La dislipidemia nella malattia renale cronica:...

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Stefano Bianchi, Livorno

La dislipidemia nella malattia renale cronica: dobbiamo trattare tutti i nostri pazienti ?

La dislipidemia della CKD contribuisce alla (sfavorevole) prognosi CV e renale dei pazienti con CKD?

La dislipidemia della CKD ha un profilo aterogenico?

La terapia della dislipidemia della CKD modifica la prognosi CV e renale?

Struttura della relazione

Dobbiamo trattare la dislipidemia in tutti pazienti con CKD?

Lipid/Lipoprotein Metabolism Abnormalities in Patients with Chronic Kidney Disease

↑ApoCIII:↑TG ↓ApoA-I: ↓HDL ↓LCAT: ↓HDL

HDL2/HDL3 −preβ HDL:

−↓HDL, ↓ LPL

↑ACAT: ↑VLDL, ↓HDL

↓HL : ↑IDL, CMr, HDL-TG,

↓ LDL-TG; ↓HDL ↑CETP: ↓HDL

↓LPL: ↑TG ↓(delipidation CM and VLDL)

↓LDLR: ↓↑LDL

APO B/E Receptors

c. : ↑

Dyslipidemia of Chronic Kidney Disease

± LDL ↑Small-dense LDL

↑Ox-LDL

↑TG Large VLDL

↓HDL-C ↑Small-Dense HDL

Chronic Kidney Disease Metabolic Syndrome

Type 2 Diabetes

Keech AC et al, Lancet 371:117-25, 2008

Most Common Lipid Profile in Pts with Coronary Artery

Disease (60%)

•Enhanced Arterial Cholesterol Deposition •Attenuated Reverse Cholesterol Transport •Accelerated Atherogenesis

• VLDL • VLDL Remnants • IDL • LDL ; Dense LDL • Oxidized LDL

Dysfunctional Small Dense HDL

Dyslipidemia in patients with CKD Dyslipidemia in CKD involves a disequilibrium characterised by an excess of

atherogenic apoB-containing lipoproteins relative to low concentrations of anti-atherogenic HDL whose functional properties are defective.

Go AS et al. N Engl J Med. 2004.

Kaiser Permanente Renal Registry; N = 1,120,295

Estimated GFR

Age-standardized rate of CV events/ 100 person-years

No. of events 73,108 34,690 18,580 8809 3824

0 ≥60 45–59 30–44 15–29 <15

5 2.11 3.65

Rate of CV events with progressively ↓ GFR

15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0

>60 45-59 30-44 15-29 <15

Estimated GFR (ml/min/1.73 m2)

150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0

>60 45-59 30-44 15-29 <15

0.76 1.08

13.5 17.2

Rates of Death from Any Cause (left) and Hospitalization (right), According to the Estimated GFR

Go, A. S. et al. N Engl J Med 2004

Kaiser Permanente Renal Registry; N = 1,120,295

Risk factors for development of CVD in patients with stage I-V CKD

Common to GP

Older age Hypertension LDL cholesterol HDL cholesterol Triglycesides Diabetes Diabetes Physical inactivity Menopause Family history of CVD Left ventricular hypertrophy

More important to patients with CKD

RAAS activity Albuminuria/proteinuria Oxidized and small-dense LDLcholesterol Lipoprotein(a) Anemia Vascular calcification Oxidative stress Inflammation Malnutrition Thrombogenic Factors Endothelial dysfunction Extracellular fluid overload Sympathetic overactivity

CVD, cardiovascular disease; CKD, chronic kidney disease; GP, general population; LDL, low-density lipoprotein; HDL, high-density lipoprotein

1° 2° 3° 4° RR

GFR 15-59 GFR 60-89 GFR>90

Relationship of total cholesterol with major coronary events in 17,898 CKD pts followed for 10.5 yrs

Modificato da Muntner P, J Am Soc Nephrol, 2005 Total cholesterol (quartiles)

*GFR=mL/min/1.73 m2

Association between LDL-C and Risk of Myocardial Infarction in CKD

LDL-C Category (mmol/L)

HR (95% CI) eGFR=15–59.9 ml/min per 1.73 m2(n=47,092)

eGFR=60–89.9 ml/min per 1.73 m2(n=351,849)

eGFR≥90 ml/min per 1.73

m2 (n=437,119) <2.6 0.93 (0.82, 1.04) 0.93 (0.85, 1.01) 0.98 (0.87, 1.12) 2.6–3.39 1.00 1.00 1.00 3.4–4.09 1.22 (1.06, 1.39) 1.20 (1.11, 1.30) 1.35 (1.19, 1.52) 4.1–4.89 1.68 (1.42, 1.99) 1.39 (1.26, 1.54) 1.99 (1.73, 2.29) ≥4.9 2.06 (1.59, 2.67) 2.30 (2.00, 2.65) 3.01 (2.46, 3.69)

Adjusted HRs of MI for eGFR subgroups

Marcello Tonelli et al for the Alberta Kidney Disease Network JASN 2013

836,000 outpatients evaluated

Predictors of Risk in the RENAAL Study (Doubling of serum creatinine and/or end-stage Renal Disease)

Appel GB et al., Diabetes Care 2003

LDL-cholesterol (mg/dL)

137-167

<111 111-137

Metabolic parameter

3. In questi pazienti e’ necessario un controllo particolarmente accurato dei fattori di rischio delle malattie cardiovascolari, tra cui la dislipidemia

Studies supporting the evidence that statins reduce CV morbidity and mortality in pazients with CKD

1.Heart Protection Study, 2002 2.Greace Study, 2002 3.CARE Study and Pravastatin Pooling Project, 2003 4.Alliance Study, 2007 5.TNT STUDY, 2007 6.Sparcl, 2007 7. Air Force/Texas CAPS, 1998 (2010) 8. Jupiter, 2010 8.Sharp Study, 2010

Statins and chronic kidney disease

4Study Pts Statin Follow-

up (years)

LDL reduction RRR% P<

HPS 1329 pts with slightly elevated creatinine

Simva 40 5 29% 28 0.001

ASCOT-LLA

6517 pts with hypertension and “renal dysfunction”

Atorva 10 3.3 29% 40 0.0025

PPP 4491 pts with moderate CKD

Prava 40 5 31% 23 0.02

TNT 1602 pts with CKD stage 3/4

Atorva 80 5 36% 32 0.0003

JUPITER 3267 pts GFR< 60ml/min

Rosuva 20 mg 4 40% 45 0.002

HPS Collaborative Group. Lancet 360: 7-22, 2002 ; ASCOT-Lipid Lowering Arm. Lancet 361: 1149-1158, 2003 Pravastatin Pooling Project. Circulation 110: 1557-1563, 2004 ; LaRosa JC, et al. N Engl J Med. 2005 Ridker PM et al.. JACC 2010; 55; doi:10.1016

CARDIOVASCULAR END-POINTS

0 1 2 3 4 5 6 Time (years)

s with

* 0.15

TNT Study:Time to First Major CV Event By Treatment

Atorvastatin 10 mg (n=3324) Atorvastatin 80 mg (n=3225)

Normal eGFR Relative risk reduction = 15% (Absolute risk reduction = 1.4%) HR = 0.85 (95% CI 0.72, 1.00) P = 0.049

CKD (Stages 3-4) Relative risk reduction = 32% (Absolute risk reduction = 4.1%) HR = 0.68 (95% CI 0.55, 0.84) P = 0.0003

Atorvastatin 10 mg (n=1505) Atorvastatin 80 mg (n=1602)

CHD death,Nonfatal MI, non–procedure-related MI Resuscitated cardiac arrest, Fatal or nonfatal stroke

Clin J Am Soc Nephrol 2: 1131–1139, 2007

Primary and Secondary Event Rates in Patients with CKD and Patients with Normal eGFR

Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.

Any coronary event All Patients* 1078 (21.6%) 1326 (26.5%) Patients with CKD 356 (22.2%) 431 (28.6%) Patients with normal eGFR 676 (21.0%) 828 (24.9%) P=0.285

Major cardiovascular event All Patients* 434 (8.7%) 548 (10.9%) Patients with CKD 149 (9.3%) 202 (13.4%) Patients with normal eGFR 254 (7.9%) 307 (9.2%) P=0.113 Any cardiovascular event All Patients* 1405 (28.1%) 1677 (33.5%) Patients with CKD 489 (30.5%) 574 (38.1%) Patients with normal eGFR 857 (26.6%) 1027 (30.9%) P=0.225 Major coronary event All Patients* 334 (6.7%) 418 (8.3%) Patients with CKD 110 (6.9%) 157 (10.4%) Patients with normal eGFR 198 (6.1%) 226 (6.8%) P=0.040

Cerebrovascular event All Patients* 196 (3.9%) 250 (5.0%) Patients with CKD 74 (4.6%) 104 (6.9%) Patients with normal eGFR 111 (3.4%) 139 (4.2%) P=0.281 CHF with hospitalization All Patients* 122 (2.4%) 164 (3.3%) Patients with CKD 49 (3.1%) 84 (5.6%) Patients with normal eGFR 71 (2.2%) 72 (2.2%) P=0.011 Peripheral artery disease All Patients* 275 (5.5%) 285 (5.6%) Patients with CKD 121 (7.6%) 112 (7.4%) Patients with normal eGFR 147 (4.6%) 160 (4.8%) P=0.629 All-cause mortality All Patients* 284 (5.7%) 282 (5.6%) Patients with CKD 112 (7.0%) 113 (7.5%) Patients with normal eGFR 132 (4.1%) 124 (3.7%) P=0.401

0.4 0.6 0.8 1.0 1.2 1.4 1.6 Hazard ratio (95% CI)

Atorvastatin 80 mg better Atorvastatin 10 mg better

Event rate 80 mg

P-value for heterogeneity 10 mg

Cumulative Incidence of CV End Points in CKD patients from JUPITER Study

*Primary end point: non-fatal MI, nonfatal stroke, hospital stay for unstable angina, arterial revascularization, or CV death

1638 1574 1538 1281 871 550 352 247 129 39 1629 1557 1510 1234 838 516 345 243 131 40 7259 7054 6871 5256 3020 1407 1000 736 409 118 7269 7061 6840 5272 3033 1447 988 712 400 134

Follow-up (yrs)

No. at Risk 0

CKD Rosuvastatin Placebo

No CKD Rosuvastatin Placebo

1 0.00

CKD, placebo

No CKD, placebo

No CKD, rosuvastatin

CKD, rosuvastatin

Ridker P et al. JACC, 2010

Statin therapy reduced progression of renal disease in a prospective study of patients with CKD

UPE=urinarry protein excretion, grms/24 hrs * p<0.05; **p<0.01 vs no statin

Bianchi S et al. Am J Kidney Dis 2003; 41: 565–570

CrCl=creatinine clearance mL/min/1.73m2 p<0.05; **p<0.01 vs no statin

Change From Baseline eGFR in All TNT Patients in Renal Analysis

Mean change from baseline at the final visit (LOCF) was +3.5 mL/min/1.73 m2 with atorvastatin 10 mg and +5.2 mL/min/1.73 m2 with atorvastatin 80 mg (P<0.0001)

Baseline 12 24 36 48 60 Atorva 80 mg 4827 4700 4580 4400 4240 3659 Atorva 10 mg 4829 4727 4582 4386 4220 3635

Atorvastatin 80 mg Atorvastatin 10 mg

P<0.0001 for all comparisons of atorvastatin 80 mg vs 10 mg

Months

Total cardiovascular risk estimation Those with: 1.known CVD 2.type 2 diabetes or type 1 diabetes with microalbuminuria 3.very high levels of individual risk factors 4.chronic kidney disease (GFR <60 ml/min/1.73 m2 or presence of proteinuria/hematuria ) are automatically at VERY HIGH or HIGH TOTAL CARDIOVASCULAR RISK and need active management of all risk factors.

Target C-LDL <70 mg/dl in patients with very high CV risk

<100 mg/dl in patients with high CV risk

ESC/EAS Guidelines for the management of dyslipidemia, 2011

Le statine sembrano efficaci nella prevenzione degli eventi CV in pazienti vasculopatici con

insufficienza renale cronica stadio I-IV

In azienti adulti con MRC stadio 1-4 va considerato un trattamento farmacologico ipocolesterolemizzante ….. con TT per LDl-col almeno<100 mg/dl…….. e <70-80 mg/dl in prevenzione CV secondaria od in presenza di diabete mellito

Le statine sono in grado di ridurre la proteinuria e di rallentare la progressione della malattia renale

Withdrawal rates for statins compared with placebo in predialysis, dialysis and transplant patients

Relative risk of abnormal LFT or CK = 1.5 (0.86 - 2.59)

BMJ 2008:336:645

CTT: Lack of evidence for reduction in MVE risk in people with eGFR below 30 mL/min/1.73m2

0.4 0.6 0.8 1 1.2 1.4

No. of events Statin Control Relative risk (CI)

Statin/more better

Control/less better

Estimated GFR (mL/min/1.73m2)

>30 < 45

>45 < 60

>60 < 90

46 (4.8%)

313 (4.7%)

1154 (3.9%)

3416 (3.2%)

671 (2.9%)

5802 (3.1%)

43 (6.1%)

393 (6.0%)

1480 (5.1%)

4244 (4.1%)

915 (4.1%)

7344 (4.0%)

0.82 (0.44 - 1.55)

0.77 (0.65 - 0.93)

0.79 (0.72 - 0.86)

0.80 (0.76 - 0.84)

0.73 (0.65 - 0.82)

0.78 (0.76 - 0.81)

99% or 95% CI

Trend test: χ2 on 1 df = 0.61 ; p=0.43

CTT Collaboration , Lancet 2010

4-D and AURORA: Kaplan-Meier estimate of time to first major CV event

(cardiac death, nonfatal MI and stroke)

4-D AURORA

0 1 5 6 2 3 4

Year No. at Risk Placebo 636 532 383 252 136 51 19 Atorvastatin 619 515 378 252 136 58 29

Placebo

Atorvastatin

0 1 5 2 3 4

Years since randomization No. at Risk Placebo 1384 1163 952 809 534 153 Rosuvastatin 1390 1152 962 826 551 148

Placebo

Rosuvastatin 30

10 Hazard ratio, 0.96 95% CI 0.84-1.11 P=0.59

Hazard ratio, 0.92 95% CI 0.77-1.10 P=0.37

Annual mortality rate 12% 13.7%

Wanner C et al. N Engl J Med 2005 Fellström BC et al. N Engl J Med 2009

www.thelancet.com Published online June 9, 2011 DOI:10.1016/S0140-6736(11)60739-3

Randomised (9438)

Randomised (886)

Not re-randomised (168)

Placebo (4191)

Simvastatin (1054)

Simva/Eze (4193)

Simv/Eze (4650)

Placebo (4620)

SHARP: Randomisation structure

Median follow-up 4.9 years Lost to mortality follow-up 1.5%

1 year

SHARP: Baseline characteristics

Age (years) 62 ± 12 Men 63% Systolic BP (mmHg) 139 ± 22 Diastolic BP (mmHg) 79 ± 13 Body mass index (kg/m2) 27 ± 6 Current smoker 13% Vascular disease 15% Diabetes mellitus 23%

Non-dialysis patients only (n=6247)

eGFR (ml/min/1.73m2) 27 ± 13 Albuminuria 80%

Renal status at randomization Number Percent

Pre-dialysis eGFR* Stages 1/2 ≥60 88 1% Stage 3A 45-59 302 3% Stage 3B 30-44 1853 20% Stage 4 15-29 2565 28% Stage 5 <15 1221 13%

Subtotal: pre-dialysis 6029 67%

Hemodialysis 2527 28% Peritoneal dialysis 496 5% Subtotal: dialysis 3023 33%

ALL PATIENTS 9052 100% *eGFR in mL/min/1.73m2

Lipid profile (mg/dL) at randomization

Number Percent Total-C (mean 189 mg/dL)

<174 3434 39%

≥174 <212 3049 34%

≥213 2410 27%

LDL-C (mean 108 mg/dL)

<97 3483 39%

≥97 <116 2096 24%

≥116 3313 37%

SHARP: Major atherosclerotic events*

0 1 2 3 4 5 Years of follow-up

Risk ratio 0.83 (0.74-0.94) Logrank 2P=0.0022

Placebo

Eze/simva

*coronary death, MI, non-haemorrhagic stroke, or any revascularization

SHARP: Major Vascular Events

0 1 2 3 4 5

Years of follow-up

) placebo

eze/simva Risk ratio 0.85 (0.77-0.94) Logrank 2P=0.0012

Major vascular events (cardiac death, MI, any stroke, or any revascularization) Components of major atherosclerotic events

↓ 16.5% SE 5.4 (P=0.0022)

0.6 0.8 1.0 1.2 1.4 Eze/simva

better Placebo better

SHARP: Major atherosclerotic events by renal status at randomization

Non-dialysis (n=6247) Dialysis (n=3023) Major atherosc. event

(9.5%)

(15.0%)

(11.3%)

(11.9%)

(16.5%)

(13.4%)

No significant heterogeneity between non-dialysis and dialysis patients (P=0.25)

Risk ratio (95% CI) Placebo (n=4620)

Eze/simva (n=4650)

0.6 0.8 1.0 1.2 1.4 Eze/simva

better Placebo better

Main renal outcome End-stage renal disease (ESRD) Tertiary renal outcomes ESRD or death ESRD or 2 x creatinine

(33.9%)

(47.4%)

(38.2%)

(34.6%)

(48.3%)

(40.2%)

0.97 (0.89-1.05)

0.97 (0.90-1.04)

0.94 (0.86-1.01)

SHARP: Renal outcomes

Risk ratio (95% CI) Placebo (n=3130)

Eze/simva (n=3117)

Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.

CKD Stage Strength of Evidence

1 (≥ 90) 2 (60-89) 3 (30-59) 4 (< 30) 5-Dialysis 5-Transpl

Strength of Evidence for Treating Dyslipidemia in CKD

High Cholesterol: Prevalence, Awareness, Treatment and Control

Values are %. CKD = Chronic kidney disease; LDL = low-density lipoprotein; HDL = high-density lipoprotein. 1 Taking lipid-lowering agents, dieting, or not meeting National Cholesterol Education Program Adult Treatment Panel III LDL cholesterol targets. 2. National Cholesterol Education Program Adult Treatment Panel III, ≥40 mg/dL. Unadjusted. 3. Unadjusted Adapted from Snyder JJ, et al: Am J Nephrol 2009; 30(1):44-54.

No prior CVD Prior CVD

No CKD CKD stages 1-2

CKD stages 3-4 No CKD CKD

stages 1-2 CKD

stages 3-4

High LDL-C prevalence1 32 46 81 90 84 83

High cholesterol Unaware 38 40 53 35 37 33

Aware, untreated 10 9 10 9 8 4

Aware, treated, not controlled 21 26 10 35 37 37

Aware, treated, controlled 31 26 11 21 18 26

Within HDL target range2 81 76 81 69 73 76

Lipid-lowering agent use3 20 21 22 41 48 55

Are cardiologists doing a better job?

Statin use at discharge in MI hospital survivors according to eGFR values

Dobbiamo quindi trattare tutti i pazienti con CKD con una terapia ipolipemizzante?

Riflessioni (personali) finali

1. Il trattamento con farmaci ipolipemizzanti (statine, statine+ezetimibe) riduce la probabilità di presentare eventi CV secondari ad aterosclerosi nei pazienti con malattia renale cronica in fase conservativa, anche evoluta. 2. E’ possibile che gli stessi risultati possano essere evidenziabili nei pazienti in terapia sostitutiva (HD, PD), anche se il livello di evidenza non appare altrettanto forte rispetto a quanto osservato nella fase conservativa (selezione dei pazienti a rischio?, trattamento a partire da un valore soglia LDL colesterolo?). 3. Il profilo di tollerabilità della terapia ipolipemizzante (statine, statine+ ezetimibe) nei pazienti con malattia renale cronica, inclusi quelli in terapia sostitutiva, non differisce da quello osservato nella popolazione generale. 4. Non ci sarà un altro “grande studio” su questo aspetto di terapia del paziente con malattia renale cronica a toglierci da residue incertezze e dubbi.

Back-up sides

Cholesterol Treatment Trialists (CTT) Collaboration

• Collaborative meta-analysis of individual participant data from randomized trials of LDL-cholesterol (LDL-C) lowering therapy

• Allows detailed analyses of effects of statins: – Efficacy outcomes: Major vascular events (major coronary events,

stroke, or coronary revascularization); vascular mortality – Safety outcomes: Cancer (site-specific); non-vascular mortality – Major subgroups: Efficacy and safety in different types of patients

(eg, by baseline LDL cholesterol, or by stage of kidney disease) – By follow-up time (eg, with more prolonged treatment)

• Current cycle: – 21 trials of statin versus control – 5 trials of more versus less intensive statin – 24,000 major vascular events among 170,000 participants

CTT Collaboration Lancet 2010

Risk of CHD

LDL-C= 119 mg/dl LDL-C= 124 mg/dl

Subject A Control

Normal LDL-C

TG 113 HDL-C 51

Lipoprotein phenotype ↑TG, ↓ HDL-C, ↑ sd LDL; Apo B: Marker of circulating LDL particles

Apo B= 93 mg/dl Apo B= 112 mg/dl

LDL Mean diameter

233 Å

LDL Mean diameter

273 Å

“Normal” LDL cholesterol levels: misleading information in CKD patient

TG 113 mg/dL HDL 51 mg/dL

TG 224 mg/dL HDL 48 mg/dL

Normal LDL-C ↑Small Dense LDL ↑Ox-LDL

Subject B CKD

Time to First Major CV Event Among Patients with CKD at Baseline

0 0 1 2 3 4 5 6

Patients with CKD at baseline Atorvastatin 10 mg Atorvastatin 80 mg

HR=0.68 (95% CI 0.55, 0.84) P=0.0003, ARR=4.1%, NNT=24

Time (Years) No. of CKD patients at risk Atorva 10 mg 1505 1468 1422 1367 1310 687 0 Atorva 80 mg 1602 1579 1539 1495 1450 701 0

Adapted from Shepherd J, et al: J Am Coll Cardiol 2008; 51(15):1448-54.

CKD=chronic kidney disease, UPE, grms/24 hrs * p<0.05; **p<0.01 vs no statin

Months

Change (%) in urine protein

excretion (UPE)

Atorvastatin (n=28)

No statin (n=28) *

** –60

0 0 3 6 9 12

CKD=chronic kidney disease; CrCl mL/min/1.73m2* p<0.05; **p<0.01 vs no statin

Months

Change (%) in CrCl

Atorvastatin (n=28)

No statin (n=28)

0 0 3 6 9 12

Baseline 12 24 36 48 60 CKD 3107 3040 2955 2806 2681 2264 Normal eGFR 6549 6387 6207 5980 5779 5030

FR CKD patients

Atorvastatin 80 mg Atorvastatin 10 mg

Patients with normal eGFR Atorvastatin 80 mg Atorvastatin 10 mg

P<0.0001 for all comparisons of atorvastatin 80 mg vs 10 mg

Percent Change From Baseline eGFR in TNT Patients by CKD Status

Months

How well are nephrologists doing treating dislipidemia in CKD patients?

0102030405060708090

Hypertension (≥130/80 mmHg)

Hypercholesterolemia (> 190 mg/dl)

Anemia (<11 gr/dl F; <12 gr/dlM)

10.9 12.6 19.0

Prevalence %Treated %Controlled

Modified from De Nicola, Kidney IntI, 2006 (TABLE in CKD Study Group)

Net compliance and LDL reduction differed between non-dialysis and dialysis patients

CKD status

LDL-lowering drug use Mean LDL difference (mg/dL)

eze/ simva

placebo Absolute difference

eze/ simva

placebo Absolute difference

Not on dialysis 73% 8% 65% -43 -6 37

Dialysis 65% 11% 54% -29 -6 23

All patients 71% 9% 61% -39 -6 33

La dislipidemia nella malattia renale cronica:...

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