Statin Role in High

Risk Primary
Prevention Patients:
What’s new?

1
Tsunami of Cardiovascular Disease Targets Indonesia
 Age-Standardized Stroke and CHD Death
Rates by Country, 2002
Stroke death rate per 100,000 person-years CHD death rate per 100,000 person-years

3
Ueshima H et al. Circulation. 2008;118:2702-2709.
 Indonesia is rank #1
worldwide in terms of
the highest death rate
caused by Stroke Indonesia is rank #5 for the most country
with Diabetes prevalence

International Diabetes Federation 2014

Data Source: Published By WHO May 2014 ( .
http://www.worldlifeexpectancy.com/), (http://
www.worldlifeexpectancy.com/country-health-
profile/indonesia
)
 CHD risk increases with increasing levels of LDL-C

3.7

Relative risk for CHD

2.9

(log scale)
2.2

1.7
1.3

1.0

40 70 100 130 160 190

LDL-C (mg/dL)
 For every 30 mg/dL increase in LDL-C, the relative risk for CHD
increases by about 30%
 Elevated LDL-C or total cholesterol levels increase the risk of CHD,
independent of other risk factors

Grundy SM, et al. Circulation 2004;110:227–239

CHD, coronary heart disease Figure available for electronic presentation per Wolters Kluwer Health.
LDL-C, low-density lipoprotein-cholesterol Contact AHA 214-706-1131 for print permissions
Need for optimization of treatment dyslipidemia
to maximize benefit and improve outcome
Rationale For Primary Prevention
Occlusive Plaque
Fatty Fibrous Atherosclerotic Rupture/ Unstable
Normal Streak Plaque Plaque Fissure &
Thrombosis Angina
MI
Coronary
Death
Stroke
Critical Leg
Ischemia
Most MI’s arise from less % stenosis
8
68%
0

% MI Patients
6
0

Clinically Silent Effort Angina 4

0
Claudication 2
18%
14%
0

Increasing Age 0
<50 50%–70% >70
% %
% Stenosis
Adapted from Falk et al. Circulation. 1995;92:657–671. Rioufol G, et al. Circulation 2002;106:804-8
7 CVD Primary Prevention
Guidelines updates for high risk
primary prevention patients:
Diabetes, Multiple risk factors &
Kidney Diseases?

8
 Guidelines identify four statin benefit groups
The guidelines: ACC/AHA, November 2013

Group 1 Group 2

Clinical ASCVD LDL-C ≥190 mg/dL

CHD, stroke, and
peripheral arterial disease,
all of presumed
atherosclerotic origin

Group 3 Group 4

Diabetes mellitus ASCVD risk ≥7.5% =

Multiple Risk Factors
+ aged 40–75 years Patients
+ LDL-C 70–189 mg/dL No diabetes
+ aged 40–75 years
+ LDL-C 70–189 mg/dL

ASCVD, atherosclerotic cardiovascular disease

CHD, coronary heart disease
9
LDL-C, low-density lipoprotein-cholesterol Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print
 Guideline recommendations for patients with diabetes: Lipids

ACC/AHA 2013: Treatment decision flow

Type 1 or 2 diabetes
No Consider statin for
Age 40–75 years
individual patients
Yes

Estimate 10-year ASCVD risk

with pooled cohort equations • No RCT evidence to
support treating to
specific LDL–C and/or
non-HDL–C treatment
ASCVD risk ≥7.5% ASCVD risk <7.5% targets
• The appropriate
High-intensity statin Moderate-intensity statin intensity of statin
Expected to reduce LDL-C Expected to reduce LDL-C therapy should be
by ≥50% by 30-50% used to reduce
ASCVD risk in patients
most likely to benefit

Stone NJ, et al. J Am Coll Cardiol 2014;63(25 Pt B):2889-2934.

10
 Intensity of Statin Therapy
High Moderate Low
 LDL-C ≥50%  LDL-C 30 to <50%  LDL-C <30%
Atorva 40-80 mg Atorva 10-20 mg Simva 10 mg
Rosuva 20-40 mg Rosuva 5-10 mg Prava 10-20 mg
Simva 20-40 mg Lova 20 mg
Pravas 40 mg Fluva 20-40 mg
Lova 40 mg Pitava 1 mg
Fluva XL 80 mg
Fluva 40 mg bid
Pitava 2-4 mg

Statins in bold were evaluated in randomized controlled trials;

those in italics were not

2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce

Atherosclerotic Cardiovascular Risk in Adults, p 34 11
ACC/AHA Guidelines Recommendations for Nonstatin
Drugs (Fibrates & Ezetimibe)

 The panel could find no data supporting the routine use of nonstatin
drugs added to statin therapy to further reduce ASCVD events
 In addition, identification of any RCT’s that assessed ASCVD outcomes in statin-
intolerant patients was not found

Fenofibrate dapat dipertimbangkan untuk digunakan bersama moderate/low

intensity statin hanya bila manfaatnya untuk menurunkan risiko ASCVD
ATAU menurunkan TG ketika kadarnya > 500 mg/dL, melebihi
risiko efek samping yang potensial
1. Stone NJ et al. J Am Coll Cardiol 2014;63:2889–2934
12
 FIELD: Fenofibrate did not reduce primary outcome
(CHD death or nonfatal MI) in patients with diabetes
FIELD: fenofibrate 200 mg/d vs placebo in 9795 patients with type 2 diabetes
Median follow-up: 5 years
3.5
Mean lipid level (mmol/L)

3.07 3.1
Placebo, baseline Fenofibrate, baseline
3.0
2.6
2.43 Placebo, study end Fenofibrate, study end
2.5
1.93 2.0 1.87
2.0
1.47
1.5
1.1 1.1 1.121.13
1.0
0.5
0.0
LDL-C HDL-C TGs
HR 0.79
95% CI 0.68 to 0.93
HR 0.89 p=0.003
Fenofibrate Placebo
Rate/1000 person-years

95% CI 0.75 to 1.05 p=0.18

16 15.0
p=0.16† HR 0.76 14.2
14 12.9
11.7
95% CI 0.62 to 0.94 11.9
12 10.4 p=0.01
10 p=0.36
8.4
8 p=0.22 6.4 6.4
7.1

6 4.4
3.7
4
2
0
Primary outc... CHD mortality Nonfatal MI Stroke All-cause morta... Coronary
*CHD mortality or nonfatal MI; revasculariza...
†
ARR over course of study=0.7%; NNT=143
NNT, number needed to treat Keech A, et al. Lancet 2005;366:1849–1861
Group 4. ASCVD risk ≥7.5%
LDL-C 70–189 mg/dL, no diabetes or clinical ASCVD
ACC/AHA 2013: Treatment decision flow

No diabetes, age 40–75 years,

LDL-C 70–189 mg/dL

Estimate 10-year ASCVD risk

with AHA/ACC risk calculator

ASCVD risk ≥7.5% ASCVD risk 5–<7.5% ASCVD risk <5%

• Initiate moderate-to- high • Consider moderate

intensity statin
• Re-emphasize lifestyle
habits
• Additional factors may be
intensity statin
considered before
• Re-emphasize lifestyle
initiating statin therapy
habits

Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print 14
Pooled Cohort Equations for ASCVD Risk
Prediction

ACC/AHA Guideline on the Assessment of cardiovascular Risk : A report of the American College of Cardiology/American
Heart Association Taskforce on practice guideline, 2013
ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of
the American College of Cardiology/American Heart Association Taskforce on practice guideline, 2013
15
UK NICE guidelines 2014: Primary Prevention part
Statin LDL-cholesterol reduction • 1 = 20–30% reduction in LDL-C:
Dose (mg/day) 5 10 20 40 80 low-intensity statin
• 2 = 31–40% reduction in LDL-C:
Fluvastatin – – 21%1 27%1 33%2 medium-intensity statin
Pravastatin – 20%1 24%1 29%1 – • 3 = >40% reduction in LDL-C:
high-intensity statin
Simvastatin – 27%1 32%2 37%2 42%3§
Atorvastatin – 37%2 43%3 49%3 55%3
Rosuvastatin 38%2 43%3 48%3 53%3 –

National Institute for Health and Care Excellence Lipid modification July
2014 http://www.nice.org.uk/Guidance/CG181. The information used to
make the table is from Law MR et al BMJ 2003;326:142
 KDIGO Guidelines for Lipid Management in
CKD 2013
KDIGO guidelines recommend
statin for patients with CKD and
coronary disease
 KDIGO recommends statin treatment in adults
aged 18–49 years with CKD, not treated with
dialysis or transplantation, who have markers
of high risk, including known coronary disease

 In patients with CKD and prior vascular

disease, the rate of coronary death or incident
MI is sufficiently high to warrant statin
treatment
KDIGO, Kidney Disease Improving Global Outcomes
17
MI, myocardial infarction KDIGO Lipid Management Guidelines. Kidney Inter Suppl. 2013;3:259–305
Publication: Eur Heart J online 27 August 2016
http://eurheartj.oxfordjournals.org/content/early/2016/08/26/eurheartj.ehw272

Evidence-based consensus of European Task Force including

European Society of Cardiology (ESC) and European
Atherosclerosis Society (EAS)

Catapano AL et al. Atherosclerosis.2016;253:281-344 18

Total CV risk

 Guidelines focus on total CV risk

 The higher the total CV risk, the more intense the action should be
 Risk is estimated in apparently healthy individuals using SCORE charts
 Charts for countries at high and low CV risk
 Estimates 10-year absolute risk of first fatal ASCVD event
 Calibrated or electronic versions available for many individual countries
 Charts available for:
 Total cholesterol
 Total: HDL-C ratio
 Effect of HDL-Cl on risk

ASCVD=atherosclerotic cardiovascular disease; CV=cardiovascular;

SCORE=systematic coronary risk evaluation Catapano AL et al. Atherosclerosis.2016;253:281-344 19
SCORE chart: 10-year risk of fatal CVD in
population at high CVD risk
Women Men
Non-smoker Smoker Age Non-smoker Smoker

180 7 8 9 10 12 13 15 17 19 22 14 16 19 22 26 26 30 35 41 47
160 5 5 6 7 8 9 10 12 13 16 9 11 13 15 16 18 21 25 29 34
65
140 3 3 4 5 6 6 7 8 9 11 6 8 9 11 13 13 15 17 20 24
120 2 2 3 3 4 4 5 5 6 7 4 5 6 7 9 9 10 12 14 17 SCORE
180 4 4 5 6 7 8 9 10 11 13 9 11 13 15 18 18 21 24 28 33 15% and over
160 3 3 3 4 5 5 6 7 8 9 6 7 9 10 12 12 14 17 20 24 10%-14%
60
140 2 2 2 3 3 3 4 5 5 6 4 5 6 7 9 8 10 12 14 17 5%-9%
120 1 1 2 2 2 2 3 3 4 4 3 3 4 5 6 6 7 8 10 12 3%-4%
2%
180 2 2 3 3 4 4 5 5 6 7 6 7 8 10 12 12 13 16 19 22 1%
160 1 2 2 2 3 3 3 4 4 5 4 5 6 7 8 8 9 11 13 16 <1%
55
140 1 1 1 1 2 2 2 2 3 3 3 3 4 5 6 5 6 8 9 11
120 1 1 1 1 1 1 1 2 2 2 2 2 3 3 4 4 4 5 6 8
10-year risk of fatal
180 1 1 1 2 2 2 2 3 3 4 4 4 5 6 7 7 8 10 12 14 CVD in populations
160 1 1 1 1 1 1 2 2 2 3 2 3 3 4 5 5 6 7 8 10 at high CVD risk
Systolic blood pressure

0 1 1 1 1 1 1 1 1 2
50 2 2 2 3 3 3 4 5 6 7
140
120 0 0 1 1 1 1 1 1 1 1 1 1 2 2 2 2 3 3 4 5

180 0 0 0 0 0 0 0 0 1 1 1 1 1 2 2 2 2 3 3 4
160 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 2 2 3
40
140 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 2 2
120 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1
4 5 6 7 8 4 5 6 7 8 4 5 6 7 8 4 5 6 7 8

Cholesterol (mmol/L) 150 200 250 300

mg/dL

Catapano AL et al. Atherosclerosis.2016;253:281-344 20

Very high-risk subjects

 Risk estimation is not needed

 Immediate management of risk factors is indicated
Very high-risk Subjects with any of the following:
• Documented cardiovascular disease (CVD), clinical or unequivocal on
imaging. Documented CVD includes previous myocardial infarction
(MI), acute coronary syndrome (ACS), coronary revascularization
(percutaneous coronary intervention (PCI), coronary artery bypass graft
surgery (CABG)) and other arterial revascularization procedures, stroke
and transient ischemic attack (TIA), and peripheral arterial disease
(PAD). Unequivocally documented CVD on imaging is what has been
shown to be strongly predisposed to clinical events, such as significant
plaque on coronary angiography or carotid ultrasound
• DM with target organ damage such as proteinuria or with a major risk
factor such as smoking, hypertension, or dyslipidemia
• Severe CKD (GFR <30 mL/min/1.73m2)
• A calculated SCORE ≥10% for 10-year risk of fatal CVD

CKD=chronic kidney disease; DM=diabetes mellitus;

GFR=glomerular filtration rate Catapano AL et al. Atherosclerosis.2016;253:281-344 21
Other risk categories

 In high-risk patients:
 Risk estimation is not needed
 Immediate management of risk factor is indicated

High-risk Subjects with:

• Markedly elevated single risk factors, in particular cholesterol
>8 mmol/L (>310 mg/dL) (eg in familial hypercholesterolemia)
or BP ≥180/110 mmHg
• Most other people with DM (some young people with type 1
diabetes may be at low or moderate risk)
• Moderate CKD (GFR 30–59 mL/min/1.73m2)
• A calculated SCORE ≥5% and <10% for 10-year risk of fatal CVD

Moderate-risk SCORE is ≥1% and <5% for 10-year risk of fatal CVD

Low-risk SCORE <1% for 10-year risk of fatal CVD

BP=blood pressure Catapano AL et al. Atherosclerosis.2016;253:281-344 22

Choice of lipid treatment target

 Guidelines retain goal approach to lipid management

 Specific goals for patient groups help to individualize management
 Goals can aid doctor–patient communication and encourage adherence
 LDL-C is primary treatment target
 Guidelines introduce two secondary targets:
 Non-HDL-C (= LDL-C + 0.8 mmol/L [30 mg/dL])
 ApoB if available
 If LDL-C goal achieved, consider intensification to reach secondary target in
patients at very high risk
 HDL-C or TGs:
 Should be measured before treatment starts
 Markers of risk but not treatment targets

Catapano AL et al. Atherosclerosis.2016;253:281-344 23

Lipid targets: Summary
Level of risk Primary target Secondary target
Very high LDL-C <70 mg/dL Non-HDL-C <100 mg/dL
Or Or
≥50% ↓ if baseline 70−135 mg/dL ApoB <80 mg/dL
High LDL-C <100 mg/dL Non-HDL-C <130 mg/dL
Or Or
≥50% ↓ if baseline 100−200 mg/dL ApoB <100 mg/dL
Moderate LDL-C <115 mg/dL Non-HDL-C <145 mg/dL
Low LDL-C <115 mg/dL Non-HDL-C <145 mg/dL

Sequence of therapies for hypercholesterolemia

 Statin to highest recommended dose or highest tolerable dose
 Statin intolerance: ezetimibe ± bile acid sequestrant
 Goal not reached: statin + cholesterol-absorption inhibitor
 Goal not reached: statin + bile acid sequestrant
 Very high-risk patient, high LDL-C despite maximal tolerated statin + ezetimibe
(or statin intolerance): consider PCSK9 inhibitor PCSK9=protein convertase subtilisin/kexin type 9
Catapano AL et al. Atherosclerosis.2016;253:281-344 24
ESC / EAS 2016: Type 2 diabetes

 All patients are high or very high risk

 Formal assessment not needed: treat risk factors immediately
 Statins are drugs of choice
 In all patients with type 2 diabetes and CVD or CKD, and in type 2 diabetes
without CVD who are >40 years of age with ≥1 CVD risk factor or markers of
target organ damage:
 LDL-C <70 mg/dL is the primary goal
 Non-HDL-C <100 mg/dL and apoB <80 mg/dL are the secondary goals
 In all patients with type 2 diabetes and no additional risk factors and/or
evidence of target organ damage:
 LDL-C <100 mg/dL is the primary goal
 Non-HDL-C <130 mg/dL and apoB <100 mg/dL are the secondary goals

Catapano AL et al. Atherosclerosis.2016;253:281-344 25

ESC / EAS 2016: Chronic kidney disease
 Severe CKD (eGFR <30 mL/min/1.73m2): very high risk
 Moderate CKD (eGFR 30–59 mL/min/1.73m2): high risk
 No need for risk estimation in these groups
 Statins ↓ death and major coronary events by 20%
 Statin or statin + ezetimibe is indicated in non-dialysis-dependent CKD
 Statins eliminated by hepatic route (atorvastatin, fluvastatin,
pitavastatin) may be preferred
 Atorvastatin is the only high-intensity statin eliminated by
hepatic route
 Statin should not be initiated in dialysis-dependent CKD free of ASCVD
 In patients already on statins, ezetimibe, or statin + ezetimibe at time of dialysis
initiation, these drugs should be continued
 Statins may be considered in adult kidney transplant recipients

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate Catapano AL et al. Atherosclerosis.2016;253:281-344 26
But … what is the
evidence behind ?

27
 CARDS: Type 2 diabetes outcomes
trial
CARDS was a multicenter, randomized, double-blind study

Patient population
 Type 2 diabetes, no
clinically evident Atorvastatin 10 mg/day
CHD
 ≥1 other CHD risk
factor (smoking, n=2838
HTN, albuminuria,
retinopathy) Placebo
 LDL-C ≤160 mg/dL
 TG ≤600 mg/dL
 Aged 40–75 years 3.9-year median follow-up

 Primary endpoint: Time to first occurrence of a major CV event, defined as

acute CHD events (ie MI including silent MI, unstable angina, acute fatal CHD,
resuscitated cardiac arrest), coronary revascularization, or stroke

28
CARDS, Collaborative AtoRvastatin Diabetes Study Colhoun HM, et al. Lancet. 2004;364:685–696
 CARDS: Atorvastatin 10 mg reduced LDL-C by 40%
VS Placebo in patients with type II diabetes

LDL-C (mmol/L) TC (mmol/L)

Average difference 40% Average difference 26%
(1.2 mmol/L, p<0.0001) (1.4 mmol/L, p<0.0001)
4 6

3
4
mmol/L

mmol/L
2

2
1

0 0
0 1 2 3 4 4.5 0 1 2 3 4 4.5
Years of Study Years of Study
Placebo Atorvastatin

Colhoun H, et al. Lancet 2004;364:685-696

29
 CARDS: Efficacy results in patients with
type 2 diabetes
 CARDS: Atorvastatin 10 mg provided a significant reduction in CV events in
patients with type 2 diabetes and ≥1 risk factor compared with placebo
Incidence of major CV events*
15 Placebo (n=1410); final LDL-C=121 mg/dL Fatal/non-
Stroke fatal MI
Atorvastatin 10 mg (n=1428); final LDL-C=82 mg/dL
Cumulative incidence (%)

10 37% 48% 42%

RRR RRR RRR
95% CI 95% CI 95% CI
0.17–0.52 0.31–0.89 0.39–0.86
(p=0.001) 1 (p=0.016) 2 (p=0.007) 3

5 ARR=3.2% ARR=1.3% ARR=1.9%

0 //
2.0 0.0
3.0 1.0
3.9
Time (years)
CARDS was stopped ~2 years early due to significant CV benefits with atorvastatin
Reprinted from The Lancet, 364, Colhoun HM, Betteridge DJ et al. Primary prevention of cardiovascular disease with atorvastatin in type 2
diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, 685–96., Copyright (2004),
1. Colhoun HM, et al. Lancet. 2004;364(9435):685–696; 2. Hitman GA, et al. Diabet Med.with2007;24(12):1313–1321; 30
permission from Elsevier
*Primary endpoint 3. Lipitor Highlights of US Prescribing Information, 2013
 CARDS: Safety results in patients
with
type 2 diabetes
Data from the CARDS study of 2,838 patients with type 2 diabetes
Atorvastatin 10 mg Placebo
%
(n=1428) (n=1410)
Withdrawals due to muscle-related AEs 0.5 0.6
Myopathy 0.1 0.1
Myalgia 4.3 5.1
≥1 ALT elevation >3 x ULN 1.2 1.0
≥1 AST elevation >3 x ULN 0.4 0.3
Rhabdomyolysis 0 0

31
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal Colhoun HM et al. Lancet. 2004;364:685–696
 ASCOT-LLA: lipid-lowering in hypertensive
patients

Patient population
Double-blind period
4-week
run-in period Atorvastatin 10 mg
 10,305 patients with
hypertension and mild-to- Only patients with (n=5168)
moderate elevations in Total-C non-fasting Total-
C of 250 mg/dL
 No history of CHD
not receiving
 ≥3 other CHD risk factorsa statin or fibrate
 BP ≥160/100 mmHg treatment were Placebo
 Aged 40–79 years randomized to (n=5137)
receive treatment
3.3-year median follow-up

 Primary endpoint: composite of nonfatal myocardial infarction and fatal

CHD

a
Left-ventricular hypertrophy, other specified abnormalities on electrocardiogram, type 2 diabetes, peripheral 32
arterial disease, previous stroke or transient ischemic attack, male sex, age ≥ 55 years, microalbuminuria or
proteinuria, smoking, ratio of plasma Total-C to HDL-C ≥6 or higher, or premature family history of CHD Sever PS, et al. Lancet 2003;361:1149–1158
 ASCOT-LLA: Efficacy results in patients
with hypertension

Incidence of nonfatal MI and fatal CHD over 3.3 years

Atorvastatin 10 mg (n=5168); final LDL-C=90 mg/dL

4
Placebo (n=5137); final LDL-C=126 mg/dL
36%
Cumulative incidence

3 RRR
HR 0.64
95% CI
(%)

2 0.50–0.83
(p=0.0005)
ARR=1.1%

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.3 5.0
Years
ASCOT-LLA was stopped 2 years early due to significant CV benefits with
atorvastatin
Reprinted from The Lancet, 361, Sever PS, Dahlöf B et al, Prevention of coronary and stroke events with atorvastatin in hypertensive patients who
have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA):
a multicentre randomised controlled trial. , 1149–58., Copyright (2003), with permission from Elsevier 33
RRR, relative risk reduction Sever PS, et al. Lancet 2003;361:1149–1158 33
But … are all high intensity
statins the same in renal
safety?

34
CARDS: Beneficial effect of atorvastatin on eGFR,
most apparent in albuminuric diabetic patients
Mean change in eGFR from baseline

Colhoun HM et al. Am J Kidney Dis 2009;54:810-819.

35
PLANET I and II investigated the effects of atorvastatin and
rosuvastatin on renal function
in patients with CKD with and without diabetes

PLANET I and II were multicenter, randomized, double-blind studies

Patient population 52 weeks follow-up

PLANET I
 Type I or II diabetes
Rosuvastatin 40 mg/day
PLANET II
 No diabetes PLANET I: n=325*
Both studies PLANET II: n=220*
Rosuvastatin 10 mg/day
 Moderate proteinurea1
 Hypercholesterolemia2 Atorvastatin 80 mg/day
 ACEis or ARBs for ≥3
months prior to screening

 Primary endpoint: Within-group change in urinary protein/creatinine ratio (UPCR) from

baseline to Week 52 or last on-treatment observation carried forward (Week 52 LOCF)

*Intention-to-treat (ITT) populations

1.Urinary protein/creatinine ratio 500–5,000 mg/g;
2.Fasting LDL-C ≥90 mg/dL (2.33 mmol/L);
ACEi, angiotensin converting enzyme inhibitor; De Zeeuw D, et al. Lancet 2015. http://dx.doi.org/10.1016/S2213-
ARB, angiotensin receptor blocker 8587(14)70246-3 36
 37
PLANET I: Effect of atorvastatin or rosuvastatin on
urinary protein/creatinine ratio
Rosuvastatin 10 mg
1.4 Rosuvastatin 40 mg
Atorvastatin 80 mg
UPCR (Baseline: on-treatment)

1.2

1.0 p=0.83
p=0.53
p=0.033
0.8

0.6
0
0 14 26 39 52 LOCF
Number of patients Time (weeks)
Rosuvastatin 10 mg 107 103 97 96 95 107
Rosuvastatin 40 mg 116 112 107 106 106 116
Atorvastatin 80 mg 102 96 91 88 82 102

Data are mean baseline: on-treatment ratios

Error bars are 95% CIs. LOCF marks 52-week data accounting for all
patients in ITT population Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of
LOCF, last observation carried forward; UPCR, urinary atorvastatin and rosuvastatin in patients with diabetes who
protein/creatinine ratio have progressive renal disease (PLANET I): a randomised clinical
p values are vs baseline trial, 181–190. Copyright (2015), with permission from Elsevier 37
 38
PLANET I: Effect of atorvastatin or rosuvastatin on
estimated glomerular filtration rate
Rosuvastatin 10 mg
2 Rosuvastatin 40 mg
Atorvastatin 80 mg
0
(mL/min per 1.73 m2)

p=0.21
Change in eGFR

–2

–4

–6
p=0.0098
p=0.0002
–8

–10
0 4 8 14 26 39 52 LOCF
Number of patients Time (weeks)
Rosuvastatin 10 mg 107 106 104 103 99 95 95 107
Rosuvastatin 40 mg 116 115 112 111 109 104 109 116
Atorvastatin 80 mg 102 99 98 97 92 86 86 102

Data are mean changes from baseline

Error bars are 95% CIs. LOCF marks 52-week data accounting for all
patients in ITT population Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of
eGFR, estimated glomerular filtration rate; LOCF, last observation atorvastatin and rosuvastatin in patients with diabetes who
carried forward have progressive renal disease (PLANET I): a randomised clinical
p values are vs baseline trial, 181–190. Copyright (2015), with permission from Elsevier 38
 39

PLANET I: Reported adverse events

n (%) Rosuvastatin Rosuvastatin Atorvastatin

10 mg (n=116) 40 mg (n=123) 80 mg (n=110)
Any adverse event 69 (59.5) 79 (64.2) 63 (57.3)
Any serious adverse
18 (15.5) 20 (16.3) 21 (19.1)
event*
Any renal adverse event 9 (7.8) 12 (9.8) 5 (4.5)
Acute renal failure 0 5 (4.1) 1 (0.9)
Serum creatinine doubling 0 6 (4.9) 0
Serum creatinine doubling
0 9 (7.3) 1 (0.9)
or acute renal failure
Death 4 (3.4) 1 (0.8) 0

Statistical analysis of adverse events was not presented

One serious AE (2 episodes of cardiac failure in rosuvastatin 10 mg group) was considered related to study drug

No episodes of acute renal failure were considered related to study drug

Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of atorvastatin and rosuvastatin
in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical
trial, 181–190. Copyright (2015), with permission from Elsevier 39
 PLANET I: Conclusions

 In people with proteinuria with diabetes (PLANET I) or without

diabetes (PLANET II):
 Atorvastatin 80 mg reduced proteinuria; rosuvastatin 10 or 40
mg had no effect
 Atorvastatin 80 mg had no effect on eGFR; rosuvastatin 10 or
40 mg reduced eGFR
 Doubling of serum creatinine and acute renal failure were more
common with rosuvastatin
 Results suggest that atorvastatin and rosuvastatin have different
renal profiles

 According to the authors, atorvastatin seems to have more

renoprotective effects for the studied CKD population

De Zeeuw D, et al. Lancet 2015.http://dx.doi.org/10.1016/S2213-8587(14)70246-3

40
Han E, et al. Endocrinol Metab 2017;32:274-280
 Background
• Hyperglycemia and dyslipidemia is an important risk factor for renal
function loss
• When DM and Dyslipidemia co-occur  risk of CKD is synergistically
increased

Research Study shown that statins have the potential to protect kidney via
anti-inflammatory and anti-proliferative pathway

How about the effect of statin in Diabetic Asian Patient on

kidney function in clinical practice?
1. Han E, et al. Endocrinol Metab 2017;32:274-280
2. Campese VM, Park J. Kindney Int 2007;71:1215-1222
 Methods
Patient Population Baseline: End of Study:
• FBG, HbA1C • FBG, HbA1C
• Lipid profile (TC, LDL-C, • Lipid profile (TC, LDL-C,
• Aged ≥ 20 years HDL-C, Triglyceride) HDL-C, Triglyceride)
• Diabetes Mellitus • eGFR • eGFR
• Naïve and started
moderate-intensity
statin
Atorvastatin 10 – 20 mg/day
484 patients
Rosuvastatin 5 – 10 mg/day
Primary Endpoint

• Change in eGFR
• Rapid renal decline - 12 months
>3% reduction in eGFR
Clinical Parameter at baseline: eGFR : estimated GFR; FBG : fasting Blood Glucose;
• Age, sex, height, weight TC : Total Cholesterol; DM : Diabetes Mellitus; HTN :
• Duration of DM Hypertension
• History of HTN and cardiac
disease
• Statin treatment information Han E, et al. Endocrinol Metab 2017;32:274-280
Han E, et al. Endocrinol Metab 2017;32:274-280
Han E, et al. Endocrinol Metab 2017;32:274-280
 Primary Endpoint : Change in eGFR
eGFR Reduction
eGFR Change
Atorvastatin Rosuvastatin
81
80.3 0
80
79.1 -0.5
79 * 78.7
mL/min/1.73m2

78 -1

77 -1.5
76.1 -1.6 *
76 **
-2
75
-2.5
74
Baseline 12 months
-3 **
* p = 0.012 -3
** p = 0.01 Atorvastatin Rosuvastatin

• Among all patients, eGFR was slightly decreased from 79.8 to 77.7 mL/min/1.73m 2 (P<0.001)
• There was a greater reduction of eGFR in rosuvastatin-treated group compared to
atorvastatin
Han E, et al. Endocrinol Metab 2017;32:274-280
 Renal Function Decline
Renal Function Decline
P = 0.029

50.0%
45.0%
40.0%
35.0%
30.0%
48.7%
25.0%
20.0% 36.8%
15.0%
10.0%
5.0%
0.0%
Atorvastatin Rosuvastatin

• More individuals receiving rosuvastatin treatment experienced rapid renal function

decline than those receiving atorvastatin treatment.
• After adjusting confounding factors : compared with atorvastatin, rosuvastatin
treatment increased risk for rapid renal function loss by approximately 60% (OR,
1.60; 95% CI, 1.06 to 2.42) Han E, et al. Endocrinol Metab 2017;32:274-280
 Other Parameters

The proportion of individuals who achieved an LDL-C response (>30% reduction) was similar
between the statin groups (52% and 59.6% for atorvastatin and rosuvastatin, respectively,
P=0.115) Han E, et al. Endocrinol Metab 2017;32:274-280
 Discussion
• There is increasing evidence that statin have reno-
protective effect. However renal outcome according to
statin potency is more controversial.
• Regarding statin types and renal funtion, atorvastatin
seems to be more beneficial than rosuvastatin
• Although differences between mechanism in kidney
function remains unknown, previous study demonstrated
– greater decrease in serum uric acid level with artorvastatin than
with rosuvastatin treatment
– Increased endothelial function and renal blood flow on
atorvastatin

Han E, et al. Endocrinol Metab 2017;32:274-280

Summary

 European and US guidelines both recommend initiation of statin

therapy for primary prevention patients
 ACC/AHA guidelines suggest moderate-to-high intensity treatment

 Atorvastatin has been proven to reduce the risk of CV events across a

broad range of patients, including primary prevention patients (CARDS
& ASCOT LLA trials)

 Atorvastatin has an established safety profile, which is similar for low-

and high-intensity therapy

 Not all Statins are the same in Renal Safety

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