Statins in patients with chronic kidney disease – an attempt at recommendations

Keywords::

• Cardiovascular disease
• Chronic kidney disease
• Dyslipidaemia
• Statins

Chronic kidney disease (CKD) is associated with cardiovascular disease (CVD) even in the early stages of the disease and a large number of patients die from CVD before developing advanced CKD1–3. Beyond established risk factors (e.g. hypertension, dyslipidaemia, obesity, smoking and diabetes) these patients might also have additional predictors of CVD such as proteinuria, electrolyte imbalances, inflammation, oxidative stress and endothelial dysfunction that amplify vascular risk2–5. Dyslipidaemia is an independent risk factor for the progression of CKD4,6. CKD with significant proteinuria is commonly associated with substantial alteration of serum lipid levels. The most common changes being lowered high density lipoprotein cholesterol (HDL-C) levels and elevated level of triglycerides (TG)3; hypercholesterolemia per se might be present in around 50% of patients on dialysis7.

Among lipid lowering drugs, statins are the most effective in improving the lipid profile and cardiovascular (CV) outcomes in patients with CKD5–10. However, despite several studies and meta-analyses there are still questions regarding their role in CKD. For example, the role of statins in primary prevention of CVD risk in CKD patients still remains to be clarified, as no large randomized clinical trial has provided evidence that they reduce CVD in these patients10–12. We still do not know at what stage of renal insufficiency statin therapy might be the most effective (stage 1–3, and possibly 1–4?; what is the glomerular filtration rate [GFR] cut-off value for their efficiency?) and at what stage is statin administration not effective or even harmful (dialysis patients?). Should we use statins in patients on dialysis? If yes – which statin, what dose and is duration of treatment important10–14?

The available data suggest that statins are effective and appear safe for secondary prevention of cardiovascular (CV) events in individuals with mild chronic renal insufficiency and not in end-stage renal disease (ESRD)10,14. According to the update of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) Clinical Practice Guideline for Diabetes and Chronic Kidney Disease withholding statin treatment initiation in dialysis patients is suggested15. The effect of statins in CKD patients is due to their lipid-lowering properties, but also (or even mainly?) attributable to their protective role on the endothelium, anti-inflammatory and anti-oxidant effects, as well as enhancement of renal perfusion and reduction of abnormal permeability to plasma proteins5,8,11,16. Their role in the inhibition of renal damage progression has still to be confirmed in large interventional trials in humans17.

As mentioned above, studies in ESRD patients on dialysis gave conflicting, mostly negative results, and no significant effects were found in the 4D (Die Deutsche Diabetes Dialyse) (except for the fatal stroke and cardiac events) and AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events) studies18,19. Even in the SHARP (Study of Heart and Renal Protection) study despite significant reduction in major atherosclerotic (by 17%; p = 0.0022) and vascular (by 15.3%, p = 0.0012) events, there was only an insignificant trend toward reducing CV events in dialysis patients; this trial also had several design limitations18–23.

Taking into account the existing doubts we performed three meta-analyses to evaluate the impact of statin therapy on: (1) lipid parameters, (2) CV events and death from all causes, and (3) renal outcomes. These meta-analyses were conducted by the Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) group6,11,24.

In the first meta-analysis we evaluated the hypolipidaemic properties of statins in CKD patients requiring and not requiring dialysis, treated with short (<3 months) or long-term (≥3 months) statin therapy6. We included 16 trials with 3594 individuals with CKD, of whom 1938 were treated with statins as monotherapy6. Statin therapy was highly effective in patients with CKD not on dialysis therapy (with longer treatment showing a more effective trend: 56.3 vs. 66.8, 22.5 vs. 24.1, and 53 vs. 56.1 mg/dL, for total cholesterol [TC], TG, and low density lipoprotein cholesterol [LDL-C], respectively). In patients requiring dialysis TC and LDL-C improved only with short-term (<3 months) treatment. Comparing statin therapy in patients on dialysis for ≤3 and >3 months a reduction in TC and LDL-C levels was observed (26.3 vs. 25.9, and 42.2 vs. 29.8 mg/dL, respectively), with an increase in TG (4.5 vs. 13.4 mg/dL) and a fall in HDL-C levels (mean 2.4 mg/dL for long-term therapy)6. We concluded that statin therapy in dialysis patients is not effective, and might even be harmful (TG increase and HDL-C decrease)6.

The second meta-analysis evaluated the effect of statin therapy on CV outcomes, stroke and all-cause mortality11. We included 21,295 CKD non-dialysis and dialysis-dependent patients from 11 randomized trials. The use of statins resulted in a 34% reduction in death from all causes (p < 0.0001), 31% reduction in death from cardiac causes (p = 0.0012), 45% reduction in CV events (p = 0.0001) and 34% reduction in stroke (p = 0.004) in CKD patients not on dialysis11. Clinical studies in ESRD patients on dialysis did not confirm these results – we showed no effect on death from all causes (relative risk [RR] 0.99, 95% CI: 0.88–1.11; p = 0.85) and stroke (RR 1.31; 95% CI: 0.9–1.89; p > 0.05), but noted the effect of reducing death from cardiac causes (by 21%) and CV events (by 19%; p < 0.05 for both). However, these results should be treated with caution since they are based only on one available study. We emphasized that we still lack studies in dialysis patients in order to definitively evaluate the effect of statins11. We concluded that the use of statins should be indicated in CV prevention especially in patients with non-dialysis-dependent CKD, but we suggested caution in expecting a reduction in CV events after starting statin therapy in patients on haemodialysis11.

In the last meta-analysis (unpublished data) we evaluated whether statins modulate renal function in CKD patients, and whether this effect might depend on the duration of therapy25. We included 12 trials with 6452 subjects with CKD treated with either statins or placebo. Statins exerted renoprotective effects especially in patients not on dialysis therapy, influencing urinary protein with an effect both for short-term (≤1 year) and long-term therapy (3 years), and serum creatinine but only for long-term therapy (3 years). Statins modestly preserved GFR, with a significant increase for between 1–3 years (this interesting observation requires further investigation)25. These results support those from the first meta-analysis, showing a trend for greater effectiveness with longer statin therapy in patients with CKD not requiring dialysis6. On the basis of these findings and due to the lack of well designed studies (as emphasized in the meta-analysis on CV endpoints11) that include dialysis patients we cannot answer the question regarding role of statins on renal outcomes in these patients, and we cannot recommend using statins in CKD patients requiring dialysis25.

In the current European Society of Cardiology (ESC)/European Society of Atherosclerosis (EAS) 2011 guidelines, it is clearly stated that CKD patients should be automatically treated as subjects at very high or high total cardiovascular risk who need active management of all risk factors26. CKD is acknowledged as a coronary artery disease equivalent. Also, for these patients additional analyses of such biomarkers as non-HDL-C and apolipoprotein B (IIa/C level of recommendation/evidence) should be considered for screening for CVD risk26. According to these guidelines statin therapy should be considered to slow the rate of kidney function loss, and protect against the development of ESRD requiring dialysis (IIa/C level of recommendation/evidence)26. Statin should be also considered in CKD patients at stages 2–4, and in moderate to severe CKD statins in monotherapy or in combination with other drugs should be considered to achieve LDL-C <70 mg/dL (1.8 mmol/L) (IIa/C level of recommendation/evidence)26. In the recent 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidaemia for the prevention of cardiovascular disease in the adult it is also recommended that all individuals with CKD should be treated as high risk patients, for whom statin therapy should be considered27. Finally, in the just published International Atherosclerosis Society (IAS) Position Paper: Global Recommendations for the Management of Dyslipidemia, the authors confirm the suggestion of considering CKD patients as subjects from the moderately high-risk group of patients, for whom the optimal range of LDL-C should be <100 mg/dL (2.6 mmol/L)28. The results of the meta-analyses support the above recommendations concerning treating of CKD patients as high risk subjects and the efficacy of statin therapy in this group of patients. However, our meta-analyses also add new data on the lack of effect of statin therapy in dialysis patients, on the role of duration of the therapy, and on the influence of statins on renal outcomes (and not only proteinuria)6,11,25,29–32.

On the basis of the results from the meta-analyses the following suggestions seem appropriate:

1. Patients with CKD not requiring dialysis should be treated with statins as appropriate for high CV risk.

2. Statin therapy in patients not requiring dialysis significantly decrease TC, LDL-C and TG, with a trend for longer duration of treatment to be more effective. Statins also significantly influence all-cause and cardiac mortality, stroke and cardiovascular events, and exert significant renoprotective effects, especially for urinary protein, serum creatinine and GFR (with the similar trend for treatment as for the lipid parameters analysis).

3. Duration of treatment might be important in order to achieve better effects of statin therapy (on lipid and renal outcomes) in CKD patients not on dialysis (the longer, the better trend). However this requires further investigations.

4. On the basis of available data we cannot recommend initiating statin treatment in ESRD patients requiring dialysis. On the other hand we do not have enough data to stop treatment in patients who are already on statins. Finally, it should be emphasized that we still need large, well designed, randomized trials in well selected CKD patients on dialysis, in order to finally confirm or refute the limited benefits of statin therapy.

Transparency

Declaration of funding

The author received no payment in preparation of this manuscript.

Declaration of financial/other relationships

M.B. has given talks, attended conferences and participated in trials and advisory boards sponsored by various pharmaceutical companies.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.