Ziad A Massy1,2,3, Thomas Merkling4, Sandra Wagner3,4, Nicolas Girerd3,4, Marie Essig5,2,3, Christoph Wanner6, Bengt C Fellstrom7, Patrick Rossignol3,4, Faiez Zannad3,4. 1. Centre for Research in Epidemiology and Population Health, Univ Paris-Saclay, UVSQ, Institut National de la Santé et de la Recherche Médicale Equipe Epidemiologie Clinique, Villejuif, France ziad.massy@aphp.fr. 2. Department of Nephrology, Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne Billancourt Cedex, France. 3. French Clinical Research Infrastructure Network, Investigation Network Initiative Cardiovascular and Renal Clinical Trialist, Nancy, France. 4. Université de Lorraine, INSERM CIC 1433, Nancy Centre Hospitalier Régional et Universitaire, Institut National de la Santé et de la Recherche Médicale U1116, FCRIN INI-CRCT, Nancy, France. 5. Centre for Research in Epidemiology and Population Health, Univ Paris-Saclay, UVSQ, Institut National de la Santé et de la Recherche Médicale Equipe Epidemiologie Clinique, Villejuif, France. 6. Division of Nephrology, University Hospital of Wurzburg, Wurzburg, Germany. 7. Department of Nephrology, University Hospital, Uppsala, Sweden.
Abstract
BACKGROUND AND OBJECTIVES: Statins are less efficacious in reducing cardiovascular disease risk in patients on dialysis than in the general population. Recent experimental data showed that phosphate excess promotes cellular de novo cholesterol synthesis through 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activation. Whether this mechanism might account for the resistance of patients on dialysis to statins has not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this post hoc analysis, we examined the efficacy of statin treatment according to serum phosphate levels in the patients on dialysis who were participants of the A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial using serum phosphate levels at baseline and during the trial course. We first classified the patients by groups of similar phosphate trajectories over time and tested whether phosphate as a longitudinal exposure (summarized by the identified trajectory groups) modulated the occurrence of major adverse cardiovascular events and all-cause death. We replicate the analysis in the Deutsche Diabetes Dialyze Studie (4D) trial. RESULTS: In the AURORA trial, using multivariable analysis, we found that the treatment effect of statin on major adverse cardiovascular events and all-cause death was significant and protective effects in patients with low values of serum phosphate gradually faded for higher phosphate levels >5 mg/dl. A similar lack of statin treatment efficacy for both outcomes was observed with high baseline phosphate levels (>5 mg/dl). In the 4D trial, we found a comparable but not significant trend toward losing treatment efficacy in the presence of high serum phosphate levels for both outcomes. CONCLUSIONS: Our results demonstrated the limited treatment efficacy of statins in patients on dialysis in the presence of hyperphosphatemia.
BACKGROUND AND OBJECTIVES: Statins are less efficacious in reducing cardiovascular disease risk in patients on dialysis than in the general population. Recent experimental data showed that phosphate excess promotes cellular de novo cholesterol synthesis through 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase activation. Whether this mechanism might account for the resistance of patients on dialysis to statins has not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this post hoc analysis, we examined the efficacy of statin treatment according to serum phosphate levels in the patients on dialysis who were participants of the A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial using serum phosphate levels at baseline and during the trial course. We first classified the patients by groups of similar phosphate trajectories over time and tested whether phosphate as a longitudinal exposure (summarized by the identified trajectory groups) modulated the occurrence of major adverse cardiovascular events and all-cause death. We replicate the analysis in the Deutsche Diabetes Dialyze Studie (4D) trial. RESULTS: In the AURORA trial, using multivariable analysis, we found that the treatment effect of statin on major adverse cardiovascular events and all-cause death was significant and protective effects in patients with low values of serum phosphate gradually faded for higher phosphate levels >5 mg/dl. A similar lack of statin treatment efficacy for both outcomes was observed with high baseline phosphate levels (>5 mg/dl). In the 4D trial, we found a comparable but not significant trend toward losing treatment efficacy in the presence of high serum phosphate levels for both outcomes. CONCLUSIONS: Our results demonstrated the limited treatment efficacy of statins in patients on dialysis in the presence of hyperphosphatemia.
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