Efficacy of statins in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials

Background The effects of statins in patients with diabetic nephropathy are controversial. With increasing interest in the potential therapeutic role of statins in diabetic nephropathy, it is essential to evaluate its real effects. Methods PubMed, EMBASE, Web of Science databases, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure were systematically searched for randomized controlled trials (RCTs) of statins in patients with diabetic nephropathy. Results Fourteen trials with 2866 participants were included in our meta-analysis. Compared with placebo, albuminuria and urinary albumin excretion rates in the statin group were reduced by 0.46 [95 % confidence interval (CI),−0.68 to −0.25, P < 0.0001] and 1.68 (95 % CI, −3.23 to −0.12, P = 0.03), respectively. The reduction of albuminuria was greater in patients of type 2 diabetes mellitus with diabetic nephropathy [standardized mean difference (SMD), −0.56; 95 % CI, −0.80 to −0.32, P < 0.00001] and the decrease was significant during the 1 to 3 years period of statin therapy (SMD, −0.57; 95 % CI, −0.95 to −0.19, P = 0.003). Subgroup analysis demonstrated the effects of statins were much stronger in subjects with pathologic albuminuria: change of −0.71 (95 % CI, −1.09 to −0.33, P = 0.0003) for those with urinary protein excretion 30 to 300 mg/day, −0.37 (95 % CI, −0.67 to −0.06, P = 0.02) for those with excretion more than 300 mg/day and −0.29 (95 % CI, −0.78 to 0.21, P = 0.26) for those with excretion less than 30 mg/day. In contrast, statins did not significantly reduce estimated glomerular filtration rate, serum creatinine and blood urea nitrogen levels. Conclusions Statins decrease the albuminuria and urinary albumin excretion rates significantly. The efficacy of statins on renal function is time dependent and better in type 2 diabetic patients with nephropathy.

safety. Recently, there are growing studies suggested that statins may offer renoprotective effects and beneficial effect on pathologic albuminuria and decrease the reduction of estimated glomerular filtration rate (eGFR) [6][7][8]. However, some trials [9,10] failed to demonstrate that statin improve eGFR.
To assess whether statins have beneficial effects on renal outcomes in diabetic nephropathy, we performed this meta-analysis to investigate the potential therapy of statins in patients with diabetic nephropathy.

Literature search
We conducted a search of PubMed, EMBASE, Web of Science databases, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure (CNKI). All relevant articles were published in English and Chinese. The following Medical Subject Headings (MeSH) and text words were used: Hydroxymethylglutaryl-CoA reductase inhibitors, atorvastatin, simvastatin, rosuvastatin, pravastatin, lovastatin, fluvastatin, cerivastatin, mevastatin, pitavastatin, statin, kidney, renal, diabetic nephropathy, randomized controlled trial (RCT), controlled clinical trial and random allocation. We also searched the additional trials at the trial register centres (http://www.clinicaltrials.gov). Clinical trials were included if the following criterias were met: (1) Primary study of statins versus control (placebo or usual care); (2) Diabetic nephropathy patients with type 1 and type 2 diabetes mellitus at least 18 years old without pregnancy; (3) Patients with diabetic nephropathy in experimental group were defined as those who used statins, regardless of dosages, mode of administration or treatment duration; (4) RCT design; (5) Report of baseline and the end of follow-up data on renal function [estimated glomerular filtration rate (eGFR), urinary albumin excretion rates (UAER), serum creatinine (Scr), blood urea nitrogen (BUN) or albuminuria). Exclusion criteria included: (1) Kidney damage due to diseases other than type 1 or type 2 diabetes. (2) The final stage of diabetic nephropathy or endstage-renal disease (ESRD), defined as onset of renal replacement therapy or death attributed to diabetic nephropathy.

Study selection and data extraction
Two reviewers independently screened abstracts according to the inclusion criteria, and disagreements between reviewers were resolved by consensus. We developed a data extraction sheet based on the Cochrane Consumers and Communication Review Group's data extraction template. One reviewer extracted the following data from included studies and the second reviewer verified the extracted data. Disagreements were resolved by discussion between the two reviewers. If an agreement could not be reached between two reviewers, a third author would decide. Information extracted included: (1) characteristics of trial subjects (including age, sex ratio, duration of diabetes and baseline value of renal function) and the trial's inclusion/exclusion criteria; (2) type of intervention (including dosage, duration and frequency); and (3) type of outcome and measurement.

Statistical analysis
The primary outcome was the change of albuminuria from the baseline. Other outcomes include: change from baseline in eGFR, UAER, Scr, BUN. The meta-analysis with fixed-model or random-model was performed by weighted mean difference (WMD), standardized mean difference (SMD) and 95 % confidence interval (CI) for outcome of continuous variables. Subgroup analysis by characteristics of patients (i.e., ethnicity, stage of diabetes nephropathy) and study design (i.e., whether ACEI/ARB was used or not) were performed. I 2 was calculated as an index of heterogeneity between studies. If I 2 was higher than 50 %, the sensitive analysis should be performed to find out the source of heterogeneity and to assess whether the results could be significantly influenced.

Quality assessment and publication bias
Study quality and bias risk were assessed via predefined categories: randomization, allocation concealment, quality of blinding (participants,personnel and outcome assessment), withdrawal and loss and reporting bias. Two reviewers independently determined these items. Sensitive analysis was performed in studies with low quality. The analyses were performed using Review Manager 5.2 (Cochrane Collaboration, http://www.cochrane.org).

Quantitative data analysis Effect of statins on albuminuria
Pooled data from 10 studies [11-17, 19, 21, 22] (Fig. 3). Although the statins were not the same subtype, there was no significant heterogeneity among all trials in our study (I 2 = 24 %).
Statin did not decrease the urine albumin for those with excretion less than 30 mg/d (SMD,-0.29; 95 % CI,-0.78 to 0.21; P = 0.26, Fig. 3). In statin treated group, there was    Table 3). However, there was no significant difference between Asians (SMD −0.46, 95 % CI −0.80 to −0.12) and Caucasians population (SMD −0.54, 95 % CI −0.82 to −0.27; Table 3). Therefore, the results suggested that statins can reduce albuminuria significantly in patients of T2DM with diabetic nephropathy. And the beneficial effect of statins on renal function are significantly better in those with statin therapy longer than one year than that of less than one year.

Effect of statins on urinary albumin excretion rates (UAER)
The effect of statins on UAER was favorable in 5 studies [15,16,18,20,22]. Overall, the change in the SMD for UAER was −1.68 (95 % CI, −3.23 to −0.12, P = 0.03; Fig. 5) which indicated that compared with placebo, there was statistically significant reduction in UAER in  [19] was removed, the heterogeneity was no longer existence, which showed that the heterogeneity may came from the country difference of patients in the study. The fixed-effect model was used to merge SMD values and the pooled SMD was −0.10 (95%CI,-0.38 to 0.19; P = 0.50; Table 3), which means statins may have no effect on the Scr in patients with DN.

Effect of statins on blood urea nitrogen (BUN)
The result showed that there was no statistically difference in BUN in statin group compared with that in control group (SMD, −0.26; 95 % CI, −0.64 to 0.13; P = 0.20) and the heterogeneity among trials was not significant (I 2 = 0 %, Table 3).

Assessment of publication bias
Publication biases were examined by funnel plot and no significant publication bias was found among studies included in our meta-analysis (Fig. 6).

Subgroup and sensitivity analysis
Because of study heterogeneity, subgroup and metaregression analyses were conducted by ethnicity, baseline of albuminuria, treatment duration, and dose of statins (Table 3). However, the results of statin on renal function were not influenced. In consideration of the different baseline of UAER, sensitivity analysis was performed to assess the impact of every study on the overall  [20] were eliminated, the heterogeneity test (the I 2 reduces from 93 % to 0 %, P from <0.00001 to 0.76) indicated that baseline of UAER may be a source of heterogeneity (Fig. 7).

Discussion
Statins are frequently used to improve lipid profile and they are also reported to reduce cardiovascular events [23], albuminuria [6] and diabetic glomerulosclerosis in experimental animals [24]. However, the efficacy of statins in improving renal function in patients with diabetic nephropathy is still controversial. To answer this question, we did this study and found that statins could reduce the albuminuria and UAER compared with that in control groups. The beneficial effect of statins on renal function is time dependent and better in type 2 diabeties with nephropathy.
As we all know, the degree of albuminuria is a risk factor for renal failure [25]. Some studies have demonstrated a benefit of statins on albuminuria [6,26,27], while others failed to indicate such an effect [16,28]. Our meta-analysis suggested an overall significant decrease of albuminuria after statin therapy (decrease by 0.46, P < 0.0001), with the greater improvement of albuminuria among studies with greater baseline albuminuria. Notably, our results are consistent with the meta-analysis performed by Kevin Douglas et al. [29]. The beneficial effect of statins on albuminuria may be potentially explained by cholesterol dependent effects and cholesterol independent effects [30]. Keane et al. [31] have showed that dyslipidemia contributes to glomerular and interstitial injury and the severity of the hypercholesterolemia correlates with albuminuria. In addition, statins may have other cholesterol-independent renoprotective actions, such as reducing neutrophil and macrophage infiltration, up-regulating endothelial nitric oxide (NO) synthase, inhibition of renal cell proliferation, antifibrotic and antioxidant effects, and down-regulation of inflammatory cytokines [32]. Researches suggested that statins reduce albuminuria at least in part by reducing inflammation and fibrosis in the renal interstitium, seemingly through actions on monocyte chemotactic protein-1 and transforming growth factor-β (TGF-β) [33,34].
A recent review [32] reported that the benefit of statins may depend on the duration of treatment. We also investigated the effect of statin treatment less than 1 year and between 1 and 3 years. A greater decrease of albuminuria was observed in patients received statin therapy for 1 to 3 years compared with those for less    [35,36]. Some authors found statins may slow the decline in eGFR [37,38]. Nikolic et al. [32] suggested an overall significant increase of GFR after statin therapy (increase by 0.29 ml/min/1.73 m 2 , p = 0.04), with the greatest GFR improvement after between 1 and 3 years of statin therapy (0.50 ml/min/1.73 m 2 ; p < 0.0001). However, our meta-analysis found that statins did not improve eGFR significantly. Just as Satirapoj said [30], as a post hoc analysis, using estimates of renal function, some limitations were observed in interpreting these data, so a small proportion of patients, who had DN, were included in this analysis, whereas our findings in the statin group revealed eGFR did not improve, but no significant decline was observed among DN subjects. Therefore, the available data on statin with eGFR in DN patients are still conflicting, because of possible outcome reporting bias.
Findings from our meta-analysis revealed that statins could reduce both albuminuria and the rate of progression of diabetic nephropathy. The benefits appear to supplement those derived from treatment with reninangiotensin system (RAS) inhibitors [10]. The pathogenesis of diabetic nephropathy is multifactorial and its precise mechanisms of action remain unclear. However, it is now widely accepted that the rate of functional deterioration correlates with the degree of the renal tubulointerstitial fibrosis [36]. Statins is effective in protecting against tubulointerstitial injury [10] and may slow down the progression of diabetic nephropathy, but this needs to be further validated in large-scale and long follow-up period randomized controlled trials.
As with any study, our meta-analysis had some limitations. Frist, the number of randomized controlled trials was small and only published data included. Second, the detection technique of albuminuria was different. Third, the results are heavily based on the findings of the CARDS trial, which represents more than 90 % of the population of the meta-analysis. So, more clinical researches with larger sample, higher quality and strictly RCT study should be taken in the future.

Conclusion
Statins reduce albuminuria and UAER significantly . The beneficial effect of statins on renal function is time dependent and better in type 2 diabeties patients with nephropathy. Our findings, though exciting, still require larger and high-quality studies to confirm the kidney benefit of statins in patients with diabetes.