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Abstract

Statins are the standard of care in the treatment of hypercholesterolemia, and their use is supported by extensive evidence demonstrating their effectiveness in primary and secondary cardiovascular risk reduction. However, clinical and epidemiologic data have clearly demonstrated that patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease. However, the efficacy of statins in the reduction of cardiovascular risk has not been definitively confirmed in patients with CKD and especially those with stage 5 CKD or on dialysis. This review aims to provide the current clinical and scientific data pertaining to the effects of statins on cardiovascular outcomes in patients with CKD.

Keywords

Statins chronic kidney disease cardiovascular disease cardiovascular risk

Introduction

Statins are well known to reduce cardiovascular (CV) events and mortality in patients with coronary artery disease. The main effect of the statins is to lower low-density lipoprotein cholesterol (LDL-C). However, statins also exert important pleiotropic effects, including anti-inflammatory and antithrombotic actions, as well as improvement of endothelial function. Several studies have proven the benefits of statins in patients with coronary heart disease (CHD).¹

Statins act by blocking the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, which catalyzes the rate-limiting step in de novo cholesterol synthesis.² This causes a reduction in intrahepatic cholesterol levels, leading to an increase in the activity/nuclear translocation of the transcription factor sterol regulatory element–binding protein 2, which in turn activates the low-density lipoprotein receptor (LDLR) gene with subsequent upregulation of LDLRs, eventually leading to a decrease in circulating LDL-C levels.³ Statins also reduce very-low-density lipoprotein production via an effect mediated by reduced hepatic apolipoprotein B secretion.⁴

The benefits of statin therapy far outweigh any possible serious adverse effects, even in people at very low risk of cardiovascular disease (CVD).^5,6

However, it is well known that the chronic kidney disease (CKD) is associated with an increased risk of CVD,⁷ and CVD continues to be the leading cause of morbidity and mortality among people with CKD worldwide with rates of CV events and mortality consistently increasing as kidney function declines.⁸ Once CKD has been established, results from small series have indicated an association between progression of renal disease and dyslipidemia.⁹

Several patients with CKD will eventually develop end-stage renal disease (ESRD), and those patients have a high prevalence of clinical CHD, reaching approximately 40%. In addition, their CVD mortality rate is exceedingly high, ranging from 10 to 30 times higher than that of the general population of the same sex, age, and race.^10-12 However, most of the patients with CKD will die due to CVD before they progress to a dialysis-dependent stage.¹³

Chronic kidney disease is associated with dyslipidemia, involving the whole spectrum of plasma lipoproteins.^14,15 The specific lipoprotein abnormalities in patients with CKD may vary depending on the degree and the primary cause of renal impairment, as well as the type of dialysis in patients with ESRD.¹⁶

The increased atherogenicity of LDL in patients with CKD stage 5 has been attributed to several potential causes. The most critical factor is the presence of small, dense LDL particles, which readily penetrate the endothelial barrier and have decreased affinity for the LDLR with preferential uptake by the scavenger receptor. In addition, there is enhanced susceptibility of LDL to oxidation, as well as more avid proteoglycan binding.¹⁷

In this review, we will discuss the effects of statins in patients with CKD and especially their impact on CV outcomes. We will also briefly discuss the available evidence regarding the effects of statins on renal function.

Effects of Statins on Renal Function

End points for the evaluation of the effect of statin therapy on renal function in patients with CKD have included protein excretion and progression of CKD.

Initial analysis showed different rates of increased protein excretion with various statins.¹⁸ Higher rates were observed with simvastatin and rosuvastatin than with pravastatin and atorvastatin. However, clinical studies that specifically evaluated the effect of statin therapy on protein excretion yielded conflicting results, with some demonstrating a reduction in proteinuria^19-21 and others showing no effect.^22,23

There are conflicting data concerning the effect of statins on progression of CKD. Some studies have suggested that statins may slow the rate of decline in renal function in patients with mild to moderate renal dysfunction,^24-29 whereas others have found that statins were not superior to placebo and usual care.³⁰ In a very recent large meta-analysis including 57 studies with 143 888 participants, statins did not reduce the risk for kidney failure in patients with CKD not on dialysis but did modestly reduce proteinuria and rate of estimated glomerular filtration rate (eGFR) decline.³¹ These results are consistent with the results of another very recent meta-analysis of 23 randomized controlled trials (RCTs) with 39 419 participants with non–end-stage CKD, which showed that statins caused a statistically significant reduction in microalbuminuria, proteinuria, and clinical deaths but did not effectively slow the clinical progression of non–end-stage CKD.³² Furthermore, in another meta-analysis, which studied the efficacy of statins in patients with diabetic nephropathy and included 14 trials with 2866 participants, it was shown that statins decreased albuminuria and this reduction in albuminuria was greater in patients of type 2 diabetes mellitus with diabetic nephropathy.³³

There are some plausible explanations for the potential beneficial effects of statins on the rate of kidney disease progression and proteinuria. Statins may protect the kidneys through a variety of immunomodulatory effects. Statin therapy attenuates endothelial dysfunction, enhances renal perfusion, and reduces abnormal permeability to plasma proteins.³⁴ It has been suggested that statins may reduce blood pressure.³⁵ A meta-analysis showed that this effect is small. In general, the higher the baseline blood pressure, the greater the effect of statins on blood pressure.³⁶ Investigators, though, question whether all these are simply the results of better kidney perfusion, as a response to an improved endothelial and cardiac function and/or decreased exposure to the risk of acute renal failure from all the coronary revascularization procedures.³⁷ However, in the “real-world” clinical practice, other factors may also play a role, such as the different risk factors (hypertension, diabetes mellitus, and smoking) in the specific patient population studied, as well as the use of other urine protein lowering agents (angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers [ACE-I/ARB]).

Effects of Statins on Primary CV Prevention in Patients With CKD

In a large meta-analysis, which included 8834 participants with stage 1–3 CKD and 32 846 person-years of follow-up, statin therapy was shown to be beneficial for the primary CV prevention in CKD.³⁶ More specifically, statins reduced the risk of CVD by 41% (P < .001) and decreased total mortality by 34% (P = .005) and the risk of CHD by 45% (P < .001).³⁸ For stage 3 CKD only, statins reduced the risk of CVD by 44% (P < .001) and decreased total mortality by 38% (P < .001), the risk of CHD by 45% (P < .001), and the risk of stroke by 57% (P = .003).³⁸ In another study, low-cost generic statins were shown to be cost-effective for the primary prevention of CVD in hypertensive patients with mild to moderate CKD.³⁹

Effects of Statins on CV Outcomes in Patients With CKD or at High Risk for CVD

Patients with renal dysfunction were excluded from early statin trials, limiting the availability of data on the efficacy of statin therapy in these patients. However, at the time of this writing, several studies have reported the impact of statin therapy on CV outcomes.^40–57

In the 4D study (Die Deutsche Diabetes Dialyse Studie), 1255 patients with type 2 diabetes mellitus receiving hemodialysis (HD) were randomized to atorvastatin 20 mg daily versus placebo. The primary end point was the composite of death from cardiac causes, nonfatal myocardial infarction (MI), and stroke. After 4 weeks of therapy, there was a reduction in LDL-C by 42% in the atorvastatin group, as compared with 1.3% in the placebo group. However, during a median follow-up of approximately 4 years, treatment with atorvastatin led only to a nonsignificant relative risk (RR) reduction for the primary end point of 8%, as compared with placebo (P = .37). Thus, based on the above findings, the authors concluded that in patients with type 2 diabetes on HD, routine statin therapy to improve CV outcomes would not be warranted.⁴⁰ However, in a post hoc analysis of the 4D study, it was shown that in patients with type 2 diabetes mellitus on HD, treatment with atorvastatin significantly reduces the risk of fatal and nonfatal cardiac events and death from any cause if pretreatment LDL-C is >145 mg/dL.⁴¹

The AURORA trial (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) randomized 2776 patients between the age of 50 and 80 years, who were receiving maintenance HD, to receive rosuvastatin 10 mg daily versus placebo. The primary end point was the composite of CV death, nonfatal MI, or nonfatal stroke. At 3 months, the LDL-C levels were reduced by 42.9% in the rosuvastatin group versus only 1.9% in the patients who received placebo. Furthermore, there was a reduction in high-sensitivity C-reactive protein by 11.5% in the rosuvastatin group versus an increase in the placebo group (P < .001). However, during a median follow-up period of 3.8 years, there was no significant effect of active treatment (hazard ratio [HR] for the primary end point in the rosuvastatin group vs the placebo group: 0.96; P = .59).⁴²

However, in a meta-analysis including 7051 patients with CKD on chronic dialysis from 3 studies, lipid-lowering therapy produced a 11% reduction in the risk of atherosclerotic CV events but without statistically significant reduction in mortality.⁴³ Notwithstanding, in a larger meta-analysis including 8289 participants with CKD treated with dialysis from 50 RCTs, statins showed little or no beneficial effects on mortality or CV events despite clinically relevant reductions in serum cholesterol levels.⁴⁴

In another earlier trial (Assessment of Lescol in Renal Transplantation [ALERT] Study), the effects of fluvastatin on cardiac outcomes were assessed in renal transplant recipients. After a mean follow-up of 5.1 years, fluvastatin decreased LDL-C levels by 32%. There were fewer cardiac deaths or nonfatal MI in the fluvastatin group compared with the placebo group (RR = 0.65; P = .005); however, fluvastatin failed to significantly decrease the incidence of the primary end point, which was the occurrence of a major adverse cardiac event, defined as cardiac death, nonfatal MI, or coronary intervention procedure (RR = 0.83; P = .139).⁴⁵

In a post hoc subgroup analysis of the Cholesterol and Recurrent Events (CARE) study, which included 1711 patients with mild chronic renal insufficiency and a history of previous MI with total plasma cholesterol levels <240 mg/dL, after a median follow-up of 58.9 months, pravastatin reduced the incidence of the primary end point (death from coronary disease or symptomatic nonfatal MI) by 28% (P = .02).⁴⁶

In another meta-analysis, which included 4491 subjects with or at risk for CHD and concomitant moderate CKD, pravastatin significantly reduced the incidence of the primary end point (MI, coronary death, or percutaneous/surgical coronary revascularization) by 23%.⁴⁷

The SHARP (Study of Heart and Renal Protection) trial included 9270 patients with CKD (3023 on dialysis and 6247 not) with no known history of MI or coronary revascularization. The patients were randomly assigned to receive simvastatin 20 mg/d plus ezetimibe 10 mg/d versus matching placebo. The key prespecified outcome was the first major atherosclerotic event (nonfatal MI or coronary death, nonhemorrhagic stroke, or any arterial revascularization procedure). Most of the patients with nondialysis-dependent CKD were in CKD stages 3 and 4. The median follow-up of the study was 4.9 years. The combination of simvastatin with ezetimibe, as compared with placebo, reduced LDL-C by an average of 0.85 mmol/L during the trial and led to a 17% reduction in the primary end point (P = .0021).⁴⁸ Notwithstanding, there was no statistically significant difference in the incidence of CHD death or nonfatal MI between the simvastatin-ezetimibe and the placebo-treated groups (RR = 0.92; P = .37). Analysis of the subgroups suggested that patients with the highest baseline levels of cholesterol and body mass index, as well as smokers, appear to benefit the most from the lipid-lowering therapy.⁴⁹ Thus, in contrast to the previous trials (ALERT trial, 4D study, and AURORA trial), the SHARP trial achieved statistical significance in its primary outcome. The authors of the SHARP trial suggested that the absence of significant reductions in earlier trials could have been due to their smaller trial size and the much smaller proportion of vascular events in their primary outcome, which would be preventable by lowering of LDL-C. Furthermore, the absolute benefit would be expected to be even larger in patients with CKD with a previous history of CHD, who were excluded from SHARP, but whose absolute risk is estimated to be 2 to 3 times higher.⁴⁸ However, it has to be noted that although there were proportional decreases in the primary end point for the subgroups of patients with eGFR < 15 mL/min/1.73 m² and on dialysis in the SHARP trial, these did not reach statistical significance (HR: 0.82; 95% confidence interval [CI]: 0.59-1.13 and HR: 0.90; 95% CI: 0.75-1.08, respectively).⁴⁸

In a large meta-analysis including 45 285 participants with CKD not requiring dialysis from 50 RCTs, statins significantly decreased the risk of all-cause mortality, CV mortality, and major CV events (RR: 0.79, 95% CI: 0.69-0.91; RR: 0.77, 95% CI: 0.69-0.87; and RR: 0.72, 95% CI: 0.66-0.79, respectively). Statins had uncertain effects on stroke and progression of CKD.⁵⁰

In another recent very large meta-analysis including 183 419 patients with different stages of CKD from 28 trials, it was clearly shown that the relative reductions in major vascular events observed with statin therapy became smaller as eGFR declined, with little evidence of benefit in patients on dialysis.⁵¹

In a very recent meta-analysis of 13 studies, including 19 386 patients with stage 3 CKD, 2565 patients with stage 4 CKD, 7051 patients with stage 5 CKD or on dialysis, and 2102 patients with a functioning renal transplant, statins were proven to be beneficial in stage 3 CKD, probably beneficial in stage 4 CKD, not beneficial in patients with stage 5 CKD and dialysis, and probably beneficial in patients with a functioning transplant. However, the authors concluded that too few patients with stage 4 CKD and renal transplants have been included in lipid-lowering trials for definitive conclusions to be drawn.⁵² Thus, it becomes evident that more studies are needed, especially for patients with stage 4 CKD and renal transplants, to ascertain the effects of statins on CV outcomes of these patients. Furthermore, as patients with CVD risk factors are commonly on treatment with other cardioprotective agents, such as β-blockers and ACE-I/ARB, this factor should be taken into account to prevent confounding during analysis of the effects of statins on CVD outcomes in patients with CKD.

The effects of statins appear also to be dose related in CKD. A subanalysis of the Treating to New Targets (TNT) study, which included 3107 patients with CKD, showed that compared with atorvastatin 10 mg, atorvastatin 80 mg reduced the relative risk of major CV events by 32% in patients with CKD and 15% in patients with normal eGFR.⁵⁶ Furthermore, in a meta-analysis, which included 6 RCTs with 10 993 adult patients with CKD, high-intensity statin therapy was shown to effectively reduce the risk of stroke, although its effects on all-cause mortality, MI, heart failure, and renal protection were unclear.⁵⁷

Conclusions and Guidelines

Clinical and epidemiologic data have clearly demonstrated that patients with CKD are at high risk for CVD. Moreover, there is significant evidence showing that patients with nondialysis-dependent CKD benefit from statin therapy with improvement of CV outcomes. However, in patients with stage 5 CKD or on dialysis, the benefits of statin therapy on CV outcomes are less certain, and further large RCTs may be needed to clarify this matter.

Based on the current data, several national medical professional societies have issued guidelines pertaining to the use of statins in patients with CKD. According to the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults, CKD is not considered as a separate major risk factor for CVD, and patients with nondialysis-dependent CKD should undergo evaluation by the Pooled Cohort Equations to determine the need for statin therapy for primary prevention. The 2013 ACC/AHA Blood Cholesterol Guideline makes no recommendation regarding the initiation or maintenance of statin therapy for patients with CKD on dialysis.⁵⁸

The National Lipid Association (NLA) Recommendations for Patient-Centered Management of Dyslipidemia: Part 1 considers CKD stage 3B or 4 as a high-risk condition for CVD and recommends statin therapy to bring LDL-C below 100 mg/dL and non-HDL-C below 130 mg/dL. The NLA recognizes that CKD stage 5 or on dialysis is a very high-risk condition for CVD; however, no treatment recommendations are made for these patients because results from RCTs have not provided convincing evidence that statin therapy improves CV outcomes.⁵⁹

According to the Kidney Disease: Improving Global Outcomes (KDIGO) 2013 guidelines for lipid management in CKD, in patients aged ≥50 years with an eGFR < 60 mL/min/1.73 m² but not treated with chronic dialysis or kidney transplantation, use of statins or statin/ezetimibe combination is strongly recommended (recommendation level 1A). In patients aged 18 to 49 years with CKD but not treated with chronic dialysis or kidney transplantation, the KDIGO guidelines recommend that statin therapy should be employed only in patients with one or more of the following factors: known CHD, diabetes mellitus, prior ischemic stroke, or an estimated 10-year risk of CHD death or nonfatal MI > 10%. In addition, the KDIGO guidelines recommend not initiating statins in patients receiving chronic dialysis but continuing statin therapy in these patients if they are already being treated with statins. Statin therapy in adult kidney transplant recipients is also suggested. In adults with CKD, follow-up measurements of serum lipids are not usually recommended unless there is a need to assess adherence to statin therapy, or new potential causes of dyslipidemia are present, or there is a change in the type of renal replacement therapy.⁶⁰

Footnotes

Peer review:

Three peer reviewers contributed to the peer review report. Reviewers’ reports totaled 681 words, excluding any confidential comments to the academic editor.

Funding:

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests:

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author Contributions

CEK conceived the concepts, analyzed the data, jointly developed the structure and arguments for the paper, and made critical revisions and approved final version. ED and CEK wrote the first draft of the manuscript. ES, RM, PDM, and EG contributed to the writing of the manuscript. CEK, ED, ES, RM, PDM, and EG agree with manuscript results and conclusions. All authors reviewed and approved the final manuscript.

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Effects of Statins on Cardiovascular Outcomes in Patients With Chronic Kidney Disease

Abstract

Keywords

Introduction

Effects of Statins on Renal Function

Effects of Statins on Primary CV Prevention in Patients With CKD

Effects of Statins on CV Outcomes in Patients With CKD or at High Risk for CVD

Conclusions and Guidelines

Footnotes

Peer review:

Funding:

Declaration of conflicting interests:

Author Contributions

References