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

Shen et al. Lipids in Health and Disease (2016) 15:179 DOI 10.1186/s12944-016-0350-0 REVIEW Open Access Efficacy of statins in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials Xue Shen1†, Zhongwen Zhang2†, Xiaoqian Zhang2, Junyu Zhao2, Xiaojun Zhou2, Qinglei Xu1, Hongxia Shang2, Jianjun Dong3 and Lin Liao2* Abstract 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. Keywords: Statins, Diabetic Nephropathy, Meta-analysis Background According to the International Diabetes Federation [1], it is projected that the number of people with diabetes worldwide will increase from 382 million in 2013 to 592 million by 2035. Diabetic nephropathy (DN) is one of the most common and serious chronic complication of diabetes and it is the leading cause of end-stage renal disease [2]. However, beyond angiotensin II-receptor * Correspondence: † Equal contributors 2 Department of Medicine, Division of Endocrinology, Shandong Provincial Qianfoshan Hospital, Shandong University, No.16766, Jingshi Road, Lixia District, Jinan 250014, Shandong Province, China Full list of author information is available at the end of the article blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEI), therapeutic options to block the progression of diabetic nephropathy are limited and other strategies to preserve kidney function are needed. A number of potential mechanisms for kidney damage in DN have been identified. Hyperlipidemia may play an important role in the progression of DN and it may impair the messangial cells through its lipotoxicity or by promoting intrarenal atherosclerosis [3–5]. Statin, 3hydroxy-3 methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, is a kind of antihyperlipidemic drug that used worldwide for its strong low-density lipoprotein cholesterol (LDL-C)-lowering effects and established © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Shen et al. Lipids in Health and Disease (2016) 15:179 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) [6–8]. 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. Methods 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 di (...truncated)