Un nuevo horizonte en el tratamiento de las dislipemias 14/09/15 18:00h-19:30h Casa del Corazón (Madrid) http://objetivoLDL.secardiologia.es #objetivoLDL Abordaje terapéutico de la dislipemia en el paciente con enfermedad renal crónica Dr. Jesús Egido de los Ríos, Jefe Servicio Nefrología e Hipertensión Fundación Jiménez Díaz (Madrid)

1. Abordaje terapéutico a la dislipemia del
paciente con enfermedad renal crónica.
Jesús Egido MD, PhD
Catedrático de Medicina UAM
Jefe del Servicio de Nefrología e Hipertensión
Director Laboratorio de Patología Renal, Vascular y Diabetes
Fundación Jimenez Díaz. Madrid
Casa Del Corazón ,Septiembre 2015

2. Independent effects of CKD on CVD morbidity/mortality
Association between
LDL-c and CV risk

4. Cardiovascular mortality rate by age group
Jardine AG et al. Lancet 2011: 15;378:1419-27

5. The prevalence of CKD in patients with Coronary Artery
Disease is greater than that seen in the general population.
-28% in 782 patients (González-Juanatey. Circulation. 2010)
-22.1% in 22,272 patients ( CLARIFY Study . PLoSOne 2014)
-20.3% in 704 patients ( Tuñon J et al ; PLoSOne 2014 ; J Bone Miner Metab. 2015 Aug 23 )
CKD stages 3-5
20
55
24
G1
G2
G3-5
CKD-EPI
N=172
24.4%
20.3%
N=143
55.3%
N=389
72 ± 9 y
61 ± 11 y
51 ± 8 y

6. Lancet 2010; 375: 2073–81
Association of eGFR and albuminuria with
all-cause and CV mortality in general population cohorts
A collaborative metaanalysis
Hazardratiosand95%CIs
All-cause mortality :eGFR All-cause mortality :ACR (albumine/creatinine ratio)
Cardiovascular mortality : eGFR Cardiovascular mortality : ACR
eGFR (mL/min/1.73m²) ACR (mg/g[mg/mmol])
105,872 participants from 14 studies

7. Yamamoto and Kon. Curr Opin Nephrol Hypertens. 2009 May ; 18: 181–188
Deaths from cardiovascular disease in the general
population and chronic kidney disease
CVD mortality in US (1980-2000)
<40%
>100%

8. Shepherd et al J Am Coll Cardiol2008;51:1448–54
Aggressive lipid lowering reduces CV events in a high-risk population with CKD and CHD.
The TNT (Treating to New Target) Study (3,107 CKD vs 9,656 non CKD with CHD)

9. Athyros et al.Expert Opin. Pharmacother. (2015) 16:1449-1461
Studies evaluating the effect of statin treatment on the progression
of chronic kidney disease

10. Trial SHARP ( Study of Heart And Renal Protection )
Simvastatin 20mg + ezetimibe 10mg daily vs placebo
9,270 patients with CKD
-6,947 non dialysis
- 3,023 dialysis
Unknown history of myocardial infarction or coronary
Revascularization 4.9 years of follow up
Lancet 2011:377:2181-2192
Specific trial on CKD and hemodialysis

11. SHARP (Study of Heart and Renal Protection)
Major atherosclerotic events
0 1 2 3 4 5
Years of follow-up
0
5
10
15
20
25
Proportionsufferingevent(%)
Risk ratio 0.83 (0.74-0.94)
Logrank 2P=0.0022
Placebo
Eze/simva
N= 4650
N= 4620
Lancet 2011; 377: 2181–92
17%
39mg/dL
LDL-c

12. Major atherosclerotic events subdivided by type in SHARP
Lancet 2011; 377: 2181–92
28%
25%
27%
21%
17%
16%
There were not differences between non-dialysis and dialysis patients

13. Benefits of Statin Therapy for Persons With Chronic Kidney Disease
A Systematic Review and Meta-analysis
Eighty trials comprising 51,099 participants compared statin with placebo or no treatment
Palmer et al. Ann Intern Med. 2012;157:263-275.

14. Effect of statins on cardiovascular and renal outcomes in CKD
A systematic review and meta-analysis
Thirty-one trials, 48,429 patients
9%
23%
18%
21%
Hou W et al . Eur Heart J. 2013 Jun;34(24):1807-17.
Statin therapy reduces the risk of major cardiovascular events in patients with chronic
kidney disease including those receiving dialysis.

15. The Kidney Disease :Improving Global Outcomes (KDIGO)
recommendations on lipids (2013)
Adults aged ≥ 50 with CKD
Kidney International Supplements (2013) 3, 284–285; doi:10.1038/kisup.2013.37

16. KDIGO recommendations on lipids in adults
aged <50 years with CKD
Kidney International Supplements (2013) 3, 284–285; doi:10.1038/kisup.2013.37

17. KDIGO recommendations on lipids in adults with
dialysis-dependent CKD/transplant

18. Algorithm for cholesterol-lowering treatment in CKD.
Tonelli M et al Ann Intern Med. 2014;160:182-189.
*
*
* Strong recommendation
If eGFR<60 ml/min/1.73m2
Statin+ezetimibe
Keeping statins or statin + ezetimibe
If already treated

19. Septiembre 2013-2014
Criterios de utilización de fármacos hipolipemiantes para el tratamiento y
control de la dislipemia como factor de riesgo cardiovascular
Enfermedad renal crónica (ERC)
En pacientes con ERC estadio 3b a 5 (eGFR < 45 ml/min/1.73m2) sin eventos cardiovsculares previos ,
la utilización de simvastatina y ezetimiba a dosis fijas (20/10) reduce el riesgo
de eventos CV.
Estaría indicado el tratamiento farmacológico en este grupo de pacientes sin evaluar
previamente el RCV.
Febrero 2015

20. Potential advantages of Simvastatin/Ezetimibe
and Atorvastatin/Ezetimibe in patients with CKD
• Reduces LDL-c by the equivalent of around 2 increases of the statin dose
• Facilitates the therapeutic target (< 70 mg/dl LDL-c) according ESC 2012.
• Improves compliance by better tolerance (generally absence of miopathy)
Two drugs in a single pill.
• Reduces the physician concerns about side-effects
• Could decrease complications compared with high potency statins
The 10 year risk for coronary death or nonfatal MI among CKD
patients older than 50 years is consistently greater than 10%, even
in those without diabetes or previous MI

21. Some risk factors
Anthropometric - Age : 80 years old (general caution advised for age .75)
- Female
- Low body mass index
Concurrent
conditions - Impaired renal (chronic kidney disease classification 3, 4, and 5)
- Organ transplant recipients
- Diabetes mellitus
- Vitamin D deficiency
- High level of physical activity
- Excess alcohol
- Intolerance to statins

22. Canadian Network for Observational Drug Effect Studies
2,067,639 patients >40 years treated with statins (1997-2008)
59,636 with CKD
4,691 hospitalizations for AKI in patients with non-CKD (0.23%)
1,896 hospitalizations for AKI in those with CKD (3.17%)
Conclusion :
Treatment with high potency statins is associated with an increased
rate of AKI in hospital admissions compared with low potency statins
( mostly in the first 120 days after initiation of statin treatment) .
13.78 fold-increase

23. •Higher potency statin use is associated with a moderate increase in the risk of
new onset diabetes ( 12% increase) compared with lower potency statins in
patients treated for secondary prevention of cardiovascular disease.
•Clinicians should consider this risk when prescribing higher potency statins in
secondary prevention patients, mainly in patients with CKD
136 966 patients aged ≥40 years newly treated with statins between 1 January 1997
and 31 March 2011
Canadian Network for Observational Drug Effect Studies (CNODES) Investigators
Conclusion :

24. Comparative adverse effects of the addition of
ezetimibe to statin vs statin titration in CKD patients.%adverseeffects
6,2
10,3
17
38,4
0
5
10
15
20
25
30
35
40
45
N=145 N=141 N=8 N=52
286 patients with CKD and LDL-c> 120mg/dl randomized to usual
statin + ezetimibe 10mg/dl or double doses of statin
Total CKD population CKD 3-5
Ther Adv Cardiovasc Dis. 2013 Dec;7(6):306-15
Statin + Ezetimibe = Similar efficacy
with less adverse effects (myalgia/transaminases)
Atorvastatin does not require dose adjustment and is the statin of choice in patients
with severe renal impairment

25. Filippatos TD et al Angiology 2015:1-4
IMPROVE-IT Study in
Diabetic Patients
Combination statin + ezetimibe therapy is an
effective and safe option to treat diabetic dyslipidemia.
Diabetic patients gained greater benefit, in terms of CV events
13%
When added to statin therapy, ezetimibe resulted in incremental lowering of LDL
cholesterol levels and improved cardiovascular outcomes ( IMPROVE-IT)
Cannon CP et al . N Engl J Med 2015;372:2387-97.

26. Achievement of Dual LDL-c and hs-CRP Targets More
Frequent With the Addition of Ezetimibe to Simvastatin
and Associated With Better Outcomes in IMPROVE-IT
Bohula EA et al. Circulation. 2015;132:00-00
1 month

27. Effect of Ezetimibe Coadministered With Atorvastatin in
628 Patients With Primary Hypercholesterolemia
A Prospective, Randomized, Double-Blind Trial
Ballantyne C et al .Circulation. 2003;107:2409-2415
LDL-c
Hs-CRP

28. Evaluating the safety of ezetimibe and atorvastatin :
what are the potential beneficts beyong low-density
lipoprotein cholesterol-lowering effect?
Husain NE, Hassan AT, Elmadhoun WM, Ahmed MH.
Expert Opin Drug Saf. 2015 Sep;14(9):1445-55.

29. Modified from Cannon CP et al . N Engl J Med 2015;372:2387-97.
Atorvastatin +ezetimibe (?)
IMPROVE-IT Trial Data and Statin Trials for Change
in LDL-c versus Clinical Benefit.
Extrapolation of Ezetimibe added to Atorvastatin
(40-80) on changes in LDL vs clinical benefit

30. Resúmen
Las estatinas disminuyen los eventos cardiovasculares y la mortalidad en
pacientes en los estadios 1-5 de la enfermedad renal crónica.
Evidencia de calidad moderada-alta
La combinación Simvastatina/Ezetimiba y Atorvastatina/Ezetimiba
incrementa el efecto hipolipemiante, con menos efectos adversos, y está
particularmente indicada en pacientes con CKD mayores de 50 años y en
pacientes con alto riesgocardiovascular
La disponibilidad de todas las dosis de Atorvastatina (10 a 80) con
Ezetimiba en un solo comprimido permite una indicación mas
personalizada y un mejor cumplimiento por el paciente