Treatment of dyslipidemia using inclisiran in a case series of patients after kidney and liver transplantation

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Resumo

Background. Hyperlipidemia is one of the main factors in the development of atherosclerotic cardiovascular diseases, leading to the death of patients in the long-term period after kidney or liver transplantation.

Objective. Evaluation of the effectiveness and safety of inclisiran in patients with a transplanted kidney or liver.

Material and methods. A pilot multicenter observational uncontrolled study of inclisiran use was conducted in 11 patients after kidney or liver transplantation. The drug was administered subcutaneously on days 1 and 90. Efficacy was assessed based on decrease in low-density lipoprotein (LDL) levels and achievement of blood LDL level <1.4 mmol/L. The dynamics of changes in triglycerides (TG) and high-density lipoproteins (HDL) in the blood were also studied. Safety was assessed based on complaints, data from general examination, examination of injection site, alanine aminotransferase and aspartate aminotransferase levels, glomerular filtration rate, blood concentration of immunosuppressive drugs, and the frequency of unplanned patient visits associated with acute dysfunction of the transplanted organ. Biochemical parameters were assessed before the first injection - day 0 (one day before the 1st injection - 1st time point), as well as 30 days after the 1st injection (2nd time point), before the 2nd injection (90- 1st day after the 1st injection – 3rd time point) and 1 month after the 2nd injection of the drug (4 months after the 1st injection – 4th time point). Efficacy and safety criteria were determined at the 2nd, 3rd and 4th time points.

Results. Statistically significant decrease in LDL levels (the difference between the mean difference at the 4th and 1st time points was 2.4 mmol/l (95% CI 1.7–3.2; p <0.001) was noted. The dynamics of HDL and TG levels were not statistically significant (p = 0.828 and p = 0.248, respectively). Four patients received inclisiran monotherapy and 7 received combination therapy (statins + ezetimibe + inclisiran). The type of therapy was statistically significantly associated with the rate of decrease in LDL levels (p < 0.001 for the interaction of time and therapy factors). but not HDL and TG levels (p=0.902 and p=0.299, respectively).

Conclusion. Two-fold use of inclisiran in the study group of patients showed effectiveness in reducing the mean LDL level by 57.1% in the entire group (n=11), while in patients on inclisiran monotherapy (n=4) - by 45.3%, and on combined lipid-lowering therapy (n=7) – by 61.4%. Three (18.2%) patients achieved LDL levels <1.4 mmol/L. There were no signs of poor tolerability of the drug.

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Sobre autores

Olga Kordonova

Burnazyan Federal Medical and Biological Center of the Federal Medical and Biological Agency of Russia

Autor responsável pela correspondência
Email: kkgubarev@gmail.com
ORCID ID: 0009-0003-9173-4535

Therapist at the Surgical Department No. 2

Rússia, Moscow

Konstantin Gubarev

Burnazyan Federal Medical and Biological Center of the Federal Medical and Biological Agency of Russia

Email: kkgubarev@gmail.com
ORCID ID: 0000-0001-9006-163X

Dr.Sci. (Med.), Head of the Surgical Department of Coordination of Organ and (or) Human Tissue Donation

Rússia, Moscow

Nadiya Frolova

City Clinical Hospital No. 52 of the Moscow Healthcare Department; Russian University of Medicine

Email: kkgubarev@gmail.com
ORCID ID: 0000-0002-6086-5220

Cand.Sci. (Med.), Associate Professor at the Department of Nephrology, Faculty of Additional Professional Education, Deputy Chief Physician for Nephrology

Rússia, Moscow; Moscow

Daria Svetlakova

Burnazyan Federal Medical and Biological Center of the Federal Medical and Biological Agency of Russia

Email: kkgubarev@gmail.com
ORCID ID: 0000-0002-2274-6204

Junior Reseacher at the Laboratory of New Surgical Technologies, Surgeon of the Surgical Department for Coordination of Organ and (or) Human Tissue Donation

Rússia, Moscow

Sergey Voskanyan

Burnazyan Federal Medical and Biological Center of the Federal Medical and Biological Agency of Russia

Email: kkgubarev@gmail.com
ORCID ID: 0000-0001-5691-5398

Dr.Sci. (Med.), Professor, Corresponding Member of RAS, Deputy Chief Physician for Surgical Care, Head of the Center for Surgery and Transplantology

Rússia, Moscow

Lyudmila Artyukhina

City Clinical Hospital No. 52 of the Moscow Healthcare Department

Email: kkgubarev@gmail.com
ORCID ID: 0000-0003-3353-1636

Cand.Sci. (Med.), Head of the Nephrological Department No. 1

Rússia, Moscow

Bibliografia

  1. Black C.K., Termanini K.M., Aguirre O., et al. Solid organ transplantation in the 21st century. Ann. Transl. Med. 2018;6(20):409. doi: 10.21037/atm.2018.09.68.
  2. Landreneau K., Lee K., Landreneau M.D. Quality of life in patients undergoing hemodialysis and renal transplantation – a meta-analytic review. Nephrol. Nurs. J. 2010;37(1):37–44.
  3. Восканян С. Э., Сюткин В. Е., Сушков А. И. и др. Внепеченочные причины заболеваемости и смертности реципиентов печени в отдаленном посттрансплантационном периоде. Вестник медицинского института «РЕАВИЗ». Реабилитация, Врач и Здоровье. 2023;13(4):134–44. doi: 10.20340/vmi-rvz.2023.4.TX.1. [Voskanyan S.E., Syutkin V.E., Sushkov A.I., et al. Extrahepatic causes of morbidity and mortality of liver recipients in the long-term posttransplantation period. Bull. Med. Instit. "REAVIZ" (Rehabilitation, Doctor and Health). 2023;13(4):134–44 (In Russ.)].
  4. De Luca L., Kalafateli M., Bianchi S., et al. Cardiovascular morbidity and mortality is increased post-liver transplantation even in recipients with no pre-existing risk factors. Liver Int. 2019;39(8):1557–65. doi: 10.1111/liv.14185.
  5. Agostini C., Buccianti S., Risaliti M., et al. Complications in Post-Liver Transplant Patients. J. Clin. Med. 2023;12(19):6173. doi: 10.3390/jcm12196173.
  6. Tsai H.I., Liu F.C., Lee C.W., et al. Cardiovascular disease risk in patients receiving organ transplantation: a national cohort study. Transpl. Int. 2017;30(11):1161–71. doi: 10.1111/tri.13010.
  7. Dutkowski P., De Rougemont O., Müllhaupt B., et al. Current and future trends in liver transplantation in Europe. Gastroenterology. 2010;138(3):802–9.e1–4. doi: 10.1053/j.gastro.2010.01.030.
  8. Iannuzzo G., Cuomo G., Di Lorenzo A., et al. Dyslipidemia in Transplant Patients: Which Therapy? J. Clin. Med. 2022;11(14):4080. doi: 10.3390/jcm11144080. [PMID: 35887846, PMCID: PMC9318180].
  9. Gansevoort R.T., Correa-Rotter R., Hemmelgarn B.R., et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet. 2013;382(9889):339–52. doi: 10.1016/S0140-6736(13)60595-4.
  10. Mansell H., Stewart S.A., Shoker A. Validity of cardiovascular risk prediction models in kidney transplant recipients. Sci.W. J. 2014;2014:750579. doi: 10.1155/2014/750579.
  11. Visseren F.L.J., Mach F., Smulders Y.M., et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice [published correction appears in Eur Heart J. 2022 Nov 7;43(42):4468]. Eur. Heart J. 2021;42(34):3227–337. doi: 10.1093/eurheartj/ehab484.
  12. Devine P.A., Courtney A.E., Maxwell A.P. Cardiovascular risk in renal transplant recipients. J. Nephrol. 2019;32(3):389–99. doi: 10.1007/s40620-018-0549-4.
  13. Lentine K.L., Brennan D.C., Schnitzler M.A. Incidence and predictors of myocardial infarction after kidney transplantation. J. Am. Soc. Nephrol. 2005;16(2):496–506. doi: 10.1681/ASN.2004070580.
  14. Methven S., Steenkamp R., Fraser S. UK Renal Registry 19th Annual Report: Chapter 5 Survival and Causes of Death in UK Adult Patients on Renal Replacement Therapy in 2015: National and Centre-specific Analyses. Nephron. 2017;137(Suppl. 1):117–50. doi: 10.1159/000481367.
  15. Saran R., Robinson B., Abbott K.C., et al. US Renal Data System 2017 Annual Data Report: Epidemiology of Kidney Disease in the United States [published correction appears in Am. J. Kidney Dis. 2018;71(4):501.]. Am. J. Kidney Dis. 2018;71(3 Suppl. 1):A7. doi: 10.1053/j.ajkd.2018.01.002.
  16. Dawber T.R., Moore F.E., Mann G.V. Coronary heart disease in the Framingham study. Am. J. Public. Health Nations Health. 1957;47(4 Pt. 2):4–24. doi: 10.2105/ajph.47.4_pt_2.4.
  17. Pan L., Yang Z., Wu Y., et al. The prevalence, awareness, treatment and control of dyslipidemia among adults in China. Atherosclerosis. 2016;248:2–9. doi: 10.1016/j.atherosclerosis.2016.02.006.
  18. Pinto A.S., Chedid M.F., Guerra L.T., et al. Dietary management for dyslipidemia in liver transplant recipients. Arq. Bras. Cir. Dig. 2016;29(4):246–51. doi: 10.1590/0102-6720201600040008. [PMID: 28076479, PMCID: PMC5225864].
  19. Wang J., Guo R., Liu S., et al. Molecular mechanisms of FK506-induced hypertension in solid organ transplantation patients. Chin. Med. J. (Engl.). 2014;127(20):3645–50.
  20. Vathsala A., Weinberg R.B., Schoenberg L., et al. Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients. Transplantation. 1989;48(1):37–43. doi: 10.1097/00007890-198907000-00009.
  21. Agarwal A., Prasad G.V. Post-transplant dyslipidemia: Mechanisms, diagnosis and management. World J. Transplant. 2016;6(1):125–34. doi: 10.5500/wjt.v6.i1.125.
  22. Jurewicz W.A. Immunological and nonimmunological risk factors with tacrolimus and Neoral in renal transplant recipients: an interim report. Transplant. Proc. 1999;31(7A):64S–6. doi: 10.1016/s0041-1345(99)00798-8.
  23. Markell M.S., Armenti V., Danovitch G., Sumrani N. Hyperlipidemia and glucose intolerance in the post-renal transplant patient. J. Am. Soc. Nephrol. 1994;4(Suppl. 8):S37–47. doi: 10.1681/ASN.V48s37.
  24. Hüsing A., Kabar I., Schmidt H.H. Lipids in liver transplant recipients. World J. Gastroenterol. 2016;22(12):3315–24. doi: 10.3748/wjg.v22.i12.3315.
  25. Gitto S., Villa E. Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant. Int. J. Mol. Sci. 2016;17(4):490. Published 2016 Apr 2. doi: 10.3390/ijms17040490.
  26. Клинические рекомендации «Нарушения липидного обмена». 2023-2024-2025 (15.02.2023). Утверждены Минздравом РФ Интернет-ссылка: http://disuria.ru/load/zakonodatelstvo/klinicheskie_rekomendacii_protokoly_lechenija/54.
  27. Authors/Task Force Members; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk [published correction appears in Atherosclerosis. 2020;292:160–2, published correction appears in Atherosclerosis. 2020;294:80–2]. Atherosclerosis. 2019;290:140–205. doi: 10.1016/j.atherosclerosis.2019.08.01.
  28. Page R.L., Miller G.G., Lindenfeld J. Drug therapy in the heart transplant recipient: part IV: drug-drug interactions. Circulation. 2005;111(2):230–39. doi: 10.1161/01.CIR.0000151805.86933.35.
  29. Ballantyne C.M., Corsini A., Davidson M.H., et al. Risk for myopathy with statin therapy in high-risk patients. Arch. Intern. Med. 2003;163(5):553–64. doi: 10.1001/archinte.163.5.553.
  30. Warden B.A., Duell P.B. Management of dyslipidemia in adult solid organ transplant recipients. J. Clin. Lipidol. 2019;13(2):231–45. doi: 10.1016/j.jacl.2019.01.011.
  31. Shaw S.M., Chaggar P., Ritchie J., et al. The efficacy and tolerability of ezetimibe in cardiac transplant recipients taking cyclosporin. Transplantation. 2009;87(5):771–75. doi: 10.1097/TP.0b013e318198d7d0.
  32. Mir O., Poinsignon V., Arnedos M., et al. Pharmacokinetic interaction involving fenofibrate and everolimus. Ann. Oncol. 2015;26(1):248–49. doi: 10.1093/annonc/mdu492.
  33. Bhatt D.L., Steg P.G., Miller M., et al. Effects of Icosapent Ethyl on Total Ischemic Events: From REDUCE-IT. J. Am. Coll. Cardiol. 2019;73(22):2791–802. doi: 10.1016/j.jacc.2019.02.032.
  34. Schwartz G.G., Steg P.G., Szarek M., et al. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N. Engl. J. Med. 2018;379(22):2097–107. doi: 10.1056/NEJMoa1801174.
  35. Sabatine M.S., Giugliano R.P., Keech A.C., et al. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N. Engl. J. Med. 2017;376(18):1713–22. doi: 10.1056/NEJMoa1615664.
  36. Warden B.A., Kaufman T., Minnier J., et al. Use of PCSK9 Inhibitors in Solid Organ Transplantation Recipients. JACC Case Rep. 2020;2(3):396–99. Published 2020 Feb 12. doi: 10.1016/j.jaccas.2019.09.026.
  37. Медведева Е.А., Григоренко Е.А., Митьковская Н.П. Инновационная гиполипидемическая терапия: опыт применения инклизирана в Республике Беларусь. Росс. кардиол. журн. 2023;28(4):5417. https://doi.org/10.15829/1560-4071-2023-5417 [Medvedeva E.A., Grigorenko E.A., Mitkovskaya N.P. Innovative lipid-lowering therapy: experience of inclisiran use in the Republic of Belarus. Russ. J. Cardiol. 2023;28(4):5417 (In Russ.)].
  38. Зырянов С.К., Бутранова О.И. Новые возможности снижения уровня холестерина липопротеидов низкой плотности: сравнительные характеристики PCSK9-таргетной терапии. Росс. кардиол. журн. 2022;27(11):5271. https://doi.org/10.15829/1560-4071-2022-5271. [Zyryanov S.K., Butranova O.I. New opportunities for lowering low-density lipoprotein cholesterol: comparative characteristics of PCSK9-targeted therapy. Russ. J. Cardiol. 2022;27(11):5271 (In Russ.)].
  39. Raal F.J., Kallend D., Ray K.K., et al. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N. Engl. J. Med. 2020;382(16):1520–30. doi: 10.1056/NEJMoa1913805.
  40. Ray K.K., Wright R.S., Kallend D., et al. Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. N. Engl. J. Med. 2020;382(16):1507–19. doi: 10.1056/NEJMoa1912387.
  41. Ueberdiek L., Jehn U., Pavenstädt H., et al. Novel Therapeutic Strategies for Dyslipidemia: First Report of Inclisiran Therapy in a Kidney Transplanted Patient. Transpl. Int. 2023;36:11104. doi: 10.3389/ti.2023.11104. Erratum in: Transpl. Int. 2023;36:11313. [PMID: 36776901, PMCID: PMC9908609].
  42. Симоненко М.А., Алиева А.С., Ситникова М.Ю., Федотов П.А. Первый опыт в Российской Федерации лечения дислипидемии препаратами миРНК у пациентов после трансплантации сердца. Росс. кардиол. журн. 2024;29(1):5747. https://doi.org/10.15829/1560-4071-2024-5747. EDN: ISMANC. [Simonenko M.A., Alieva A.S., Sitnikova M.Yu., Fedotov P.A. First Russian experience of treating dyslipidemia with siRNA drugs in patients after heart transplantation. Russ. J. Cardiol. 2024;29(1):5747 (In Russ.). EDN: ISMANC].

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2. Fig. 1. Dynamics of decrease in LDL level (mmol/l) in patients (n=11) at time points 1, 2, 3 and 4. Individual values, arithmetic means and standard deviations are given

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3. Fig. 2. Dynamics of changes in TG levels (mmol/l) in patients (n=11) at time points 1, 2, 3 and 4. Individual values, arithmetic means and standard deviations are given

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4. Fig. 3. Dynamics of changes in HDL levels (mmol/l) of patients (n=11) at time points 1, 2, 3 and 4. Individual values, arithmetic means and standard deviations are given

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5. Fig. 4. Dynamics of decrease in LDL level (mmol/l) in patients on inclisiran monotherapy (n=4) and combined lipid-lowering therapy (n=7). Individual values, arithmetic means and standard deviations are given. The p value is given for the interaction between the factors “time” and “type of therapy”

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6. Fig. 5. Dynamics of changes in TG levels in patients on inclisiran monotherapy (n=4) and combined lipid-lowering therapy (n=7). Individual values, arithmetic means and standard deviations are given. The p value is given for the interaction between the factors “time” and “type of therapy”

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7. Fig. 6. Dynamics of changes in HDL levels in patients on inclisiran monotherapy (n=4) and combined lipid-lowering therapy (n=7). Individual values, arithmetic means and standard deviations are given. The p value is given for the interaction between the factors “time” and “type of therapy”

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8. Fig. 7. Deviation of concentrations of immunosuppressive drugs from the established range of target concentrations

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9. Fig. 8. Dynamics of changes in GFR (Cockcroft-Gault) in patients (n=11) at time points 1, 2, 3 and 4. Individual values, arithmetic means and standard deviations are given

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