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Is a treat-to-target approach to lipid-lowering therapy appropriate in patients with chronic kidney disease? A prospective French cohort study

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Abstract

Background

Whereas European guidelines recommend adjusting lipid-lowering therapy (LLT) to meet prespecified targets (‘treat-to-target’) for low-density lipoprotein cholesterol (LDL-C), other guidelines do not (‘fire and forget’). In a large observational prospective cohort, we sought to evaluate which strategy could be associated with better cardiovascular outcomes in chronic kidney disease (CKD).

Methods

In CKD-REIN, patients (CKD stages 3 and 4) on LLT were categorized according to achievement of LDL-C targets for high and very high cardiovascular risk (< 2.6 and < 1.8 mmol/L, respectively) at baseline. Primary outcome was fatal/non-fatal atheromatous cardiovascular disease (CVD). Secondary outcomes were non-atheromatous CVD, atheromatous or non-atheromatous CVD, and major adverse cardiovascular events.

Results

The population comprised 1521 patients (68 ± 12 years, 31% women, mean estimated glomerular filtration rate [eGFR] 35 mL/min/1.73 m2). Overall, 523 (34%) met their LDL-C targets at baseline. Median follow-up was 2.9 years (interquartile range 2.2–3.0). Incidence rates per 100 patient-years were 6.2% (95% confidence interval [CI] 5.5–7.0) for atheromatous CVD, 9.2% (8.3–10.1) for non-atheromatous CVD, 15.2% (14.0–16.4) for atheromatous/non-atheromatous CVD, and 6.3% (5.5–7.1) for major adverse cardiovascular events. Corresponding rates in patients who achieved targets were 6.6%, 9.8%, 16.1%, and 6.3%, respectively. Target achievement was not associated with risk of fatal/non-fatal atheromatous CVD (adjusted hazard ratio 1.04, 95% CI 0.76–1.44, p = 0.77) or fatal/non-fatal atheromatous or non-atheromatous CVD (0.98, 0.78–1.23, p = 0.91).

Conclusions

These findings do not appear to support a treat-to-target approach in CKD patients on LLT, and may favor the hypothesis of an advantage of fire-and-forget. Randomized trials are needed to confirm this theory.

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The investigators will consider requests for data sharing on a case-by-case basis, without any data transfer outside CKD REIN center.

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Acknowledgements

We acknowledge the CKD-REIN study coordination staff for their efforts in setting up the CKD-REIN cohort: Marie Metzger, Elodie Speyer, Céline Lange, Sophie Renault, Reine Ketchemin, Natalia Alencar de Pinho and all the clinical research associates. Sophie Rushton-Smith, PhD (MedLink Healthcare Communications) provided medical writing assistance, under the direction of the authors, and was funded by MSD France and the authors.

Funding

CKD-REIN is funded by the Agence Nationale de la Recherche through the 2010 Cohortes-Investissements d’Avenir program (ANR-IA-COH-2012/3731) and by the 2010 national Programme Hospitalier de Recherche Clinique. CKD-REIN is also supported through a public–private partnership with Amgen, Fresenius Medical Care, and GlaxoSmithKline (GSK), since 2012, Lilly France since 2013, and Otsuka Pharmaceutical since 2015, Baxter and Merck Sharp & Dohme-Chibret (MSD France) from 2012 to 2017, Sanofi-Genzyme from 2012 to 2015, Vifor Fresenius, and AstraZeneca, since 2018. Inserm Transfert set up and has managed this partnership since 2011.

Author information

Author notes

  1. Ziad A. Massy and Sophie Liabeuf contributed equally to this work.

Authors and Affiliations

  1. Centre for Research in Epidemiology and Population Health (CESP), Inserm UMRS 1018, Team 5, Villejuif, France

    Ziad A. Massy, Epiphane Kolla, Oriane Lambert & Bénédicte Stengel

  2. University Versailles-Saint Quentin, Univ Paris-Saclay, 91190, Villejuif, France

    Ziad A. Massy

  3. Department of Nephrology, CHU Ambroise Paré, APHP, 92104, Boulogne Billancourt Cedex, France

    Ziad A. Massy

  4. Department of Cardiology, Toulouse Rangueil University Hospital (CHU), Toulouse, France

    Jean Ferrières

  5. Department of Epidemiology and Public Health, UMR INSERM 1027, INSERM-Université de Toulouse, Toulouse, France

    Jean Ferrières

  6. Service d’Endocrinologie Métabolisme et Prévention Cardiovasculaire, Unité Fonctionnelle d’Aphérèse, Institut E3M et IHU Cardiométabolique, Hôpital Pitié Salpêtrière, Paris, France

    Eric Bruckert

  7. Department of Cardiology, CHU Ambroise Paré, APHP, 92104, Boulogne Billancourt Cedex, France

    Nicolas Mansencal

  8. AURAL, 124 rue Villon, 69008, Lyon, France

    Maurice Laville

  9. Nephrology Department, CHRU de Nancy, 54000, Vandoeuvre-lès-Nancy, France

    Luc Frimat

  10. Lorraine University, APEMAC, 54000, Vandoeuvre-lès-Nancy, France

    Luc Frimat

  11. Nephrology Department, Centre Hospitalier Lyon Sud, Université de Lyon, Carmen, 69495, Pierre-Bénite, France

    Denis Fouque

  12. Service de Néphrologie Transplantation Dialyse Aphérèse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France

    Christian Combe

  13. INSERM, U1026, Univ Bordeaux, Bordeaux, France

    Christian Combe

  14. DOPPS Program Area, Arbor Research Collaborative for Health, Ann Arbor, MI, USA

    Roberto Pecoits-Filho

  15. School of Medicine, Pontificia Universidade Catolica do Parana, Curitiba, PR, Brazil

    Roberto Pecoits-Filho

  16. Paris-Sud, Univ Paris-Saclay, Villejuif, France

    Bénédicte Stengel

  17. Pharmacology Department, Amiens University Hospital, 80054, Amiens, France

    Sophie Liabeuf

  18. MP3CV Laboratory, EA7517, University of Picardie Jules Verne, 80054, Amiens, France

    Sophie Liabeuf

  19. Division of Nephrology, Ambroise Paré Hospital, 9 Avenue Charles de Gaulle, 92104, Boulogne Billancourt Cedex, France

    Ziad A. Massy

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  1. Ziad A. Massy
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  2. Epiphane Kolla
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CKD-REIN Collaborators

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Correspondence to Ziad A. Massy.

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Conflict of interest

CKD-REIN is supported by a public–private partnership with seven academics and support from nine pharmaceutical companies (Merck Sharp & Dohme-Chibret [MSD France], Amgen, Fresenius Medical Care, GlaxoSmithKline [GSK], Baxter, Lilly France, Otsuka Pharmaceutical, Vifor Fresenius, and Sanofi-Genzyme). Dr. Massy reports public funding, grants to charities, travel and accommodation support from Amgen; public funding, travel and accommodation support from Sanofi-Genzyme; and grants from the French Government, MSD, GSK, Lilly, FMC, Baxter, Outsuka, and AstraZeneca. Dr. Ferrieres reports personal fees from Amgen, Sanofi, Merck, and Servier. Dr. Bruckert reports personal fees from MSD, Akcea, Servier, Sanofi Aventis, Amgen, Genfit, Regeneron, Mylan, Danone, and Silence Therapeutics; and grants and personal fees from Aegerion Amryt. Dr. Fouque reports personal fees from Sanofi, Vifor, Fresenius, Lilly; grants and personal fees from kabi; and personal fees and non-financial support from AstraZeneca. Dr. Pecoits-Filho reports grants from Fresenius Medical Care; non-financial support from AstraZeneca, Akebia, Novo Nordisk, and Boehringer-Lilly. Dr. Stengel reports grants from Amgen, AstraZeneca, Fresenius medical care, Otsuka, Vifor Fresenius, and GSK. Drs. Kolla, Lambert, Mansencal, Laville, Frimat, Combe, and Liabeuf have nothing to disclose.

Ethics approval

The study protocol was approved by the French National Institute of Health and Medical Research (Inserm) institutional review board (IRB00003888).

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This work has not been published previously and is not under consideration for publication elsewhere. The manuscript has been approved by all authors and by the responsible authorities where the work was carried out. If the article is accepted, it will not be published elsewhere by the authors, including electronically in the same form, in English or in any other language, without the written consent of the copyright-holder.

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Massy, Z.A., Kolla, E., Ferrières, J. et al. Is a treat-to-target approach to lipid-lowering therapy appropriate in patients with chronic kidney disease? A prospective French cohort study. J Nephrol 34, 1467–1477 (2021). https://doi.org/10.1007/s40620-021-01086-y

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