Association between dipeptidyl peptidase-4 inhibitor use and diabetic retinopathy

Methodology

This systematic review followed PRISMA guidelines and was registered with PROSPERO (CRD42023443942). A comprehensive literature search was conducted across five major databases (PubMed, CENTRAL, Embase, Scopus, Web of Science) through July 20, 2023, with additional searches of gray literature via Google Scholar. Studies were eligible if they were retrospective or prospective cohort studies of adults with type 2 diabetes that reported adjusted effect estimates for the association between DPP4i use and diabetic retinopathy incidence or progression.

Seven cohort studies met inclusion criteria, all retrospective in design, published between 2016 and 2023. Four studies used propensity score matching to compare DPP4i users with non-users. Sample sizes ranged from 48 to over 126,000 participants. Study populations came from Taiwan, Korea, Germany, the USA, and Denmark. Mean age of participants ranged from 57 to 77 years, with diabetes duration typically between 3 and 8 years where reported. Diabetic retinopathy was primarily identified using ICD diagnostic codes from medical records, with one study using the validated Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Follow-up periods ranged from 2 to 10 years.

Two independent reviewers conducted study selection, data extraction, and quality assessment using the Newcastle-Ottawa Scale. Meta-analysis was performed using Review Manager 5.3 software with a random-effects model to account for methodological heterogeneity. Separate analyses were conducted for diabetic retinopathy incidence and progression. Sensitivity analyses were performed by sequentially removing individual studies. Heterogeneity was assessed using I² statistics and Q tests. Publication bias was evaluated with funnel plots.

Interventions

The intervention group consisted of patients with type 2 diabetes treated with dipeptidyl peptidase-4 inhibitors (DPP4i), a class of oral hypoglycemic agents that work by inhibiting the DPP-4 enzyme involved in incretin hormone breakdown. This mechanism increases incretin levels, which in turn reduces glucagon secretion and increases insulin secretion in a glucose-dependent manner. DPP4i agents included in the studies were sitagliptin, vildagliptin, saxagliptin, linagliptin, alogliptin, and gemigliptin.

DPP4i could be used as monotherapy or add-on therapy to other diabetes medications. The duration and intensity of DPP4i treatment varied across studies, with most requiring at least 90 days to 6 months of continuous therapy for inclusion. These medications are typically used as second-line therapy in type 2 diabetes management due to their favorable safety profile with minimal risk of weight gain and hypoglycemia.

Comparator groups varied across studies but predominantly included patients treated with sulfonylureas (SU), metformin, thiazolidinediones (TZD), or other oral hypoglycemic agents without DPP4i exposure. Four studies used propensity score matching to balance baseline characteristics between DPP4i users and non-users, adjusting for factors such as age, sex, diabetes duration, glycemic control, and other medications.

Key Findings

The meta-analysis of seven real-world cohort studies found no significant association between DPP4i use and diabetic retinopathy outcomes. For diabetic retinopathy incidence, pooled analysis of four studies showed an odds ratio of 0.86 (95% CI: 0.70-1.06, I² = 78%), indicating no statistically significant difference compared to other diabetes medications. For diabetic retinopathy progression, three studies yielded a pooled odds ratio of 0.87 (95% CI: 0.47-1.59, I² = 86%), again showing no significant effect. Sensitivity analyses removing individual studies one at a time did not change the overall conclusions. Among individual studies, results were mixed: one industry-funded German study showed significantly reduced retinopathy risk with vildagliptin compared to sulfonylureas, while a large Taiwanese study showed increased progression risk. Most studies, however, found no significant association in either direction. The high heterogeneity (I² > 75%) suggests substantial variation between studies in patient populations, treatment protocols, or outcome measurement methods.

Comparison with other Studies

The neutral findings from this systematic review of real-world studies contrast somewhat with a previous network meta-analysis by Tang et al., which analyzed randomized controlled trials and suggested that DPP4i may be associated with increased diabetic retinopathy events. However, the discrepancy likely reflects differences between the controlled environment of RCTs with restrictive inclusion criteria and the more heterogeneous real-world patient populations captured in observational studies.

The current review's findings are more consistent with evidence from large cardiovascular outcome trials. The TECOS trial comparing sitagliptin with placebo found diabetic retinopathy rates of 2.8% in the sitagliptin group versus 2.2% in controls—a non-significant difference. Similarly, the CARMELINA trial comparing linagliptin with placebo reported no difference in composite ocular endpoints (1% vs 1.4%). A small crossover RCT by Ott et al. even suggested potential benefits, showing that saxagliptin normalized retinal blood flow and improved central hemodynamics in 43 patients over six weeks.

Animal and in-vitro studies have yielded conflicting results. Some research by Goncalves et al. and Kolibabka et al. suggests DPP4i may have protective effects through reducing inflammation, apoptosis, and abnormal angiogenesis in retinal cells. Conversely, more recent studies have raised concerns that long-term DPP4i exposure may weaken the blood-retina barrier and increase vascular permeability through effects on cellular junctions. The biological mechanisms remain unclear. Compared to evidence on other diabetes medications, studies by Xie et al. and Ma et al. have shown that SGLT2 inhibitors and GLP-1 receptor agonists may offer renal protective benefits not seen with DPP4i, though these agents also show neutral effects on diabetic retinopathy risk. The totality of evidence suggests DPP4i neither substantially increases nor decreases retinopathy risk in clinical practice.

Journal Reference

Wang M, Lu J, Dong J. Association between dipeptidyl peptidase-4 inhibitor use and diabetic retinopathy: a systematic review and meta-analysis of real-world studies. BMC Ophthalmol. 2024;24:272. doi:10.1186/s12886-024-03535-1