Insulin and risk of diabetic retinopathy in patients with Type 2 diabetes mellitus: Data from a meta-analysis of seven cohort studies

Methodological quality of the review: Medium confidence

Author: Zhao C, Wang W, Xu D, Li H, Li M, Wang F

Region: Europe, America and Asia

Sector: Diabetic retinopathy

Sub-sector: Type 2 diabetes, Insulin

Equity focus: None specified

Review type: Other review

Quantitative synthesis method: Meta-analysis

Qualitative synthesis method: Not applicable

Background:

Type 2 diabetes mellitus (T2DM) is a chronic incurable disease associated with multi-systemic complications. The chronic complications related to T2DM induce growing burden to the national health system. Diabetic retinopathy (DR) is the most serious ocular complication associated with T2DM and one of the leading causes of secondary blindness. The association between insulin use and DR risk has also been reported in different studies.

Objectives:

Determine the association between insulin use and DR risk.

Main findings:

A total of seven cohort studies were included in the review. Six of these studies were population-based studies, and the remaining one study was a hospital-based study. Among all the studies, five studies were conducted in Europe, one in America and one in Asia. The records of all the studies included both male and female cases. Authors reported that all the studies were at a relatively high-quality level, indicating a high methodological quality of the enrolled studies.

Authors noted that the pooled result of all the seven included studies showed that insulin use is associated with increased risk of DR (risk ratio (RR) = 2.30; 95% confidence interval (CI), 1.35-3.93). In addition, authors observed a significant correlation between insulin use and incidence rate of DR was observed in both prospective studies (RR, 2.38; 95% CI, 1.28-4.41) and retrospective studies (RR, 2.30; 95% CI, 1.11-3.43) subgroups.

When subgroup analyses were conducted according to the geographic locations, authors noted significant associations were detected in Europe (RR, 1.85; 95% CI, 1.12-3.08), Asia (RR, 3.43; 95% CI, 1.93-6.08) and America (RR, 4.90; 95% CI, 2.63-5.79). Moreover, authors observed similar results in the subgroup analyses by data source (population based or hospital based), follow-up duration (over five years or less than five years) and adjustments of diabetic status (HbA1c adjusted or HbA1c not adjusted). When DM duration was adjusted, authors reported no significant association between insulin use and risk of DR (RR, 2.18; 95% CI, 0.80-5.93).

A significant heterogeneity was observed by the authors when all the seven cohort studies were included (I2, 89.3%; P < 0.001). In the subgroup analyses, the heterogeneity remained significant. Authors identified no significant publication bias was found in the seven enrolled studies (Begg’s test, P for bias = 0.30; Egger’s test, P for bias = 0.297).

Methodology: 

Studies were selected if they met the following criteria: (1) a cohort study design was obtained; (2) the association between insulin use and DR risk was reported; (3) Studies reporting different measures of RR like risk ratio, rate ratio, hazard ratio (HR), and odds ratio (OR) were reported. Authors conducted a search on electronic databases including Pubmed and EMBASE to identify all available relevant studies until February 2014. In addition, authors reviewed references of included studies and reviews as part of the search strategy. Medical subject heading terms and key words used by the authors include: ‘hypoglycemic agents’, ‘insulin’ combined with ‘diabetic retinopathy’. No language or other restrictions were set in this study.

Two authors independently conducted the screening of studies for eligibility and extracted data of included studies. Authors used Newcastle-Ottawa Scale (NOS) to assess the methodological quality of included cohort studies.

Authors used the method of a random-effect model to calculate summary RR and 95% CIs for assessing the association between insulin use and risk of DR. The square of the SEM was used as the estimated variance of the logarithm of the OR. Heterogeneity was assessed using the χ² and I² statistics. The subgroup analyses were performed according to the following indexes including study design (prospective cohort or retrospective cohort), data source (population based or hospital based), study population (Europe, America and Asia), and control for confounding factors.

Applicability/external validity:

Authors reported that despite of the significant heterogeneity, significant association between insulin use and DR was detected. When subgroup analyses by study design, region, data source and adjustment of HbA1c were conducted, similar results were observed. However, in the group when the DM duration was adjusted, no significant result was reported.

Geographic focus:

Authors noted significant associations were detected in Europe (RR, 1.85; 95% CI, 1.12-3.08), Asia (RR, 3.43; 95% CI, 1.93-6.08) and America (RR, 4.90; 95% CI, 2.63-5.79).

Summary of quality assessment:

Medium confidence was attributed in conclusions about the effects of this study as important limitations were identified. Authors used appropriate methods to pool data of included studies and used rigorous methods to screen studies for inclusion, extract data and quality assess included studies. However, the literature search was not comprehensive enough to ensure that all relevant studies were included in the review.