Lipid lowering treatment in CKD

Marcello Tonelli MD SM FRCPC

Alberta Kidney Disease Network

University of Alberta

Disclosure: advisory boards for Merck

Associated honoraria were donated to charity

Outline

• CKD and ESRD are high risk populations

• Link between LDL-C and outcomes in CKD

• Evidence for efficacy of statins (alone/combination):

• in CKD

• in ESRD (dialysis)

• not kidney transplant recipients

• Implications for practice

3

Key Message 1

• Premature mortality and CVD are very common in CKD and ESRD

Current staging system for

chronic kidney disease (CKD)

Prevalence

(1000s)

391 < 15 or Dialysis Kidney Failure 5

300 15-29 Severe GFR 4

7,400 30-59 Moderate GFR 3

5,700 60-89 Kidney damage with mild GFR

2

5,600 90 Kidney damage with

normal or GFR 1

GFR

(ml/min/1.73 m2) Description Stage

NKF-K/DOQI, 2002

CKD and ESRD are associated

with exceedingly high mortality

ESRD vs general population Stage 3-4 CKD vs general population

Jager, from ERA-EDTA and USRDS data Alberta Kidney Disease Network, unpublished data

50

60

40

30

20

10

0 20 25 30 35 40 45 50 55 60 65 70 75 80

General population

Dialysis

7.8 10.6

13.9 17.6

2.5

Expected remaining life-years

Age (years)

Europe US Whites

250

80-85

200

150

100

50

0 70-75 60-65 50-55 40-45 30-35 20-25

Age groups

Stage 0 males Stage 3 males Stage 4 males

Stage 0 females Stage 3 females Stage 4 females

Mortality rate per 1000 pt-yr

What do people with ESRD die of?

Cardiovascular disease is a major cause

USRDS, 2010 ADR National Vital Statistics Report, CDC 2010

Cardiovascular disease 42.0%

Infection 3.6%

Withdrawal 9%

All other 33.0%

Malignancy 4%

Cardiovascular disease 31.0%

All other 33.1%

Malignancy 23.2%

Lung disease 5.3%

Self-harm 1.4% Alzheimers

3.1%

Infection 12%

ESRD, USA General population, USA

…but “cardiovascular disease” is different for

ESRD patients than the general pop’n

CVD in ESRD CVD in general population

USRDS, 2010 ADR Lloyd-Jones, Circulation 2009

AMI 12%

CHF 7%

Arrhythmias/cardiac arrest 61%

Other cardiac 5% CVA

10%

Other cardiac 17%

CVA 25%

AMI 51%

CHF 12%

8

Key Message 2

• LDL-C does not predict CV risk in patients with ESRD or advanced CKD

9

Prevalence of dyslipidemia in

stages 1-4 CKD is a moving target

• Prevalence varies: • DM

• proteinuria

• GFR

Kasiske, AJKD 2001

• As GFR decreases: • lower LDL and TC

• lower HDL

• higher TG

• higher non-HDL

0

10

20

30

40

50

60

70

80

90

100

General population

CKD without protienuria

CKD with protienuria

LDL-C >3.4 mmol/l

HDL-C <1.0 mmol/l

Triglyc. >2.3 mmol/l

Lp (a) >74 nmol/l

Link between hyperlipidemia and

CVD is complex in advanced CKD

Neaton, Arch Intern Med 1992; Iseki et al, Kidney Int 2002

Men Screened for MRFIT (N=316 009)

Serum cholesterol (mmol/l)

CA

D m

ort

alit

y r

ate

per

1000 o

ver

10 y

3.6 4.6 5.7 6.7 7.8

70

60

50

40

30

20

10

0 8.8

Prevalent HD Patients (N=11,167)

0

10

20

30

40

50

60

70

3.1 -3.6

3.6 -3.9

4.1 -4.4

4.7 -4.9

5.2 -5.4

5.7 -6.5

Serum cholesterol (mmol/l)

Link between AMI and LDL is

attenuated at lower eGFR

GFR >90 HR 1.44 per mmol/l

GFR 60-89.9 HR 1.22 per mmol/L

GFR 15-29.9 HR 1.04 per mmol/L

GFR 30-59.9 HR 1.20 per mmol/L

N=868,450

12

Key Message 3

• Relative benefit of statins for CV events appears similar in people with stage 1-3 CKD to those without CKD

Summary of literature:

benefits of statins in CKD 1-4

• Consistent RRR of 20-25% for CV events

• Consistent RRR of 15-20% for mortality

• ARR greater in CKD populations

N=36,033

Palmer, Ann Intern Med in press

14

Key Message 4

• No RCT demonstrates efficacy of statin (alone or in combination) for dialysis patients

Study design

• Type 2 diabetes on dialysis for <24 mo

• 18-80 years of age

• LDL-C 2.1 - 4.9 mmol/L

• No CV events in 3 mo prior to screening

• Could be on lipid lowering Rx prior to randomization

Wanner C et al, Kidney Blood Press Res 2004

mean LDL-C reduction at 1y: 1.2 mmol/l

Primary composite end point

RR 0.92 (95 % CI: 0.77-1.10, P=0.37)

Median follow-up time of 4 years

Cu

mu

lati

ve

in

cid

en

ce

(%

)

0

10

20

30

40

50

60

1 2 3 4 5 0 5.5 years

Placebo

Atorvastatin

Years from Randomization

CV death, non-fatal MI, any CVA

N=1255

Wanner et al, NEJM 2005

AURORA: study design

Matching placebo (n~1385)

Screening

6-monthly 6

Final†

Patients (n~2750) Inclusion criteria • ESRD, on HD for ≥3 mo • 50–80 years Exclusion criteria • Statin within 6 months • KTx expected within 1y • CK or ALT >3xULN

–14 days 1

0 2

6 4

Month: Visit:

Rosuvastatin 10 mg daily (n~1391)

3 3

12 5

Treatment

Fellström B et al, Curr Control Trials Cardiovasc Med 2005

Randomization 1:1

mean LDL-C reduction at 1y: 1.1 mmol/l

Placebo

AURORA: primary endpoint

CV death, non-fatal MI, or stroke

No. at risk:

Rosuvastatin 1390 1152 962 826 551 148

Placebo 1384 1163 952 809 534 153

Cumulative incidence of primary endpoint (%)

Years from randomization

Rosuvastatin

HR=0.96 (95% CI 0.84–1.11), p=0.59

0

5

10

15

20

25

30

35

40

0 1 2 3 4 5

Fellström B et al, NEJM 2009

N=2774

SHARP: study design

Placebo (n=4191)

Screening

Final†

Men: SCr ≥150 µmol/L Women: SCr ≥130 µmol/L) or ESRD (HD or PD)

Age ≥40 years No history of MI/CABG/PTCA

Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated

0 2

Month:

Eze 10/ Simva 20 (n=4193)

0

12

Treatment

Simva 20 (n=1054)

mean LDL-C reduction at 2.5y - non-ESRD 1.0 mmol/l - ESRD 0.6 mmol/l

Baigent et al, Lancet 2011

0 1 2 3 4 5

Years of follow-up

0

5

10

15

20

25

Pro

po

rtio

n s

uff

erin

g ev

ent

(%)

RR 0.83 (0.74 – 0.94) p=0.0022

Placebo

Eze/simva

Eze/simva significantly reduced risk of major atherosclerotic events

coronary death, any MI, non-hemorrhagic stroke, coronary revasc.

N=9270

Baigent et al, Lancet 2011

SHARP: Major Atherosclerotic Events

Risk ratio & 95% CI Event Placebo Eze/simv (n=4620) (n=4650)

Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%)

Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)

0.6 0.8 1.0 1.2 1.4 Eze/simv

better Placebo better

Baigent et al, Lancet 2011

Results similar when other CV events included

Risk ratio & 95% CI Event Placebo Eze/simv (n=4620) (n=4650)

Major coronary event 213 (4.6%) 230 (5.0%) Non-haemorrhagic stroke 131 (2.8%) 174 (3.8%) Any revascularization 284 (6.1%) 352 (7.6%)

Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)

0.6 0.8 1.0 1.2 1.4 Eze/simv

better Placebo better

Other cardiac death 162 (3.5%) 182 (3.9%) Haemorrhagic stroke 45 (1.0%) 37 (0.8%)

Other major vascular events 207 (4.5%) 218 (4.7%) 5.4% SE 9.4 reduction (p=0.57)

Major vascular event 701 (15.1%) 814 (17.6%) 15.3% SE 4.7 reduction (p=0.0012)

Baigent et al, Lancet 2011

Risk ratio & 95% CI Placebo Eze/simv

Eze/simv better

Placebo better

(n=4620) (n=4650)

Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%)

Dialysis (n=3023) 230 (15.0%) 246 (16.5%)

Major atherosclerotic event 526 (11.3%) 619 (13.4%) 16.5% SE 5.4 reduction (p=0.0022)

0.6 0.8 1.0 1.2 1.4

SHARP: Major Atherosclerotic Events by renal status at randomization

No significant heterogeneity between non-dialysis and dialysis patients

(p=0.25)

Baigent et al, Lancet 2011

Palmer, Ann Intern Med in press

0.009

0.03

0.07

0.08

0.0001

ACM

CV death

MACE

MI

Stroke

less benefit in ESRD

0.89 (0.82, 0.97)

0.86 (0.78, 0.95)

0.77 (0.70, 0.84)

0.76 (0.68, 0.86)

0.86 (0.62, 1.20)

0.009

0.03

0.07

0.08

0.0001

Palmer, Ann Intern Med in press

0.009

0.03

0.07

0.08

0.0001

ACM

CV death

MACE

MI

Stroke

Statins improve outcomes in stage 1-4 CKD

benefits are smaller/questionable for dialysis patients

Is CKD 1-4 a CHD risk equivalent?

0

5

10

15

20

25

MI Diabetes GFR<60 None0

5

10

15

20

25

MI

Diabetes

GR<60

GFR<45

GFR<45 + Upr

None

status quo: diabetes is a risk equivalent and thus trumps CKD

N=1,268,029 ESRD excluded

No MI No MI & no diabetes

AMI per 1000 pt-y

What if CKD 1-4 trumped diabetes when

assessing CHD risk equivalency?

0

5

10

15

20

25

MI GR<60 GFR<45 GFR<45 + Upr Diabetes None

No MI & no CKD No MI N=1,268,029 ESRD excluded

Grundy, Diabetes Care 2006

High event rate High case fatality rate

Proven treatment efficacy

✔ ✔

✔ = risk equivalency status for CKD stage 1-4? i.e initiate statin for all? or all >40 y.o?

How should statins be adjusted

after Rx, in CKD 1-4 patients?

• Treat-to-target:

vs

• Fire-and-forget:

• no direct evidence • labor intensive • more costly • pop’n at high risk for toxicity • lower LDL ≠ better outcomes

• simple • evidence-based • focus on treating pts at risk

Summary and opinion

• Statins will not solve CVD in dialysis patients

• benefit is uncertain

• new Rx may be worthwhile in selected pts

• no evidence to stop statins at ESRD onset

• For both ESRD and CKD:

• importance of “appropriate adherence”

Summary and opinion

• Initiation: consider CKD as risk equivalent or as heavily weighted factor in global risk assessment

• Maintenance: “fire-and-forget”

• prescribe an adequate starting dose to all at risk

• ?initial Rx based on regimens safely used in RCTs

• prava 40 / simva 40 / atorva 20 / simva 20 + eze 10

• These findings emphasize the need for early identification and treatment of CKD pts at risk

Acknowledgements

• Christoph Wanner

• Bengt Fellstrom

• SHARP investigators

• Province of Alberta A-ARP

• Alberta Heritage Foundation for Medical Research

• Canada Research Chairs Program