CORRESPONDENCE: LETTER TO THE EDITOR
New Hope for Chronic Kidney Disease Patients After the JUPITER TrialMyth or Reality?
Theodoros I. Kassimatis, MD, PhD* and
David J.A. Goldsmith, MA
* Department of Nephrology, "Asklipieio" General Hospital, Athens 16673, Greece (Email: tkassimatis{at}yahoo.gr).
In their recent paper, Ridker et al. (1) performed a secondary analysis of JUPITER (Justification for the Use of Statins in Prevention–an Intervention Trial Evaluating Rosuvastatin) to assess the efficacy of rosuvastatin for primary prevention in patients with moderate chronic kidney disease (CKD). According to their results, rosuvastatin reduces first cardiovascular events and all-cause mortality among men and women with low-density lipoprotein cholesterol <130 mg/dl, elevated high-sensitivity C-reactive protein, and moderate CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2).
The authors' results are in accordance with previous secondary/post hoc analyses of major secondary prevention statin trials. In particular, the HPS (Heart Protection Study) (2), the CARE (Cholesterol And Recurrent Events) study (3), and the Pravastatin Pooling Project (4) suggested a beneficial effect of statins on cardiovascular end points. Conversely, both the PREVENT IT (Prevention of Renal and Vascular End Stage Disease Intervention Trial) (5)—the only prospective randomized trial evaluating the role of statins in patients with mild CKD—and ALERT (Assessment of Lescol in Renal Transplant Trial) (6) failed to detect any cardiovascular benefit of statins in nondialysis CKD patients. To further complicate things, a recent meta-analysis involving 25,017 pre-dialysis patients concluded that statins significantly reduced the all-cause and cardiovascular mortality (7).
The results of this secondary analysis of the JUPITER trial should be interpreted with caution for the following reasons. First, the JUPITER trial enrolled patients without overt diabetes mellitus, in contrast to the 4D (Die Deutsche Diabetes Dialyse) study, which employed diabetic dialysis patients (8). Moreover, in AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events), there was an almost statistically significant predominance of patients with diabetes or diabetic nephropathy as the cause of end-stage renal disease in the statin group (9). Because diabetes is an independent cardiovascular risk factor, statins might not confer any benefit in terms of primary prevention in diabetic CKD patients. Second, of 3,267 patients included in the study, only 14 had stage IV CKD. It is well established that cardiovascular mortality increases progressively through the stages of CKD (10), and thus it might be too late for statins to provide any benefit in stage IV to V CKD patients. Therefore, the findings of this analysis cannot be extrapolated to patients with CKD and diabetes or beyond stage III CKD.
Regarding the effects of statins on renal function, the present study did not detect a significant difference in the change of estimated glomerular filtration rate between the rosuvastatin and the placebo arms after 1 year of follow-up. However, the follow-up was short, and again, this study enrolled almost only a specific subgroup of CKD patients (stage III CKD). It should be noted that data from secondary/post hoc analyses of the major statin trials are more robust in supporting a renoprotective effect of statins in CKD patients compared with their cardioprotective effects (11), whereas 2 recent large meta-analyses did not show an impact of statins on glomerular filtration rate (7,12).
Given the conflicting findings on the cardioprotective and renoprotective role of statins along with their potentially harmful effects (13), the results of SHARP (Study of Heart and Renal Protection) (14) and PLANET (Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease Trial) (15) are eagerly anticipated.
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1. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of rosuvastatin among men and women with moderate chronic kidney disease and elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for the Use of Statins in Prevention–an Intervention Trial Evaluating Rosuvastatin) trial J Am Coll Cardiol 2010;55:1266-1273.[Abstract/Free Full Text]2. Heart Protection Study Collaborative Group MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial Lancet 2002;360:7-22.[CrossRef][Web of Science][Medline] 3. Tonelli M, Moye L, Sacks FM, Kiberd B, Curhan G. Pravastatin for secondary prevention of cardiovascular events in persons with mild chronic renal insufficiency Ann Intern Med 2003;138:98-104.[Abstract/Free Full Text] 4. 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.[Abstract/Free Full Text] 5. Asselbergs FW, Diercks GF, Hillege HL, et al. Effects of fosinopril and pravastatin on cardiovascular events in subjects with microalbuminuria Circulation 2004;110:2809-2816.[Abstract/Free Full Text] 6. 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;361:2024-2031.[CrossRef][Web of Science][Medline] 7. Navaneethan SD, Pansini F, Perkovic V, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis Cochrane Database Syst Rev 2009CD007784. 8. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis N Engl J Med 2005;353:238-248.[CrossRef][Web of Science][Medline] 9. Kassimatis TI, Konstantinopoulos PA. Rosuvastatin in patients undergoing hemodialysis N Engl J Med 2009;361:93author reply 94–5.[CrossRef][Web of Science][Medline] 10. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention Circulation 2003;108:2154-2169.[Free Full Text] 11. Kassimatis TI, Konstantinopoulos PA. The role of statins in chronic kidney disease (CKD): friend or foe? Pharmacol Ther 2009;122:312-323.[CrossRef][Medline] 12. Strippoli GF, Navaneethan SD, Johnson DW, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials BMJ 2008;336:645-651.[Abstract/Free Full Text] 13. Kassimatis TI, Konstantinopoulos PA. Statins in patients with chronic kidney disease: a double-edged sword? J Am Coll Cardiol 2008;52:1679.[Free Full Text] 14. Baigent C, Landry M. Study of Heart and Renal Protection (SHARP) Kidney Int 2003;84(Suppl):S207-S210.[Medline] 15. Prospective Evaluation of Proteinuria and Renal Function in Diabetic Patients With Progressive Renal Disease Trial http://clinicaltrials.gov/ct2/show/NCT00296400?term=planet&rank=1 2003Accessed April 11, 2010.
Related Article
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Efficacy of Rosuvastatin Among Men and Women With Moderate Chronic Kidney Disease and Elevated High-Sensitivity C-Reactive Protein: A Secondary Analysis From the JUPITER (Justification for the Use of Statins in Prevention–an Intervention Trial Evaluating Rosuvastatin) Trial
- Paul M. Ridker, Jean MacFadyen, Michael Cressman, and Robert J. Glynn
J. Am. Coll. Cardiol. 2010 55: 1266-1273.
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