What Is the Available Evidence for the Use of Statins in Patients with Renal Impairment?

Q&A 125.8

What is the available evidence for the use of statins in patients with renal impairment?

Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at

Date prepared: 15th June 2016

Background

Dyslipidaemia in patients with chronic kidney disease (CKD) is complex and lipoprotein abnormalities may differ from those in the general population. Triglycerides (TG) are often raised whereas low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) can be normal or low. The lipid profile may deteriorate as kidney function declines; most patients with stage 3-5 CKD have a highly atherogenic lipid profile with adverse changes in all lipoproteins (1,2). The unique lipid abnormalities that affect patients with renal impairment have a complex role in the pathogenesis of cardiovascular disease (CVD) and may cause relative resistance to usual interventions (3). Compared to the general population, evidence of mortality benefit of lipid-lowering medications in CKD population is scarce (3).

Answer

The Study of Heart and Renal Protection (SHARP) was the first randomised controlled trial (RCT) to evaluate the effects of CV outcomes in CKD patients (4). SHARP included 6247 patients with CKD, not on dialysis, with mean GFR of 26.6mL/min/1.73m2. Patients were randomly assigned to simvastatin 20mg daily plus ezetimibe 10mg daily vs placebo with a median follow up of 4.9 years. The primary outcome was the first major atherosclerotic event. Simvastatin/ezetimibe was associated with a 2.1% ARR reduction (NNT= 48) in major atherosclerotic events (11.3% simvastatin/ezetimibe vs. 13.4 % placebo, (RR = 0.83, P = 0.0021); a reduction in non-haemorrhagic stroke (RR = 0.75, P = 0.01) and need for revascularisation procedure (RR = 0.79, P = 0.0036)(4). There was no significant difference between the two groups for major coronary events and the study did not show any significant difference in progression to end-stage renal disease among non-dialysis patients (3).

Most of the data regarding statins in CKD patients comes from subgroup/post hoc analysis of major clinical trials (3). An increasing number of meta-analyses report on the effects of statins on renal and CV outcomes in CKD patients but data may exhibit significant heterogeneity so should be interpreted with caution (2). A 2014 Cochrane systematic review found moderate-to-high quality data to indicate that statins consistently reduced the risk of death and major CV events by 20% to 25% in people with CKD not on dialysis (5). Post hoc analyses of three RCTS (CARE, LIPID and WOSCOPS) showed pravastatin reduced CV event rates (HR = 0.77, 95%CI: 0.68-0.86) in patients with moderate CKD (defined as an eGFR of 30 to 60mL/min/1.73 m2). This reduction in CV endpoints was equivalent to the reductions achieved in patients with normal renal function (3,6). Two meta-analyses (7,8) from 2012 summarized results from RCTs (18 and 80 trials respectively) that reported on clinical endpoints and major adverse events associated with statin therapy in CKD patients. Whilst these meta-analyses provided reasonably strong evidence for statins in non-dialysis-dependent CKD patients, there was limited evidence to recommend statin use in patients on dialysis (9).

A further review of 31 trials with more than 48000 individuals supports the use of statin therapy to reduce the risk of CV events in patients with CKD and cautiouslyextends the benefits of statin therapy across a broad range of kidney function including dialysis (10). The authors reported a lowering of the risk of major CV events by 23%, including a 22% reduction in coronary events, and 9% reduction in CV or all-cause death. Sub-group analysis demonstrated the relative effects of statin therapy in CKD were significantly reduced in people with advanced CKD but that the absolute risk reductions were comparable. This review notes that due to the heterogeneity of adverse effect reporting, caution should be exercised when interpreting the data on the incidence of adverse effects related to statins and that further data are still needed to evaluate the safety of statins in dialysis patients (10).

Three major RCTs have been conducted in dialysis populations; SHARP, AURORA and 4D (4,11-12). A 2013 Cochrane review of 25 studies incorporated these trials and concluded that statins have little or no beneficial effects on all-cause mortality (RR = 0.96, 95%, CI; 0.90-1.02), or major CV events (RR = 0.95, 95%CI; 0.88-1.03). The risk of adverse effects from statin therapy in adults treated with dialysis is uncertain as adverse events were only reported in 9 studies. There was insufficient information to evaluate the difference between haemodialysis and peritoneal dialysis populations. Despite clinically relevant reductions in serum cholesterol levels, they conclude statins cannot be recommended for prevention of CV events among dialysis patients (13).

A very recent meta-analysis of individual participant data from 28 trials of statin-based therapy in patients with various degrees of renal impairment has been conducted by the Cholesterol Treatment Trialists’ Collaboration. This review found that the relative risk reductions for major coronary events and strokes became smaller as eGFR declined and that there was little evidence of benefit in patients starting treatment after dialysis had been initiated (14).

There is a lack of reliable data on the effects of statins in transplant patients. The only major RCT to date is the ALERT study which followed 2102 renal transplant patients treated with fluvastatin or placebo (15). A Cochrane review updated in 2014 concludes that statins may reduce CV events in kidney transplant recipients, although treatment effects are imprecise. The effects of statins on overall mortality, stroke, renal function and toxicity outcomes are uncertain in this population (16).

There is evidence that the beneficial effects of statins extend beyond lipid-lowering and may include

anti-inflammatory, anti-oxidant and immunomodulatory effects (2). The use of statins to reduce

proteinuria and improve renal outcomes in CKD patients has been reported but no RCT or meta-analysis has shown that statins delay the progression of CKD (2,5,9).

Current guidance

Whilst there is evidence that the benefits of statin therapy on CVD outcomes are similar in individuals with normal kidney function and in patients with early stages of CKD, the results from patients with more advanced CKD (stage 4-5) and on dialysis are less clear. There is a lack of robust data comparing individual statins for CV outcomes in CKD. Until further conclusive evidence is available, the choice of therapy can be guided by the following recommendations:

NICE guidance on lipid modification recommends not using a risk assessment tool to assess CVD risk in people with an eGFR less than 60 mL/min/1.73 m2 and/or albuminuria as these people are at increased risk of CVD. Atorvastatin 20mg should be offered for the primary or secondaryprevention of CVD to peoplewith CKD. Increase the dose if a greater than 40% reduction in non-HDL cholesterol is not achieved and eGFR is 30 mL/min/1.73 m2 or more. The use of higher doses should be agreed with a renal specialist if eGFR is less than 30 mL/min/1.73 m2(17).

The Joint British Societies’ recommendations for the prevention of CV disease, state that although elevated lipid concentrations may not be the main driver of CVD in the context of CKD, the available data generally support the use of lipid lowering regimens to reduce the risk of CVD events. In adults with stages 3–5 CKD, lipid-lowering therapy with statins should be considered in all patients (18).

The Kidney Disease: Improving Global Outcomes (KDIGO) organisation recommends statins be offered to adults aged 18-49 with CKD not treated with chronic dialysis or kidney transplantation, and an estimated 10 year risk of coronary death or non-fatal MI>10%. Adults aged 50 with all stages of CKD (but not on dialysis or post-transplant) should be offered a statin irrespective of CV status (19).

Choice and dose of statin

Data comparing different statins or different doses of statins are sparse in adults with CKD (5). Since coming off-patent and thus being cost effective, NICE recommend atorvastatin in all populations, including CKD, citing its potency, lower risk of adverse interactions and the convenience of not needing to take it at night (17). European Society of Cardiology and the European Atherosclerotic Society (ESC/EAS) guidelines reinforce this recommendation in CKD patients stating statins with minimal renal excretion should be the drug of choice e.g. atorvastatin or fluvastatin (1). The manufacturers of atorvastatin advise that renal disease has no influence on the plasma concentrations or lipid effects of atorvastatin therefore no dose adjustment is required (20). The Renal Drug Database, which reflects UK practice in specialist renal units, recommends no dose adjustment of atorvastatin is required in any degree of renal impairment (21). The BNF advises a starting dose of 20mg atorvastatin in CKD for primary and secondary prevention of CV events increasing if necessary (on specialist advice if eGFR < 30 mL/minute/1.73m2) to 80mg (22). It should be noted that 20mg atorvastatin is an unlicensed starting dose in primary prevention and unlicensed in secondary prevention (17,20,22).

For patients with eGFR ≥60mL/minute/1.73m2, KDIGO states no dose adjustments are required for CKD patients. They recommend using doses used in clinical trials for particular statins, for patients with eGFR below 60mL/minute/1.73m2. Table 1, adapted from KDIGO, displays doses of statins (currently licensed in the UK) that have been shown to be beneficial in the CKD population in clinical trials (19). Patients with progressive renal dysfunction who are tolerating alternative regimens do not necessarily need to have doses reduced although it may be prudent in patients with severe kidney dysfunction who are receiving very aggressive regimens (19). Patients with dialysis-dependent CKD should not be initiated on statin or statin+/-ezetimibe treatment, however this treatment should not necessarily be discontinued among existing users if dialysis is commenced (19).

Table 1: Recommended doses (mg/day) of statins in adults with CKD

*For full CKD nomenclature and range of GFR categories used by KDIGO see reference 19.

Statins are generally well tolerated with the most common side-effects being hepatic toxicity and muscle toxicity including myopathy, myalgia and rhabdomyolysis. Renal impairment may be a pre-disposing factor for rhabdomyolysis and the manufacturer of atorvastatin recommends creatinine kinase should be measured before starting treatment and monitored thereafter (20). All major RCTs and meta-analyses have not detected an increased risk of serious adverse events in CKD patients using statins in terms of muscle and liver toxicity (2). If statin intolerance develops in any patient, the Joint British Societies’ guidelines for the prevention of CV disease recommend switching agents and re-dosing (18).

Summary

Dyslipidaemia is common in CKD patients and contributes to high CV morbidity and mortality. The lipid profile may deteriorate with declining renal function. The unique lipid abnormalities that affect patients with renal impairment have a complex role in the pathogenesis of CVD and consequently the results of studies of LDL-C reduction and CV endpoints have been difficult to interpret.

RCTs of simvastatin, pravastatin, fluvastatin, rosuvastatin and atorvastatin have included patients with varying degrees of renal impairment. Meta-analyses and reviews of these RCTs have found evidence of beneficial effects on CV outcomes in patients with early stages of CKD. CKD patients in stages 3-5 are underrepresented in clinical trials and administration of statins to these patients who have not yet had a CV event remains controversial. Large controlled trials of statins in this group of patients are needed.

NICE guidance suggests atorvastatin 20mg for the primary or secondary prevention of CVD in people with CKD. The dose should be increased if a greater than 40% reduction in non-HDL cholesterol is not achieved and eGFR is 30 mL/min/1.73 m2 or more. If eGFR is less than 30 mL/min/1.73 m2higher doses should be agreed with a renal specialist.

There are no comparative studies of different statins in CKD. Whilst atorvastatin is currently the statin of choice according to NICE guidance, other statins have been shown to be beneficial in CKD populations. Advice on dosing is available in standard sources although there is some inconsistency in their recommendations. It would be reasonable to dose conservatively at lower levels of renal function with close monitoring of desired effect on lipid levels and adverse effects.

Patients with dialysis-dependent CKD should not be initiated on a statin, however treatment should not be routinely discontinued among existing users if dialysis is commenced.

Statins may have beneficial effects beyond lipid lowering in CKD patients, e.g. a reduction in oxidative stress and inflammation and a nephroprotective role. Further research is required in this area.

Limitations

A review of the beneficial effects of statins independent of lipid-lowering e.g. anti-inflammatory, anti-oxidant and immunomodulatory effects, is beyond the scope of this Q&A.

A detailed discussion of the use of statins in transplant patients or on renal replacement therapy is outside the scope of this review.

Whilst some trials reported adverse effects, this has not been reviewed in detail.

Clinically important drug interactions with statins in patients with CKD are not discussed here.

Statins not licensed in the UK at the time of writing are not included in this review.

Please ensure you are using the latest version of the manufacturers’ Summary of Product Characteristics for dosing information.

References

1. Task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerotic Society (EAS). Guidelines for the management of dyslipidaemias. Željko Reiner, Alberico L. Catapano et al. European Heart Journal Jul 2011, 32 (14) 1769-1818
2. Kassimatis T, Goldsmith D. Statins in chronic kidney disease and kidney transplantation. Pharmacol Res 2014;88: 62-73
3. Pandya V, Rao A, Chaudhary K. Lipid abnormalities in kidney disease and management strategies. World Journal of Nephrology. 2015;4(1):83-91. doi:10.5527/wjn.v4.i1.83.
4. Baigent C, Landray MJ, Reith C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.Lancet 2011;377:2181–2192.
5. Palmer SC, Navaneethan SD, Craig JC et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD007784. DOI: 10.1002/14651858.CD007784.pub2.
6. Tonelli M, Isles C, Curhan GC et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease. Circulation. 2004;110:1557–1563
7. Upadhyay A, Earley A, Lamont JL, Haynes S, Wanner C, Balk EM. Lipid-lowering therapy in persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157:251–262
8. Palmer SC, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GF. Benefits and harms of statin therapy for persons with chronic kidney disease: a systematic review and meta-analysis. Ann Intern Med. 2012;157:263–275
9. Upadhyay A. Statins in chronic kidney disease: what do meta-analyses tell us? Clin Exp Nephrol. 2014;18:278-281
10. Hou W, Lv J, Perkovic V, Yang L, Zhao N, Jardine MJ, Cass A, Zhang H, Wang H. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: a systematic review and meta-analysis. Eur Heart J. 2013;34:1807–1817
11. Fellstrom BC, Jardine AG, Schmieder RE et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360(April (14)):1395–407
12. Wanner C, Krane V, Marz W et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 2005;353(July (3)):238–48
13. Palmer SC, Navaneethan SD, Craig JC et al. HMG CoA reductase inhibitors (statins) for dialysis patients. Cochrane Database of Systematic Reviews 2013, Issue 9. Art. No.: CD004289. DOI: 10.1002/14651858.CD004289.pub5.
14. Cholesterol Treatment Trialists’ Collaboration. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol 2016. Published online 28.07.16
15. Holdaas H, Fellstrom B, Jardine AG et al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial. Lancet 2003;361(June(9374)):2024–31
16. Palmer SC, Navaneethan SD, Craig JC et al. HMG CoA reductase inhibitors (statins) for kidney transplant recipients. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD005019. DOI: 10.1002/14651858.CD005019.pub4
17. National Institute for Health and Care Excellence. NICE clinical guideline 181 (July 2014, last modified January 2015). Lipid Modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Accessed via on 15.06.16
18. JBS3 Board. Joint British Societies’ consensus recommendations for the prevention of cardiovascular disease (JBS3). Accessed via on 26.05.16
19. KDIGO Clinical Practice guideline for lipid management in chronic kidney disease. November 2013. Accessed via on 15.06.16
20. Summary of Product Characteristics – Lipitor 28mg film-coated tablets. Pfizer Limited. Accessed via on 26/05/16 [date of revision of text – 03/2016]
21. Ashley, C. Dunleavy, A. editors. Renal Drug Database. Oxford, Radcliffe Medical Press Ltd. Accessed via on 15.06.16
22. Joint Formulary Committee. British National Formulary (online) London: BMJ Group and Pharmaceutical Press. Accessed online via: on 15.06.16

Quality Assurance

Prepared by

Jill Forrest, South West Medicines Information, Bristol (based on earlier work by Julia Kuczynska)

Date Prepared

14th July 2016

Checked by
Julia Kuczynska, South West Medicines Information, Bristol

Date of check

27th July 2016

Search strategy

Embase [*hydroxymethylglutaryl-Coenzyme-A-reductase-Inhibitor AND exp chronic kidney failure] Limit to Human and Year Published Last 5 years (date of search 31.03.16)

Medline [*hydroxymethylglutaryl-Coenzyme-A-reductase-Inhibitors AND exp renal insufficiency, chronic] Limit to Human and Publication year 2010-2016 (date of search 31.03.16)

PubMed (("Hydroxymethylglutaryl-CoA Reductase Inhibitors"[Mesh]) AND "Renal Insufficiency"[Mesh]) AND "Renal Insufficiency, Chronic"[Mesh] Filters: Review, Free full text, 5 years, Humans (date of search 31.03.16)

In-house database/ resources – Renal File, specialist renal textbooks, previous enquiries

NHS Evidence [statin AND renal] [statin AND kidney]

The Renal Association:

NICE guidelines:

Cochrane Library:

Clinical Knowledge Summaries:

SIGN guidance:

UpToDate:

Clinical expert: Specialist Renal Pharmacist, Royal Devon and Exeter NHS Foundation Trust

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Available throughNICE Evidence Search at