Efficacy and Safety of Aldose Reductase Inhibitor for the Treatment of Diabetic Cardiovascular Autonomic Neuropathy: Systematic Review and Meta-Analysis

<div><p>Background</p><p>Aldose reductase inhibitors (ARIs) can block the metabolism of the polyol pathway, and have been used to slow or reverse the progression of diabetic cardiovascular autonomic neuropathy (DCAN). The purpose of this study was to review the effectiveness and safety of ARIs in the treatment of DCAN as determined by five cardiac autonomic neuropathy function tests.</p><p>Methods</p><p>CENTRAL, MEDLINE, EMBASE, Scopus databases (inception to May 2012) were searched to identify randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) investigating ARIs for the treatment of DCAN with an English-language restriction. The data were analyzed using RevMan 5.0, and the heterogeneity between the trials was evaluated using the Cochrane's Q-test as well as the I² test. The type of model (random or fixed) used for analysis was based on heterogeneity. Weighted mean differences (WMD) with 95% confidence intervals (CI) were computed for the five cardiac automatic neuropathy function tests to evaluate the effects.</p><p>Results</p><p>Ten articles met the prerequisites for this review. Analysis of the results showed that ARIs significantly improved function in at least three of the five automatic neuropathy tests, including the resting heart rate variation coefficients (WMD = 0.25, 95%CI 0.02 to 0.48, P = 0.040); the 30∶15 ratio (WMD = 0.06, 95%CI 0.01 to 0.10, P = 0.010) and the postural systolic blood pressure change (WMD = −5.94, 95%CI −7.31 to −4.57, P = 0.001). The expiration/inspiration ratio showed a marginally significant benefit (WMD = 0.05, 95%CI 0.00 to 0.09, P = 0.040). Glycaemic control was not significantly affected by ARIs. Adverse effects of ARIs except for Tolerestat were minimal.</p><p>Conclusions</p><p>Based on these results, we conclude that ARIs could ameliorate cardiac automatic neuropathy especially mild or asymptomatic DCAN but need further investigation.</p></div

Summary of General information and Methodological quality of included studies.

<p><b>*</b>RCT = randomized controlled trial; non-RCT = non-randomized controlled trial; po = per os; tid = three times a day; qd = once a day. NR = not report. SD =  standard deviation.</p

Summary of the comparisons about the five automatic tests and HbA_1c.

<p><b>*</b>IV = Inverse variance; Random = random effects model; Fixed = fixed effects model; WMD = weighted mean difference; CI = confidence interval.</p

Results of meta-analysis of the five cardiovascular autonomic reflex tests and HbA_1c.

<p>Results of meta-analysis of the five cardiovascular autonomic reflex tests and HbA_1c.</p

Funnel plot of the five cardiovascular autonomic reflex tests and HbA_1c.

<p>Funnel plot of the five cardiovascular autonomic reflex tests and HbA_1c.</p

Flowchart of search strategy and results.

<p>Flowchart of search strategy and results.</p

Additional file 1 of NOD1 deficiency ameliorates the progression of diabetic retinopathy by modulating bone marrow–retina crosstalk

Additional file 1. Supplementary data