Sompongse Suwanwalaikorn, MD. Options to achieve low LDL-C targets Use maximal doses of currently available statins Consider new mega-statins Consider

Sompongse Suwanwalaikorn, MD

Options to achieve low LDL-C Options to achieve low LDL-C targetstargets


Use maximal doses of currently

available statins

Consider new mega-statins

Consider combination therapy


available statins



Simvastatin Efficacy in Familial Simvastatin Efficacy in Familial HypercholesterolemiaHypercholesterolemia

Simvastatin Efficacy in Familial Simvastatin Efficacy in Familial HypercholesterolemiaHypercholesterolemia

randomized, double blind study, N = 110 pts. LDL 251 mg/dl; Trig 168 mg/dl; HDL 50 mg/dl

Clin Drug Invest 1995;10:127-138

randomized, double blind, placebo controlled study N = 2221 pts. LDL 188 mg/dl; TG 132 mg/dl; HDL 45 mg/dl

4S Study. Lancet 1994;344:1383-1389Nutr Metab Cardiov Dis 1998;8:135-143;

randomized, double blind study N = 355 LDL 240 mg/dl; Trigl 159 mg/dl (TG-1); HDL 48.6 Subgroup of pts with triglycerides 200-350 mg/dl (TG-2, N = 83)

Simvastatin 10 mg

Simvastatin 40 mg

Simvastatin 20 mg

Simvastatin 80 mg

IDEAL Trial: IDEAL Trial: Safety & Tolerability Profile in Real WorldSafety & Tolerability Profile in Real World

IDEAL Trial: IDEAL Trial: Safety & Tolerability Profile in Real WorldSafety & Tolerability Profile in Real World

ParameterSimvastatin 20/40mg

(n = 4,449)

Atorvastatin 40/80mg

(n = 4,439)P value

Any adverse event resulting in permanent discontinuation of

study drug186 (4.2%) 426 (9.6%) <.001

AST ≥ 3 X ULN at 2 consecutive measurements

2 (0.04%) 18 (0.41%) <.001

ALT ≥ 3 X ULNat 2 consecutive measurements

5 (0.11%) 43 (0.97%) <.001

Down-titration to atorvastatin 40mg (from Atorvastatin 80mg) due to adverse events: 587 (13%)

JAMA, Nov 16, 2005-Vol 294, No. 19

Br J Cardiol 2004

Adverse event withdrawal rates of statins Adverse event withdrawal rates of statins

Br J Cardiol 2004

Myopathy in association with statins is dose-related




available statins




available statins



8

LDL Reduction by Individual LDL Reduction by Individual StatinsStatins

5 mg 10 mg 20 mg 40 mg 80 mg

Fluvastatin 21% 24%

Lovastatin 21% 24% 30% 40%

Pravastatin 22% 32% 34%

Simvastatin 22% 30% 35% 41% 47%

Atorvastatin 39% 43% 50% 60%

Rosuvastatin 45% 52% 58% 69%

In general, doubling dose = additional 6% reduction in LDL

Source: Gau G, Mayo Clinic Cardiovascular Review

0

20

30

40

50

60

Atorvastatin(n=78)

Simvastatin(n=76)

Lovastatin(n=78)

Fluvastatin(n=76)

First titration

% P

atie

nts

rea

chin

g g

oal

Percentage of Patients Reaching Goal Percentage of Patients Reaching Goal with Starting Dose and after First with Starting Dose and after First

TitrationTitration

Percentage of Patients Reaching Goal Percentage of Patients Reaching Goal with Starting Dose and after First with Starting Dose and after First

TitrationTitration

Adapted from Brown AS J Am Coll Cardiol 1998;32:665–672.

32% 31%

53%

22%

39%

10%

1%

10%10

Initial dose

LDL-C reduction across statin dose ranges in the STELLAR study

LDL-C reduction across statin dose ranges in the STELLAR study

Br J Cardiol 2004

Change in HDL-C across statin dose ranges in the STELLAR study

Change in HDL-C across statin dose ranges in the STELLAR study




available statins




available statins



13

Theoretical Basis for Combination RxTheoretical Basis for Combination Rx

Multiple pathogenetic pathways of Multiple pathogenetic pathways of

cholesterol in development of CADcholesterol in development of CAD

Differential effects of various lipid-Differential effects of various lipid-

lowering agents: lowering agents:

Act on different pathways Act on different pathways

Target different lipid particlesTarget different lipid particles

Net Cholesterol Balance in Net Cholesterol Balance in HumansHumans

Net Cholesterol Balance in Net Cholesterol Balance in HumansHumans

Indications for Combination RxIndications for Combination RxIndications for Combination RxIndications for Combination Rx

Treatment goals not met with single agentTreatment goals not met with single agent Risk of intolerance, toxicity, or adverse Risk of intolerance, toxicity, or adverse

drugdrug interactions with higher dose of single interactions with higher dose of single

agentagent Perceived benefit from ≥ 2 agents due to Perceived benefit from ≥ 2 agents due to

complementary: complementary: • Mechanisms of actionMechanisms of action

• Effects on different lipidsEffects on different lipids

• Effects on CHD riskEffects on CHD risk

Agents Commonly Used in Agents Commonly Used in Combination with StatinsCombination with Statins


Bile acid sequestrants

PPAR agonists (fibrates)

Fish oils

Niacin

Ezetimibe



Fish oils

Niacin

Ezetimibe

17





Fish oils

Niacin

Ezetimibe

Bile Acid Sequestrants: Favorable Lipid Bile Acid Sequestrants: Favorable Lipid Effects of Colesevelam with StatinsEffects of Colesevelam with Statins

Bile Acid Sequestrants: Favorable Lipid Bile Acid Sequestrants: Favorable Lipid Effects of Colesevelam with StatinsEffects of Colesevelam with Statins

% Change vs Statin Alone

Colesevelam Statin TC LDL-C HDL-C TG

2300 mg(~4 tablets)

Lovastatin10 mg

–7 –12 to –10 –3 to –1 –8 to +4

2300 mg(~4 tablets)

Simvastatin20 mg

–6 –8 –3 0

3750 mg(6 tablets)

Simvastatin10 mg

–9 –16 +7 +5

3750 mg(6 tablets)

Atorvastatin10 mg

–4 –10 +3 +23

Bays H, et al. Expert Opin Pharmacother. 2003;4:779-790.





Fish oils

Niacin

Ezetimibe



Fish oils

Niacin

Ezetimibe

PPAR-PPAR- Agonists (Fibrates) and Statins Agonists (Fibrates) and StatinsPPAR-PPAR- Agonists (Fibrates) and Statins Agonists (Fibrates) and Statins

Combination may significantly improve TG, LDL-C, Combination may significantly improve TG, LDL-C,

and HDL-C levelsand HDL-C levels

Fibrates plus statins associated with increased Fibrates plus statins associated with increased

risk for myopathy and rhabdomyolysisrisk for myopathy and rhabdomyolysis

Probably not due to cytochrome P450 drug Probably not due to cytochrome P450 drug

interactioninteraction

Gemfibrozil may impair glucuronidation of statins Gemfibrozil may impair glucuronidation of statins

Fenofibrate may have relatively less potential for Fenofibrate may have relatively less potential for

impairment of statin metabolismimpairment of statin metabolism

Combination may significantly improve TG, LDL-C, Combination may significantly improve TG, LDL-C,

and HDL-C levelsand HDL-C levels

Fibrates plus statins associated with increased Fibrates plus statins associated with increased

risk for myopathy and rhabdomyolysisrisk for myopathy and rhabdomyolysis

Probably not due to cytochrome P450 drug Probably not due to cytochrome P450 drug

interactioninteraction

Gemfibrozil may impair glucuronidation of statins Gemfibrozil may impair glucuronidation of statins

Fenofibrate may have relatively less potential for Fenofibrate may have relatively less potential for

impairment of statin metabolismimpairment of statin metabolism

Ballantyne CM, et al. Arch Intern Med. 2003;163:553-564. Ballantyne CM, et al. Arch Intern Med. 2003;163:553-564.

Bays H. Am J Cardiol. 2002;90:30K-43K. Bays HE, et al. Expert Opin Pharmacother. 2003;4:1901-1938.Bays H. Am J Cardiol. 2002;90:30K-43K. Bays HE, et al. Expert Opin Pharmacother. 2003;4:1901-1938.

Adding Fibrate to Statin Rx Improves Profile of Adding Fibrate to Statin Rx Improves Profile of Atherogenic Dyslipidemia in Patients with Atherogenic Dyslipidemia in Patients with

Metabolic SydromeMetabolic Sydrome

Adding Fibrate to Statin Rx Improves Profile of Adding Fibrate to Statin Rx Improves Profile of Atherogenic Dyslipidemia in Patients with Atherogenic Dyslipidemia in Patients with

Metabolic SydromeMetabolic Sydrome

Mean mg/dLMean ratio large/small LDL

Vega. Am J Cardiol. 2003;91:956.

* P ≤0.05 vs. placebo; † P ≤0.05 vs. simvastatin alone

*

* †

* †

†

simvastatin fenofibrate simvastatin+fenofibrate

Percentage of patients reaching Percentage of patients reaching ADA lipid targetsADA lipid targets

Percentage of patients reaching Percentage of patients reaching ADA lipid targetsADA lipid targets

Diabetes Care 2002;25:1198-1202

8075

5

30

97.5

60

17.5

92.5100

0

20

40

60

80

100

120

LDL TG HDL

% o

f pat

ient

s re

achi

ng A

DA

goa

ls

Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg + Fenofibrate 200 mg

Clinical Trials of Fibrates Clinical Trials of Fibrates Statins StatinsClinical Trials of Fibrates Clinical Trials of Fibrates Statins Statins

FIELD (Fenofibrate Intervention and Event Lowering in Diabetes)

9,000 patients with diabetes Fenofibrate vs. placebo No statistically significant difference in the primary

composite endpoint of CHD death or nonfatal MI. A significant reduction in nonfatal MI

ACCORD (Action to Control Cardiovascular Risk in Diabetes)

5800 patients with type 2 diabetes in fibrate substudy Fenofibrate + statin vs. placebo + statin Study completion - 2010

FIELD. Available at: http://www.cvm.controlled-trials.com/content/2/5/218. Accessed March 2, 2005. ACCORD. Available at: http://www.accordtrial.org/public/index.cfm. Accessed March 2, 2005.

PPAR-PPAR- Agonists (TZDs) and Statins Agonists (TZDs) and StatinsPPAR-PPAR- Agonists (TZDs) and Statins Agonists (TZDs) and Statins

Metabolic effects of TZDs may be Metabolic effects of TZDs may be

complementary to lipid-altering effects of complementary to lipid-altering effects of

statins: statins: Increased LDL-C particle size Increased LDL-C particle size

Reduced TG levels (with pioglitazone)Reduced TG levels (with pioglitazone)

Increased HDL-C levels (with pioglitazone and Increased HDL-C levels (with pioglitazone and

rosiglitazone)rosiglitazone)

Number of LDL particles Number of LDL particles Unchanged with pioglitazone Unchanged with pioglitazone

Potentially worsened with rosiglitazonePotentially worsened with rosiglitazone

Bays HE. Bays HE. Br J Diabetes Vascular DisBr J Diabetes Vascular Dis. 2003;3:356-360.. 2003;3:356-360.

Ginsberg HN. Ginsberg HN. Am J CardiolAm J Cardiol. 2003;91:29E-39E.. 2003;91:29E-39E.





Fish oils

Niacin

Ezetimibe



Fish oils

Niacin

Ezetimibe

Fish Oils and StatinsFish Oils and StatinsFish Oils and StatinsFish Oils and Statins

Marine fish oils rich in omega-3 fatty acids:Marine fish oils rich in omega-3 fatty acids:• Lower TG levels Lower TG levels • May be alternative to fibrate plus statinMay be alternative to fibrate plus statin

Other CV effects complementary to statins: Other CV effects complementary to statins: • Reduction in malignant ventricular dysrhythmiasReduction in malignant ventricular dysrhythmias• Increased heart rate variabilityIncreased heart rate variability• Antithrombotic effectsAntithrombotic effects• Improved endothelial reactivity/relaxationImproved endothelial reactivity/relaxation• Anti-inflammatory effectsAnti-inflammatory effects• Slight lowering of blood pressureSlight lowering of blood pressure

Marine fish oils rich in omega-3 fatty acids:Marine fish oils rich in omega-3 fatty acids:• Lower TG levels Lower TG levels • May be alternative to fibrate plus statinMay be alternative to fibrate plus statin

Other CV effects complementary to statins: Other CV effects complementary to statins: • Reduction in malignant ventricular dysrhythmiasReduction in malignant ventricular dysrhythmias• Increased heart rate variabilityIncreased heart rate variability• Antithrombotic effectsAntithrombotic effects• Improved endothelial reactivity/relaxationImproved endothelial reactivity/relaxation• Anti-inflammatory effectsAnti-inflammatory effects• Slight lowering of blood pressureSlight lowering of blood pressure

Bays HE, et al. Bays HE, et al. Expert Opin PharmacotherExpert Opin Pharmacother. 2003;4:1901-1938.. 2003;4:1901-1938.

Kris-Etherton PM, et al. Kris-Etherton PM, et al. CirculationCirculation. 2002;106:2747-2757.. 2002;106:2747-2757.

27

Commercial Fish Oil PreparationsCommercial Fish Oil PreparationsCommercial Fish Oil PreparationsCommercial Fish Oil Preparations

Capsules available containing >1000 mg omega-3 fatty acids, including: Eicosapentaenoic acid (EPA)

Docosahexaenoic acid (DHA)

TG benefits usually associated with combined dose of EPA + DHA of 4 g/d to 9 g/d

Side effects include fishy aftertaste and dyspepsia

Inconsistent reports of early, short-lived, potential increase in blood glucose levels in patients with diabetes mellitus



Fish Oil and Hematologic Fish Oil and Hematologic FactorsFactors

Fish Oil and Hematologic Fish Oil and Hematologic FactorsFactors

May impair platelet aggregation and May impair platelet aggregation and

increase bleeding timeincrease bleeding time

Potentially reduces risk for thrombosisPotentially reduces risk for thrombosis

Concomitant use with anticoagulants Concomitant use with anticoagulants

(aspirin or warfarin):(aspirin or warfarin):

No significant increase in risk of bleeding No significant increase in risk of bleeding

in clinical trialsin clinical trials

May impair platelet aggregation and May impair platelet aggregation and

increase bleeding timeincrease bleeding time

Potentially reduces risk for thrombosisPotentially reduces risk for thrombosis

Concomitant use with anticoagulants Concomitant use with anticoagulants

(aspirin or warfarin):(aspirin or warfarin):

No significant increase in risk of bleeding No significant increase in risk of bleeding

in clinical trialsin clinical trials







Fish oils

Niacin

Ezetimibe



Fish oils

Niacin

Ezetimibe

Role of Niacin in Combination Role of Niacin in Combination TherapyTherapy

Role of Niacin in Combination Role of Niacin in Combination TherapyTherapy

As monotherapy, niacin effects include: As monotherapy, niacin effects include: Increases in HDL-CIncreases in HDL-C

Decreases in LDL-C, triglycerides, lipoprotein(a)Decreases in LDL-C, triglycerides, lipoprotein(a)

Converts small LDL into more buoyant (less Converts small LDL into more buoyant (less

atherogenic) particlesatherogenic) particles

Safe and effective in combination with statins or Safe and effective in combination with statins or

bile acid sequestrants bile acid sequestrants Consider tolerability profiles of different Consider tolerability profiles of different

formulationsformulations

May adversely effect glucose, insulin sensitivityMay adversely effect glucose, insulin sensitivity

As monotherapy, niacin effects include: As monotherapy, niacin effects include: Increases in HDL-CIncreases in HDL-C

Decreases in LDL-C, triglycerides, lipoprotein(a)Decreases in LDL-C, triglycerides, lipoprotein(a)

Converts small LDL into more buoyant (less Converts small LDL into more buoyant (less

atherogenic) particlesatherogenic) particles

Safe and effective in combination with statins or Safe and effective in combination with statins or

bile acid sequestrants bile acid sequestrants Consider tolerability profiles of different Consider tolerability profiles of different

formulationsformulations

May adversely effect glucose, insulin sensitivityMay adversely effect glucose, insulin sensitivity

Miller M. Mayo Clin Proc. 2003;78:735. Miller M. Mayo Clin Proc. 2003;78:735.

31

NiaspanNiaspan®® Combination Therapy When Combination Therapy When Response to Statin is InsufficientResponse to Statin is Insufficient

Addition of Niaspan to Stable Dose of a Statin

Wolfe et.al. Am J Cardiol 2001; 87:476-489

1g NIASPAN (n=66) 2g NIASPAN (n=29)

Per

cent

Cha

nge

from

bas

elin

e

-40

-30

-20

-10

0

10

20

30

TC LDL HDL TG

-23%

23% 24%

-24%-30%

-8%-8%

-18%

Niacin in Combination with StatinsNiacin in Combination with StatinsNiacin in Combination with StatinsNiacin in Combination with Statins

Stein et alStein et al—17-week randomized trial; N=180 —17-week randomized trial; N=180 Immediate-release niacin plus simvastatin more Immediate-release niacin plus simvastatin more

effective than either drug alone at raising HLD-C effective than either drug alone at raising HLD-C and lowering VLDL-C and lowering VLDL-C

Guyton et alGuyton et al—48-week open-label trial; N=269—48-week open-label trial; N=269 ER niacin plus statin (lovastatin, pravastatin, ER niacin plus statin (lovastatin, pravastatin,

simvastatin): simvastatin): Reduced TC 23%; LDL-C 32%; TG 30%; Lp(a) 19%Reduced TC 23%; LDL-C 32%; TG 30%; Lp(a) 19% Increased HDL-C 26% Increased HDL-C 26%

Stein et al. J Cardiovasc Pharmacol Ther. 1996;1:107. Guyton et al. Am J Cardiol. 1998;82:737.

% Change from Baseline

Week 8 Week 12

Niacin ER+L(1000/40 mg)

Atorvastatin (10 mg)

Niacin ER+L(1000/40 mg)

Simvastatin (20 mg)

LDL-CLDL-C –38%* –38%* –42%* –35%

HDL-CHDL-C +20%*† +3% +19%*† +8%

TGTG –30%*† –20% –36%*† –15%

Lp(a)Lp(a) –16%*† +8% –20%*† –1%

Enhanced Lipid-lowering with Combination Niacin Enhanced Lipid-lowering with Combination Niacin Extended-release Plus Lovastatin vs Statin Extended-release Plus Lovastatin vs Statin

MonotherapyMonotherapy

Enhanced Lipid-lowering with Combination Niacin Enhanced Lipid-lowering with Combination Niacin Extended-release Plus Lovastatin vs Statin Extended-release Plus Lovastatin vs Statin

MonotherapyMonotherapy

Bays H, et al. Am J Cardiol. 2003;91:667-672.Bays H, et al. Am J Cardiol. 2003;91:667-672.

**PP≤ 0.05 vs simvastatin; ≤ 0.05 vs simvastatin; ††P P ≤≤ 0.05 vs atorvastatin0.05 vs atorvastatin

Issues of Safety and Tolerability Issues of Safety and Tolerability of Niacin and Fibratesof Niacin and Fibrates

Issues of Safety and Tolerability Issues of Safety and Tolerability of Niacin and Fibratesof Niacin and Fibrates

NiacinNiacin Chief complaint is flushing, intolerable in 10% of patientsChief complaint is flushing, intolerable in 10% of patients Also conjunctivitis, nasal stuffiness, loose stools/diarrhea, Also conjunctivitis, nasal stuffiness, loose stools/diarrhea,

acanthosis nigricans, ichthyosis, hepatitisacanthosis nigricans, ichthyosis, hepatitis FibratesFibrates

Abdominal discomfort, possible gallstonesAbdominal discomfort, possible gallstones Myositis with impaired renal functionMyositis with impaired renal function

Increased risk of rhabdomyolysis with fibrate or niacin + statinIncreased risk of rhabdomyolysis with fibrate or niacin + statin

Knopp RH. N Engl J Med. 1999;341:498-511; Jones PH, Davidson MH. Am J Cardiol. 2005;95:120-122; Bellosta S, et al. Circulation. 2004;109(23 Suppl 1):III50-57

StatinStatin No. of Cases of Rhabdomyolysis Associated With:No. of Cases of Rhabdomyolysis Associated With:

FibratesFibrates NiacinNiacin

AtorvastatinAtorvastatin 1010 Not reportedNot reported

FluvastatinFluvastatin 44 Not reportedNot reported

LovastatinLovastatin 55 11

PravastatinPravastatin 66 11

SimvastatinSimvastatin 3333 22





Fish oils

Niacin

Ezetimibe



Fish oils

Niacin

Ezetimibe

Increased biliary cholesterol secretion in Increased biliary cholesterol secretion in patients with obesitypatients with obesity

Increased biliary cholesterol secretion in Increased biliary cholesterol secretion in patients with obesitypatients with obesity

Ref; Mok, von Bergmann,Grundy, Journal of Lipid Research 20, 389, 1979

Non-obese Obese

Ch

ole

ster

ol s

ecre

tio

n

(mg/day)

Absorption

1451 mg/day

Absorption

666 mg/day

Absorption rate 63% 59%

CHD (+) CHD (-)0

5

10

15

20

25

30

35

0

5

10

15

20

25

CHD (+) CHD (-)

Increased cholesterol absorption in Increased cholesterol absorption in diabetic patients with CHDdiabetic patients with CHD

Increased cholesterol absorption in Increased cholesterol absorption in diabetic patients with CHDdiabetic patients with CHD

Cholesterol Absorption

p<0.05 NS

(%) (mg/kg/d)

Gylling H, Miettinen TA: Atherosclerosis 1996; 126: 325-332.

CHD (+) ： n=7, Total chol: 6.01±0.33 (mmol) CHD (-): n=6, Total chol: 6.25±0.27 (mmol)

Cholesterol Synthesis

BLOOD

Chylomicrons

Remnants

DIET

Micelles

Free cholesterol

Cholesterol

Bile acids

Unstirredwaterlayer

Synthesis

FC biosynthesis

ACAT

Cholesteryl Ester (CE)FC

ENTEROCYTE

Bru

sh

Bord

er

Plaque formation

CE

CE


X

Sterols/stanols

XX

Statins

X

Cholesterol Absorption Inhibitors (e.g., ezetimibe)

X

Ezetimibe Blocks Cholesterol Metabolism Ezetimibe Blocks Cholesterol Metabolism

at a New Siteat a New Site

Ezetimibe Blocks Cholesterol Metabolism Ezetimibe Blocks Cholesterol Metabolism

at a New Siteat a New Site

Ezetimibe: IndicationsEzetimibe: IndicationsEzetimibe: IndicationsEzetimibe: Indications

Hypercholesterolemia Monotherapy

Combination therapy with statins

Homozygous familial

hypercholesterolemia

Homozygous sitosterolemia

Note: no data are yet available on effects of ezetimibe (alone or

in combination therapy) on CHD morbidity and mortality

Hypercholesterolemia Monotherapy

Combination therapy with statins

Homozygous familial

hypercholesterolemia

Homozygous sitosterolemia

Note: no data are yet available on effects of ezetimibe (alone or

in combination therapy) on CHD morbidity and mortality

Bays H. Bays H. Expert Opin Investig DrugsExpert Opin Investig Drugs. 2002;11:1587-1604.. 2002;11:1587-1604.

Ezetimibe: Mechanism of ActionEzetimibe: Mechanism of ActionEzetimibe: Mechanism of ActionEzetimibe: Mechanism of Action

Selective inhibition of intestinal cholesterol

absorption Intestinal delivery of cholesterol to liver

Expression of hepatic LDL receptors

Cholesterol content of atherogenic particles

Enterohepatic circulation of ezetimibe and

active glucuronide metabolite

• Delivers agent back to site of action

• Limits systemic exposure

Selective inhibition of intestinal cholesterol

absorption Intestinal delivery of cholesterol to liver

Expression of hepatic LDL receptors

Cholesterol content of atherogenic particles

Enterohepatic circulation of ezetimibe and

active glucuronide metabolite

• Delivers agent back to site of action

• Limits systemic exposure

Bays H. Bays H. Expert Opin Investig DrugsExpert Opin Investig Drugs. 2002;11:1587-1604.. 2002;11:1587-1604.

Low Systemic Exposure of Ezetimibe May Low Systemic Exposure of Ezetimibe May Reduce Potential for Adverse Effects/ Drug Reduce Potential for Adverse Effects/ Drug

InteractionsInteractions

Low Systemic Exposure of Ezetimibe May Low Systemic Exposure of Ezetimibe May Reduce Potential for Adverse Effects/ Drug Reduce Potential for Adverse Effects/ Drug

InteractionsInteractions

van Heek M, et al. Br J Pharmacol. 2000;129:1748-1754.

3 h post-3 h post-33H ezetimibe IV dosingH ezetimibe IV dosing

IntestinalIntestinalwallwall

PlasmaPlasma LiverLiver BileBileIntestinalIntestinallumenlumen

33H

-DP

M (

x 1

0H

-DP

M (

x 1

0–6–6))

Ezetimibe: Dosage and Ezetimibe: Dosage and AdministrationAdministration

Ezetimibe: Dosage and Ezetimibe: Dosage and AdministrationAdministration

10 mg once daily10 mg once daily Any time of day, with or without foodAny time of day, with or without food

May be taken concomitantly with statinMay be taken concomitantly with statin

Dosage adjustment not necessary according Dosage adjustment not necessary according

to to GenderGender

Mild hepatic or renal insufficiencyMild hepatic or renal insufficiency

Age (ie, elderly)Age (ie, elderly) Ezetimibe not recommended in children <10 years oldEzetimibe not recommended in children <10 years old

10 mg once daily10 mg once daily Any time of day, with or without foodAny time of day, with or without food

May be taken concomitantly with statinMay be taken concomitantly with statin

Dosage adjustment not necessary according Dosage adjustment not necessary according

to to GenderGender

Mild hepatic or renal insufficiencyMild hepatic or renal insufficiency

Age (ie, elderly)Age (ie, elderly) Ezetimibe not recommended in children <10 years oldEzetimibe not recommended in children <10 years old

Bays H. Bays H. Expert Opin Investig DrugsExpert Opin Investig Drugs. 2002;11:1587-1604. . 2002;11:1587-1604.

Ezetimibe: ContraindicationsEzetimibe: ContraindicationsEzetimibe: ContraindicationsEzetimibe: Contraindications

Hypersensitivity to any component of agentHypersensitivity to any component of agent

Combination with statins in patients with Combination with statins in patients with active liver disease or unexplained persistent active liver disease or unexplained persistent elevations in serum transaminaseselevations in serum transaminases

Pregnancy C category as monotherapy (no Pregnancy C category as monotherapy (no adequate studies in pregnant women) adequate studies in pregnant women) All statins are contraindicated in pregnant and All statins are contraindicated in pregnant and

nursing womennursing women

Precaution: Moderate or severe hepatic Precaution: Moderate or severe hepatic insufficiencyinsufficiency

Hypersensitivity to any component of agentHypersensitivity to any component of agent

Combination with statins in patients with Combination with statins in patients with active liver disease or unexplained persistent active liver disease or unexplained persistent elevations in serum transaminaseselevations in serum transaminases

Pregnancy C category as monotherapy (no Pregnancy C category as monotherapy (no adequate studies in pregnant women) adequate studies in pregnant women) All statins are contraindicated in pregnant and All statins are contraindicated in pregnant and

nursing womennursing women

Precaution: Moderate or severe hepatic Precaution: Moderate or severe hepatic insufficiencyinsufficiency

Bays H. Expert Opin Investig Drugs. 2002;11:1587-1604.

LDL-CLDL-C

Ezetimibe “Add On” Study: Ezetimibe “Add On” Study: Improved Lipid ProfilesImproved Lipid Profiles

Ezetimibe “Add On” Study: Ezetimibe “Add On” Study: Improved Lipid ProfilesImproved Lipid Profiles

Gagné C, et al. Gagné C, et al. Am J CardiolAm J Cardiol. . 2002;90:1084-10912002;90:1084-1091..

**PP<0.001; <0.001; ††PP<0.05; <0.05; ‡‡PP<0.001<0.001

––25.1*25.1*

1.01.0

––2.92.9

––14.014.0‡‡

HDL-CHDL-C TGTG

––3.73.7

2.72.7††

% R

edu

cti

on

fro

m

% R

edu

cti

on

fro

m

Ba

sel

ine

at

We

ek

8B

as

elin

e a

t W

ee

k 8

-30

-25

-20

-15

-10

-5

0

5

Statin + Placebo (n=390)

Statin + Ezetimibe 10 mg (n=379)

LDL-C Reduction across the Dose RangeLDL-C Reduction across the Dose RangeLDL-C Reduction across the Dose RangeLDL-C Reduction across the Dose Range

*p<0.001 vs. corresponding dose of simvastatin

Adapted from Goldberg AC et al Mayo Clin Proc 2004;79:620–629.VYTORIN™ (ezetimibe/simvastatin) is a trademark of MSP Singapore Company, LLC.

Mea

n %

ch

ang

e fr

om

bas

elin

e to

wee

k 12

0

–20

–30

–40

–50

–10

–70

–60

10/20 mg(n=86)

–51%*

20 mg(n=89)

–35%

10/40 mg(n=89)

–55%*

40 mg(n=90)

–42%

10/80 mg(n=91)

–61%*

80 mg(n=87)

–46%

Simvastatin

VYTORIN™ vs. Simvastatin Efficacy Study

VYTORIN

Ezetimibe “Add On” Study: Marked Ezetimibe “Add On” Study: Marked Increase Increase

in Patients Reaching Treatment Goalsin Patients Reaching Treatment Goals

Ezetimibe “Add On” Study: Marked Ezetimibe “Add On” Study: Marked Increase Increase

in Patients Reaching Treatment Goalsin Patients Reaching Treatment Goals

Gagné C, et al. Gagné C, et al. Am J CardiolAm J Cardiol. 2002;90:1084-1091.. 2002;90:1084-1091.

72% *72% *72% *72% *

19%19%19%19%

Statin + Placebo Statin + Placebo (n=390)(n=390)

Statin + Placebo Statin + Placebo (n=390)(n=390)

Statin + Ezetimibe Statin + Ezetimibe (n=379)(n=379)

Statin + Ezetimibe Statin + Ezetimibe (n=379)(n=379)

Pa

tie

nts

at

NC

EP

Go

al (

%)

Pa

tie

nts

at

NC

EP

Go

al (

%)

Pa

tie

nts

at

NC

EP

Go

al (

%)

Pa

tie

nts

at

NC

EP

Go

al (

%)

**PP<0.001<0.001**PP<0.001<0.001

00

2020

4040

6060

8080

100100

Effect of Ezetimibe on LDL-C in Effect of Ezetimibe on LDL-C in Type 2 Diabetes SubgroupType 2 Diabetes Subgroup

Effect of Ezetimibe on LDL-C in Effect of Ezetimibe on LDL-C in Type 2 Diabetes SubgroupType 2 Diabetes Subgroup

-25

-4 -2

-28-30

-25

-20

-15

-10

-5

0Total Population

% C

han

ge

Fro

m B

asel

ine

% C

han

ge

Fro

m B

asel

ine

Statin and EZE (n=90) Statin and PBO (n=98)

* p<0.001 vs statin + placebo

**

Simons et al. EASD 2002Simons et al. EASD 2002

Diabetes Subgroup

**

Changes in Other Cardiovascular Changes in Other Cardiovascular ParametersParameters

Changes in Other Cardiovascular Changes in Other Cardiovascular ParametersParameters

*Except for CRP, shown as median percent changes**p<0.001 vs. simvastatin 10–80 mg

Mea

n*

% c

han

ge

fro

m b

asel

ine

to w

eek

12M

ean

* %

ch

ang

e fr

om

bas

elin

e to

wee

k 12

–20–20

–40–40

–60–60

00

–29%–29%

–42%**–42%**

–9%–9%

–33%**–33%**

Apo BApo B CRPCRP

–34%–34%

–49%**–49%**

Non–HDL-CNon–HDL-C

Eze/Simva 10/10–10/80 mg pooled dosesSimvastatin 10–80 mg pooled dosesEze/Simva 10/10–10/80 mg pooled dosesSimvastatin 10–80 mg pooled doses

(n=340)(n=340) (n=328)(n=328) (n=353)(n=353) (n=345)(n=345) (n=209)(n=209) (n=204)(n=204)

1-STEP 1-STEP COADMINISTRATIONCOADMINISTRATION1-STEP 1-STEP COADMINISTRATIONCOADMINISTRATION

3-STEP 3-STEP TITRATIONTITRATION3-STEP 3-STEP TITRATIONTITRATION

Statin and Complementary GI-Acting Statin and Complementary GI-Acting Drugs vs Statin TitrationDrugs vs Statin Titration

Statin and Complementary GI-Acting Statin and Complementary GI-Acting Drugs vs Statin TitrationDrugs vs Statin Titration

Statin at starting doseStatin at starting dose 1st1st1st1st 2nd2nd2nd2nd 3rd3rd3rd3rd

Statin at starting doseStatin at starting dose

18%18%18%18%

DoublingDoublingDoublingDoubling

+ GI-acting + GI-acting drugdrug+ GI-acting + GI-acting drugdrug

% Reduction in LDL-C% Reduction in LDL-C% Reduction in LDL-C% Reduction in LDL-C

6%6%6%6% 6%6%6%6% 6%6%6%6%

Bays H, et al. Bays H, et al. Expert Opin PharmacotherExpert Opin Pharmacother. 2003;4:779-790.. 2003;4:779-790.

Optional LDL-C Goal to <1.8 mmol/L (<70 mg/dL) Optional LDL-C Goal to <1.8 mmol/L (<70 mg/dL)

in Diabetes Patients: Ezetimibe/Simvastatin Superior to in Diabetes Patients: Ezetimibe/Simvastatin Superior to

AtorvastatinAtorvastatin

Optional LDL-C Goal to <1.8 mmol/L (<70 mg/dL) Optional LDL-C Goal to <1.8 mmol/L (<70 mg/dL)

in Diabetes Patients: Ezetimibe/Simvastatin Superior to in Diabetes Patients: Ezetimibe/Simvastatin Superior to

AtorvastatinAtorvastatin

VYTAL Study

Adapted from Goldberg RB, et al. Mayo Clin Proc. 2006;81:1579–1588.

Pat

ien

ts W

ith

LD

L-C

<1.

8 m

mo

l/L a

t W

eek

6, %

Ezetimibe/Simvastatin 10/20 mg(n=238)

Usual Starting Doses Next-Higher Doses

20

40

60

80

0

70

50

30

10

Atorvastatin10 mg(n=237)


Ezetimibe/Simvastatin 10/40 mg(n=242)


P<0.00159.7

21.5

35

P<0.001

P<0.001

74.4

55.2

52

Large Clinical Outcomes Program in Large Clinical Outcomes Program in >21,000 Patients at High-Risk of CV >21,000 Patients at High-Risk of CV EventsEvents

Study, N Study Population TreatmentsPrimary Endpoint

ENHANCE,~725

HeFH Ezetimibe/simvastatin 10/80 mgSimvastatin 80 mg

CA IMT

SHARP,~9000

Chronic kidney disease Ezetimibe/simvastatin 10/20 mgPlacebo

CV outcomes (MI, stroke, coronary revascularization)

SEAS,~1400

Asymptomatic aortic stenosis with LDL-C <6 mmol/L

Ezetimibe/simvastatin 10/40 mgPlacebo

CV death, aortic surgery, CV outcomes

IMPROVE-IT,~10,000

ACS Ezetimibe/simvastatin 10/40 mgSimvastatin 40 mg

CV death, major coronary events, stroke

CA IMT = Carotid artery intima-media thickness

Adapted from Kastelein JJP, et al. Am Heart J. 2005;149:234–239; Baigent C, Landry M. Kidney Int. 2003;63(suppl 84):S207–S210; Oxford Clinical Trial Service Unit. The Study of Heart and Renal Protection (SHARP). Available at: http://www.ctsu.ox.ac.uk/ ~sharp/. Accessed June 2005; Rossebo A, et al, for the SEAS Steering Committee. Presented at: XIII International Symposium on Atherosclerosis; September 23–October 2, 2003; Kyoto, Japan. Poster 3P-0870; Schering-Plough. IMPROVE-IT: Examining outcomes in subjects with acute coronary syndrome: Vytorin (ezetimibe/simvastatin) vs simvastatin (Study P04103). Available at: http://www.clinicaltrials.gov/ct/show/NCT00202878. Accessed November 2006.

T Killilea et al Am J Managed Care Vol 12, No. 11 Sup. Pps S 325-332

54

Conclusion:Conclusion:Conclusion:Conclusion:

Different lipid-lowering agents affect different lipid parameters

Combination therapy may further reduce CHD risk vs monotherapy

Consider combination therapy if: Treatment goals cannot be met with statins alone

Risk for intolerance, toxicity, or adverse drug interactions with higher dose of single lipid-lowering agent

55

ConclusionsConclusionsConclusionsConclusions

Inhibition of cholesterol absorption and production via coadministration of ezetimibe with a statin or ezetimibe/simvastatin in the single tablet

Is helping to set a new standard

Provides greater efficacy than statin therapy alone to get patients to a lower LDL-C goal

Outcomes studies will determine if the risk of cardiac endpoints decreases as LDL-C levels decrease with ezetimibe/simvastatin

Treatment ParadigmTreatment ParadigmCombination therapy-Statin plus what?Combination therapy-Statin plus what?

Treatment ParadigmTreatment ParadigmCombination therapy-Statin plus what?Combination therapy-Statin plus what?

For LDL

Cholesterol absorption inhibitor – Ezetimibe/Ezetrol®

Bile acid sequestrant

For HDL

Niacin/Niaspan®/Fibrate

For TG

Fibrate (fenofibrate)/Niacin/Niaspan®

For LDL

Cholesterol absorption inhibitor – Ezetimibe/Ezetrol®

Bile acid sequestrant

For HDL

Niacin/Niaspan®/Fibrate

For TG

Fibrate (fenofibrate)/Niacin/Niaspan®

Thank youThank youThank youThank you

58

© Continuing Medical Implementation ® …...bridging the care gap

Statin Evidence/Cost/Efficacy Grid Statin Evidence/Cost/Efficacy Grid © © Continuing Medical Implementation Continuing Medical Implementation ®®

STATIN Dose Cost/tab $ %LDL Red %LDL Red %LDL Red %LDL Reduction [1] Law[7] Stellar[8] 30% 35% 40% 45% 50% 55% 60%

Lovastatin 20mg 1.30 26 29(generic) 40mg 2.40 31 37 2.4Pravastatin 10mg 1.05 22 20 20(generic) 20mg 1.25 25 24 24

40mg 1.50 30 29 30 1.5Simvastatin 5mg 0.45 27 23(generic) 10mg 0.89 30 27 28 0.89

20mg 1.10 35 32 35 1.1040mg 1.10 40 37 39 1.1080mg 1.10 46[2] 42 46 1.10

Fluvastatin 20mg 0.75 19 21(generic) 40mg 1.05 29 27 1.05

XL 80mg 1.30 36 33 1.30Atorvastatin 10mg 1.66 40[3] 37 37 1.66

20mg 2.08 45 43 43 2.0840mg 2.24 51 49 48 2.2480mg 2.24 58[4] 55 51 2.24

Rosuvastatin 5 mg 1.29 42[5] 38 1.2910mg 1.36 52 43 46 1.3620mg 1.70 55 48 52 1.7040mg 1.99 63[6] 53 55 1.99

Revised January 2007 ** Average % reduction: Use to estimate initial statin dose. Actual response varies by patient and subgroup (age and gender).

Cost based on Ontario ODB pricing-updated February 2003. For cost to patient, add 10% plus prescribing fee.

Select Statin based on efficacy, safety, evidence and cost.Evidence © Continuing Medical Implementation ®CostHPS/ASCOT/CARDS REVERSAL PROVE-IT/TNT/IDEAL/AtoZ/SPARCL ASTEROID

[1]Ann Intern Med. 1996;125:990-1000.[2]Am J Card;1998:82:311-316.[3]Arterioscler Thromb Vasc Biol. 1995;15:678-682.[4]Am J Card 1998;81: 582-587 [5] Am J Cardiol 2003;91:33–41 [6]EHJ 2002, 4, (August) Abstract Supplement: Abs 212, page 19.[7]BMJ 326 974040:1423.[8]JACC 2003 (suppl):315A-316A. Abs 876-2.

59


Statin Evidence/Cost/Efficacy Grid Statin Evidence/Cost/Efficacy Grid © ©

Continuing Medical Implementation Continuing Medical Implementation ®®

STATIN Dose Cost/tab $ %LDL Red %LDL Red %LDL Red %LDL Reduction [1] Law[7] Stellar[8] 30% 35% 40% 45% 50% 55% 60%

Lovastatin 20mg 1.30 26 29(generic) 40mg 2.40 31 37 2.4Pravastatin 10mg 1.05 22 20 20(generic) 20mg 1.25 25 24 24

40mg 1.50 30 29 30 1.5Simvastatin 5mg 0.45 27 23(generic) 10mg 0.89 30 27 28 0.89

20mg 1.10 35 32 35 1.1040mg 1.10 40 37 39 1.1080mg 1.10 46[2] 42 46 1.10


XL 80mg 1.30 36 33 1.30Atorvastatin 10mg 1.66 40[3] 37 37 1.66

20mg 2.08 45 43 43 2.0840mg 2.24 51 49 48 2.2480mg 2.24 58[4] 55 51 2.24

Rosuvastatin 5 mg 1.29 42[5] 38 1.2910mg 1.36 52 43 46 1.3620mg 1.70 55 48 52 1.7040mg 1.99 63[6] 53 55 1.99

Revised January 2007 *

* Average % reduction: Use to estimate initial statin dose. Actual response varies by patient and subgroup (age and gender).

Cost based on Ontario ODB pricing-updated February 2003. For cost to patient, add 10% plus prescribing fee.

Select Statin based on efficacy, safety, evidence and cost.Evidence © Continuing Medical Implementation ®CostHPS/ASCOT/CARDS REVERSAL PROVE-IT/TNT/IDEAL/AtoZ/SPARCL ASTEROID

[1]Ann Intern Med. 1996;125:990-1000.[2]Am J Card;1998:82:311-316.[3]Arterioscler Thromb Vasc Biol. 1995;15:678-682.[4]Am J Card 1998;81: 582-587 [5] Am J Cardiol 2003;91:33–41 [6]EHJ 2002, 4, (August) Abstract Supplement: Abs 212, page 19.[7]BMJ 326 974040:1423.[8]JACC 2003 (suppl):315A-316A. Abs 876-2.

60


Statin/Combination TherapyStatin/Combination TherapyCost EfficacyCost EfficacySTATIN Dose Cost/tab % LDL Red % LDL Red % LDL Red Cost ($) for % LDL reduction on mono or combination therapy

$ [1] Law [7]* Stellar [8] 30% 35% 40% 45% 50% 55% 60% 65% 70%Lovastatin 20mg 1.30 26 29(generic) 40mg 2.40 31 37 2.4Pravastatin 10mg 1.05 22 20 20(generic) 20mg 1.25 25 24 24

40mg 1.50 30 29 30 1.5Simvastatin 5mg 0.45 27 23(generic) 10mg 0.89 30 27 28 0.89 2.52

20mg 1.10 35 32 35 1.10 2.7340mg 1.10 40 37 39 1.10 2.7380mg 1.10 46[2] 42 46 1.10 2.73


XL 80mg 1.30 36 33 1.30Atorvastatin 10mg 1.66 40[3] 37 37 1.66 3.29

20mg 2.08 45 43 43 2.08 3.7140mg 2.24 51 49 48 2.24 3.8780mg 2.24 58[4] 55 51 2.24 3.87

Rosuvastatin 5 mg 1.29 42[5] 38 1.2910mg 1.36 52 43 46 1.36 2.9920mg 1.70 55 48 52 1.7040mg 1.99 63[6] 53 55 1.99 3.62

Ezetimibe 10mg 1.63 18[9] (Co-administration with statin yields incremental 21-25% LDL reduction)

* Average % reduction: Use to estimate initial statin dose. Actual response varies by patient and subgroup (age and gender). Select combination therapy

Cost based on Ontario ODB pricing-updated February 2003. For cost to patient, add 10% plus prescribing fee. with ezetimibe 10 mg to achieve

Select Statin based on efficacy, safety, evidence and cost. greater LDL reduction

Evidence With ezetimibe 10 mg - $ > statin

Cost monotherapy or alternate statin

HPS/ASCOT/CARDS REVERSAL PROVE-IT/TNT/IDEAL/AtoZ/SPARCL ASTEROID [1]Ann Intern Med. 1996;125:990-1000.[2]Am J Card;1998:82:311-316.[3]Arterioscler Thromb Vasc Biol. 1995;15:678-682.[4]Am J Card 1998;81: 582-587 [5] Am J Cardiol 2003;91:33–41 [6]EHJ 2002, 4, (August) Abstract Supplement: Abs 212, page 19.[7]BMJ 326 974040:1423.[8]JACC 2003 (suppl):315A-316A. Abs 876-2. [9] Dujovne CA et al. Am J Cardiol 2002; 90. (10):1092-7.Knopp RH et al. Eur Heart J 2003;24:729-41 Revised January 2007 © Continuing Medical Implementation ®

Documents

Sompongse Suwanwalaikorn, MD. Options to achieve low LDL-C targets Use maximal doses of currently available statins Consider new mega-statins Consider