Knowing what we do not know: statin therapy in advanced chronic kidney disease
Authors: Muh Geot Wong, Vlado Perkovic
Journal: The Lancet Diabetes & Endocrinology (2016)

Lowering LDL cholesterol with statins clearly reduces the risk of cardiovascular events among individuals at increased cardiovascular risk, and is a mainstay of contemporary approaches to cardiovascular disease prevention. Chronic kidney disease is a well established independent risk factor for cardiovascular events, but guidelines vary in their approach to lipid-lowering in this population. The European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines suggest that chronic kidney disease is an indication for statin therapy, whereas the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines do not.1Ray KK Kastelein JJ Boekholdt SM et al.The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain—a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011.Eur Heart J. 2014; 35: 960-968Crossref PubMed Scopus (245) Google Scholar The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines recommend that lipid-lowering should not be initiated in adults with dialysis-dependent chronic kidney disease, but should be continued in patients already receiving such treatment at the time of dialysis initiation.2KDIGOClinical practice guideline for lipid management in chronic kidney disease.Kidney Int. 2013; 3: 259-303Summary Full Text Full Text PDF Google Scholar Several reviews in this area have generally concluded that lipid-lowering is beneficial in early-stage chronic kidney disease, but results in advanced disease differ.3Palmer SC Navaneethan SD Craig JC et al.HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.Cochrane Database Syst Rev. 2014; 5 (CD007784.)PubMed Google Scholar, 4Hou W Lv J Perkovic V et al.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: 1807-1817Crossref PubMed Scopus (142) Google Scholar Inevitably, the limitations of literature-based systematic reviews amplify the uncertainty in this patient population. In The Lancet Diabetes & Endocrinology, the Cholesterol Treatment Trialists' (CTT) Collaboration report the results of a prespecified meta-analysis of 28 randomised control trials assessing the effects of LDL cholesterol reduction with statins according to baseline renal function.5The Cholesterol Treatment Trialists' (CTT) CollaborationImpact 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 July 28.)http://dx.doi.org/S2213-8587(16)30156-5Google Scholar As well as having access to individual participant data from all the trials, the investigators were also able to reclassify outcomes in one of the key trials (AURORA) to improve assessment consistency, and to standardise the results to the degree of LDL cholesterol lowering achieved. These approaches reduce some of the potential sources of noise and uncertainty when trial data are pooled. The CTT Collaboration reports that, overall, statin-based therapy reduced the risk of a first major vascular event by 21% per 1·0 mmol/L reduction in LDL cholesterol (rate ratio [RR] 0·79, 95% CI 0·77–0·81; p<0·0001). Smaller relative effects on major vascular events were recorded as estimated glomerular filtration rate (eGFR) declined (p=0·008 for trend). The results provide convincing evidence that statin therapy is beneficial in a wide range of patients with chronic kidney disease, with benefits proportional to the absolute LDL cholesterol reduction achieved. They also provide further evidence that the relative risk reductions achieved for major cardiovascular events diminish in magnitude with reducing kidney function.3Palmer SC Navaneethan SD Craig JC et al.HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.Cochrane Database Syst Rev. 2014; 5 (CD007784.)PubMed Google Scholar, 4Hou W Lv J Perkovic V et al.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: 1807-1817Crossref PubMed Scopus (142) Google Scholar In people with end-stage kidney disease, the effects of statins were uncertain, with no clear benefits shown (RR 0·94, 99% CI 0·79–1·11 for patients on dialysis).5The Cholesterol Treatment Trialists' (CTT) CollaborationImpact 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 July 28.)http://dx.doi.org/S2213-8587(16)30156-5Google Scholar Importantly, although the magnitude of the relative risk reduction was less with reducing kidney function, the increasing cardiovascular risk observed in people with reduced kidney function (for major coronary events, p=0·01 for trend; for vascular mortality, p=0·03 for trend), means that the absolute risk reductions (and the resultant number needed to treat [NNT] to prevent an event) are potentially similar. For example, the Study of Heart And Renal Protection (SHARP)6Baigent C Landray MJ Reith C et al.on behalf of the SHARP InvestigatorsThe 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: 2181-2192Summary Full Text Full Text PDF PubMed Scopus (1883) Google Scholar included people with chronic kidney disease, including a substantial number who needed dialysis, and showed an absolute risk reduction among participants receiving dialysis of 1·5%, compared with 2·4% for those with earlier stage chronic kidney disease (figure), resulting in NNTs of 67 and 42, respectively. Therefore, it is unclear whether the statistically uncertain, smaller relative risk reductions in patients with end-stage kidney disease result from a true lack of efficacy of statins in these individuals, or whether a similar reduction in risk attributable to statin therapy is not detectable, owing to reduced power associated with event differences being drowned out by a larger number of less statin-sensitive cardiovascular events such as arrhythmias and heart failure. How do we move forward? Although large clinical trials in individuals with advanced chronic kidney disease can be challenging because of difficulties with recruitment, retention, tolerability, comorbidities, and other factors, they have proven feasible and are very important because of the high cardiovascular risk and disease burden in this population. Promising new treatments (eg, PCSK9 inhibitors) are effective at lowering LDL cholesterol, and early results of randomised trials suggest they might reduce the risk of cardiovascular events substantially.7Navarese EP Kolodziejczak M Schulze V et al.Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis.Ann Intern Med. 2015; 163: 40-51Crossref PubMed Scopus (357) Google Scholar Studies of these agents in people with advanced kidney disease could, therefore, be especially important, for assessing whether they significantly reduce the substantially increased risk of cardiovascular disease in this population. An additional important consideration is the effect of statin therapy on kidney function in people with chronic kidney disease. A combined analysis from the PLANET studies8de Zeeuw D Anzalone DA Cain VA et al.Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.Lancet Diabetes Endocrinol. 2015; 3: 181-190Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar showed that individuals randomly assigned to atorvastatin not only had lower levels of proteinuria at the end of the 12-month study but also had significantly slower decline in kidney function. Findings of other studies have suggested that at least some statins might have beneficial effects on kidney function.8de Zeeuw D Anzalone DA Cain VA et al.Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial.Lancet Diabetes Endocrinol. 2015; 3: 181-190Summary Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 9Shepherd J Kastelein JJ Bittner V et al.Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study.Clin J Am Soc Nephrol. 2007; 2: 1131-1139Crossref PubMed Scopus (278) Google Scholar Although effects on kidney function were not assessed in the CTT Collaboration's current meta-analysis, it is an important topic worthy of more detailed analysis, and ideally suited to the CTT Collaboration's datasets, and perhaps studies of PCSK9 inhibitors. Although the results from this CTT Collaboration meta-analysis provide clear evidence of the role of statins in chronic kidney disease, they raise further questions about the effects of lipid-lowering in advanced disease and highlight the importance of new trials with highly effective agents in this population. By defining what we still do not know, this analysis will hopefully encourage further studies that improve outcomes for this high-risk patient group. VP is a member of steering committees or advisory boards for trials funded by Abbvie, Boehringer Ingleheim, Janssen, GlaxoSmithKline, and Bristol-Myers Squibb; has received honoraria for speaking at scientific symposia from Boehringer Ingleheim, AstraZeneca, Pfizer, Roche, Merck, Eli Lilly, and Servier; has received a grant for a clinical trial from Baxter and Pfizer; and was a member of the regional coordinating centre for the SHARP trial and has published and served on other trial steering committees with several of the SHARP investigators. MGW declares no competing interests. 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 trialsEven after allowing for the smaller reductions in LDL cholesterol achieved by patients with more advanced chronic kidney disease, and for differences in outcome definitions between dialysis trials, the relative reductions in major vascular events observed with statin-based treatment became smaller as eGFR declined, with little evidence of benefit in patients on dialysis. In patients with chronic kidney disease, statin-based regimens should be chosen to maximise the absolute reduction in LDL cholesterol to achieve the largest treatment benefits. Full-Text PDF Open Access