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Effect of Statins on Kidney Disease Outcomes:
A Systematic Review and Meta-analysis
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Download the PDF here
Am Jnl Kidney Diseases June 2016
"Chronic kidney disease (CKD) is a major health problem and is associated with increased risk for all-cause mortality, cardiovascular disease, and end-stage renal disease (ESRD)".....
Chronic kidney disease (CKD) is a major health problem and is associated with increased risk for all-cause mortality, cardiovascular disease, and end-stage renal disease (ESRD).1, 2, 3, 4, 5 Abnormal lipid metabolism is common in patients with kidney disease.6 Experimental studies have shown that dyslipidemia is causally associated with glomerular injury, resulting in glomerulosclerosis.7, 8 Post hoc analyses of several large trials have demonstrated that dyslipidemia is significantly associated with increased risk for developing reduced kidney function or faster estimated glomerular filtration rate (eGFR) decline in a general population without kidney disease.9, 10
"In conclusion, this review suggests that statin therapy does not reduce the risk for kidney disease progression in adults not receiving dialysis in whom kidney disease outcomes were reported. However, statin therapy seems to modestly reduce proteinuria and rate of eGFR decline. The effects of kidney protection may differ according to the type of statin. The clinical significance of the results requires confirmation with further studies......However, this study might not be the final answer for the question of lowering LDL-C levels and progression of kidney disease. First, the study cannot exclude that intensive LDL-C lowering would have an effect on reducing the risk for kidney disease progression. We observed that an intensive strategy reduced the risk for kidney failure by 31% compared to the usual dose of statin (mainly dominated by the TNT Study36). Second, there is heterogeneity in terms of the effects of kidney protection among different types of statins. In direct comparison trials, atorvastatin was reported to confer the greatest renal benefit. Furthermore, atorvastatin, pravastatin, and simvastatin showed a trend in reducing the risk for kidney failure, with the pooled risk reduction for kidney failure of 6% (95% CI, 1%-12%), whereas other statins did not show the same effect. The current study cannot exclude the possibility of a more moderate kidney protective effect of some statins.
Chronic kidney disease (CKD) is a major health problem and is associated with increased risk for all-cause mortality, cardiovascular disease, and end-stage renal disease (ESRD)......As shown in Fig 2, when compared with placebo or usual-care control groups, statin treatment did not produce an apparent beneficial effect for kidney failure events in general (OR, 0.98; 95% CI, 0.87-1.10; P = 0.7) or for ESRD events specifically (OR, 0.98; 95% CI, 0.90-1.07, P = 0.7).....Three trials reported in 2 publications36, 40 with 10,905 patients and 158 kidney failure events compared effects of a high-dose statin to a low-dose statin. Intensive lipid lowering reduced the risk for kidney failure (OR, 0.69; 95% CI, 0.50-0.96;.....When considering studies that were placebo or usual-care controlled, statin therapy slowed the rate of eGFR decline by 0.41 mL/min/1.73 m2 per year (95% CI, 0.11-0.70; Fig 3). There was evidence of significant heterogeneity for effects across included studies (I2 = 90%; 95% CI, 87%-92%). Intensive lipid lowering reduced the rate of eGFR decline by 0.35 (95% CI, 0.27-0.42) mL/min/1.73 m2 per year (Fig S4). .....The standardized mean difference in change in proteinuria or albuminuria was statistically significant at -0.65 (95% CI, -0.94 to -0.37) compared with the placebo or usual-care control groups, with substantial heterogeneity.....Overall, statin therapy significantly reduced the risk for cardiovascular events (OR, 0.69; 95% CI, 0.61-0.79; P < 0.001) without evidence of heterogeneity in results of individual trials
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Background
The effects of statin administration on kidney disease outcomes remain controversial. We undertook a systematic review and meta-analysis to assess the efficacy of statins on kidney outcomes.
Study Design
We conducted a meta-analysis of randomized controlled trials (RCTs) using MEDLINE (1946 to August 31, 2015), EMBASE (1966 to August 31, 2015), and the Cochrane Library database (no date restriction).
Setting & Population
Adults who were not receiving dialysis, for whom kidney disease outcomes were reported.
Selection Criteria for Studies
RCTs in which statins were given for at least 6 months and kidney outcomes were measured.
Intervention
Statins versus control, including placebo, usual care, and different types or doses of statins.
Outcomes
Kidney failure events, rate of change in estimated glomerular filtration rate (eGFR) per year, change in proteinuria or albuminuria, and, in patients with chronic kidney disease, major cardiovascular events.
Results
57 eligible studies with 143,888 participants were included. Statin treatment did not produce an apparent beneficial effect for kidney failure events (OR, 0.98; 95% CI, 0.87-1.10; P = 0.7) or end-stage renal disease events (OR, 0.98; 95% CI, 0.90-1.07; P = 0.7). However, mean difference for rate of decline in eGFR (0.41 [95% CI, 0.11-0.70] mL/min/1.73 m2 per year slower in statin recipients) and standardized mean difference for change in proteinuria or albuminuria (-0.65 [95% CI, -0.94 to -0.37] standard deviation units, statin recipients vs controls) were statistically significant. In addition, statin therapy significantly reduced the risk for cardiovascular events (OR, 0.69; 95% CI, 0.61-0.79; P < 0.001) in patients with chronic kidney disease.
Limitations
Inclusion of several post hoc analyses from large RCTs and substantial heterogeneity in secondary outcome analyses.
Conclusions
Statin therapy does not reduce the risk for kidney failure events in adults not receiving dialysis for whom kidney disease outcomes were reported, but may modestly reduce proteinuria and rate of eGFR decline.
Results
Search Results and Characteristics of Included Studies
The literature search yielded 4,192 articles, of which 176 were reviewed in full text (Fig 1). As shown in Table 1 and Table S1, a total of 57 eligible trials reported in 67 publications11, 12, 13, 14, 15, 16, 17, 18, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94 with a total of 143,888 participants were included in this review. Overall, 8 different statins were studied, and follow-up duration ranged from approximately 6 months to 6 years. Thirty-four trials were placebo controlled and 14 trials were usual-care controlled. Six trials compared different statins, and 3 trials compared intensive lipid-lowering therapy and conventional or low-dose therapy with the same statin. Twenty-one trials reported post hoc analysis of the subgroup with all patients.
The reported trial quality varied substantially (Figs S1 and S2). In the meta-analysis for primary outcome, data were obtained from studies that generally had lower risk of bias than other included studies: random sequence generation was assessed as low risk in 57%, allocation concealment was low risk in 50%, participants and personnel were blinded in 93%, outcome assessors were blinded in 79%, and attrition and reporting bias were low risk in 86%. However, in meta-analyses for secondary outcome, data were obtained from studies with higher risk of bias (Fig S1). In all included studies, biases of conflicts of interest from pharmaceutical industry study funding and author-industry financial relationships were high risk in 40% and 42%, respectively (Figs S1 and S2). In order to investigate reporting/published bias, we searched and found that 27 studies reported their protocols in 176 full-text peer-reviewed articles. In studies in which no outcomes of interest for this systematic review were reported, we did not find any preplanned kidney outcome.
Effect of Statins on Designated Outcomes
Effect on Kidney Function
Data for effects of statin treatment on kidney failure events were available from 13 publications11, 12, 13, 14, 15, 16, 36, 37, 38, 39, 40, 41, 42 concerning 16 trials, which included 81,487 participants and 8,498 events, and on ESRD events, from 4 trials,12, 14, 16, 41 which included 18,776 participants and 2,543 events. As shown in Fig 2, when compared with placebo or usual-care control groups, statin treatment did not produce an apparent beneficial effect for kidney failure events in general (OR, 0.98; 95% CI, 0.87-1.10; P = 0.7) or for ESRD events specifically (OR, 0.98; 95% CI, 0.90-1.07, P = 0.7); there was no evidence of heterogeneity in the magnitude of effect across included studies (I2 = 50% [95% CI, 0%-75%]; I2 = 0% [95% CI, 0%-80%]). Three trials reported in 2 publications36, 40 with 10,905 patients and 158 kidney failure events compared effects of a high-dose statin to a low-dose statin. Intensive lipid lowering reduced the risk for kidney failure (OR, 0.69; 95% CI, 0.50-0.96; Fig S3). This effect was mainly dominated by the TNT (Treating to New Targets) Study.36 There was no statistical heterogeneity in all subgroup analyses apart from the borderline significance for effects of different types of statins (P = 0.07; Table S2).
The effect of statin administration on rate of change in eGFR was available in 47 trials of 128,601 participants.11, 12, 13, 14, 15, 16, 36, 37, 38, 39, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76 When considering studies that were placebo or usual-care controlled, statin therapy slowed the rate of eGFR decline by 0.41 mL/min/1.73 m2 per year (95% CI, 0.11-0.70; Fig 3). There was evidence of significant heterogeneity for effects across included studies (I2 = 90%; 95% CI, 87%-92%). Intensive lipid lowering reduced the rate of eGFR decline by 0.35 (95% CI, 0.27-0.42) mL/min/1.73 m2 per year (Fig S4). Compared to rosuvastatin or simvastatin, atorvastatin significantly slowed the rate of eGFR decline in direct comparison trials (mean differences of 2.45 and 0.33, respectively; Fig S5). Subgroup analysis showed that there was heterogeneity for the effects of different types of statins (P < 0.001; Table 2).
Effect on Proteinuria and Albuminuria
Twenty-nine trials with 4,968 participants reported data regarding the effects of statins on changes in proteinuria or albuminuria. Of these, 11 studies with a total of 2,833 participants provided data for urinary protein excretion12, 38, 46, 47, 48, 49, 51, 58, 62, 67, 73; 12 studies with 1,227 participants, urinary albumin excretion43, 44, 45, 52, 54, 55, 63, 77, 78, 79, 80, 81; 5 studies with 788 participants, ACR60, 71, 76, 82; and 1 study with 120 participants, PCR.69 The standardized mean difference in change in proteinuria or albuminuria was statistically significant at -0.65 (95% CI, -0.94 to -0.37) compared with the placebo or usual-care control groups, with substantial heterogeneity (I2 = 89%; 95% CI, 86%-92%; Fig 4). Compared to rosuvastatin, atorvastatin significantly reduced ACR/PCR in direct comparison trials (standardized mean difference, -0.23; 95% CI, -0.39 to -0.07; Fig S6). Similar to results seen with rate of change in eGFR, subgroup analysis showed that there was heterogeneity for the effects of different types of statins (P < 0.001; Table 2).
Effect on Major Cardiovascular Events in CKD Patients
Data regarding effects of statin administration on major cardiovascular events in patients with CKD were available from 13 publications13, 15, 12, 57, 37, 39, 38, 56, 11, 52, 14, 55, 50 comprising 15 trials, including 34,853 participants and 5,491 events. Overall, statin therapy significantly reduced the risk for cardiovascular events (OR, 0.69; 95% CI, 0.61-0.79; P < 0.001) without evidence of heterogeneity in results of individual trials (I2 = 33%; 95% CI, 0%-66%; Fig S7).
Discussion
There is epidemiologic and clinical evidence supporting the idea that dyslipidemia is a risk factor for CKD initiation or progression.9, 10, 95 Effects of statin administration on kidney disease outcomes remain controversial. This large quantitative review, including 57 trials, more than 140,000 participants, and 8,498 kidney failure events, suggests that statin therapy produces a mild reduction in proteinuria and rate of decline in eGFR of 0.41 mL/min/1/73 m2 per year. However, these effects did not translate into a risk reduction of kidney failure events. Similar to our prior study,18 this study showed that statin therapy induced a 30% risk reduction in major cardiovascular events in patients with CKD. Although this study did not show clear renal benefits, the lack of evidence for an adverse effect of statin on kidney outcomes is important, particularly in light of the clear cardiovascular benefits of statins.
The large volume of data available was beneficial for this meta-analysis. To our knowledge, the current study represents the largest systematic review of statin administration on kidney disease progression and the first meta-analysis that evaluates the effect of statin treatment on kidney failure events. Several prior overviews have evaluated effects of statins on kidney disease outcomes in patients with cardiovascular risk or CKD. Meta-analyses that included 26 trials with 39,704 participants reported significant benefits of statins, with differences in eGFR decline of 1.22 (95% CI, 0.44-2.00) mL/min per year.17 A recent review that included 41 studies with a total of 88,523 patients found that statin therapy reduced the slope of eGFR decline.96However, both studies focused on effects of proteinuria reduction or eGFR decline and not on clinically relevant renal benefits, such as kidney failure events. Additionally, these studies cannot exclude the possibility that statin administration increases creatinine excretion and influences serum creatinine level. The findings of these studies therefore have limited application in clinical practice. Our study, which examined nearly double the number of participants in prior reviews, found a nonsignificant beneficial effect in composite kidney failure events and ESRD. This finding aligns with SHARP, a large trial.14
However, this study might not be the final answer for the question of lowering LDL-C levels and progression of kidney disease. First, the study cannot exclude that intensive LDL-C lowering would have an effect on reducing the risk for kidney disease progression.
We observed that an intensive strategy reduced the risk for kidney failure by 31% compared to the usual dose of statin (mainly dominated by the TNT Study36). Second, there is heterogeneity in terms of the effects of kidney protection among different types of statins. In direct comparison trials, atorvastatin was reported to confer the greatest renal benefit. Furthermore, atorvastatin, pravastatin, and simvastatin showed a trend in reducing the risk for kidney failure, with the pooled risk reduction for kidney failure of 6% (95% CI, 1%-12%), whereas other statins did not show the same effect. The current study cannot exclude the possibility of a more moderate kidney protective effect of some statins. Despite its large size, even SHARP did not reach sufficient statistical power to detect such a modest proportional risk reduction, in which the relative risk reduction for kidney failure or doubling of serum creatinine level was 7% (95% CI, -1% to 14%; P = 0.09).14 A population of nearly 20,000 patients will be required for a future study to have sufficient power to demonstrate an absolute risk reduction in patients with high risk for kidney disease progression and whether such a risk reduction is clinically relevant. IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial), which had 18,144 participants, has provided an example of a 6% relative cardiovascular risk reduction with ezetimibe therapy, which translates into a worthwhile absolute risk reduction in patients with coronary disease.97, 98 Statin administration for kidney protection remains to be debated. Regardless, statins also should be used for patients with kidney disease and high-risk cardiovascular disease when considering atherosclerotic disease according to the KDIGO (Kidney Disease: Improving Global Outcomes) lipid guidelines and European lipid guidelines.
The study has some potential limitations. First, post hoc analyses from large RCTs accounted for a considerable proportion of the study's included trials (21 of 57 trials). Most large RCTs of statins were principally designed to evaluate cardiovascular outcomes in persons presenting with cardiac disease. They were not specifically designed to test kidney function. In secondary outcome analyses, the relative paucity of high-quality RCTs limited the conclusions able to be drawn about eGFR and proteinuria, although the quality of the studies included in the primary outcome was considered good. Second, we found evidence of substantial heterogeneity in secondary outcome analyses, although we tried to address this by using random-effects models. We acknowledge the possibility that this heterogeneity had an impact on our results. Third, findings related to changes in proteinuria are based on a much smaller number of patients (n = 4,977) compared with the other analyses. Fourth, as discussed, a potential effect on creatinine generation and/or tubular secretion from statin treatment has not been removed.99 Large prospective randomized trials including measured (not estimated) GFR are needed to definitively prove a positive effect of statins on kidney function progression. Fifth, we included only published studies in this analysis, and reporting bias could not be excluded because not all studies reported each outcome. In particular, kidney outcomes were not primary end points in most included trials and thus it is likely that some were not reported because they were not significant. Because we did not find an overall benefit of statins on kidney failure, this effect may be limited. However, this may produce much bias in comparison of a high versus low dose of statin for which a renal benefit was shown in 3 high-dose statin therapy trials. Finally, there were 21 missing standard deviations of change in eGFR and proteinuria, and we used the imputation of correlation referred to in the Cochrane Handbook.23 We concede that doing so may produce uncertainty and underestimate the width of CIs, although most of these missing standard deviations were from trials with relatively small sample sizes.
In conclusion, this review suggests that statin therapy does not reduce the risk for kidney disease progression in adults not receiving dialysis in whom kidney disease outcomes were reported. However, statin therapy seems to modestly reduce proteinuria and rate of eGFR decline. The effects of kidney protection may differ according to the type of statin. The clinical significance of the results requires confirmation with further studies.
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