Statin Therapy in Patients with Diabetes or CKD: Friend or Foe?

John J.P. Kastelein, MD PhD FESCAcademic Medical Center / University of Amsterdam

Dept. Vascular MedicineAmsterdam, The Netherlands

Ho Chi Minh City, VietnamAugust 7, 2014

Summary: The kidney & statin therapy: Friend or Foe?

• Friend

– Kidney disease and CVD

– Prevention of CVD and death

– Reduction of CKD progression?

• Foe

– Can cause renal

failure?

CKD Stages :

Stage DescriptionGFR

(ml/min/1.73 m2)

1Kidney Damage with

Normal or GFR 90

2Kidney Damage with

Mild GFR60-89

3 Moderate GFR 30-59

4 Severe GFR 15-29

5 Kidney Failure < 15 or Dialysis

* GFR estimated from serum creatinine using MDRD Study equation based on age, gender, race and calibration for serum

creatinine. For Stage 1 and 2, kidney damage estimated by spot albumin-to-creatinine ratio 17 mg/g in men or 25 mg/g in

women in two measurements.

Age-Standardized Rates of Death from Any Cause (Panel A) and Cardiovascular Events (Panel B),

According to the Estimated GFR among 1,120,295 Ambulatory Adults

Go A et al. NEJM 200; 351: 1296-305

Causes of death in renal failure patients : studies with statins

Lewis D et al. J Ren Care. 2010;36 Suppl 1:27-33

Friend: Can statins reduce CVD in subjects with CKD?

Wanner, C. et al. N Engl J Med 2005;353:238-248Fellstrom et al. NEJM 2009;360:1395-407

Pro

po

rtio

nal

red

uct

ion

inat

her

osc

lero

tic

even

t ra

te (

95

% C

I)

0%

5%

10%

15%

20%

25%

30% Statin vs control(21 trials)

Mean LDL cholesterol differencebetween treatment groups (mg/dL)

More vs Less(5 trials)

SHARP32 mg/dL

0 20 4010 30

SHARP17% risk reduction

SHARP and CTT : Major atheroscleroroticevents by LDL-C reduction

Lancet 2011; 377: 2181-2192

Summary of the effects of statin therapy on major

cardiovascular events stratified by kidney function.

Hou W et al. Eur Heart J 2013;34:1807-1817

Overall 23% reduction18% per mmol/L

48 429 patients with CKD, including 6690 major

cardiovascular events and 6653 deaths.

Statins and cardiovascular outcomes in CKD according to

dialysis or not

Hou W et al. Eur Heart J 2013;34:1807-1817

Impact of Statin Treatment According to Renal Status

Hou W et al. Eur Heart J 2013;34:1807-1817

Friend: Can statins reduce renal function loss?

1

313

Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes

“A modest beneficial effect of atorvastatin on eGFR, particularly in those with albuminuria, was observed.

Atorvastatin did not influence albuminuria incidence. Atorvastatin was effective at decreasing CVD in those with and

without a moderately decreased eGFR and achieved a high absolute benefit.”

American Journal of Kidney Diseases 2009: 54: 810-819

This slide deck is intended for medical to medical communications and not for promotional use.This slide deck is intended for medical to medical communications and not for promotional use.

Proportion of patients with decline or improvement from baseline eGFR:TNT

9.2%

37.8%

6.6%

45.6%

0%

10%

20%

30%

40%

50%

Atorvastatin 10mg Atorvastatin 80mg

eGFR improvement from

<60mL/min/1.73m2

eGFR decline from

≥60mL/min/1.73m2

P<0.0001

P<0.0001

% o

f p

atie

nts

with

ch

an

ge

in e

GF

R

(n = 3,324) (n = 3,225) (n = 1,505) (n = 1,602)

American Journal of Kidney Diseases 2009: 54: 810-819

Are all statins similar regarding renal function?

This slide deck is intended for medical to medical communications and not for promotional use.This slide deck is intended for medical to medical communications and not for promotional use.

PLANET I: Prospective evaLuation of proteinuriA and reNal function in diabETic patients with progressive renal disease

Primary end point:

Change in urinary/creatinine ratio from baseline to Week 52

Ongoing, report date unknown

Key secondary end points:

Assessment of relationship between renal effects and lipid parameters from baseline to weeks 26 and 52

Change in GFR from baseline toweeks 26 and 52

Rosuvastatin 20mg

Atorvastatin 40mg

Rosuvastatin 10mg

Rosuvastatin 40mg

Atorvastatin 80mg

Weeks 0 4 52

353 patients

Type 1 or 2 diabetes

Mild hypercholesterolemia

Fasting LDL-C ≥90mg/dL

Moderate proteinuria

Receiving ACE inhibitor and/or

ARB treatment for >3 months Period 1 Period 2

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany

This slide deck is intended for medical to medical communications and not for promotional use.This slide deck is intended for medical to medical communications and not for promotional use.

Planet 1: change in eGFR

-2.73

-3.7

-5.46

-7.29

-10

-8

-6

-4

-2

0

Week 26 Week 52

RSV 10/10 RSV 20/40 ATV 40/80

*eGFR data not providedThese results have not been published and have not been peer-reviewed

Ch

an

ge

in

eG

FR

(m

L/m

in)

Week 26 Week 52

Mean change in eGFR significantly different between RSV 20/40 and ATV 40/80 at Week 26 (P=0.04) and Week 52 (P=0.01)

P=0.03

P=0.0001

P=0.01

P=0.0002

NSNS

*

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany

This slide deck is intended for medical to medical communications and not for promotional use.This slide deck is intended for medical to medical communications and not for promotional use.

Planet II: prospective evaluation of proteinuria and renal function in non-

diabetic patients with progressive renal disease

Primary end point:

Change in urinary/creatinine ratio from baseline to 52 weeks

Key secondary end points:

Assessment of relationship between renal effects and lipid parameters from baseline to 26 and 52 weeks

Change in GFR from baseline to 26 and52 weeks

Rosuvastatin 20mg

Atorvastatin 40mg

Rosuvastatin 10mg

Rosuvastatin 40mg

Atorvastatin 80mg

Weeks 0 4 52

237 patients

Mild hypercholesterolemia

Fasting LDL-C ≥90mg/dL

Moderate proteinuria

Receiving ACE inhibitor and/or

ARB treatment for >3 months

Period 1 Period 2

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany

This slide deck is intended for medical to medical communications and not for promotional use.This slide deck is intended for medical to medical communications and not for promotional use.

Planet 2: change in eGFR

-4

-3

-2

-1

0

1

2

Week 26 Week 52

RSV 10/10 RSV 20/40 ATV 40/80

*P 0.03, †P=NS vs. baseline

Cha

ng

e in e

GF

R (

mL

/min

)

Week 26 Week 52

†NS

1.39

-3.41*

-1.61

†NS

-2.71

†NS-3.30*

-1.74

†NS

de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany

Foe: Can statins damage the kidney?

CTT meta-analysis: muscle damage with

statins

• Myopathy: 0.5/1,000

• Rhabdomyolysis :0.1/1,000

Lancet 2012;380:581-590

Adverse events of statin reported in the trials with chronic

kidney disease.

Hou W et al. Eur Heart J 2013;34:1807-1817

Conclusions: Friend of foe?

• CKD

– is increasing in South East Asia

– raises CVD risk

• Statins reduce CVD and mortality in CKD

– Benefit proportional do LDL-C lowering

– Less benefit in those with more advanced disease

• Statins are safe in CKD

• Improvement in GFR (Atorva trials)