Association of long-term use of dipeptidyl peptidase-4 inhibitors with the risk of diabetic retinopathy in patients with diabetes mellitus: A real-world evidence study

Yu-Ching Li ¹ Yu-Hsiang Kuan ² Yih Yang ³ Shuo-Yan Gau ^4,5 Kun-Yu Su ⁴ Tung-Han Tsai ⁶ Kuang-Hua Huang ^6* Chien-Ying Lee ^2*

• ¹ Department of Public Health, China Medical University, Taichung, Taiwan
• ² Department of Pharmacology, Chung Shan Medical University, Taichung, Taiwan, Taichung, Taiwan
• ³ Department of Surgery, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
• ⁴ School of Medicine, Chung Shan Medical University, Taichung, Taiwan
• ⁵ Department and Graduate Institute of Business Administration, National Taiwan University, Taipei, Taiwan
• ⁶ Department of Health Services Administration, China Medical University, Taichung, Taiwan, Taichung, Taiwan

Background: In this study, we investigated the association of long-term use of a dipeptidyl peptidase-4 inhibitor (DPP-4i) with the risk of diabetic retinopathy (DR) in patients with diabetes mellitus (DM).: This study was a secondary analysis based on the nationwide database from 2008 to 2022 in Taiwan. Patients with new-onset DM who were treated with either a DPP-4i or sulfonylurea from 2009 to 2017 were included in this study. Patients who received a DPP-4i were included in the case group and further divided on the basis of the cumulative defined daily dose (cDDD) as follows: ≤90, 91-180, 181-300, and >300 cDDD. Propensity score matching was performed to select patients who used a sulfonylurea, and these patients were assigned to the control group. With adjustment for sex, age, income, urbanization level, comorbidities, and other anti-diabetic agents, the Cox proportional hazard model was used to estimate the risk of DR associated with DPP-4i use over the 5-year follow-up. Results: There were 83 503 patients with DPP-4i use and 167 006 patients with sulfonylurea use after matching. Compared with patients with sulfonylurea use, patients with DPP-4i use at ≤90 cDDD had a hazard ratio (HR) of 1.43 (95% confidence interval [CI] = 1.38-1.49) for DR development, whereas those with DPP-4i use at 91-180,181-300 or >300 cDDD had HRs of 1.66 (95% CI: 1.59-1.74), 1.82 (95% CI: 1.74-1.90), and 2.32 (95% CI: 1.91-2.82) for DR development, respectively. Of the different DPP-4is, linagliptin at ≤90 or 181-300 was associated with the highest risk of DR. Significant differences were discovered at ≤90, 91-181, and 181-300 cDDD in the risk of DR between patients using Saxagliptin versus sitagliptin. Vildagliptin at ≤90 or 91-180 cDDD was associated with an increased risk of DR, but not at 181-300 cDDD.In patients with DM, DPP-4i at ≤90, 91-180, 181-300 and >300 cDDD was linked to an increased risk of DR over the 5-year follow-up. Sitagliptin at cDDD 181-300 was associated with the greatest DR risk. The potential for DPP-4i to accelerate DR progression should be considered.