Diabetic retinopathy (DR) is one of the most prevalent microvascular complications of diabetes mellitus (DM), and remains a leading cause of preventable blindness worldwide. With the steadily increasing global prevalence of type 2 diabetes mellitus (T2DM), identifying modifiable risk factors for DR has become increasingly important for developing effective preventive strategies and improving patient outcomes. Vitamin D deficiency (VDD) has emerged as a potential contributor to diabetic complications owing to its effects on inflammation, oxidative stress, and vascular function (1–3). The active form of vitamin D, 1,25-dihydroxyvitamin D3, exerts its biological effects through vitamin D receptors, which are widely expressed in retinal tissues including the retinal pigment epithelium, photoreceptors, and retinal vasculature (4). This specific localization in ocular structures provides a direct biological rationale for investigating the role of vitamin D in retinopathy. Growing evidence suggests that vitamin D may protect against retinal damage by inhibiting inflammation, reducing oxidative stress, and improving microvascular function (2, 5).

A recent systematic review and meta-analysis by Petrea et al. (6) analyzed data from 20 studies involving 22,408 participants and found a significant association between lower vitamin D levels and increased risk of DR [odds ratio (OR): 1.17]. Their analysis also revealed lower mean serum vitamin D levels in individuals with DR than in those without DR, with progressively declining levels across DR severity stages. However, most studies included (7–9) have been limited by their cross-sectional design, small sample sizes, and inadequate control for confounding factors. A 5-year prospective study by Herrmann et al. (10), which included 9,524 participants, found that lower serum 25(OH)D levels were associated with an increased risk of macrovascular and microvascular complications, including retinopathy, requiring laser therapy. However, their analysis involved patients with varying durations of diabetes and focused only on advanced DR (10). Moreover, vitamin D status was not assessed at the time of T2DM diagnosis. These limitations highlight the need for longitudinal studies in newly diagnosed patients.

We hypothesized that VDD at T2DM diagnosis is associated with an increased risk of DR and other adverse outcomes. This study aimed to investigate the association between VDD at the time of T2DM diagnosis and the subsequent risk of developing DR over a 3-year follow-up period. Additionally, we examined important secondary outcomes, including hospitalization, emergency department visits, pneumonia, and all-cause mortality, to provide a more comprehensive understanding of the potential impact of vitamin D status on overall health outcomes in newly diagnosed T2DM patients.

This retrospective cohort study revealed a significant association between VDD and DR in patients with newly diagnosed T2DM. Patients with VDD had a 45% higher risk of developing retinopathy over 3 years than those with sufficient vitamin D levels. This association remained consistent in both the 1-year and 3-year follow-up analyses. Sensitivity analyses, including one restricted to survivors and another incorporating anti-diabetic medication use, confirmed the robustness of the findings. Sex-stratified analysis showed that the association was primarily significant in female patients. Notably, patients with vitamin D insufficiency did not show an increased risk, suggesting a threshold effect. Beyond retinopathy, VDD has also been linked to higher risks of hospitalization, emergency department visits, pneumonia, and mortality, highlighting its potential as a marker of the overall health status of patients with diabetes.

Our findings revealed a robust association between VDD at the time of T2DM diagnosis and the subsequent development of DR. The novelty of this study lies in several key aspects. First, we specifically focused on patients with newly diagnosed T2DM, allowing us to examine the impact of baseline vitamin D status on long-term diabetes complications and treatments. This approach minimizes potential reverse causality, whereby diabetic complications may lead to reduced outdoor activity and consequently lower vitamin D levels (18, 19). Second, our study employed rigorous propensity score matching to balance a comprehensive set of confounding variables to enable more reliable estimates of the association between vitamin D status and diabetic outcomes. Third, our dose-response analysis comparing VDD (<20 ng/mL) and insufficiency (20–30 ng/mL) against sufficiency (≥30 ng/mL) suggests a threshold effect, where the risk of DR significantly increases only when vitamin D levels fall below 20 ng/mL. This finding has important clinical implications and suggests that maintaining vitamin D levels above the deficiency threshold may mitigate the risk of DR. The biological mechanisms potentially mediating this association include anti-inflammatory, antioxidant, and anti-angiogenic properties (20–24). Vitamin D receptors are expressed in retinal tissues, and experimental studies have shown that vitamin D can inhibit VEGF-induced endothelial cell proliferation and angiogenesis (24). Additionally, vitamin D may regulate retinal microvascular integrity by modulating inflammatory pathways and reducing oxidative stress, which are key factors in DR pathogenesis (2, 25).

While our analysis focused on VDD, it is important to consider that DR is a multifactorial condition. Hypertension, dyslipidemia, and chronic kidney disease are among the established comorbidities that independently elevate the risk of developing DR (26–28). Although our propensity score matching balanced these conditions between the VDD and control groups, their complex interactions and varying severities may not have been fully captured in our analysis. Additionally, the duration and control of these comorbidities prior to diabetes diagnosis could influence baseline retinal health. While we adjusted for these factors as categorical variables, residual confounding from disease severity or duration remained possible.

A recent meta-analysis by Petrea et al. (6) found a significant association between lower vitamin D levels and increased odds of DR (OR, 1.17). However, most prior studies in that meta-analysis (6) employed cross-sectional designs, which precluded the establishment of temporal relationships between VDD and retinopathy development (29). Furthermore, previous studies in that meta-analysis (6) often included heterogeneous diabetes populations with varying disease durations, making it difficult to distinguish the effects of VDD from those of long-standing diabetes complications (6, 30). Notably, many previous studies had limited adjustments for confounding factors and relatively small sample sizes, limiting their statistical power and generalizability (31, 32). Our large sample size from a multi-institutional database enhances both the precision of our estimates and their applicability to diverse clinical settings. Finally, only a few studies have examined sex-specific differences in the association between VDD and DR. Our stratified analysis revealed stronger associations among females contributing valuable insights into potential effect modification by sex, which may inform personalized preventive strategies.

The sex-specific association between VDD and DR requires consideration of several biological mechanisms. Sex hormones, particularly estrogen, may provide vascular protection through their antioxidant effects (33). Sex-based differences in vitamin D metabolism and vitamin D receptor expression might make females more responsive to the vascular protective effects of vitamin D. Additionally, fundamental sex differences in immune responses, adiposity distribution, insulin sensitivity, and genetic factors affecting the vitamin D pathway could contribute to the observed sex-specific vulnerability to DR in vitamin D-deficient states (34). These mechanisms warrant further investigation in future targeted studies.

Our study found that VDD was associated with a 23% increased risk of hospitalization and a 17% increased risk of emergency department visits over 3 years. These associations remained consistent in the 1-year analysis and across the sensitivity analyses. Increased healthcare utilization in patients with VDD may reflect several underlying mechanisms. VDD may serve as a marker of poor overall health status and behavior, including reduced physical activity, poor nutrition, and suboptimal self-care, which can contribute to diabetes complications requiring acute care (35, 36). Additionally, vitamin D has immunomodulatory effects that may influence susceptibility to infections and inflammatory conditions, which are common reasons for hospitalization in patients with diabetes (37). The economic implications of these findings are significant. Hospitalizations and emergency department visits represent significant healthcare costs in diabetes management (38–40). If vitamin D supplementation in deficient patients could reduce these events, it might offer a cost-effective intervention to improve outcomes and reduce healthcare expenditures.

Our finding of an 18% increased risk of pneumonia in vitamin D-deficient patients with newly diagnosed T2DM is consistent with emerging evidence regarding the role of vitamin D in immune function and respiratory health. This association remained significant in both 1-year and 3-year analyses, with hazard ratios of 1.16 and 1.18, respectively. Interestingly, our sex-stratified analysis revealed that the association between VDD and pneumonia was significant only in females (HR 1.26) and not in males (HR 0.99). This sex-specific effect mirrors our findings on DR and suggests potential biological differences in vitamin D metabolism (41) or immune responses between the sexes (42). Previous studies have reported an association between VDD and an increased risk of respiratory infections, including pneumonia (37). A meta-analysis of individual participant data from 25 randomized controlled trials found that vitamin D supplementation reduced the risk of acute respiratory infections, with greater benefits in those with baseline VDD (43). Our results extend these findings specifically to patients with newly diagnosed type 2 diabetes, a population with increased susceptibility to infections due to immune dysfunction.

Perhaps the most striking finding in our study is the 51% increased risk of all-cause mortality over 3 years associated with VDD in patients with newly diagnosed T2DM. The association was even stronger in the 1-year analysis (HR, 1.58), suggesting that VDD may be particularly predictive of short-term mortality risk. Our sex-stratified analysis revealed that while mortality risk was elevated in both sexes, the association was stronger in females (HR 1.57) than in males (HR 1.34), consistent with our other findings of sex-specific effects. Several mechanisms may explain this association. Vitamin D has direct cardiovascular effects, including regulation of the renin-angiotensin system, endothelial function, and vascular smooth muscle cell proliferation (44, 45). VDD may contribute to cardiovascular events, which are the leading cause of death in patients with diabetes.

Our findings have several important clinical implications. For newly diagnosed T2DM patients, vitamin D status assessment could serve as a simple, cost-effective screening tool for identifying those at a higher risk of developing DR and other complications. Based on the threshold effect observed, maintaining serum 25(OH)D levels above 20 ng/mL may be sufficient to reduce DR risk, particularly in female patients. Healthcare providers might consider more vigilant retinal monitoring in vitamin D-deficient patients, especially females, with early ophthalmologic referral and more frequent retinal examinations during the first 3 years after diagnosis. Although randomized controlled trials are needed to establish definitive supplementation guidelines, our results suggest that correcting vitamin D deficiency in patients newly diagnosed with T2DM might represent a modifiable intervention to potentially reduce diabetic complications. The sex-specific associations also highlight the importance of personalized approaches for both risk assessment and management strategies.

Our study has several limitations that should be acknowledged. First, residual confounding factors cannot be entirely ruled out in observational studies. Unmeasured factors, such as physical activity, sun exposure, dietary habits, and vitamin D supplementation, may influence both vitamin D levels and diabetes outcomes (46). Additionally, missing data for certain laboratory parameters (e.g., hemoglobin and albumin) were addressed through complete-case analysis during propensity score matching, which excluded patients with missing values for these variables. While this ensured that matching was based on actual observed data, it may have introduced a selection bias or limited the generalizability of our findings. Second, the study relied on a single 25(OH)D measurement within 6 weeks prior to T2DM diagnosis, which may not fully represent the long-term vitamin D status. Seasonal fluctuations could influence serum levels; however, adjustment for seasonality was not feasible within the TriNetX platform because of the unavailability of the test date and geographic data. Although we performed a sensitivity analysis using patients with multiple vitamin D measurements, the resulting sample size was markedly reduced, limiting the statistical power. This limitation should be considered when interpreting our findings. Third, while we focused on newly diagnosed type 2 diabetes to minimize reverse causality, some patients might have had undiagnosed diabetes for varying periods before their formal diagnosis (47), potentially influencing baseline vitamin D levels and complication risks. Fourth, the ascertainment of DR and other outcomes relied on diagnostic codes in electronic health records, which may lack sensitivity for detecting early or mild cases and could be subject to coding errors or variations in clinical practice. Fifth, our database primarily included patients from the United States, which may limit the generalizability of our findings to populations with different genetic backgrounds, healthcare systems, and sunlight exposure patterns. Furthermore, although race was recorded in our dataset, the sample sizes of several racial subgroups were insufficient to perform statistically reliable stratified analyses. Finally, our study design could not establish causality between VDD and diabetes outcomes. Although our findings suggest associations, randomized controlled trials of vitamin D supplementation are needed to determine whether correcting VDD can reduce the risk of complications in patients with newly diagnosed diabetes.

In newly diagnosed T2DM, VDD was independently associated with increased risks of DR, hospitalization, emergency department visits, pneumonia, and all-cause mortality over a three-year follow-up period. These associations are particularly pronounced in female patients and appear to follow a threshold effect, with significantly elevated risks observed primarily in vitamin D-deficient rather than insufficient individuals. Our findings suggest that assessment of vitamin D status may be valuable for risk stratification in newly diagnosed T2DM, and addressing VDD may represent a modifiable risk factor for improving outcomes. Large-scale randomized controlled trials are warranted to determine whether vitamin D supplementation can effectively reduce the burden of diabetic complications and mortality in this population.