used for the treatment of T2D. Their use in clinical practice is often for the regulation of blood glucose in patients with T2D prone to heart failure, due to their associated benefit to cardiovascular outcomes.

However, there are insufficient reports from a large-scale population study on the effect of SGLT2 inhibitors on diabetic retinopathy, without validation from real-world outcomes. To bridge this gap in knowledge, Lin and colleagues investigated the effect of SGLT2 inhibitor add-on therapy to metformin on diabetic retinopathy progression in T2D.1

Conducted from January 2016 - December 2018, the nationwide cohort consisted of 3,432,911 adults with T2D in Taiwan. Patients were eligible for the study if they were aged 40 years or older and had a diagnosis of T2D and metformin monotherapy for ≥90 cumulative days before 2016. Once SGLT2 inhibitors were used, the period of use was tracked to December 2019, death, or withdrawal from the NHI Research Database.

To adjust for potential confounders, investigators collected data on age, sex, income, comorbidities, diabetes complication severity index score, kidney disease staging, anti-diabetic medications, and index year. The primary outcome was the progression of diabetic retinopathy, as discerned by procedure codes, or the incorporation of ICD-9-CM or ICD-10-CM codes into the medical records of patients during the study period.

After applying exclusion criteria, investigators used 1:1 propensity score matching to obtain 85,550 pairs of patients treated and not treated with SGLT2 inhibitors. The population was 44% female and had a mean age of 60 years. The overall mean follow-up duration was 7.78 years for T2D and 2.29 years for diabetic retinopathy among those receiving SGLT2 inhibitors.

Upon analysis, a total of 819 patients who received SGLT2 inhibitor add-on therapy developed diabetic retinopathy progression during the follow-up, with an incidence rate of 4.19 per 1000 person-years. Those receiving SGLT2 inhibitor add-on therapy showed a significantly decreased risk of diabetic retinopathy (adjusted hazard ratio [aHR], 0.89; 95% CI, 0.81 - 0.98; P = .023), compared to the non-SGLT2 inhibitor cohort.

In addition, investigators identified other clinical parameters associated with a higher risk of diabetic retinopathy progression, including higher age, increases in diabetes complication severity index scores, and the use of sulfonylureas. The co-administration of metformin, SGLT2 inhibitors, and other antidiabetic medications, was observed to significantly reduce the risk of DR progression.

A Kaplan-Meier curve of the cumulative incidence rate revealed the cumulative incidence of diabetic retinopathy progression was significantly lower in the SGLT2 inhibitor cohort than in the non-SGLT2 inhibitor cohort in 4 years (log-rank P = .0233).

Importantly, the adjusted risk of diabetic retinopathy progression in those receiving SGLT2 inhibitor therapy for less than 1 year and 1 to 2 years was significantly increased (aHR, 1.54 versus 1.86; both P <.001). However, this risk was notably reduced if patients received an SGLT2 inhibitor regimen for ≥2 years (aHR, 0.41; 95% CI, 0.35 - 0.47; P <.001).

Lin and colleagues noted the use of real-world data is a major strength of the study, but misclassification in the database and the lack of relevant clinical and laboratory information could limit the translation of these results. The team indicated more clinical studies are required to confirm the protective effect of SGLT2 inhibitors, particularly for a global population.

“The findings of the present study may only be related to the Taiwanese population; thus, other similar studies should be performed in different countries to check if the association holds,” investigators wrote.


  1. Li JX, Hung YT, Bair H, Hsu SB, Hsu CY, Lin CJ. Sodium-glucose co-transporter 2 inhibitor add-on therapy for metformin delays diabetic retinopathy progression in diabetes patients: a population-based cohort study. Sci Rep. 2023;13(1):17049. Published 2023 Oct 10. doi:10.1038/s41598-023-43893-2
  2. Sha, W. et al. The role of SGLT2 inhibitor on the treatment of diabetic retinopathy. J. Diabetes Res. 2020, 8867875.[publishedOnlineFirst:2020/12/05] (2020).
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