Kevin Douglas, MD; Patrick G. O'Malley, MD, MPH; Jeffrey L. Jackson, MD, MPH
Albuminuria is an independent risk factor for cardiovascular and renal disease with limited therapeutic options. Data on the effects of statins on albuminuria are conflicting.
To determine whether and to what degree statins affect albuminuria.
English-language and nonâ€“English-language studies found in PubMed, MEDLINE, EMBASE, BIOSIS, SciSearch, PASCAL, and International Pharmaceutical Abstracts (IPA) databases and the Cochrane Central Register of Controlled Trials that were published between January 1974 and November 2005.
Randomized, placebo-controlled trials of statins reporting baseline and follow-up measurements of albuminuria or proteinuria measured by 24-hour urine collection or the urinary albumin-to-creatinine ratio.
Two investigators independently abstracted study quality, characteristics, and outcomes.
Fifteen studies involving a total of 1384 patients and averaging 24 weeks in duration were included. Meta-analysis of the proportional reduction in proteinuria showed that statins reduced albuminuria (11 studies) and proteinuria (4 studies) in 13 of 15 studies. The reduction in excretion was greater among studies with greater baseline albuminuria or proteinuria: change of 2% (95% CI, âˆ’32% to 35%) for those with excretion less than 30 mg/d, âˆ’48% (CI, âˆ’71% to âˆ’25%) for those with excretion of 30 to 300 mg/d, and âˆ’47% (CI, âˆ’67% to âˆ’26%) for those with excretion more than 300 mg/d. Statistical heterogeneity was evident only in the group with excretion greater than 300 mg/d (excretion < 30 mg/d, I2Â = 23% [PÂ = 0.27]; excretion of 30 to 299 mg/d, I2Â = 0% [PÂ = 0.64]; excretion â‰¥ 300 mg/d, I2Â = 63% [PÂ = 0.020]).
Published studies were not of high quality on average and varied markedly in effect size, as well as in characteristics of the cohorts. Unpublished studies showing no effect could impact these results.
Statins may have a beneficial effect on pathologic albuminuria. The validity of this finding, and whether this effect translates into reduction of cardiovascular or end-stage renal disease, requires larger studies.
Albuminuria is a marker of endothelial dysfunction and is a risk factor for cardiovascular disease. We do not know whether or to what degree statins affect albuminuria.
This meta-analysis of 15 randomized, placebo-controlled trials found that statins reduced albuminuria and proteinuria. Studies with greater baseline albuminuria showed greater reductions.
Studies were small, showed heterogeneous effects, and were often of poor quality.
Statins might reduce albuminuria. We need larger, better studies to confirm these findings and to determine whether reducing albuminuria affects the incidence of end-stage renal disease or cardiovascular disease.
RCT = randomized, controlled trial.
Residual statistical heterogeneity: I = 23% ( = 0.27) for excretion < 30 mg/d; I = 0% ( = 0.64) for excretion of 30 to 299 mg/d; and I = 63% ( = 0.020) for excretion ≥ 300 mg/d. WMD = weighted mean difference in the proportional change from baseline to follow-up albuminuria (or proteinuria) between statin and placebo groups.
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Folkert W. Asselbergs
University Medical Center Groningen
July 20, 2006
The effect of statins on albuminuria
To the Editor: Dr. Douglas and colleagues(1) recently reported a systematic review of 15 randomized placebo-controlled clinical trials to determine the effect of statins on urinary albumin excretion (UAE). As stated by the authors, the effect of statins on UAE was too heterogeneous to perform a pooled analysis and therefore the investigators stratified the analyses by levels of UAE at randomization time. The authors defined three groups: UAE less than 30mg/day, between 30-299 mg/day and 300mg/day or greater. The studies included in this meta-analysis were small in size except for our study, the PREVEND Intervention Trial, which included 864 subjects(2). Pravastatin did not lower UAE in PREVEND and the null effect of statins on UAE in the excretion < 30mg/day group is mainly driven by the PREVEND Intervention Trial due to its sample size. We question the choice of the authors to include PREVEND IT into the group with a UAE <30mg/day. First, we included subjects with a UAE between 15-300mg/day. The mean UAE is 40 mg/day and the median 22.8 mg/day in PREVEND IT, and almost half of our population has microalbuminuria as defined by the traditional cut-off value of 30-300mg/day, the second group in the meta- analysis of Douglas et al. Second, more importantly, we argue the use of the term non-pathological levels of albuminuria. Besides PREVEND(3), several other studies confirmed that the increased risk reflected by UAE is already present at lower levels than the traditional 30 mg/day(4;5). Furthermore, the authors mention the 25 % lost to follow-up in PREVEND, which might indicate a low adherence and therefore might hide the potential benefit of statins on UAE. We want to clarify hereby that we do have clinical data of all participants during follow-up. Furthermore, the same study group was randomized to an ACE-inhibitor, which had a strong significant effect on UAE during follow-up which indicates the robustness of our data. A more obvious cause of the heterogeneous results may be the different patient characteristics, causes and range of UAE and concomitant medical treatment. Furthermore, even with 25% missing albuminuria data after 4 years of follow-up, PREVEND IT is one of the largest intervention trials thus far in subjects with low-grade albuminuria. We agree with the investigators that more large randomized clinical trials are necessary before we can state that statins have a beneficial effect on UAE.
1. Douglas K, O'Malley PG, Jackson JL. Meta-analysis: the effect of statins on albuminuria. Ann Intern Med. 2006;145:117-24.
2. Asselbergs FW, Diercks GF, Hillege HL, van Boven AJ, Janssen WM, Voors AA et al. Effects of Fosinopril and Pravastatin on Cardiovascular Events in Microalbuminuric Subjects. Circulation. 2004;110:2809-16.
3. Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106:1777-82.
4. Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, Scharling H et al. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004;110:32-35.
5. Arnlov J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D et al. Low-Grade Albuminuria and Incidence of Cardiovascular Disease Events in Nonhypertensive and Nondiabetic Individuals. The Framingham Heart Study. Circulation. 2005.
Douglas K, O'Malley PG, Jackson JL. Meta-Analysis: The Effect of Statins on Albuminuria. Ann Intern Med. 2006;145:117-124. doi: 10.7326/0003-4819-145-2-200607180-00009
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Published: Ann Intern Med. 2006;145(2):117-124.
Cardiology, Coronary Risk Factors, Dyslipidemia, Nephrology, Urological Disorders.
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