Role of Most Potent Statin for

Dyslipidemia with Chronic Kidney

Disease Patients

Haerani Rasyid
CNEMU 2018
 Incidence of CKD in Indonesia
o based on the 2007 National Health Survey by the Ministry of
Health – Indonesia
o 16,779 subjects (age >15 y.o)
o kidney dysfunction : 3.8% (CKD-EPI eGFR <60)
o associated w/ age, female gender, hypertension, diabetes,
smoking, high LDL cholesterol & low HDL cholesterol

Kidney Dysfunction in Adult Population in Indonesia

Pringgodigdo Nugroho, Laurentius A. Pramono, Laurentia Mihardja, Suhardjono
The risk of CV events increases with worsening
renal function
All death CV events
18.6 folds 17.3 folds
5 5
4

3b 3b

3a 3a

N Engl J Med 2004;351:1296-305

 Why Is CKD Strongly Associated With
Cardiovascular Morbility and Mortality?
Coagulopathy and Fibrinolysis
platelet dysfunction Dyslipidemia
Vascular Calcification
Hypertension Ca/Phosphate/PTH

Diabetes
Hyperhomocystinemia

Inflammation Cardiovascular
CKD-related Stress of End-
Oxidative Stress Vascular Stage Renal
Disease/Dialysis
Oxidized LDL-C Pathobiology
Endothelin/Nitric
Oxide Volume Overload

Sympathetic Nervous Anemia

System Hyperactivation
LV hypertrophy Renin-Angiotensin
System

McCullough PA. JACC. 2003;41:725-28.

 PATHOGENESIS

Cardiovascular
Disease

Inflammatory mediators
GFR & Oxidative injury Lipoprotein
Proteinuria Abnormalities
Insulin resistance
Other mediators

Kidney Injury
Visconti L, et al. / J Clini & Trans Endocrinol 6 (2016) 8–14
Mechanism of Dyslipidemia in CKD

What Science Can Do

 Dyslipidemia of Chronic Kidney Disease

± LDL ↑TG
↑Small-dense Large VLDL
LDL
↑Ox-LDL

Chronic Kidney
Disease
Metabolic
Syndrome
HDL- Type 2 Diabetes

C Most Common Lipid

Profile in Pts with
↑Small-Dense
Coronary Artery
HDL
Disease (60%)

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

 “Normal” LDL cholesterol levels:
misleading information in CKD
patient
Subject A Subject B
Control CKD
TG 113 mg/dL TG 224 mg/dL
HDL 51 mg/dL HDL 48 mg/dL
LDL LDL
Mean diameter Mean diameter
273 Å 233 Å

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

Apo B= 93 mg/dl Normal LDL-C Normal LDL-C ↑Apo B= 112 mg/dl

↑Small Dense LDL
↑Ox-LDL

Increased Risk of Atherosclerosis

Lipoprotein phenotype TG,  HDL-C,  sd LDL;

Apo B: Marker of circulating LDL particles
•The evidence to date suggests
comparable relative benefit of
statins in patients with CKD to
decreased CVD complication

American Heart Journal, Baber U et al,April 2007

Can statins reduce CVD in subjects
with CKD?
 Summary of the effect of statin therapy on major CVE
stratified by kidney function
Trials published between 1970 and November 2011. Prospective,
randomized, controlled trials assessing the effects of statins on
cardio- vascular outcomes in people with kidney disease. Summary
estimates of relative risk (RR) reductions were calculated with a
random effects model. Thirty-one trials.
- 48 429 patients with CKD, including 6690 major cardiovascular
events and 6653 deaths.
- Statin therapy produced a 23% RR reduction (16–30) for major
cardiovascular events (P,0.001), an 18% RR reduction (8–27) for
coronary events, and 9% (1–16) reduction in cardiovascular or all-
cause deaths, but had no significantly effect on stroke (21%, 12 to
44) or no clear effect on kidney failure events (5%, 21 to 10).
Adverse events were not significantly increased by statins,
Conclusion ˘
• Statin therapy reduces the risk of major cardiovascular events in patients with
Hou W et al. Eur Heart J 2013;34:1807-1817
chronic kidney disease including those receiving dialysis.
 Burning question:
The Kidney & Statin therapy,
is it Friend or Foe ?
FRIEND: FOE:
• Prevention of CVD & • Can cause renal failure?
death in CKD?
• Reduction of CKD
progression?
 AURORA study
A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular
Hemodialysis
Pleiotropic effects of statins.

Davignon J. British J Clin Pharmacol. 2011;73(4):518-535

 When to treat CKD patients
with dislipidemia?
•Adopt an METABOLIC – HEMODYNAMIC
uncompromised
ALTERATIONS
theraputic
insistence 1-4 CKD Uremia
•Treat promptly
all Statin Statin beneficial
CV risk factors beneficial effect less evident
RR

Statins

Statins

Statins
DYSLP

• Treat LDL-C > 145 mg/dl

• Assess risk:benefit ratio
CVD •
1.
0
Stage 1→4 CKD Stage 5 CKD
What are the Guidelines says
2007 till 2017
 Key Features of the K/DOQI* Guidelines that Differ from
NCEP ATP III
NKF K/DOQI Guidelines
• CKD patients are considered to be in the highest
risk category
• Evaluation of dyslipidemias should occur at
presentation, after a change in status and
annually
• Drug therapy should be used for LDL100 to 129
mg/dl after only 3 months of TLC
• Initial drug therapy for elevated LDL should be
with a statin
• Fibrates may be used in Stage 5 CKD 1) for
patients with triglycerides > 500; and 2) for
patients with triglycerides > 200 mg/dl with
non-HDL cholesterol > 130 mg/dl who do not
tolerate statins
• Gemfibrozil may be the fibrate of choice for
treatment of high triglycerides in patients with
CKD
ATP III Guidelines
• CKD patients are not managed differently from
other patients
• Evaluation of dyslipidemias should occur every 5
years
• Drug therapy considered optional for LDL 100-129
mg/dl
• Initial drug therapy for elevated LDL should be with
a statin, bile acid sequestrant, or nicotinic acid
• Fibrates are contraindicated in CKD
• No preferences for which fibrate should be used for
hypertriglyceridemia

*Kidney Disease Outcome Quality Initiative

 KDOQI* 2007 Clinical Practice Guidelines and Clinical Practice
Recommendations for Diabetes and Chronic Kidney Disease

• Target LDL-C in people diabetes and CKD stages 1-4

should be < 100 mg/dL (<70 mg/dL is a therapeutic
option).
• People with diabetes, CKD stages 1-4, and LDL-C ≥ 100
mg/dL should be treated with a statin.
• Treatment with a statin should not be initiated in
patients with type 2 diabetes on maintenance
hemodialysis who do not have a specific cardiovascular
indication for treatment.

Am J Kidney Dis. 49, S1-S180, 2007 (Suppl 2)

 KDOQI Diabetes Guideline: 2012 Update
Summary of Recommendations
Am J Kidney Dis. 2012;60(5):850-886

• We recommend using LDL-C lowering medicines, such as

statins or statin/ezetimibe combination, to reduce risk of
major atherosclerotic events in patients with diabetes and
CKD, including those who have received a kidney
transplant.
• We recommend not initiating statin therapy in patients
with diabetes who are treated by dialysis.
 KDIGO* Clinical Practice Guideline for Lipid
Management in Chronic Kidney Disease

• The KDIGO Work Group does not recommend the “treat-

to-target” strategy because it has never been proven
beneficial in any clinical trial.
• Higher doses of statins have not been proven to be safe in
the setting of CKD.

Kidney International Supplements (2013) 3, 262

 KDIGO* Clinical Practice Guideline for Lipid
Management in Chronic Kidney Disease

• In adults aged >50 years with eGFR<60 ml/min/1.73 m2

but not treated with chronic dialysis or kidney
transplantation, we recommend treatment with a statin or
statin/ezetimibe combination.
• In adults aged >50 years with CKD and eGFR>60
ml/min/1.73m2 we recommend treatment with a statin.

Kidney International Supplements (2013) 3, 262

 KDIGO Clinical Practice Guideline for Lipid
Management in Chronic Kidney Disease

In adults aged 18–49 years with CKD but not treated with
chronic dialysis or kidney transplantation, we suggest
statin treatment in people with one or more of the
following :
• known coronary disease (myocardial infarction or coronary
revascularization)
• diabetes mellitus
• prior ischemic stroke
• estimated 10-year incidence of coronary death or non-fatal
myocardial infarction >10%

Kidney International Supplements (2013) 3, 262

 KDIGO Clinical Practice Guideline for Lipid
Management in Chronic Kidney Disease

• In adults with dialysis-dependent CKD, we suggest that

statins or statin/ezetimibe combination not be initiated.
• In patients already receiving statins or statin/ezetimibe
combination at the time of dialysis initiation, we suggest
that these agents be continued.

Kidney International Supplements (2013) 3, 262

 Fibrates for preventing CVD
Do not routinely offer fibrates for the prevention of CVD
to any of the following:
• people who are being treated for primary prevention
• people who are being treated for secondary prevention
• people with CKD
• people with type 1 diabetes
• people with type 2 diabetes.
Lipid modification: cardiovascular risk assessment and the modification
of blood lipids for the primary and secondary prevention of cardiovascular disease
NICE clinical guideline 181. Issued: July 2014 last modified: August 2015
 2013 ACC/AHA Guideline on the
Statin Treatment: Hemodialysis

No recommendation

The Expert Panel makes no

recommendations regarding the initiation
or discontinuation of statins in patients
with NYHA class II–IV ischemic systolic
heart failure or in patients on maintenance
hemodialysis.
 What are the treatment recommendations in
individuals with dyslipidemia and ascvd risk?

For individuals at high risk (i.e., with an ASCVD equivalent

including diabetes or stage 3 or 4 CKD with no other risk
factors, or individuals with 2 or more risk factors and a
10-year risk of 10%- 20%), an LDL-C goal <100 mg/dL is
recommended (Grade A).

AACE and Guidelines 2017

for Management of Dyslipidemia and Preventon of CVD
Endocrine Practice Vol 23 (Suppl 2) April 2017
 What are the treatment recommendations in
individuals with dyslipidemia and ascvd risk?

For individuals at very high risk (i.e., with established or

recent hospitalization for acute coronary syndrome (ACS); coronary,
carotid or peripheral vascular disease; diabetes or stage 3 or 4
CKD with 1 or more risk factors; a calculated 10-year risk
greater than 20%; or heterozygous familial
hypercholesterolemia [HeFH]), an LDL-C goal <70 mg/dL
is recommended (Grade A).

AACE and Guidelines 2017

for Management of Dyslipidemia and Preventon of CVD
Endocrine Practice Vol 23 (Suppl 2) April 2017
 What are the treatment recommendations in
individuals with dyslipidemia and ascvd risk?

For individuals at extreme risk (i.e., with progressive ASCVD,

including unstable angina that persists after achieving an LDL-C <70
mg/dL, or established clinical ASCVD in individuals with
diabetes, stage 3 or 4 CKD, and/or HeFH, or in individuals
with a history of premature ASCVD (<55 years of age for males or
<65 years of age for females), an LDL-C goal <55 mg/dL is
recommended (Grade A).

AACE and Guidelines 2017

for Management of Dyslipidemia and Preventon of CVD
Endocrine Practice Vol 23 (Suppl 2) April 2017
 National Kidney Foundation (NKF) Guidelines :
Dose Adjustment for reduced GFR (mL/min/1.73 m2)

30–90 <30 <15

Atorvastatin No adjustment No adjustment No adjustment

Pravastatin No adjustment No adjustment No adjustment

Starting dose 5 mg daily in patients with
Simvastatin No adjustment
severe kidney disease
Use doses >20 mg/day cautiously
Lovastatin No adjustment
in patients with GFR <30
No dose adjustments needed for mild to
moderate kidney disease; use caution in patients
Fluvastatin No adjustment with severe kidney disease; fluvastatin not
studied at doses >40 mg in these patients
Starting dose 5 mg and NOT to exceed 10 mg
Rosuvastatin No adjustment
in patients with GFR <30

National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2);S1-S179.

 KDIGO Clinical Practice Guideline
For Lipid Management in CKD 2013

1. Catapano AL, et al. Eur Heart J 2016 DOI: 10.1093/eurheart/ehw272

2. Stone N, et al. Circulation 2014;129:S1-S45
3. Diabetes Care 2016;39(Suppl. 1):S60-S71.DOI:10.2337/dc16-S011
4. Kidney Int Suppl 2013;3:271-279
 Relative LDL-lowering efficacy of different doses of
statins

% decrease in
Rosuvastatin
Atorvastatin

Pitavastatin

Simvastatin
Pravastatin
Fluvastatin

Lovastatin

LDL-C
- 40 mg 1 mg 20 mg 20 mg - 10 mg 30%

10 mg 80 mg 2 mg 40 or 80 40 mg - 20 mg 38%
mg
20 mg - 4 mg 80 mg 80 mg 5 mg 40 mg 41%

40 mg - - - 10 mg 80 mg 47%

80 mg - - - 20 mg - 55%

- - - 40 mg - 63%

US FDA. Web site http://www.fda.gov/drugs/drugsafety/ucm256581.htm. Accessed on December 9, 2013.

 Important to do…….
Kidney Disease Improving Global Outcomes (KDIGO)
(Kidney Int , 2013)
STAGING OF CKD

We recommend that CKD is classified based on

cause, GFR category and albuminuria category
(CGA)
• New staging concept: GFR and albuminuria categories
– GFR categories add “G3a” for GFR 45-59, “G3b” for GFR 30-44
– Albuminuria categories:

RECOMMENDATIONS RELATING TO THE ASSESSMENT OF LIPID STATUS IN

ADULTS WITH CKD

In adults with newly identified CKD (including those treated with chronic dialysis or kidney
transplantation),

we recommend evaluation with a lipid profile (total cholesterol, LDL cholesterol, HDL
cholesterol, triglycerides). (1C)
 Hot Issue
• a “reverse epidemiology” between total cholesterol levels and risk of
all-cause mortality such that lower
cholesterol levels are
associated with a higher mortality rate.
 Summary
• Chronic kidney disease (CKD) is a growing health burden
• Dyslipidemia is common in patients with CKD
• Patients with CKD are at high risk for cardiovascular disease
(CVD) and an increased prevalence of both CVD morbidity
and mortality is evident at all ages
• CVD is the leading cause of mortality in CKD , and
dyslipidemia is a significant contributor
• The use of statins has been shown to be safe and efficacious
in lipid lowering in CKD, and of benefit in reducing CVD
events in individuals with pre-end stage CKD, or post renal
transplant, but not in dialysis patients
Thank You