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Lipid-Lowering Therapy in Persons With Chronic Kidney Disease: A Systematic Review and Meta-analysis

Ashish Upadhyay, MD; Amy Earley, BS; Jenny L. Lamont, MS; Shana Haynes, DHSc, MS; Christoph Wanner, MD; and Ethan M. Balk, MD, MPH
[+] Article and Author Information

From Boston Medical Center and Boston University School of Medicine, and Center for Clinical Evidence Synthesis, Tufts University School of Medicine, Boston, Massachusetts, and University of Würzburg, Würzburg, Germany.

Grant Support: Dr. Upadhyay, Ms. Earley, Ms. Lamont, Dr. Haynes, and Dr. Balk were supported by KDIGO.

Potential Conflicts of Interest: Dr. Upadhyay: Grant (money to institution): National Kidney Foundation. Ms. Earley: Grant (money to institution): National Kidney Foundation. Ms. Lamont: Grant (money to institution): National Kidney Foundation. Dr. Haynes: Grant (money to institution): National Kidney Foundation. Dr. Wanner: Support for travel to meetings for the study or other purposes: National Kidney Foundation; Board membership: Boehringer Ingelheim; Grants/grants pending (money to institution): Genzyme; Payment for lectures including service on speakers bureaus: Genzyme, Abbott, Amgen. Dr. Balk: Grant (money to institution): KDIGO, National Kidney Foundation. Disclosures can be also viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-2984.

Requests for Single Reprints: Ashish Upadhyay, MD, Renal Section, Department of Medicine, Boston Medical Center and Boston University School of Medicine, 72 East Concord Street, Evans 124, Boston, MA 02118; e-mail, ashishu@bu.edu.

Current Author Addresses: Dr. Upadhyay: Renal Section, Department of Medicine, Boston Medical Center and Boston University School of Medicine, 72 East Concord Street, Evans 124, Boston, MA 02118.

Ms. Earley, Ms. Lamont, and Dr. Balk: Center for Clinical Evidence Synthesis, Tufts University School of Medicine, 800 Washington Street, Box 63, Boston, MA 02111.

Dr. Haynes: Division of Nephrology, Tufts Medical Center, 800 Washington Street, Box 391, Boston, MA 02111.

Dr. Wanner: Division of Nephrology, University of Würzburg, Oberduerrbacherstr 6, 97080 Würzburg, Germany.

Author Contributions: Conception and design: A. Upadhyay, A. Earley, S. Haynes, C. Wanner, E.M. Balk.

Analysis and interpretation of the data: A. Upadhyay, A. Earley, S. Haynes, C. Wanner, E.M. Balk.

Drafting of the article: A. Upadhyay, A. Earley, J.L. Lamont, C. Wanner, E.M. Balk.

Critical revision of the article for important intellectual content: A. Upadhyay, A. Earley, S. Haynes, C. Wanner, E.M. Balk.

Final approval of the article: A. Upadhyay, A. Earley, J.L. Lamont, S. Haynes, C. Wanner, E.M. Balk.

Statistical expertise: E.M. Balk.

Administrative, technical, or logistic support: A. Upadhyay, J.L. Lamont.

Collection and assembly of data: A. Upadhyay, A. Earley, J.L. Lamont, S. Haynes.


Ann Intern Med. 2012;157(4):251-262. doi:10.7326/0003-4819-157-4-201208210-00005
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Background: Lipid-lowering therapy is not widely used in persons with chronic kidney disease (CKD) despite a high burden of dyslipidemia and cardiovascular disease in this population.

Purpose: To synthesize evidence examining the effect of lipid-lowering therapy on clinical outcomes in persons with CKD.

Data Sources: MEDLINE, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews from January 2000 through November 2011.

Study Selection: Randomized, controlled trials (RCTs) comparing lipid-lowering therapy with control treatment in persons with CKD, including subgroup analyses of trials in the general population.

Data Extraction: Abstracts were screened and data were extracted on study methodology, population, interventions, cardiovascular and kidney outcomes, and adverse events. Data were extracted by one author and confirmed by another. Study quality was determined by consensus. Random-effects model meta-analyses were performed.

Data Synthesis: 18 RCTs, all in adults, met the eligibility criteria. Five RCTs involved CKD populations, and 13 were CKD subgroup analyses from trials in the general population. Sixteen RCTs examined statins, and 2 examined statins plus ezetimibe. Lipid-lowering therapy does not improve kidney outcomes but decreases the risk for cardiac mortality (pooled risk ratio [RR] from 6 trials, 0.82 [95% CI, 0.74 to 0.91]; P < 0.001), cardiovascular events (including revascularization) (pooled RR from 9 trials, 0.78 [CI, 0.71 to 0.86]; P < 0.001), and myocardial infarction (pooled RR from 9 trials, 0.74 [CI, 0.67 to 0.81]; P < 0.001). Significant benefit was also seen for all-cause mortality but was limited by a high degree of heterogeneity. No benefit was found for other cardiovascular outcomes. Rates of adverse events were similar between intervention and comparator groups.

Limitations: Lack of data in children, heterogeneity among reviewed studies, and the possibility of selective reporting of outcomes and adverse events.

Conclusion: Lipid-lowering therapy decreases cardiac death and atherosclerosis-mediated cardiovascular events in persons with CKD.

Primary Funding Source: Kidney Diseases: Improving Global Outcomes.

Figures

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Appendix Figure 1.

Grading the quality of CKD subgroups of non-CKD trials.

CKD = chronic kidney disease.

* Estimated glomerular filtration rate <60 mL/min per 1.73 m2.

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Appendix Figure 2.

Grading the quality of evidence across studies.

CKD = chronic kidney disease; RCT = randomized, controlled trial.

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Figure 1.

Summary of evidence search and selection.

CKD = chronic kidney disease; RCT = randomized, controlled trial.

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Figure 2.

Random-effects model meta-analyses of RR for all-cause death in patients with CKD receiving lipid-lowering interventions.

The summary RRs centered on a combined estimate and extending to 95% CIs for all statins or all interventions versus control (black diamonds) and the summary RR for individual statins versus control (white diamond) are shown. Risk ratios (diamonds) and 95% CIs (horizontal lines) for individual studies also are shown. The size of the squares is proportional to the weight of each study in the overall meta-analysis. Within drug subgroups, studies are ordered by drug dose and sample size. 4D = Die Deutsche Diabetes Dialyse Studie; 4S = Scandinavian Simvastatin Survival Study; ALERT = Assessment of Lescol in Renal Transplantation; AFCAPS/TexCAPS = Air Force Coronary Atherosclerosis Prevention Study/Texas Coronary Atherosclerosis Prevention Study; ALLIANCE = Aggressive Lipid Lowering to Alleviate New Cardiovascular Endpoints; AURORA = A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events; CARE = Cholesterol and Recurrent Events; CARDS = Collaborative Atorvastatin Diabetes Study; CKD = chronic kidney disease; JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin; LIPID = Long-Term Intervention with Pravastatin in Ischemic Disease; LIPS = Lescol Intervention Prevention Study; MEGA = Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; ND = no data; PREVEND IT = Prevention of Renal and Vascular Endstage Disease Intervention Trial; RR = risk ratio; SHARP = Study of Heart and Renal Protection; TNT = Treating to New Targets; UK-HARP-II = Second United Kingdom Heart and Renal Protection; WOSCOPS = West of Scotland Coronary Prevention Study.

* Patients with diabetes mellitus.

† Patients without diabetes mellitus.

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Appendix Figure 3.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for cardiovascular mortality.

See legend for Figure 2.

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Appendix Figure 4.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for cardiac mortality.

See legend for Figure 2.

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Figure 3.

Random-effects model meta-analyses of RR for cardiovascular events, including revascularization, in patients with CKD receiving lipid-lowering interventions.

See legend for Figure 2.

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Appendix Figure 5.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for cardiovascular events, excluding revascularization.

See legend for Figure 2.

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Appendix Figure 6.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for myocardial infarction.

See legend for Figure 2.

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Appendix Figure 7.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for stroke.

See legend for Figure 2.

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Appendix Figure 8.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for end-stage renal disease.

See legend for Figure 2.

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Appendix Figure 9.

Random-effects model meta-analyses of RR in patients with CKD with lipid-lowering interventions for end-stage renal disease or worsening kidney function.

See legend for Figure 2. eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; SCr = serum creatinine.

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