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Effects of Fibrates in Kidney Disease a Systematic Review and Meta-Analysis

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Effects of Fibrates in Kidney Disease a Systematic Review and Meta-Analysis Journal of the American College of Cardiology Vol. 60, No. 20, 2012 © 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2012.07.049 Effects of Fibrates in Kidney Disease A Systematic Review and Meta-Analysis Min Jun, BSC(HONS), MSC(CLINEPI),* Bin Zhu, MD, PHD,† Marcello Tonelli, MD, PHD,‡ Meg J. Jardine, MBBS, PHD,* Anushka Patel, MBBS, PHD,* Bruce Neal, MB, CHB, PHD,* Thaminda Liyanage, MBBS,§ Anthony Keech, MBBS, MSC (EPID),ʈ Alan Cass, MBBS, PHD,* Vlado Perkovic, MBBS, PHD* Sydney, Australia; Hangzhou, China; and Edmonton, Alberta, Canada Objectives The purpose of this systematic review and meta-analysis was to determine the efficacy and safety of fibrate therapy in the chronic kidney disease (CKD) population. Background Fibrate therapy produces modest cardiovascular benefits in people at elevated cardiovascular risk. There is lim- ited evidence about the clinical benefits and safety of fibrate therapy in the CKD population. Methods MEDLINE, EMBASE, and the Cochrane Library were systematically searched (1950 to January 2012) for prospec- tive randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes were included. Results Ten studies including 16,869 participants were identified. In patients with mild-to-moderate CKD (estimated glo- merular filtration rate [eGFR] Յ60 ml/min/1.73 m2), fibrates improved lipid profiles (lowered total cholesterol [Ϫ0.32 mmol/l, p ϭ 0.05] and triglyceride levels [Ϫ0.56 mmol/l, p ϭ 0.03] but not low-density lipoprotein cho- lesterol [Ϫ0.01 mmol/l, p ϭ 0.83]; increased high-density lipoprotein cholesterol [0.06 mmol/l, p ϭ 0.001]). In people with diabetes, fibrates reduced the risk of albuminuria progression (relative risk [RR]: 0.86; 95% confi- dence interval [CI]: 0.76 to 0.98; p ϭ 0.02). Serum creatinine was elevated by fibrate therapy (33 ␮mol/l, p Ͻ 0.001), calculated GFR was reduced (Ϫ2.67 ml/min/1.73 m2,pϭ 0.01) but there was no detectable effect on the risk of end-stage kidney disease (RR: 0.85; 95% CI: 0.49 to 1.49; p ϭ 0.575). In patients with eGFR of 30 to 59.9 ml/min/1.73 m2, fibrates reduced the risk of major cardiovascular events (RR: 0.70; 95% CI: 0.54 to 0.89; p ϭ 0.004) and cardiovascular death (RR: 0.60; 95% CI: 0.38 to 0.96; p ϭ 0.03) but not all-cause mortality. There were no clear safety concerns specific to people with CKD but available data were limited. Conclusions Fibrates improve lipid profiles and prevent cardiovascular events in people with CKD. They reduce albuminuria and reversibly increase serum creatinine but the effects on major kidney outcomes remain unknown. These results suggest that fibrates have a place in reducing cardiovascular risk in people with mild-to-moderate CKD. (J Am Coll Cardiol 2012;60:2061–71) © 2012 by the American College of Cardiology Foundation The burden of chronic kidney disease (CKD) is large and (1–3). Defined as a glomerular filtration rate (GFR) below growing, affecting 10% to 15% of the adult population 60 ml/min/1.73 m2 or the presence of other markers of From the *George Institute for Global Health, the University of Sydney, Sydney, aventis, Servier, and Tanabe. Dr. Keech has received grants for clinical trials from New South Wales, Australia; †Department of Nephrology, Hangzhou Hospital of Roche Diagnostics, Solvay, Abbott, Merck and sanofi-aventis; consulting fees from Traditional Chinese Medicine (Hangzhou Guangxing Hospital), Zhejiang Chinese Merck, Astra-Zeneca, Solvay, and Abbott; and lecture fees from Merck, Solvay, and Medical University, Hangzhou, Zhejiang, China; ‡Department of Medicine, Uni- Abbott. Dr. Tonelli has received honoraria for being on an advisory board to Merck. versity of Alberta, Edmonton, Alberta, Canada; §Royal North Shore Hospital, Dr. Cass serves on a grant advisory panel for Roche and Advisory Boards for Baxter, Sydney, New South Wales, Australia; and the ʈNHMRC Clinical Trials Centre, the Abbott, and Merck; receives grant support from Baxter, Servier, and Gambro; and University of Sydney, Sydney, New South Wales, Australia. This study was supported receives lecture fees and travel reimbursements from Servier, Fresenius, and Amgen. by Program Grants from the Australian National Health and Medical Research Dr. Perkovic has received grants for clinical trials from Baxter, Johnson and Johnson, Council (grant ID nos. 571281 and 512657). Dr. Jardine has received a grant for a Novartis, Roche, and Servier; consulting fees from Vitae Pharmaceuticals, Abbott, clinical trial from CSL Limited. Dr. Neal has received grant support from the and Boehringer Ingelheim; and lecture fees from Abbott, AstraZeneca, Roche, and Australian Food and Grocery Council, Bupa Australia, Johnson and Johnson, Merck Servier. All other authors have reported that they have no relationships relevant to the Schering Plough, Roche, Servier, and United Healthcare Group; receives consultant contents of this paper to disclose. fees from Roche and Takeda; and receives lecture fees from Amgen, AstraZeneca, Manuscript received April 10, 2012; revised manuscript received July 10, 2012, GlaxoSmithKline, Novartis, PepsiCo, Pfizer, Pharmacy Guild of Australia, Sanofi- accepted July 23, 2012. 2062 Jun et al. JACC Vol. 60, No. 20, 2012 Effects of Fibrates in Chronic Kidney Disease November 13, 2012:2061–71 Abbreviations kidney deterioration including al- ings of fibrate, clofibrate, clofibric acid, bezafibrate, gemfibrozil, and Acronyms buminuria or proteinuria (4) CKD fenofibrate, procetofen, renal insufficiency, kidney failure, chronic kidney disease, albuminuria, serum creatinine, mortality, car- confidence interval is associated with increased risk of ؍ CI kidney failure and cardiovascular diovascular disease, myocardial infarction, revascularization, chronic kidney ؍ CKD disease events (5–11). While preventing and stroke. The search was limited to randomized controlled trials but without language restriction. Reference lists from estimated progressive kidney dysfunction is a ؍ eGFR glomerular filtration rate core aspect of managing these indi- identified trials and review articles were manually scanned to end-stage kidney viduals, the risk of cardiovascular identify any other relevant studies. The U.S. government’s ؍ ESKD disease disease is greatly elevated in people Clinical Trials database was also searched for randomized high-density with CKD and is the leading cause trials that were registered as completed but not yet ؍ HDL lipoprotein of death in this population (12,13). published. low-density Treatments that can prevent 1 or Study selection. The literature search, data extraction, and ؍ LDL lipoprotein both of these adverse outcomes are quality assessment were conducted independently by 2 relative risk therefore key to improving the long- authors (M.J. and B.Z.) using a standardized approach. All ؍ RR term outcomes for this high-risk completed randomized controlled trials assessing the effects of group. a fibrate compared to placebo that reported 1 or more of the primary or secondary outcomes were eligible for inclusion. See page 2072 Data extraction and quality assessment. Published re- ports were obtained for each trial and standard information Accumulating data suggest that a range of interventions was extracted into a spreadsheet. The data sought included that are effective at preventing cardiovascular disease in the baseline patient characteristics (age, sex, history of diabetes, general population are likely to be similarly efficacious in creatinine, renal function, lipid levels, and body mass index), people with CKD. Recent evidence suggests that lipid fibrate used, dose of drug, follow-up duration, change in lowering (14), antiplatelet agents (15), and blood pressure lipid levels, outcome events, and adverse events. Study lowering (16,17) prevent cardiovascular events in CKD, and quality was judged by the proper conduct of randomization, the latter may also prevent progression of renal disease (18). concealment of treatment allocation, similarity of treatment A meta-analysis of studies assessing the effects of fibrates groups at baseline, the provision of a description of the on cardiovascular events in the broader population has eligibility criteria, completeness of follow-up, and use of reported overall benefit, with consistent evidence of greater intention-to-treat analysis, and was quantified using the effects for subgroups with elevated triglyceride and/or de- Jadad score (26). Any disagreement in abstracted data was creased HDL levels (19). However, no adequately powered adjudicated by a third reviewer (V.P.). Attempts were made outcome study of fibrate therapy has been reported to date to contact individual authors of included studies to seek specifically in the CKD population. additional data wherever possible. A total of 6 authors were While dyslipidemia is a risk factor for progressive kidney contacted, and additional data were received from 1 author. disease (8,10,20,21) the acute elevation of creatinine caused To investigate the effects of fibrates on major clinical outcomes, additional unpublished summary level data on a by fibrates (22) has resulted in concerns about the safety of ϭ this therapy in the CKD population (23) and there have subgroup (n 399) of the VA-HIT (Veterans Affairs been conflicting reports regarding the impact of fibrate High-Density Lipoprotein Intervention Trial) was sought therapy on kidney function (24,25). and obtained. In this systematic review, we sought to synthesize the Outcomes. We collected data on lipid profiles (total cho- available clinical trial evidence to better define any benefits lesterol, triglyceride, low-density lipoprotein [LDL], and of fibrate therapy on kidney-related outcomes and on high-density lipoprotein [HDL]), albuminuria, serum cre- cardiovascular events in people with CKD, as well as any atinine and renal function changes, end-stage kidney disease adverse effects. (ESKD), major clinical outcomes (cardiovascular events, cardiovascular death, stroke, all-cause mortality), and ad- verse events. Methods Data synthesis and analysis. Individual study relative risks Data sources and searches.
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