The association between vitamin D deficiency and diabetic retinopathy in Type 2 diabetes: A meta-analysis of observational studies

Methodological quality of the review: Medium confidence

Author: Luo BA, Gao F, Qin LL

Region: Asia, North America, Europe, Africa and Australia

Sector: Diabetic retinopathy

Sub-sector: Vitamin D and Type 2 diabetes

Equity focus:  None specified

Review type: Other review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background:

Emerging evidence from in-vivo and in-vitro studies have shown that vitamin D may play an important role in the development of diabetic retinopathy (DR), but individually published studies showed inconclusive results.

Objectives:

To quantitatively summarize the association between vitamin D and the risk of diabetic retinopathy.

Main findings:

A total of 15 observational studies were included in the meta-analysis. The quality assessment showed that the quality scores of these studies ranged from 8.5 to 10 according to the MOOSE guidelines, which indicates that all of the selected studies were of high quality. Included studies were published from 2000 to 2016. Among these studies, nine were conducted in Asia, two each in North America and Europe, one in Africa, and one in three countries (Australia, New Zealand, and Finland). Seven studies had cross-sectional design, five were case-control, two were prospective cohort, and one had a retrospective cohort design. Four different assay techniques were used to measure the serum 25(OH) D levels, and four different ways were used to diagnose DR. Eight of the included studies explored the association between vitamin D deficiency and diabetic retinopathy, four explored the association between vitamin D insufficiency and diabetic retinopathy, and ten explored the mean difference in vitamin D status among diabetic retinopathy and non-diabetic retinopathy. Authors note that the diversity of participant characteristics was considerable in these studies. Authors reported, the pooled odds ratio (OR) of four studies, for vitamin D insufficiency (VDI, serum 25(OH)D levels <30 ng/mL) was calculated as (OR = 0.89, 95% confidence interval (CI): 0.20, 4.02). Authors noted that only the result of vitamin D deficiency showed that low serum vitamin D status increased the risk of diabetic retinopathy.

When authors compared the mean difference between the DR group and the control group (non-DR group) using the random-effects model, the pooled effect was -1.7 ng/mL (95% CI: -2.75, -0.66) and authors observed significant heterogeneity (I² = 80%, p < 0.001). It showed that serum 25(OH) was significantly lower in diabetic retinopathy patients than the control in Type 2 diabetes. Authors noted that this result demonstrated vitamin D deficiency is significantly related with an increased risk of DR.

Based on the sensitivity analysis, authors reported no obvious changes in the pooled ORs as a result of the exclusion of any other single study.

In the subgroup with study design, authors found moderate heterogeneities in cross-sectional and prospective cohort studies for the pooled OR (I² = 52%, p = 0.15 for cross-sectional studies; I² = 61%, p = 0.11 for prospective cohort studies). Authors found that there were obvious heterogeneities in the cross-sectional and the case–control studies for the pooled WMD (I² = 79%, p = 0.0007 for cross-sectional studies; I² = 76%, p = 0.006 for case–control studies).

Authors reported no obvious publication bias based on the funnel plots of this meta-analysis.

Authors concluded there is an association between vitamin D deficient Type 2 diabetes mellitus patients and an increased risk of diabetic retinopathy. Type 2 diabetes patients with vitamin D deficiency experienced an increased risk of diabetic retinopathy. However, they noted the need further studies to better understand the relationship between vitamin D deficient Type 2 diabetes patients and diabetic retinopathy, and well-designed randomized controlled trials are needed to determine the explicit effect of vitamin D supplementation on the prevention of diabetic retinopathy. Authors also stated that screening Type 2 diabetes patients who are at risk of vitamin D deficiency should be considered.

Methodology: 

Studies were included if they met the following inclusion criteria: (a) the study population was Type 2 diabetes patients; (b) DR was the outcome, and the control group consisted of Type 2 diabetes patients without DR; (c) the study presented sample sizes and odds ratios (OR) with 95% confidence intervals (CI) or information that could be used to infer these results; (d) vitamin D deficiency was defined as a 25(OH)D level below 20 ng/mL, and vitamin D insufficiency was defined as 25(OH)D levels of 21–29 ng/mL; (e) the study was published in English; and (f) the study met the predefined methodological quality assessment criteria for observational studies. Animal experiments, chemistry, or cell-line studies and editorials, commentaries, review articles, and case reports were excluded. Other exclusion criteria consisted of studies with a score of 0 for any item or a total score less than 7 out of 10 maximal points.

Authors conducted a search on Pubmed, Medline and EMBASE through September 2016, using the following keywords: ‘vitamin D’ or ‘cholecalciferol’ or ‘25-hydroxyvitamin D’ or ‘25(OH)D’ in combination with ‘diabetic retinopathy’ or ‘retinopathy’ or ‘DR’. Additionally, authors manually searched all eligible original articles, reviews, and other relevant articles. Two authors independently screened studies for inclusion. Data extracted from each article included: the last name of first author, publication year, location of study, study design, sample size, 25(OH)D assay methods, 25(OH)D concentration, and the prevalence of vitamin D deficiency. In the case of relevant missing data, contacts were made to the main authors for more information.

To pool data for the meta-analysis, authors used the odds ratio (OR) and weight mean difference (WMD) as measures of associations between vitamin D status and risk for DR. If the OR and 95% CI were not available for the meta-analysis, these data were extracted from the selected articles to construct 2 X 2 tables of serum low vitamin D status versus the presence or absence of diabetic retinopathy. Authors used forest plots to visually assess pooled estimates and corresponding 95% CIs for each study. The heterogeneity among the results of the included studies was evaluated with I² statistical tests.

Applicability/external validity:

Authors stated that from this meta-analysis, the prevalence of vitamin D deficiency was high among Type 2 diabetes patients, although it may vary from different latitude, ethnicity, body mass index, season, and supplementation of vitamin D.

Geographic focus:

Authors emphasized that low serum 25(OH)D levels are association with an increased risk of diabetic retinopathy, including for African population.

Summary of quality assessment:

Medium confidence was attributed in the conclusions about the effects of this study, as important limitations were identified. Authors included studies written in English only, which authors acknowledged it as a limitation of the review as it may have excluded relevant studies in the meta-analysis. Authors did not report if data extraction was conducted by two reviewers independently, therefore it is not clear if characteristics and results of included studies were reliably reported.