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Manejo y selección de fármacos antihiperglucemiantes en pacientes con ERC

Manejo y selección de fármacos antihiperglucemiantes en pacientes con ERC. Juan José Gorgojo Martínez Unidad de Endocrinología y Nutrición. Selección de antihiperglucemiantes en ERC. Rojo: contraindicado . Naranja: precaución/ajuste dosis . Verde: indicado.

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Manejo y selección de fármacos antihiperglucemiantes en pacientes con ERC

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  1. Manejo y selección de fármacos antihiperglucemiantes en pacientes con ERC Juan José Gorgojo Martínez Unidad de Endocrinología y Nutrición

  2. Selección de antihiperglucemiantes en ERC Rojo: contraindicado. Naranja: precaución/ajuste dosis. Verde: indicado NationalKidneyFoundation. Am J KidneyDis. 2012 Nov;60(5): 850-86 .PerkovicV,et al. KidneyInt. 2016Dec;90(6):1175-1183. Gómez-Huelgas R,et al. MedClin (Barc). 2014 Jan 21;142(2):85.e1-10. ERBP. Nephrol Dial Transplant. 2015 May;30 Suppl 2:ii1-142.RajputR,et al. Diabetes Res ClinPract. 2017 May;127:10-20.

  3. La reducción de A1c disminuye el riesgo de nefropatía diabética en la DM2 *Intensive vs standard glucose control. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572. Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

  4. Estudio CARMELINA: objetivos renales y microvasculares (linagliptina vs placebo) High CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] >200mg/g) and high renal risk (reduced eGFR and micro- or macroalbuminuria) • Kidney composite outcome: time to first occurrence of a composite of adjudication-confirmed ESRD, death due to • renal failure, or a sustained decrease of at least 40% in eGFR from baseline. • Microvascular composite outcome : albuminuria, sustained ESRD, sustained decrease of at least 50% in eGFR, death due to renal failure, and major ocular events. Rosenstock J, et al. JAMA. 2019 Jan 1;321(1):69-79

  5. Tres iSGLT-2 reducen la progresión de la ERC... EMPAREG (-39%) CANVAS (-40%) DECLARE (-24%) JJ GORGOJO. Elaborada a partir de datos de: Zinman B, et al. N Engl J Med. 2015 Nov 26;373(22):2117-28. Neal B,et al. N Engl J Med. 2017 . N Engl J Med. 2017 Aug 17;377(7):644-657. 644-657.Wiviott SD et al. NEJM.DOI: 10.1056/NEJMoa1812389

  6. ...y dos AR GLP-1 reducen la progresión de la ERC LEADER (-22%) SUSTAIN 6 (-36%) JJ GORGOJO. Elaborada a partir de datos de Mann JFE,et al. N Engl J Med. 2017 Aug 31;377(9):839-848Marso SP, et al. N Engl J Med. 2016 Nov 10;375(19):1834-1844.

  7. Los iSGLT2 (pero no los ARGLP-1) reducen la caída del filtradoglomerular EMPAREG CANVAS LEADER JJ Gorgojo . Elaborada a partir de datos de WannerC,et al.Engl J Med. 2016 Jul 28;375(4):323-34. Neal B,et al. N Engl J Med. 2017 Aug 17;377(7):644-657.de Zeeuw D. 53rd Annual Meeting of the European Association for the Study of Diabetes;15 September 2017; Lisbon, Portugal. Mann JFE et al. N Engl J Med 2017;377:839–848.

  8. CANTATA-SU. Canagliflozina vs glimepirida añadidas a metformina. Variación de función renal a104 semanas Leiter L et al. Diabetes Care. 2015 Mar;38(3):355-64.

  9. CREDENCE: canagliflozina 100 mg vs placebo en pacientes con DM2 y ERC Canagliflozin 100 mg 2-week placebo run-in Placebo Double-blind randomization (1:1) Follow-up at Weeks 3, 13, and 26 (F2F) then every 13 weeks (alternating phone/F2F) R • Key exclusion criteria • Other kidney diseases, dialysis, or kidney transplant • Dual ACEi and ARB; direct renin inhibitor; MRA • Serum K+ >5.5 mmol/L • CV events within 12 weeks of screening • NYHA class IV heart failure • Diabetic ketoacidosis or T1DM • Key inclusion criteria • ≥30 years of age • T2DM and HbA1c 6.5% to 12.0% • eGFR 30 to 90 mL/min/1.73 m2 • UACR 300 to 5000 mg/g • Stable max tolerated labelled dose ofACEi or ARB for ≥4 weeks Primary objective:Composite outcome of ESKD, doubling of serum creatinine, or renal or CV death Jardine MJ, et al. Am J Nephrol. 2017;46(6):462-472. Perkovic V et al. NEJM. 2019. DOI: 10.1056/NEJMoa1811744

  10. CREDENCE: canagliflozinaredujo un 30% el riesgo de ERC terminal, duplicación de Cr sérica o muerte de causa CV o renal -30% (NNT 21) -32% (NNT 42) Perkovic V et al. NEJM. 2019. DOI: 10.1056/NEJMoa1811744

  11. Potential efectonefroprotector de los ISGLT2 HeerspinkHJL,et al. KidneyInt. 2018 Jul;94(1):26-39.

  12. Mecanismos potenciales de protección renal con AR GLP-1 Antiinflamatorios, antifibróticos, antiproteinúricos y hemodinámicos ARGLP-1 ACE, angiotensin I converting enzyme; AGE, advanced glycation end product; ARB, angiotensin II receptor blocker; CTGF, connective tissue growth factor; DPP4 inhibitor, dipeptidyl peptidase-4 inhibitor; ET-1, endothelin 1; GLP-1, glucagon-like peptide 1; PKC, protein kinase C; PPARγ, peroxisome proliferator-activated receptor γ; RAGE, receptor for AGE; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor. Wanner C. Nat Rev Nephrol. 2018 Feb;14(2):78-80 Fineberg D et al. Nat Rev Endocrinol2013;9:713–723.

  13. Consenso ADA/EASD 2018 Fármacos de elección en pacientes con IC ó ERC • SGLT-2is preferred over GLP-1RAs as significant, consistent reductions in hospitalisation for HF have been seen in SGLT-2i trials • SGLT-2i • GLP-1RA HF OR CKD predominates PREFERABLY SGLT-2i with evidence of reducing HF and/or CKD progression in CVOT if eGFR adequate‡ OR If SGLT-2i not tolerated or contraindicated or if eGFR less than adequate† add GLP-1RA with proven CV benefit*# Canagliflozin/Empagliflozin/Dapagliflozin If HbA1c above target • Avoid TZD in the setting of HF • Choose agents demonstrating CV safety: • Consider adding the other class with proven CVD benefit* • DPP-4i (not saxagliptin) in the setting of HF (if not on GLP-1RA) • Basal insulin§ • SU|| Liraglutide Semaglutide Exenatide ER †Be aware that SGLT-2i vary by region and individual agent with regard to indicated level of eGFR for initiation and continued use; ‡Empagliflozin, canagliflozin and dapagliflozin have shown reduction in HF and reduction in CKD progression in CVOTs; §Degludec or U100 glargine have demonstrated CVD safety; ||Choose later generation SU with lower risk of hypoglycaemia; #Caution with GLP-1RA in ESRD Davies MJ, et al. Diabetologia. 2018 Dec;61(12):2461-2498. American Diabetes Association. [web annotation]. Diabetes Care 2019;42(Suppl. 1):S90–S102.

  14. Conclusiones • En los últimos años han aparecido nuevas clases de fármacos antihiperglucemiantes, cuyo metabolismo y excreción renal es preciso conocer para su correcto manejo en pacientes con ERC • La reducción de HbA1c disminuye el riesgo de aparición y progresión de ERC • Los iSGLT-2 y algunos análogos de GLP-1 humano han demostrado protección renal en estudios de seguridad CV • Sólo los iSGLT-2 han demostrado frenar el descenso del filtrado glomerular • iSGLT-2 y ARGLP-1 son fármacos de elección en pacientes con ERC, salvo limitación por FGe en ficha técnica • Canagliflozina es el primer fármaco antihiperglucemiante que demuestra una reducción de la morbimortalidad renal y CV en pacientes con ERC

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