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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

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.

Graphic abstract

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Availability of data and material

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

References

  1. 1.

    Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton C, Graham I, Hall MS, Hobbs FDR, Lochen ML, Lollgen H, Marques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren WMM, Binno S, ESC Scientific Document Group (2016) 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 37:2315–2381

    Article  Google Scholar 

  2. 2.

    Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT, Chronic Kidney Disease Prognosis Consortium (2010) Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375:2073–2081

    Article  Google Scholar 

  3. 3.

    Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY (2004) Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351:1296–1305

    CAS  Article  Google Scholar 

  4. 4.

    Tonelli M, Muntner P, Lloyd A, Manns BJ, Klarenbach S, Pannu N, James MT, Hemmelgarn BR, Alberta Kidney Disease Network (2012) Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 380:807–814

    Article  Google Scholar 

  5. 5.

    Visconti L, Benvenga S, Lacquaniti A, Cernaro V, Bruzzese A, Conti G, Buemi M, Santoro D (2016) Lipid disorders in patients with renal failure: Role in cardiovascular events and progression of chronic kidney disease. J Clin Transl Endocrinol 6:8–14

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Florens N, Calzada C, Lyasko E, Juillard L Soulage CO (2016) Modified lipids and lipoproteins in chronic kidney disease: a new class of uremic toxins. Toxins (Basel) 8

  7. 7.

    Ferro CJ, Mark PB, Kanbay M, Sarafidis P, Heine GH, Rossignol P, Massy ZA, Mallamaci F, Valdivielso JM, Malyszko J, Verhaar MC, Ekart R, Vanholder R, London G, Ortiz A, Zoccali C (2018) Lipid management in patients with chronic kidney disease. Nat Rev Nephrol 14:727–749

    CAS  Article  Google Scholar 

  8. 8.

    Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Gronhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Suleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich RP, Gottlow M, Johnsson E, Zannad F, AURORA Study Group (2009) Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360:1395–1407

    CAS  Article  Google Scholar 

  9. 9.

    Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E, German Diabetes Dialysis Study Investigators (2005) Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:238–248

    CAS  Article  Google Scholar 

  10. 10.

    Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellstrom B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Gronhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R, SHARP Investigators (2011) 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 377:2181–2192

    CAS  Article  Google Scholar 

  11. 11.

    Barylski M, Nikfar S, Mikhailidis DP, Toth PP, Salari P, Ray KK, Pencina MJ, Rizzo M, Rysz J, Abdollahi M, Nicholls SJ, Banach M, Lipid and Blood Pressure Meta-Analysis Collaboration Group (2013) Statins decrease all-cause mortality only in CKD patients not requiring dialysis therapy—a meta-analysis of 11 randomized controlled trials involving 21,295 participants. Pharmacol Res 72:35–44

    CAS  Article  Google Scholar 

  12. 12.

    Massy ZA, de Zeeuw D (2013) LDL cholesterol in CKD—to treat or not to treat? Kidney Int 84:451–456

    Article  Google Scholar 

  13. 13.

    Ridker PM, MacFadyen J, Cressman M, Glynn RJ (2010) 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 55:1266–1273

    CAS  Article  Google Scholar 

  14. 14.

    Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Z, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WMM, Vlachopoulos C, Wood DA, Zamorano JL, Cooney MT, ESC Scientific Document Group (2016) 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 37:2999–3058

    Article  Google Scholar 

  15. 15.

    Kidney Disease: Improving Global Outcomes (KDIGO) Lipid Work Group (2013) KDIGO clinical practice guideline for lipid management in chronic kidney disease. Kidney Int 3:259–305

    Article  Google Scholar 

  16. 16.

    Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC Jr, Sperling L, Virani SS, Yeboah J (2019) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 139:e1046–e1081

    PubMed  Google Scholar 

  17. 17.

    Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O, ESC Scientific Document Group (2020) 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 41:111–188

    Article  Google Scholar 

  18. 18.

    Stengel B, Combe C, Jacquelinet C, Briancon S, Fouque D, Laville M, Frimat L, Pascal C, Herpe YE, Deleuze JF, Schanstra J, Pisoni RL, Robinson BM, Massy ZA (2014) The French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study. Nephrol Dial Transplant 29:1500–1507

    Article  Google Scholar 

  19. 19.

    Stengel B, Metzger M, Combe C, Jacquelinet C, Briancon S, Ayav C, Fouque D, Laville M, Frimat L, Pascal C, Herpe YE, Morel P, Deleuze JF, Schanstra JP, Lange C, Legrand K, Speyer E, Liabeuf S, Robinson BM, Massy ZA (2019) Risk profile, quality of life and care of patients with moderate and advanced CKD: The French CKD-REIN Cohort Study. Nephrol Dial Transplant 34:277–286

    Article  Google Scholar 

  20. 20.

    Villain C, Metzger M, Combe C, Fouque D, Frimat L, Jacquelinet C, Laville M, Briancon S, Klein J, Schanstra JP, Robinson BM, Mansencal N, Stengel B, Massy ZA (2020) Prevalence of atheromatous and non-atheromatous cardiovascular disease by age in chronic kidney disease. Nephrol Dial Transplant 35:827–836

    Article  Google Scholar 

  21. 21.

    Massy ZA, Ferrieres J, Bruckert E, Lange C, Liabeuf S, Velkovski-Rouyer M, Stengel B, CKD-REIN Collaborators (2019) Achievement of low-density lipoprotein cholesterol targets in CKD. Kidney Int Rep 4:1546–1554

  22. 22.

    KDIGO Board Members (2012) KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int (Suppl) 3:136–150

    Google Scholar 

  23. 23.

    Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, Morrow DA, Targum SL, Sila CA, Hai MTT, Jaff MR, Joffe HV, Cutlip DE, Desai AS, Lewis EF, Gibson CM, Landray MJ, Lincoff AM, White CJ, Brooks SS, Rosenfield K, Domanski MJ, Lansky AJ, McMurray JJV, Tcheng JE, Steinhubl SR, Burton P, Mauri L, O’Connor CM, Pfeffer MA, Hung HMJ, Stockbridge NL, Chaitman BR, Temple RJ, Standardized Data Collection for Cardiovascular Trials Initiative (2018) 2017 Cardiovascular and stroke endpoint definitions for clinical trials. Circulation 137:961–972

    Article  Google Scholar 

  24. 24.

    Mancini GB, Baker S, Bergeron J, Fitchett D, Frohlich J, Genest J, Gupta M, Hegele RA, Ng D, Pope J (2011) Diagnosis, prevention, and management of statin adverse effects and intolerance: proceedings of a Canadian Working Group Consensus Conference. Can J Cardiol 27:635–662

    Article  Google Scholar 

  25. 25.

    Laville SM, Gras-Champel V, Moragny J, Metzger M, Jacquelinet C, Combe C, Fouque D, Laville M, Frimat L, Robinson BM, Stengel B, Massy ZA, Liabeuf S, Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) Study Group (2020) Adverse drug reactions in patients with CKD. Clin J Am Soc Nephrol 15:1090–1102

    CAS  Article  Google Scholar 

  26. 26.

    Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, Roden M, Stein E, Tokgozoglu L, Nordestgaard BG, Bruckert E, De Backer G, Krauss RM, Laufs U, Santos RD, Hegele RA, Hovingh GK, Leiter LA, Mach F, Marz W, Newman CB, Wiklund O, Jacobson TA, Catapano AL, Chapman MJ, Ginsberg HN (2015) Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 36:1012–1022

    CAS  Article  Google Scholar 

  27. 27.

    Tunon J, Steg PG, Bhatt DL, Bittner VA, Diaz R, Goodman SG, Jukema JW, Kim YU, Li QH, Mueller C, Parkhomenko A, Pordy R, Sritara P, Szarek M, White HD, Zeiher AM, Schwartz GG, ODYSSEY OUTCOMES Investigators (2020) Effect of alirocumab on major adverse cardiovascular events according to renal function in patients with a recent acute coronary syndrome: prespecified analysis from the ODYSSEY OUTCOMES randomized clinical trial. Eur Heart J. 41(42):4114–4123

  28. 28.

    Charytan DM, Sabatine MS, Pedersen TR, Im K, Park JG, Pineda AL, Wasserman SM, Deedwania P, Olsson AG, Sever PS, Keech AC, Giugliano RP, FOURIER Steering Committee Investigators (2019) Efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial. J Am Coll Cardiol 73:2961–2970

    CAS  Article  Google Scholar 

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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.

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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.

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

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Patients provided informed consent to participate.

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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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See Supplementary Appendix for the full list of CKD-REIN collaborators.

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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 (2021). https://doi.org/10.1007/s40620-021-01086-y

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Keywords

  • Chronic kidney disease
  • Cardiovascular disease
  • Lipid-lowering drugs
  • Lipids
  • Low-density lipoprotein cholesterol