Cardiovascular outcomes
The evidence that patients at early stages of CKD benefit from lipid-lowering therapy comes from meta-analyses and post hoc analyses of large cardiovascular statin trails in the general population [
6‐
15,
87]. Tonelli et al. [
6] analyzed the data from the Pravastatin Pooling Project (PPP) and showed that moderate CKD, defined by eGFR of 30–59.9 mL/min/1.73 m
2, was independently associated with increased CV risk. Pravastatin significantly reduced the incidence of the primary outcomes (time to myocardial infarction, coronary death, or coronary revascularization) similarly in the subjects with normal kidney function (HR 0.78, 95 % CI 0.65–0.94) and in the subgroup of 4,491 patients with moderate CKD (HR 0.77, 95 % CI 0.68–0.86). Moreover, in patients with moderate CKD and high CV risk, pravastatin reduced all-cause mortality (HR 0.86, 95 % CI 0.74–1.00,
p = 0.045). Therefore, the authors suggested that patients with impaired kidney function would benefit from statin therapy more than those with normal renal function [
6]. In another post hoc analysis of data from a randomized trial of pravastatin 40 mg daily versus placebo, greater absolute risk reduction in the primary outcome (time to myocardial infarction, coronary death, or percutaneous/surgical coronary revascularization) was observed in patients with CKD (stages 2 and 3) or diabetes (6.4 %) than in individuals without any of these diseases (3.5 %) [
7].
Sever et al. [
8] in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) assessed benefits of statin therapy in primary prevention of coronary heart disease in patients with arterial hypertension and non-fasting total serum cholesterol concentrations ≤6.5 mmol/L. In a subgroup analysis of 6,517 subjects with kidney dysfunction, defined as serum creatinine concentration 130–200 μmol/L in males and 110–200 μmol/L in females, atorvastatin (10 mg/day) reduced the risk of non-fatal myocardial infarction and cardiovascular death (HR 0.61, 95 % CI 0.44–0.84). In 1,329 patients with impaired renal function (serum creatinine concentration 130–200 μmol/L in males and 110–200 μmol/L in females) from the 20,536 adults, who were enrolled into the Heart Protection Study (HPS), simvastatin use (40 mg/day) was associated with a significant reduction in major CV events [
9].
Szummer et al. [
10] analyzed data from the nationwide SWEDEHEART registry of over 42,000 patients following myocardial infarction and showed that statins use was associated with significant reduction in mortality at 1 year in patients with mild to severe chronic kidney disease, although the prescription of statins at discharge was much less frequent in patients with severe CKD (29 %) than in those with normal renal function (81 %).
A post hoc analysis of the Air Force/Texas Coronary Atherosclerosis Prevention Study assessed the efficiency of lovastatin in the prevention of first major acute CV event in participants with mild CKD, defined by eGFR < 60 mL/min/1.73 m
2. A significant decrease in CV events such as fatal and non-fatal coronary events (RR 0.35, 95 % CI 0.13–0.93;
p = 0.03), fatal and non-fatal CV events (RR 0.39, 95 % CI 0.16–0.93;
p = 0.03), and coronary revascularization procedures (RR 0.23, 95 % CI 0.07–0.77;
p = 0.01), was found in patients with renal dysfunction, even after adjustment for potential confounders [
11].
Colhoun et al. [
12], reporting data from the randomized placebo-controlled trial-Collaborative Atorvastatin Diabetes Study (CARDS), found that the risk of major CVD events and stroke decreased by 42 and 61 %, respectively, in the subgroup of 970 patients with CKD stage 3 (eGFR 30–60 mL/min/1.73 m
2) treated with atorvastatin.
In a recently performed secondary analysis of the JUPITER (Justification for the Use of Statins in Prevention-an Intervention Trial Evaluating Rosuvastatin) trial, treatment with rosuvastatin (10 mg daily) was associated with a 45 % reduction in risk of myocardial infarction, stroke, or cardiovascular death (HR 0.55, 95 % CI 0.38–0.82;
p = 0.002) and 44 % reduction in all-cause mortality (HR 0.56, 95 % CI 0.37–0.85;
p = 0.005) in participants with moderate CKD [
13].
Holdaas et al. [
14] performed a pooled analysis of 30 double-blind, randomized trials to compare the efficacy of fluvastatin in persons with moderate to severe CKD (creatinine clearance < 50 mL/min) and patients with normal renal function or mild kidney dysfunction (creatinine clearance ≥ 50 mL/min). Fluvastatin compared to placebo reduced combined cardiac death and nonfatal myocardial infarction in both groups, in patients with moderate to severe renal insufficiency and in patients with normal renal function or mild renal insufficiency, by 41 and 30 %, respectively.
The PREVEND IT (Prevention of Renal and Vascular End Stage Disease Intervention Trial) is the only published randomized, double-blind, placebo-controlled trial performed to asses the role of statins in patients with microalbuminuria and mild CKD (eGFR <60 mL/min/1.73 m
2). Contrary to previous findings, subjects treated with pravastatin had no significant risk reduction in the primary endpoints (cardiovascular mortality and hospitalization for cardiovascular morbidity) after 4 years (
p = 0.64) [
85], as well as in extended 10-year follow-up (
p = 0.99) [
86].
The Cholesterol Treatment Trialists’ (CTT) Collaboration [
15] reported a meta-analysis of data from randomized trials involving at least 1,000 participants and at least 2-year treatment duration of LDL-cholesterol-lowering therapy versus control. There was no evidence for reduction in major CV events (major coronary events, stroke, or coronary revascularization) in patients with eGFR <30 mL/min/1.73 m
2, although such a reduction was observed in patients with CKD stages 2 and 3.
A Cochrane Collaboration summarized 26 studies (25,017 participants) to evaluate the effects of statins in pre-dialysis CKD. Statins significantly decreased total and LDL cholesterol, as well as the risk of all-cause (RR 0.81, 95 % CI 0.74–0.89) and cardiovascular mortality (RR 0.80, 95 % CI 0.70–0.90) in this group of patients [
87].
The Assessment of LEscol in Renal Transplantation (ALERT) trial [
88] compared fluvastatin (
n = 1,050) with placebo (
n = 1,052) in patients after renal transplantation. After a mean follow-up of 5 years, fluvastatin failed to impact the composite primary endpoint, defined as cardiac death, non-fatal myocardial infarction, or coronary intervention procedure (
p = 0.139). However, there was a slight reduction in cardiac death and non-fatal myocardial infarction in the group treated with fluvastatin (RR 0.65, 95 % CI 0.48–0.88;
p = 0.005). During a 2-year extension of the ALERT trial, 1,652 renal transplant recipients who received fluvastatin demonstrated a lower risk of major cardiac events, cardiac death, or non-fatal myocardial infarction [
16]. Moreover, a post hoc analysis has suggested a beneficial effect of early introduction of lipid-lowering therapy in patients after kidney transplantation: When fluvastatin treatment was initiated at 0–2 versus >6 years after transplantation, the observed frequency of cardiac death and non-fatal MI was 3.2 versus 8.2 %, respectively [
17]. A possible impact of statins on patient and graft survival was evaluated among 2,041 first-time renal allograft recipients also by Wiesbauer et al. [
18]. The authors observed that statin use was associated with reduced all-cause mortality (adjusted HR 0.64, 95 % CI 0.48–0.86;
p = 0.003) and prolonged patient survival, while no effect on graft survival was noted.
Only a few lines of evidence suggest a role for other lipid-lowering agents in the prevention of cardiovascular disease in the CKD population. A post hoc subgroup analysis of the randomized double-blind, placebo-controlled Veterans’ Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) was performed to evaluate the cardiovascular benefits of gemfibrozil in patients with creatinine clearance ≤75 mL/min/1.73 m
2 [
89]. Treatment with gemfibrozil was associated with a lower rate of cumulative incidence of major cardiovascular events (nonfatal myocardial infarction, fatal coronary disease, or stroke) in this subgroup (adjusted HR 0.75, 95 % CI 0.59–0.96). There was, however, higher rate of non-coronary death and increase in the serum creatinine concentration in gemfibrozil-treated participants.
Finally, the SHARP (Study of Heart and Renal Protection) trial [
19] was created to assess the beneficial effect of the combination of simvastatin plus ezetimibe in patients with CKD and no history of myocardial infarction or coronary revascularization (Table
1). Of the total 9,270 participants, 6,247 were not on dialysis at the beginning of the study. They were initially randomized to receive simvastatin (20 mg) plus ezetimibe (10 mg), simvastatin (20 mg), or placebo. There was no difference in the incidence of adverse events between simvastatin alone and simvastatin plus ezetimibe group, and after the first year of observation, patients who initially received simvastatin were re-randomized to simvastatin plus ezetimibe and placebo groups. The median follow-up was 4.9 years, and the main outcome was the first major atherosclerotic event, defined as non-fatal myocardial infarction, coronary death, non-hemorrhagic stroke, or arterial revascularization procedure (excluded non-CHD cardiac death and hemorrhagic stroke). On average, there was a difference in LDL cholesterol of 0.85 mmol/L and a significant 17 % reduction in major atherosclerotic events (RR 0.83, 95 % CI 0.74–0.94;
p = 0.0021) as well as in major vascular events (RR 0.85, 95 % CI 0.77–0.94;
p = 0.0012) in patients treated with simvastatin plus ezetimibe. The use of simvastatin plus ezetimibe had no effect on vascular mortality, but the coronary heart disease was a cause of death only in 181 patients in this study. During the follow-up, there was no evidence that this combination therapy increased the risk of cancer, myopathy, or hepatitis in CKD patients.
Table 1
The effects of lipid-lowering therapy on cardiovascular outcomes in CKD patients
4D | 1,255 HD patients with DM type 2 | 4 | CHD 9 % Stroke 6 % Sudden death 26 % Heart insufficiency 6 % Other CV 3 % Non-CV 6 % | Atorvastatin 20 mg/day | 42 %a
| Composite of non-fatal MI or cardiac death (fatal MI, sudden death, death due to congestive heart failure, death after interventions to treat CHD, other death due to CHD) and non-fatal or fatal stroke HR 0.92, 95 % CI 0.77–1.11 | Death from all causes RR 0.93, 95 % CI 0.79–1.08 All cardiac events combined (death from cardiac causes, non-fatal MI, CABG, PTCA) RR 0.82, 95 % CI 0.68–0.99 All cerebrovascular events combined (ischemic, hemorrhagic or other stroke, TIA, PRIND) RR 1.12, 95 % CI 0.81–1.55 |
| 2,776 HD patients | 3.8 | CHD 10.8 % Stroke 2.7 % Other cardiac 2.4 % Other vascular 3.3 % Other CV 0.04 % Non-CV 18.6 % | Rosuvastatin 10 mg/day | 43 %b
| Composite of non-fatal MI or cardiac death, non-fatal or fatal stroke and other vascular death HR 0.96, 95 % CI 0.84–1.11 | Death from all causes HR 0.96, 95 % CI 0.86–1.07 Death from non-cardiovascular causes HR 0.92, 95 % CI 0.77–1.09 Major cardiovascular event or cause-specific death HR 0.94, 95 % CI 0.84–1.05 Atherosclerotic cardiac event (CHD and nonfatal MI) HR 0.96, 95 % CI 0.81–1.14 Vascular access procedure HR 1.10, 95 % CI 0.95–1.27 Revascularization HR 0.98, 95 % CI 0.78–1.23 |
| 9,270 CKD patients: 6,247 not on dialysis 2,527 on HD 496 on PD | 4.9 | CHD 1.95 % Stroke 1.6 % Other cardiac 3.7 % Other vascular 0.8 % Sudden death 1.1 % Nonvascular 13.8 % | Simvastatin 20 mg/day plus ezetimibe 10 mg/day | 77 %c
| Composite of MAEs: RR 0.83, 95 % CI 0.74–0.94 Non-fatal MI RR 0.84, 95 % CI 0.66–1.05) Coronary death RR 1.01, 95 % CI 0.75–1.35 Non-hemorrhagic stroke RR 0.75, 95 % CI 0.60–0.94 Arterial revascularization RR 0.79, 95 % CI 0.68–0.93 | Composite of MVEs: RR 0.85, 95 % CI 0.77–0.94 MAEs RR 0.83, 95 % CI 0.74–0.94 Other MVEs (non-coronary cardiac deaths and hemorrhagic strokes) RR 0.94, 95 % CI 0.78–1.14 |
In conclusion, there is evidence suggesting that patients with CKD stages 2 and 3 may benefit similarly or even more from statin therapy than those with normal renal function. Most of this evidence, however, comes from meta-analyses and post hoc analyses of trails in the general population and not from prospective, randomized, controlled study designed specifically for CKD population. After publication of the SHARP trial results, the US Food and Drug Administration (FDA) approved the combination of simvastatin plus ezetimibe as lipid-lowering treatment routinely used in kidney disease patients. The K/DOQI guidelines suggest that patients with pre-dialysis CKD should be treated according to the NCEP/ATP III guidelines recommended for the general population [
21].
Renal outcomes
In the last two decades, the nephroprotective effects of statins have been evaluated in numerous experimental models as well as in retrospective and prospective studies (Table
2).
Table 2
The effects of lipid-lowering therapy on renal outcomes in CKD patients
Abe et al. | 91 patients with CKD stages 1–3 | 24 weeks | Rosuvastatin | Parameters at baseline and after 24 weeks of treatment: Serum creatinine (mg/dL) 1.07 ± 0.04 (at baseline) and 1.07 ± 0.05 (after 24 weeks of treatment); p = NS eGFR (ml/min/1.73 m2) 55.1 ± 2.1 (at baseline) and versus 55.1 ± 2.1 (after 24 weeks of treatment); p = NS Cystatin C (mg/L) 1.08 ± 0.04 (at baseline) and versus 1.03 ± 0.04 (after 24 weeks of treatment); p < 0.0001 Urinary albumin/creatinine ratio (mg/g Cr) 308 ± 38 (at baseline) versus 195 ± 25 (after 24 weeks of treatment); p < 0.0001 |
| 56 patients with CKD | 1 year | Atorvastatin | Parameters at baseline and after 1 year of treatment: Urine protein excretion (g/day) 2.2 ± 0.1 (at baseline) versus 1.2 ± 1.0 (after 1 year of treatment); p < 0.01 Creatinine clearance (ml/min) 51 ± 1.8 (at baseline) versus 49.8 ± 1.7 (after 1 year of treatment); p = NS |
| 6,247 patients with CKD not on dialysis at randomization | 4.9 years | Simvastatin plus ezetimibe | Main renal outcome: ESRD (the need of dialysis or transplantation) RR 0.97, 95 % CI 0.89–1.05; p = NS Tertiary renal outcomes: ESRD or death RR 0.97, 0.90–1.04; p = NS ESRD or doubling of baseline creatinine RR 0.93, 0.86–1.01; p = 0.09 |
A protective role of rosuvastatin against puromycin and adriamycin-induced p21-dependent apoptosis in mouse podocytes has been reported by Cormack-Aboud et al. [
90], suggesting that statins may decrease proteinuria and delay the progression of CKD. Moreover, statins may exert anti-proteinuric effects through the stimulation of Akt activity and inhibition of the oxLDL-induced apoptosis and loss of nephrin [
82]. Fluvastatin significantly decreased urinary albumin excretion and glomerular sclerosis, as well as increased nephrin expression in podocytes in a murine model of HIV-associated nephropathy [
91].
In the post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GRACE) study, patients with coronary heart disease and dyslipidemia treated with atorvastatin (
n = 783) had a 12 % increase in creatinine clearance [
92]. This effect appeared to be dose-related and was more pronounced among participants with early stages of CKD. This observation has been confirmed in the subanalysis of the Treating to New Targets (TNT) study, in which a significant difference in mean change from baseline eGFR at the end of the follow-up was noted between patients with coronary heart disease treated with atorvastatin in dose 10 mg (
n = 4,829; increase of 3.5 ± 0.14 mL/min/1.73 m
2) and 80 mg daily (
n = 4,827; increase of 5.2 ± 0.14 mL/min/1.73 m
2) [
93]. Tonelli et al. [
94] have reported that compared to placebo, pravastatin reduced the rate of renal function decline in 1,702 patients with moderate CKD but did not reduce the risk of a ≥25 % decline of eGFR. In a subsequent meta-analysis of 27 randomized, controlled trials, statin therapy was associated with reduced rate of decline in eGFR (1.22 mL/min/year slower) compared to placebo [
95]. However, this effect was significant only in the CVD subpopulation but not in participants with glomerulonephritis, diabetes mellitus or hypertension. Navaneethan et al. [
87] in a Cochrane database review did not confirm the beneficial effects of statins on eGFR but found statins reduced urinary protein excretion in six studies. Similarly, in two small, prospective, controlled open-label studies rosuvastatin [
96] and atorvastatin [
97] decreased proteinuria in patients with CKD. Finally, the SHARP trial showed no protection from reaching ESRD in 6,247 participants not on dialysis at the beginning of the study [
19] (Table
2).