Diabetic nephropathy (DN), one of the most common microvascular complications in Diabetes Mellitus (DM), has become a major cause of end-stage renal disease (ESRD) [
Previous studies [
We searched Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), the Chinese Biomedical Literature (CBM), and Wanfang from Jan. 1, 2000 to July 18, 2017. The keywords included in the search strategy were: safflower yellow, early diabetic nephropathy, and diabetic kidney disease. The references of included studies were traced to dig out more relevant studies. We also browsed
RCTs, containing a control group and an intervention group, which fulfill the following criteria were eligible for inclusion: Human studies on adult (≥18 years of age) male or female participants with early diabetic nephropathy. Conventional therapy, including diabetes education, diet, exercise, snfglycemic and blood pressure control, was applied in the control group. Conventional therapy plus safflower yellow was applied in the experimental group. Clinical outcomes (effective rate, urinary albumin excretion rates, fasting blood glucose, serum creatinine, and blood urea nitrogen) were reported. Accessible full-text articles. Languages in Chinese or English.
Studies were excluded if they were not RCTs; with too long follow-up duration (e.g., 6 months); not intravenous infusion administration; duplicate publication.
For each eligible trial, we collected the following information: first author, year of publication, follow-up time, intervention, sample size, patients’ baseline characteristics, and key efficacy and safety outcomes. Our primary efficacy outcome was the effective rate, which was the proportion of participants that became markedly improved or improved. “Markedly improved” means that the symptoms of hypertension, proteinuria, and edema disappeared or improved significantly, for example, urinary albumin excretion rates decreased by 1/2 or 40% and fasting blood glucose decreased by 1/3; renal function indexes were all in the normal range at the same time. “Improved” means that all the indexes did not decline as obviously as those mentioned above. Secondary efficacy outcomes included urinary albumin excretion rates (UAER), fasting blood glucose (FBG), serum creatinine (Scr), and blood urea nitrogen (BUN). Safety outcome referred to the incidence of adverse events (nausea, headache, anaphylactic shock, fever, rash, arrhythmia, etc.).
Two authors independently assessed the quality of studies by using the Cochrane risk-of-bias tool [
Meta-analysis was conducted when at least three studies reported relevant outcomes. For dichotomous outcomes, the risk difference (RD) with 95% confidence interval (CI) was calculated. For continuous outcomes, the mean difference (MD) or the standardized mean difference (SMD) with 95% CI were calculated. Data were pooled using the fixed effects model, but the random effects model was also considered to ensure the robustness of the model. The I2 statistic was used to quantify heterogeneity, with I2 values > 50% representing high heterogeneity. The significance level was set at p < 0.05. Subgroup analysis was conducted for different follow-up time. Statistical analysis was undertaken in Review Manager 5.3 (Cochrane Collaboration, Copenhagen, Denmark).
As shown in Figure
Flow chart of the study selection.
Characteristics of the included studies were summarized in Table
Characteristics of included studies (E: experimental group; C: control group).
Num | Authors, publication year [reference] | Number of participants (% female) | Mean age (years) | Follow-up time (days) | Intervention | Outcomes | |
---|---|---|---|---|---|---|---|
Experimental group | Control group | ||||||
1 | Li Z et al. 2012 [ | E: 30(28.33) | E: 61.3 | 15 | Conventional treatment, Losartan potassium 50 mg, safflower yellow 100 mg | Conventional treatment | ①②③④⑤ |
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2 | Yang L H et al. 2010 [ | E: 30(46.67) | E: 58.3 | 14 | Conventional treatment, safflower yellow 100 mg | Conventional treatment | ①②③⑥ |
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3 | Qiu T L et al. 2013 [ | E: 42(42.86) | E: 51.6 ± 6.6 | 30 | Conventional treatment, safflower yellow 100 mg | Conventional treatment | ①②④⑤ |
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4 | Gao Y et al. 2015 [ | E: 60(45) | E: 64.6 ± 5.7 | 28 | Conventional treatment, Benazepril 10mg, safflower yellow 100 mg | Conventional treatment, Benazepril 10mg | ①③④⑤ |
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5 | Bao X J. 2017 [ | E: 40(45) | E: 50.45 ± 7.12 | 14 | Conventional treatment, Metformin 2g, safflower yellow 100 mg | Conventional treatment, Metformin 2g | ①②③④⑤⑥ |
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6 | Zhang X Y. 2010 [ | E: 36(47.22) | E: 62 | 28 | Conventional treatment, Irbesartan 150mg, safflower yellow 100 mg | Conventional treatment, Irbesartan 150mg | ②③④⑤⑥ |
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7 | Gao Y et al. 2015 [ | E: 44(42) | E: 51.13 ± 7.42 | 28 | Conventional treatment, Telmisartan 80mg, safflower yellow 100 mg | Conventional treatment, Telmisartan 80mg | ②④⑤ |
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8 | Xiao Y X. 2016 [ | E: 40(47.5) | E: 58.9 ± 13.2 | 28 | Conventional treatment, safflower yellow 100 ml | Conventional treatment | ①②⑥ |
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9 | Guo D Z. 2008 [ | E: 37(48.65) | E: 46.9 ± 13.2 | 35 | Conventional treatment, Benazepril 10mg, safflower yellow 150mg | Conventional treatment, Benazepril 10mg | ①② |
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10 | Zhang M H. 2013 [ | E: 25(48) | E: 56 ± 8.6 | 28 | Conventional treatment, safflower yellow 150mg | Conventional treatment | ② |
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11 | Fang Z F. 2015 [ | E: 45(46.67) | E: 56.0 ± 7.9 | 8 weeks | Conventional treatment, Valsartan 80mg, safflower yellow 100 ml | Conventional treatment, Valsartan 80mg | ①②⑥ |
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12 | Bai X M. 2012 [ | E: 30(46.67) | E: 56 ± 7.9 | 30 | Conventional treatment, safflower yellow 200mg | Conventional treatment | ②③⑥ |
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13 | Gao Y et al. 2015 [ | E: 30(40) | E: 59.5 ± 12.4 | 30 | Conventional treatment, safflower yellow 100mg | Conventional treatment | ②④⑤⑥ |
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14 | Shi Z M 2015 [ | E: 45 (48.89) | 51.5 | 12 weeks | Conventional treatment, Valsartan 80mg/d, safflower yellow 150mg | Conventional treatment, Valsartan 80mg/d | ②⑥ |
①Effective rate, % .
②UAER.
③FBG.
④Scr.
⑤BUN.
⑥Adverse event.
The results of the risk-of-bias assessment were provided in Figure
Risk-of-bias summary: authors’ judgments about each risk-of-bias item for each included study.
Eight studies that reported the effective rate were analyzed under a fixed mode (n=652 subjects). The meta-analysis showed a significantly higher effective rate in safflower yellow group compared with that in control group (RD, 0.24; 95% CI, 0.17 to 0.30; p<0.00001; Figure
Forest plot displaying the effect of safflower yellow on effective rate.
Thirteen trials (n=952 subjects) evaluated UAER (Figure
Forest plot displaying the effect of safflower yellow on UAER.
Six trials (n=452 subjects) measured FBG (Figure
Forest plot displaying the effect of safflower yellow on FBG.
As shown in Figure
Forest plot displaying the effect of safflower yellow on Scr.
Seven trials (n=566 subjects) examined BUN (Figure
Forest plot displaying the effect of safflower yellow on BUN.
Eight included studies (n=592 subjects) reported adverse events. The incidence of adverse events did not differ between safflower yellow group and control group (RD, -0.01; 95% CI, -0.03 to 0.01; p=0.52; Figure
Forest plot displaying the effect of safflower yellow on the adverse event.
In this meta-analysis, conventional therapy combined with safflower yellow not only significantly reduced UAER, FBG, Scr, and BUN, but also was associated with a higher effective rate, compared with conventional therapy alone. For safety outcome, there was no statistical difference between these two regimens. Similar evidence has been produced in previous studies. Yang W J [
Our meta-analysis comprehensively estimated more clinical outcomes and included a larger sample size (n=1,072 subjects) than papers published before. Subgroup analysis was carried out to identify the influence of different follow-up time. Nevertheless, heterogeneity between included trials was still conspicuous, in line with previous studies.
There are several limitations of this meta-analysis. Firstly, all of the selected studies were published in Chinese, which might cause publication bias. Secondly, selected trials were all small-scale. Thirdly, the diagnostic criteria of “early diabetic nephropathy” were not entirely consistent: nine trials [
In summary, our meta-analysis demonstrated that conventional therapy combined with safflower yellow had a more beneficial effect than conventional therapy alone in early DN patients. The differences between the two regimens were statistically significant on effective rate, UAER, FBG, Scr, and BUN, except for adverse events. However, the quality of the included studies was low. Therefore, more randomized controlled trials using standardized protocols would be required in the future to enhance our understandings of these two regimens.
The authors declare that there are no conflicts of interest regarding the publication of this paper.
This work was supported by the National Natural Science Foundation of China [Grant no. 71673298].