New Developments in the

Management of Dyslipidemia
Widjanarko. W MD
 Evolution of Lipid Management
Guidelines
NCEP ATP I NCEP ATP II NCEP ATP III
1988 1993 2001
• Exclusive focus on LDL- • Risk assessment guides • Lower LDL-C threshold
C reduction therapy for therapy initiation in
• Strong support for resins, • Goal LDL-C reduced for high-risk patients
niacin CHD (2.6 mmol/L) • LDL-C reduction to
• Statins, fibrates not first • Statins included in “major 2.6 mmol/L in patients
line drugs,” fibrates for mixed with CHD equivalent
hyperlipidemia • Low HDL-C and
triglycerides as targets

Low- to moderate-dose Moderate- to high-dose statin High-dose statin, increased

monotherapy co-administration therapy

Adapted from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA 2001;285:2486-2497;
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults JAMA1993;269:3015-3023;
NCEP Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults Arch Intern Med 1988;148:36-69.
 Pathologic Consequences
of High Cholesterol
• Atherosclerosis Human coronary artery in which there
is large, lipid-rich plaque
– Increased plasma LDL-C may
injure endothelial cells
– High LDL-C levels facilitate
progression of endothelial
injury
– Endothelial cell injury leads to
plaque formation, which
reduces lumen size and limits
blood flow
– Plaque rupture leads
to thrombosis

Adapted from Ross R. In Hurst’s The Heart, Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1139–1159;
Davies MJ.
In Hurst’s The Heart, Arteries and Veins. 9th ed. New York: McGraw-Hill, 1998:1161–1173.
 Evolution of the Lipid Treatment
Approach

NCEP/ATP I ATP II ATP III 2004

1970’s 1993 2001
1988

Framingham Angiographic trials 4S, WOSCOPS, HPS,PROVE-IT,

MRFIT (FATS, POSCH, SCOR, CARE,LIPID REVERSAL,
Helsinski Heart Study STAR, Cornish, MARS) AFCAPS/TexCAP, PROSPER,
LRC-CPT Meta-analyses VAHIT ASCOT-LLA
ALL-HAT-LLT
A to Z
ASCOT
 NCEP ATP III: LDL-C Goals
LDL-C
(2004 proposed modifications)
Moderately Moderate Lower
High Risk High Risk Risk Risk
CHD or CHD risk = 2 risk = 2 risk < 2 risk
equivalents factors factors factors
190 - (10-yr risk (10-yr risk (10-yr risk Target
>20%) 10-20%) <10%) 160
mg/dL

160 - Target Target

Clevel

130 130
mg/dL mg/dL

130 -
LDL

Target
-

or
100 optional
mg/dL
100
mg/dL**

100 -
or
optional
70
mg/dL*

70 -
*Therapeutic option in very high-risk patients and in patients with high TG, non-HDL-C<100 mg/dL;
** Therapeutic option; 70 mg/dL =1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L;
160 mg/dL = 4.1 mmol/L
Grundy SM et al. Circulation 2004;110:227-239.
 “New” CHD Risk Equivalent Category
• CHD includes history of MI. unstable angina,
stable angina, coronary artery procedures
(angioplasty or bypass surgery), or evidence of
clinically significant myocardial ischemia
• Non-coronary forms of atherosclerotic disease
– Peripheral arterial disease
– Abdominal aortic aneurysm
– Carotid artery disease (Transient ischemic
attacks or stroke of carotid origin or >50%
obstruction of a carotid artery
• Type 2 DM
• 2+ risk factors with a 10-year risk for CHD>20%
JAMA 2001. 285:2486-2497
 NCEP ATP III: The Metabolic Syndrome
Recommends a diagnosis when 3 of these risk factors are present

Risk Factor Defining Level

Abdominal obesity
(Waist circumference)
Men >102 cm (>40 in)(>35in)
Women >88 cm (>35 in) (>32in)

TG 150 mg/dL (1.7 mmol/L)

HDL-C
Men <40 mg/dL (1.0 mmol/L)
Women <50 mg/dL (1.3 mmol/L)

Blood pressure 130/85 mm Hg

Fasting glucose 110 mg/dL (6.0 mmol/L)

NCEP, Adult Treatment Panel III, 2001. JAMA 2001:285;2486-2497.

 Framingham Risk Scoring (FRS) in
patients with  2 CV risk factors

• Low Risk <10%

• Medium Risk 10-20%
• High Risk > 20% (CHD equivalent)
Limitations of FRS
1. Lack of family history of CHD
2. Unreliable if TC>280mg/dl (7.25mmol/l)
or TG>200mg/dl
3. Does not consider risk factors seen in
metabolic syndrome
4. Lower scores in women thus may
www.nhlbi.nih.gov/guidelines/cholesterol/index.htm
 Non-HDL Cholesterol

• Formula: Non-HDL-C= TC-HDL

• Convenient measure of triglyceride-rich remnanat
lipoproteins and cholesterol incorporated into
LDL-C
• More comprehensive account of atherogenic
lipoprotein
• Does not require a fasting sample
• Should be calculated if TG>200mg/dl
• Target level: 30mg/dl above the ATPIII LDL-C
goal
Szapary PO. 2004. Am Heart J. 148:211-221.
 NCEP ATP III Guidelines
(2004 proposed modifications)
Initiate TLC* Drug therapy
Patients with LDL-C
if LDL-C considered if LDL-C
goal

High risk: CHD or <100 mg/dL† 100 mg/dL† 100 mg/dL

CHD risk equivalents (optional goal: (<100 mg/dL:
(10-year risk >20%) <70 mg/dL†) PROVE-IT drug optional)

Moderately high risk: <130 mg/dL† 130 mg/dL† 130 mg/dL

>2 risk factors (10- (optional goal: (100-129 mg/dL:
year risk 10-20%) <100 mg/dL†) drug optional)

Moderate risk: >2 <130 mg/dL† 130 mg/dL† 160 mg/dL†

risk factors (10-year
risk <10%)

Lower risk: 0-1 risk <160 mg/dL† 160 mg/dL† 190 mg/dL†
factors (160-189 mg/dL:
drug optional)
†70 mg/dL = 1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L;
190 mg/dL = 5 mmol/L: * TLC: therapeutic lifestyle changes

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

 PROVE-IT: Pravastatin or Atorvastatin
Evaluation and Infection Therapy (TIMI 22)
Double-blind, randomized trial in 4,162 patients with Acute Coronary
Syndrome <10 days and Total Cholesterol < 240 mg/dL

ASA + Standard Medical Therapy

Pravastatin 40 mg, qhs Atorvastatin 80 mg, qhs

Gatifloxacin Placebo Gatifloxacin Placebo

Duration: Mean 2 year follow-up (1001 events)

Primary Endpoint: Death, MI, Documented UA

requiring hospitalization, revascularization
(> 30 days after randomization), or Stroke
 PROVE-IT: Changes from (Post-
ACS) Baseline in Median LDL-C
120 Median LDL-C (Q1, Q3)

100 95 (79, 113)

Pravastatin 40mg
80 18%
LDL-C
(mg/dL) 62 (50, 79)
60
Atorvastatin 80mg
48% 
40
P<0.001
20
Rand. 30 days 4 mos. 8 mos. 16 mos. Final

Note: Changes in LDL-C may differ from prior trials:

• 25% of patients on statins prior to ACS event
• ACS response lowers LDL-C from true baseline
Cannon CP et al, N Engl J Med 2004;350. www.nejm.org
 PROVE -IT: Greater Reductions in
PROVE-IT:
LDL -C with Intensive Statin Therapy
LDL-C

atorvastatin pravastatin
80 mg 40 mg
Reduction in LDL-C from baseline (%)

(n=2099) (n=2063)
0

-10.4%
-10

-20

-30

-40 -41.5%

p<0.001
-50

Cannon CP, Braunwald E, McCabe CH et al. N Engl J Med 2004;350:1495-1504.

PROVE-IT: All-Cause Death or Major CV Events in
All Randomized Subjects

Pravastatin 40mg
30 (26.3%)
25

20
% with Atorvastatin 80mg
Event 15 (22.4%)

10
16% RRR at 2 years
5 (p = 0.005)

0
0 3 6 9 12 15 18 21 24 27 30
Months of Follow-up
Cannon CP et al, N Engl J Med 2004;350. www.nejm.org
 NCEP ATP III Guidelines
(2004 proposed modifications)
Initiate TLC* Drug therapy
Patients with LDL-C
if LDL-C considered if LDL-C
goal

High risk: CHD or <100 mg/dL† 100 mg/dL† 100 mg/dL

CHD risk equivalents (optional goal: (<100 mg/dL:
(10-year risk >20%) <70 mg/dL†) drug optional)

Moderately high risk: <130 mg/dL† 130 mg/dL† 130 mg/dL

>2 risk factors (10- (optional goal: (100-129 mg/dL:
year risk 10-20%) HPS, ASCOT-LLA drug optional)
<100 mg/dL†)

Moderate risk: >2 <130 mg/dL† 130 mg/dL† 160 mg/dL†

risk factors (10-year
risk <10%)

Lower risk: 0-1 risk <160 mg/dL† 160 mg/dL† 190 mg/dL†
factors (160-189 mg/dL:
drug optional)
†70 mg/dL = 1.8 mmol/L; 100 mg/dL = 2.6 mmol/L; 130 mg/dL = 3.4 mmol/L; 160 mg/dL = 4.1 mmol/L;
190 mg/dL = 5 mmol/L: * TLC: therapeutic lifestyle changes

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

 HPS: Statin Benefits Patients with
Low Baseline Cholesterol Levels
40

- 24%
RR
30
p<0.0001
placebo (n=10,267)
Incidence %

simvastatin
20 - 13% RR (n=10,269)
P=0.0003

- 25% RR
10 p<0.0001

0
All-cause Major vascular All stroke
mortality events

RR - relative risk reduction vs. placebo

HPS Collaborative Group, Lancet 2002;360:7-22

 HPS: Vascular Event Reduction
versus Baseline Lipid Levels
Lipid levels simvastatin placebo Rate ratio & 95% CI
at entry (n=10269) (n=10267) simva better placebo better

LDL cholesterol (mmol/l)

< 3.0 (116 mg/dl) 598 (17.6%) 756 (22.2%)
 3.0 < 3.5 484 (19.0%) 646 (25.7%)
 3.5 (135 mg/dl) 951 (22.0%) 1183 (27.2%)

Total cholesterol (mmol/l)

< 5.0 (193 mg/dl) 360 (17.7%) 472 (23.1%)
 5.0 < 6.0 744 (18.9%) 964 (24.5%)
 6.0 (323 mg/dl) 929 (21.6%) 1149 (26.8%)

All patients 2033 (19.8%) 2585 (25.2%) 24% SE 3

reduction
(2p<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

: www.hpsinfo.org
Heart Protection Study (HPS)

• Because the HPS demonstrated the benefits of

statin therapy even in patients with LDL cholesterol
levels <100 mg/dL at baseline, simvastatin received
a label change approved by the US Food and Drug
Administration (FDA) to recommend the initiation of
the 40-mg dose for all high-risk patients, regardless
of the baseline LDL cholesterol level.
Initiate Statin therapy in moderate-risk patients
with LDL-C <130mg/dl

• If with additional risk factors such as

1. Clinical evidence of metabolic syndrome
2. Age> 70 years
3. Three or more traditional risk factors
4. Continued cigarette smoking
5. HDL-C<40mg/dl (1.0mmol/l)
6. TG>200mg/dl (2.3mmol/l)
7. Highly sensitive C-reactive protein (hs-CRP)> 3mg/l
8. Coronary calcium (CAC) in the 75th percentile for age and
sex
 REVERSAL - Reversal of Atherosclerosis
with Aggressive Lipid Lowering

160
3

% Change in plaque volume

140
LDL-cholesterol (mg/dL)

150 150 2.5 2.7

120
2
100 110
1.5
80
79 1
60
0.5
40
0
20 -0.4
-0.5
0 pravastatin atorvastatin
pravastatin atorvastatin

Comparison of atorvastatin 80 mg and pravastatin 40 mg on IVUS

coronary plaque volume in 502 patients with CHD over 18 months
Steven Nissen, AHA Scientific Sessions 2003, November 9-12, Orlando, USA
 ARBITER: Arterial Biology for the
Investigation of the Treatment Effects of
Reducing Cholesterol
120 0.03

Change in mean CIMT (mm)

LDL-cholesterol (mg/dL)

100 110 0.02 0.025

0.01
80
76 0
60
-0.01
40 -0.02
20 -0.03 -0.034

0 -0.04
pravastatin atorvastatin pravastatin atorvastatin

Comparison of atorvastatin 80 mg and pravastatin 40 mg

on carotid IMT in 161 patients with CVD over 12 months
Taylor AJ et al, Circulation 2002; 106: 2055-2060
 Is Aggressive LDL-C Lowering More
Effective in Reducing Clinical Events?

•Trials in ACS • Trials in Chronic Stable

Atherosclerosis

•PROVE-IT • TNT
• SEARCH
• IDEAL

•
• Evaluate the long term effects
•Evaluate the effects of early on clinical outcomes in
plaque stabilization on clinical patients with chronic stable
outcomes in ACS patients atherosclerosis
(2 years) • (5 years)
Ongoing Statin Trials

Trial N Study Treatment Duration Primary

population outcome

TNT 10,000 CAD Atorvastatin 10mg vs 5 yrs Coronary

atorvastatn 80mg to target death, NFMI
LDL 100mg/dl vs 75mg/dl

SEARCH 10,000 CAD Simvastatin 20mg vs 5 yrs Cardiac

simvastatin 80mg events

IDEAL 7,600 CAD Simvastatin 20 to 40mg vs 5.5 yrs Cardiac

atorvastatin 80mg events

JUPITER 15,000 Healthy Rosuvastatin 20mg vs 5 yrs Cardiac

men>55, placebo events
women>65,
CRP,
LDL<130
 General Recommendtions from
the ATPIII Update
1. When deciding to treat LDL-C, aim to
lower it by 30-40%
2. In a patient with CHD risk equivalents
with elevated TG or low HDL,
consideration should be given to adding a
fibrate or niacin to baseline statin therapy
 LDL-C Lowering capacity of statins
Drug Dose mg/dl LDL reduction

Atorvastatin 10 39 %

Lovastatin 40 31 %

Pravastatin 40 34 %

Simvastatin 20-40 35-41 %

Fluvastatin 40-80 25-35 %

Rosuvastatin 5-10 39-45 %

For every doubling of the dose above standard dose, an approximate 6% decrease in
LDL-C level can be obtained.
Aggressive Statin therapy

• Approved starting doses:

– Atorvastatin > 10mg
– Fluvastatin 80mg
– Lovastatin > 40mg
– Pravastatin > 40mg
– Rosuvastatin > 10mg
– Simvastatin > 40mg
• Titration from 40 to 80mg dose is associated with a 3-fold
increase in liver toxicity and myopathy
 Adult Population Not Reaching
LDL-C Targets
100 NHANES III
L-TAP 82.5 82
80
63
60 54.6
% not at
LDL-C 40
targets
20

0
≥2 RF CHD

Risk profile
LDL-C target levels (mg/dL)
≥2 RF: <130
CHD: <100

National Center for Health Statistics. National Health and Nutrition

Examination Survey (III); 1994. (Data collected 1991-1994.)
Pearson TA et al. Arch Intern Med. 2000;160:459-467.
 Why Are So Few Patients
Reaching Their LDL-C Goal?

 Many patients are never treated or do not follow their

treatment program.
 Most LDL-C reduction with statins occurs with the
starting dose.1
 Each doubling of the statin dose lowers LDL-C about
6%.
– Therefore, an additional 18% reduction would require
doubling the dose 3 times.2
 Most patients taking statins do not have their dose
increased.1

1. Simpson RJ Jr. Poster presentation and abstract presented at the American Heart Association; 2001.
2. Jones P et al. Am J Cardiol. 1998;81:582–587.
 Why consider combination therapy?

Many patients derive substantial benefit from effective

low dose statin therapy and lifestyle modification,
however:
– Max reduction in cardiac events in monotherapy trials vs
placebo – 40%
– Lower is better: HPS etc
– About half of patients still failing to reach recommended lipid
levels
– Combination therapy is important in specific dyslipidaemias
– European NCEP and ADA guidelines recommend
combination therapy in certain patient groups
– Different drugs with different mechanisms – attack on
multiple fronts
 Combination Therapy:
Pros and Cons
• Pros • Cons
1. LDL-C,TG,HDL 1. Less compliance
2. May  Lp (a) (more pills)
3. LDL particle size 2. Drug interaction
4. fibrinogen 3. Increased costs
5. Angiographic data 4. Few outcome studies
6. Better tolerance of 5. Increase adverse
lower doses effects
 sk:Benefit Ratio of Statin Titration

Atorvastatin Lovastatin Simvastatin

10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg
0
% Decrease in LDL-C

-10

-20

-30

-40

-50

-60
2.5
Elevated Transaminases
(% of Patients)

2.0

1.5

1.0

0.5

0.0
10 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg 20 mg 40 mg 80 mg

Data from prescribing information for atorvastatin, lovastatin, simvastatin – *20 mg includes pts on 40 mg (37%).
This does not represent data from a comparative study.
Cholesterol balance in man
Extrahepatic Dietary
Organs LDL IDL VLDL Cholesterol
300 mg/day
25%
Cholesterol
Synthesis
900 mg/day Biliary
Cholesterol Cholesterol
Synthesis 75%

Transport
via HDL & LDL Chylomicron transport
50% intestinal Faecal sterols
Cholesterol absorbed (1100mg/day)
50% cholesterol
Cholesterol lowering drugs excreted

Statins Ezetimibe Plant stanols Resins

Mechanism of Intestinal-Acting Agents
 The New “Lower Is Better” Approach
Requires More Intensive Therapy

• LDL-C of 100 mg/dl (2.5 mmol/L) was a

minimal goal of treatment in high-risk
patients in NCEP ATP III
• Standard doses of statins achieve LDL-C
<100 mg/dl
(2.5 mmol/L) in little more than half of
high-risk patients
• In high-risk patients who require more
Adapted from Grundy SM et al Circulation 2004;110:227–239.
LDL-C lowering than a standard statin dose
Dual Inhibition for Greater Efficacy

Adapted from Shepherd J Eur Heart J Supple 2001;3(Suppl E):E2–E5; Bay H Expert Opin Invest Drugs
2002;11:1587–1604.
 Ezetimibe: First New Therapy
for Hyperlipidemia in 15 years
• Niacin, 1955
• Bile acid sequestrants, 1961
• Fibrates, 1967
• Statins (HMG-CoA reductase inhibitors),
1987
• Cholesterol absorption inhibitor
Adapted from Bays H Expert Opin Investig Drugs 2002;11:1587–1604; Mahley RW, Bersot TP. In: Goodman and Gilman’s
The Pharmacological Basis of Therapeutics 10th ed. New York: McGraw Hill, 2001:971–1002; Ginsberg HN, Goldberg IJ.
(ezetimibe), 2002
In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138–2149; Van Itallie TB et al N Eng
J Med 1961;265:469–474;
Altschul R et al Arch Biochem 1955;54:558–559.
 Ezetimibe: A New Cholesterol
Absorption Inhibitor
• First of a new class of drugs with unique
mechanism of action
• May be useful as monotherapy for patients
intolerant or nonresponsive to statins
• Co-administration therapy with statins
• Favorable safety and tolerability profile
shown in clinical trials
 Ezetimibe
Unique Mechanism of Action

Radiolabeled Ezetimibe localized

at brush border of small intestine

 Ezetimibe localizes and appears

. to act at the brush border of the
small intestine and inhibits the
absorption of cholesterol.
• This results in:
Cholesterol – Decrease in delivery of intestinal
cholesterol to the liver.
Intestinal – Reduction in hepatic cholesterol
lumen stores and increase in clearance of
cholesterol from the blood.
Brush
border  Ezetimibe inhibited 54% of all
Enterocyte intestinal cholesterol absorption.
Cholesterol is transported from the
intestinal lumen, to be processed
inside the enterocyte.
Dietary cholesterol consumption and intestinal cholesterol absorption contribute
to plasma cholesterol levels, a risk factor for coronary heart disease. The molecular
mechanism of sterol uptake from the lumen of the small intestine is poorly defined.
We show that Niemann-Pick C1Like 1(NPC1 L1) protein plays a critical role in the
absorption of intestinal cholesterol. NPC1L1 expression is enriched in the small
intestine and is in the brush border membrane of enterocytes. Although otherwise
phenotypically normal, NPC1L1-deficient mice exhibit a substantial reduction in
absorbed cholesterol, which is unaffected by dietary supplementation of bile acids.
Ezetimibe, a drug that inhibits cholesterol absorption, had no effect in NPC1L1
knockout mice, suggesting that NPC1L1 resides in an ezetimibe-sensitive pathway
responsible for intestinal cholesterol absorption.

SCIENCE VOL 303 20 FEBRUARY 2004 1201 - 1204

 Niemann-Pick C1L1 (NPC1L1)

OUT

IN

SSD

• Identified in 2000 by an academic group as a gene of unknown function related to

Niemann –Pick C1 protein. It was named NPC1L1.
• DNA sequence analysis predicts features of a hypothetical cholesterol transporter
• Membrane protein expressed on cell surface
• Homologous to NPC 1 (a protein known to be involved in cholesterol movement)
• Expression regulated by cholesterol
• Sterol sensing domain

• Protein expression restricted to the enterocytes of the proximal small intestine

Advantages of Ezetimibe in Combination Therapy
for Hypercholesterolemia
 Unique mechanism of action by blocking cholesterol absorption but is not a
bile acid sequestrant
 Primary use as adjunctive therapy with a statin to achieve maximal LDL
reduction
 For patients with extreme cholesterol-lowering needs
– Homozygous familial hypercholesterolemia
 Can be used alone in patients who are statin intolerant, but LDL reduction
is modest
 Side effect profile in clinical trials to date has been favorable with
potentially reduced risk for liver and muscle toxicity
 Likely to be useful in combination with a fibrate in patients with substantial
triglyceride elevations but only modest LDL increases
Adapted from Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Gagne C et al Circulation 2002;105:2469-2475;
Leitersdorf E Eur Heart J Suppl 2001;3(suppl E):E17-E23.
Ezetimibe + Statin vs Statin
Titration

5%-6% 5%-6% 5%-6%

Statin – starting dose 1st 2nd 3rd 3-STEP STATIN

TITRATION
Doubling

15%-18%

+ Ezetimibe 1-STEP
Statin – starting dose COADMINISTRATION
10 mg

% Reduction in LDL-C
 Ezetimibe Phase III Monotherapy:
Efficacy
LDL-C TC HDL-C TG
5 * 2.4
0.8 0.6 1.0
0
-1.3 -1.7
-5

-10
-12
-15

-20 -18 Placebo (n=203)

* Ezetimibe 10 mg (n=615)

*P<0.01 vs placebo.
Knopp et al. European Atherosclerosis Society Meeting, Glasgow, Scotland, 2001.
 Effect of Ezetimibe on Lipid Levels When
co-administered with Ongoing Statin Therapy

5
LDL-C 3 ** TG
1
0
% Change From Baseline

-5 -3
-4 HDL-C
-11 %
-10

-15 -21% ***

-14
-20

-25 * Statin and PBO, N=388

-25
-30 Statin and EZE, N=375

* p<0.001 vs statin + placebo

** p<0.05 vs statin + placebo
*** p< 0.01 vs statin + placebo
Gagne et al. AJC 2002;90:1084-1091
 Consistency of Co-
administration Studies
Ezetimibe lowers LDL-C an added 19%-23% compared with statin alone
140
LDL-C (mg/dL) at study end

120 21% 19% 21%

100 23%
23%
80

60

40
Statin + EZE
20 Statin alone

0
Lova Prava Simva Atorva On top of statin

Davidson, JACC 2002;40:2125

Ballantyne, Circulation 2003;107: 2409-15
Melani, EHJ 2003;24:717-728
Kerzner, AJC 2003;91:418-424
Gagne, AJC 2002;90:1084-1091
 Ezetimibe + Statin Studies: Summary
 When initiated with statins, ezetimibe
significantly improved LDL-C, TG, and
HDL-C efficacy compared with each statin
alone.
 Typical LDL reduction is ~18% as
monotherapy
 As combination therapy to statin: additional
19-23% reduction compared to statin alone
 Ezetimibe + low-dose statin provided
comparable efficacy to the maximum dose
of every statin tested
 EASE Trial Objectives

 To examine the effectiveness and safety of

Ezetimibe 10 mg, compared to placebo, added
to any stable statin brand and dose:
 In the total population
 In each NCEP ATP III risk category
 By Sex, Age, Race, Diabetes, Metabolic
Syndrome, Statin Brand and Dose

 Endpoints:
 % reduction in LDL-C from baseline
 % NCEP ATP III LDL-C goal attainment in
patients not at goal at baseline
 EASE Trial Design
Patients on a
stable dose of any Ongoing statin + ezetimibe 10 mg (N = 2020)
statin who are not
at NCEP ATP III
LDL-C goal 2:1 Double-Blind Randomization
(N = 3030)
Ongoing statin + placebo (N = 1010)
6 weeks treatment
E R F

E = eligibility labs
V1 V2 R = randomization + baseline LDL-C V3

Wk -1 Day 0 F = final visit and post-Tx LDL-C Wk 6

Intent-To-Treat population analysis with LS means, differences and SEs from ANOVA models
 Percent Changes in LDL-C
Overall and by NCEP CHD Risk Category

CHD or CHD
Risk ≥2 Risk <2 Risk
Total Equivalent Factors Factors
LS Mean Percent (±SE) Change

129 129 124 123 148 147 167 162 Mean baseline mg/dL
0
-2.7 -1.1
-5
-4.1
-10 -5.8
-15
-20
-25 -23.8
-25.8 -25.1 -25.7
-30 125 95 120 90 140 111 152 118 Mean postbaseline
mg/dL

Placebo + Statin Ezetimibe + Statin

p<0.001 for all between-treatment differences

Percent of Patients Attaining NCEP ATP III LDL-C Goal
Overall and by NCEP Risk Category
(Patients Not at Goal at Baseline)
90.7
Percent (±SE) of Patients Attaining Goal

100

69.5 75.1
80 71.0
52.4
60

32.2
40
20.6
17.3
20

0
Total CHD or CHD ≥2 Risk <2 Risk
Risk Equivalent Factors Factors
Placebo + Statin Ezetimibe + Statin

p<0.001 for all between-treatment differences

 EASE Trial: Liver and Muscle Safety

PBO + Statin EZE + Statin P value

Parameter
% %

ALT ≥ 3 X ULN‡ 0.2 0.4 NS

AST ≥ 3 X ULN‡ 0.1 0.2 NS

CK ≥ 10 X ULN with 0.0 0.0 NS

or without muscle
symptoms

‡ Results based on either two consecutive measurements or a single, last

measurement ≥ 3 XULN, or a measurement ≥ 3 XULN followed by a measurement
< 3 X ULN taken more than 2 days after last dose of study medication.
 EASE Trial: Implications

 In the EASE study, ezetimibe reduced LDL-C

from statin baseline by an additional 23%
compared to placebo. This compares favorably
with the 6 to 8% reduction in LDL-C usually
observed by the doubling of the statin dose.

 The addition of Ezetimibe to statin therapy should

be considered in patients who have not attained
their NCEP ATP III LDL-C goal on statin therapy
alone.
What about the pleiotropic effects of
statins?
 Ezetimibe/Simvastatin Coadministration
MEAN % CHANGE IN LDL-C
10mg 20mg 40mg 80mg 10/10mg 10/20mg 10/40mg 10/80mg
0

-10
Mean % Change

-20

-30.6
-30
-34.8
-39.7
-40
-44.4 -44.8
** -48.7
-50
**
-55.0
** -60.4
-60 Simvastatin (SIMVA)
**
Ezetimibe + Simvastatin (EZE/SIMVA)

-70
** p<0.01: coadministration versus simvastatin alone
Sager et al. Circulation 2003: 108 (IV); 307
 MEDIAN % CHANGE IN HS-CRP
SIMVA EZE/SIMVA
10mg 20mg 40mg 80mg 10/10mg 10/20mg 10/40mg 10/80mg
0
-4.4
-8.3
-10
Median % Change

-20.0
-20

-26.9 -26.3
*
-30 -31.8
*
-35.9
#
-40
Simvastatin (SIMVA) -44.4
Ezetimibe + Simvastatin (EZE/SIMVA)
*
-50
*p≤0.01; # p=0.03: coadministration versus simvastatin alone
Sager et al. Circulation 2003: 108 (IV); 307
How do these results translate into
clinical practice?
 52y/o female with history of Graves’ disease s/p RAI
therapy on levothyroxine replacement therapy sought
consult for continuity of care .
• Family history : Father had a coronary stent placed for angina. Paternal
grandfather had MI at 46 but was a smoker. One of 3 paternal uncles
also has hypercholesterolemia and takes a statin.
• She is non-smoker, non-alcoholic
• She is asymptomatic
• PE: BMI: 26kg/m2, waist circumference: 36”, BP: 132/76
• Clinically euthyroid, rest of physical exam was normal
• LABS:
TC: 478mg/dl (12.35mmol/l) LDL: 341mg/dl(8.8mmol/l)
TG: 395 mg/dl (4.44mmol/l) Fasting glucose: 85mg/dl(4.7mmol/l)
HDL: 59mg/dl (1.52mmol/l) 2Hour OGTT: 70mg/dl (3.89mmol/l)
TSH: 1.25mIU/L
Lipitor Lipitor Ezetrol10mg Fenofibrate
40mg q HS 80mg q hs Crestor10mg 160mg
For 2 months for 1month Ezetrol
10mg

TC: 347, TC:99 TC:268 TC: 241

TG: 200 TG:85 TG:170 TG:135
HDL: 47 HDL: 35 HDL:55 HDL: 54
LDL:260 LDL: 47 LDL:177 LDL:157
Had myalgia Doing well Doing well;
emphasized
lifestyle
change
 62/M T2DM, s/p CABG, acromegaly s/p
TSS on adequate hormone replacement
therapy
• hgbA1C: 5.02% • Rosuvastatin (Crestor)
• Free T4: 15.2pmol/l increased to 20 mg
(NV: 10-28.2) day
• TC: 268mg/dl • Lantus
• TG: 228mg/dl • Rosiglitazone
• HDL: 43 (Avandia)
• LDL:179 • Levothyroxine
After 2 mos 6 mos after 1 week on Lipitor 10mg
On Crestor 20 mg Fenofibrate qhs
q HS 200mg qd Ezetrol 10mg
Crestor qhs
40mg q HS
TC: 111mg/dl TC: 298 TC: 145 TC: 131
TG: 92 TG: 1718 TG: 213 TG:285

HDL: 26 HDL? HDL: 3 HDL: 36

LDL: 67 LDL? LDL: 99 LDL: 38
Serum: milky Rhabdomyolysis HgbA1c: 6.6%
HgbA1c: 9% Intensive glucose Plan: start niacin or
control fish oil
What is the cause of hypercholesterolemia?