Treatment Targets and Pharmacologic Therapies

Treatment Targets
and
Pharmacologic Therapies
1
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Outline
Chapter 1:
Treatment Targets
Chapter 2:
Overview of Pharmacotherapy
• Statins
• Niacin
• Fibrates
• Bile Acid Sequestrants
• Cholesterol Absorption Inhibitors
• Omega-3 Fatty Acids
Chapter 3:
Combination Therapy and
Specific Dyslipidemias
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Lipoprotein Subclasses
Chylomicrons
VLDL
0.95
1.006
Density (g/mL)
IDL
Chylomicron Remnants
1.02
LDL
TG
LDL Cholesterol
1.06
HDL3
1.10
HDL2
Non-HDL Cholesterol
HDL-C
1.20
5
TG= Triglycerides
10
20
Apo B
40
Diameter (nm)
60
80
1000
3
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Chapter 1
Treatment Targets
4
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What is a Treatment Target?
• A variable where it is established that the
presence of this variable, or quantitative
amount of this variable, is associated with
incremental risk of harm or clinical benefit
• Therapy is guided to attain a “goal” value for
a treatment target
– Examples:
LDL-C, non-HDL-C
• Most other biomarkers, risk markers, or risk
factors, are not considered treatment targets
– Examples:
Lp(a), hs-CRP
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LDL-C and CHD Risk
Relative Risk for CHD
(Log Scale)
3.7
2.9
2.2
30
mg/dL
30
mg/dL
1.7
30
mg/dL
1.3
30
mg/dL
1.0
40
CHD=Coronary Heart Disease
70
100
130
160
190
LDL Cholesterol (mg/dL)
Grundy S et al. Circulation. 2004;110:227-239.
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NCEP ATP III Guidelines:
Dyslipidemia Targets of Treatment
• Primary Target:
LDL-C
– Goal value based on CV risk
• Secondary Target:
Non-HDL-C
– Only after LDL-C goal met and TG 200 mg/dL
– Goal is always the LDL-C goal + 30
• Tertiary Target:
HDL-C
– Only for metabolic syndrome after other targets met
– Goal >40 mg/dL in men, >50 mg/dL in women
CV/CVD= Cardiovascular Disease
Grundy SM et al. Circulation. 2004;110:227-239.
Grundy SM et al. Circulation. 2005;112:2735-2752.
Brunzell JD et al. Diabetes Care. 2008;31:811-822.
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NCEP ATP III Goals & Cutpoints
for TLC and Drug Therapy
Risk Category
High Risk: CHD or
CHD Equivalent
LDL-C
Goal
Non-HDL-C
Goal
Initiate
TLC
(mg/dL)
(mg/dL)
(mg/dL)
<100
<130
<70*
Moderately High
Risk: 2+ Risk
Factors
100
<100: for high risk patients
<160
130
130
100 – 129: consider to achieve
LDL-C goal of <100
<160
130
160
160
190
160 – 189: LDL-C Lowering
Drugs Optional
<100
<130
Optional Goal:
(10-y risk 10-20%)
Moderate Risk: 2+
Risk Factors
<100
<130
(mg/dL)
100
Optional Goal:
(10-y risk > 20%)
Consider Drug Treatment
(10-y risk < 10%)
Lower Risk: 0-1
Risk Factors
<160
<190
(10-y risk < 10%)
* For Very High Risk patients
NCEP ATP III =National Cholesterol Education Program. Adult
Treatment Panel III guidelines. TLC= Therapeutic Lifestyle changes
Grundy S et al. Circulation. 2004;110:227-239.
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NCEP ATP III: LDL-C Goal Values
CHD or CHD Risk Equivalent#
Yes
No
2 major CV risk factors*
Yes
No
Calculate
10-year CHD risk:
Framingham Score
>20%
10-20%
<10%
High Risk
<100 mg/dL,
Moderately-High Risk
If Very High Risk
High Risk
<70 mg/dL
is optional
<100 mg/dL
<130 mg/dL,
<100 mg/dL
is optional
Moderate Risk
Low Risk
<130 mg/dL
<160 mg/dL
# non-coronary atherosclerotic vascular disease (e.g., ischemic stroke, peripheral arterial disease) or diabetes
*Age (45 years men, 55 years women), hypertension, smoking, family history of premature CHD in primary
relatives, HDL-C < 40 mg/dL
Grundy S et al. Circulation. 2004;110:227-239.
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ATP III: Very High Risk Definition
• Presence of “established CVD” plus:
– multiple major risk factors (esp. diabetes)
– severe and poorly controlled risk factors (esp.
continued cigarette smoking),
– multiple metabolic syndrome risk factors (esp.
triglycerides ≥ 200 mg/dL plus non-HDL-C ≥ 130
mg/dL with HDL-C < 40 mg/dL), and
– patients with acute coronary syndromes
• Optional goal of <70 mg/dL does not apply to
individuals who are not at least high risk
Grundy SM et al. Circulation. 2004; 110:227-39.
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AHA/ACC Guidelines:
Secondary Prevention for Patients with Coronary
and Other AVD
• LDL-C goal values:
– 100 mg/dL
– Further reduction to 70 mg/dL is reasonable
– 70 mg/dL if baseline LDL-C is 70-100 mg/dL
• If LDL-C <70 mg/dL is not possible because of
a high baseline LDL-C:
– Achieve LDL-C reduction of 50% with statins or
combination regimens.
AHA= American Heart Association.
ACC= American College of Cardiology
AVD= Atherosclerotic Vascular Disease
Smith SC, Jr, et al. J Am Coll Cardiol. 2006;47:2130–2139.
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ATP III: 2004 Update
Doses that Attain 30-40% LDL-C Reductions
Dose
(mg/d)
10
40
LDL-C reduction
(%)
39
31
40
34
Simvastatin (Zocor®)
Fluvastatin (Lescol®)
20-40
40-80
35-41
25-35
Rosuvastatin (Crestor®)
5-10
39-45
Drug
Atorvastatin (Lipitor®)
Lovastatin (Mevacor®)
Pravastatin (Pravachol®)
– Pitavastatin (Livalo®) 1 mg daily provides ~ 32% LDL-C reduction
Grundy S et al. Circulation. 2004;110:227-239.
Livalo [package insert] Kowa Pharmaceuticals; 2010.
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Case Scenario 1
• Tom is a 48-year-old man with a history of
hypertension and dyslipidemia has been treated
with diet and exercise therapy for high cholesterol
for the past two years
• His present fasting lipid panel is: TC = 240 mg/dL,
HDL-C = 30 mg/dL, TG = 250 mg/dL, LDL-C = 170
mg/dL
• He does not have AVD or diabetes, but he does
have “prediabetes” and his Framingham Risk score
of 7%
TC= Total Cholesterol
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Case Scenario 1, cont.
• According to the NCEP ATP III, which of
the following is the most appropriate
primary target of therapy for Tom at this
time?
1.
2.
3.
4.
LDL-C < 70 mg/dL
LDL-C < 100 mg/dL
LDL-C < 130 mg/dL
LDL-C < 160 mg/dL
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Case Scenario 1, cont.
• Which of the following best explains why
targeting non-HDL-C lowering to a goal
value is not yet needed in this patient?
1.
2.
3.
4.
His non-HDL-C is already low enough
His triglycerides are not ≥ 500 mg/dL
His HDL-C should be raised first
His LDL-C is not yet at goal
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Polling Question…
• Which of the following patients is considered by
the ATP III as very high risk and has an optional
LDL goal of < 70 mg/dL?
1. A 50-year-old man, family history of premature CHD
(father), smoker, Framingham score is 25%
2. A 30-year-old woman, type 1 diabetes
3. A 60-year-old man, chronic stable angina, smoker,
uncontrolled hypertension
4. A 70-year-old man, uncontrolled hypertension,
Framingham score is 30%
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Chapter 2
Overview of Pharmacotherapy
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Lipid-Lowering Pharmacotherapy
Statins
(atorvastatin, fluvastatin, lovastatin, pitavastatin,
pravastatin, rosuvastatin, simvastatin)
Bile Acid Sequestrants
(colesevelam, cholestyramine, colestipol)
Nicotinic Acid
Fibric Acid Derivatives
(gemfibrozil, fenofibrate)
Cholesterol Absorption Inhibitor
(ezetimibe)
Omega-3 fatty acids
(prescription strength only)
LDL-C
HDL-C
TG
 18-63%
 5-15%
 7-30%
 15-30%
 3-5%
0 or 
 5-25%
 15-35%
 20-50%
 5-20 or 
 10-20%
 20-50%
 18%
 1%
 7%
?
 9%
 45%
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA.
2001;285:2486. Zetia [package insert] Merck/Schering-Plough Pharmaceuticals; 2005.
Crestor [package insert] AstraZeneca; 2005. Lovaza [package insert] GlaxoSmithKline; 2010.
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Acetyl CoA
Statins
HMG-CoA
Competitive
Inhibition
HMG CoA
Reductase
Inhibitors
(Statins)
Mevalonate
Cholesterol
production
VLDL=Very Low Density Lipoprotein
IDL=intermediate-density lipoprotein
HMG-CoA reductase inhibitors
 Expression of
LDL receptors
 LDL,
VLDL, and
IDL
particles
 Cholesterol
production
LDL-C Lowering
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Statins: Role in Therapy
• The most effective agents to lower LDL-C, first-line
therapy for most patients
• Clinically proven to reduce mortality and recurrent
cardiovascular events
• Stabilizing plaques, reduces progression, partial
regression
• Most well tolerated
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Statin Efficacy
% Change
LDL-C 
HDL-C 
TG 
Lovastatin (Mevacor®)*
21-42
2-10
6-27
Simvastatin (Zocor®)*
Pravastatin (Pravachol®)*
Fluvastatin (Lescol®)
Atorvastatin (Lipitor®)
Rosuvastatin (Crestor®)
Pitavastatin (Livalo®)
26-48
22-34
22-36
26-60
45-63
32-43
8-16
2-12
3-11
5-13
8-14
5-7
12-34
15-24
12-25
17-33
10-35
15-19
* Available generically
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Statin Pharmacokinetics
Half-life
BioCYP450
availability
(h)
Metabolism
Lovastatin
Simvastatin
Pravastatin
Fluvastatin
Atorvastatin
Rosuvastatin
Pitavastatin
Solubility
<5%
2-4
3A4
Lipophillic
<5%
1-3
3A4
Lipophillic
17%
2-3
none
Hydrophilic
24%
0.5-3
2C9
Lipophillic
12%
13-30
3A4
Lipophillic
20%
19
2C9
Hydrophilic
43-51%
12
2C9, 2C8
Slightly
Hydrophilic
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Landmark Statin-based Outcome Trials
Trial
LDL-C (mg/dL)
Statin Treatment
(mg/day)
Baseline Statin
4S
Simvastatin 20-40 mg
188
LIPID
Pravastatin 40 mg
CARE
Primary
Endpoint/ CV
Event Rate (%)
Placebo
Statin
122
28.0
19.4
150
112
15.0
12.3
Pravastatin 40 mg
139
98
13.2
10.2
HPS
Simvastatin 40 mg
132
93
24.4
19.9
PROSPER
Pravastatin 40 mg
147
97
16.2
14.1
WOSCOPS
Pravastatin 40 mg
192
159
7.5
5.3
AFCAPS
Lovastatin 20-40 mg
150
115
5.5
3.5
ASCOT-LLA
Atorvastatin 10 mg
133
90
3.0
1.9
CARDS
Atorvastatin 10 mg
118
77
9.0
5.8
JUPITER
Rosuvastatin 20 mg
108
55
2.8
1.6
Jacobson TA et al. Arch Intern Med. 1998;158:1977-1989. Heart Protection Study
Collaborative Group. Lancet. 2002;360:7-22. Shepherd J et al. Lancet. 2002;360:16231630. Sever PS et al. Lancet. 2003;361:1149-1158. Colhoun HM et al. Lancet.
2004;364:685-696. Ridker PM et al. N Engl J Med. 2008;359:2195-2207.
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National Lipid Association (NLA)
Statin Safety Assessment Task Force
• Definitions of muscle findings:
– Myalgia
• Muscle ache or weakness without creatine kinase
(CK) elevation
– Myopathy
• Myalgia, plus
• Elevation in serum CK >10 x ULN
– Rhabdomyolysis
• CK >10,000 IU/L, or
• CK >10 x ULN plus an elevation in serum creatinine
or medical intervention with IV hydration
McKenney JM et al. Am J Cardiol .2006;97(suppl 8A):89C–94C.
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NLA – Muscle and Statin Safety
Statin Safety Assessment Task Force
1. Rule out other etiologies of muscle symptoms or
an increased CK level.
2. Consider a baseline CK in patients who are at
high risk of experiencing a muscle toxicity.
3. Do not measure CK in asymptomatic patients.
4. Appropriately counsel patients about the
increased risk of muscle complaints.
5. Measure CK in symptomatic patients to help
gauge the severity and guide therapy.
McKenney JM et al. Am J Cardiol. 2006;97(suppl 8A):89C–94C.
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NLA – Muscle and Statin Safety
Statin Safety Assessment Task Force
6. Intolerable muscle symptoms, stop statin therapy
regardless of CK; once resolved restart the
same/different statin at same/lower dose.
7. Tolerable muscle complaints or asymptomatic
with a CK <10 the ULN, continue statin therapy
at the same or reduced doses.
8. Rhabdomyolysis (CK >10,000 IU/L or 10x ULN)
stop statin therapy and treat accordingly; once
recovered, re-evaluate the risk vs. benefit of
statin therapy.
McKenney JM et al. Am J Cardiol. 2006;97(suppl 8A):89C–94C.
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CK Elevations and LDL-C Reduction
Cerivastatin (0.2, 0.3, 0.4, 0.8 mg)
Pravastatin (40, 80 mg)
Simvastatin (40, 80 mg)
3.0
CK >10 × ULN (%)
Atorvastatin (10, 20, 40, 80 mg)
2.5
Rosuvastatin (5, 10, 20, 40, 80 mg)
0.8
2.0
80
0.4
1.5
80
80
1.0
80
0.5
10
0.2
0.3
40
40
40
20
40
5
10
0.0
20
25
30
35
40
45
50
20
55
60
65
70
LDL-C Reduction (%)
Jacobson TA. Am J Cardiol. 2006;97[suppl]:44C–51C.
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ACC/AHA/NHLBI Clinical Advisory
Risk Factors for Statin-Myopathy
•
•
•
•
•
•
•
•
Advanced age (especially >80 yr; women > men)
Severe chronic kidney disease
Impaired liver function
Perioperative periods
Alcohol abuse
Large quantities of grapefruit juice (certain statins)
Interacting medications
Hypothyroidism
Pasternak RC et al. J Am Col Cardiol. 2002;40:567-572.
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Managing Statin-Associated Myalgia
Well Accepted:
• Rule out secondary
causes
• Switching to a different
statin
• Alternate day dosing of
higher potency statins
• Use lowest statin dose
that is tolerated; adding
a second agent if
needed
Debatable:
• Red yeast rice
(Monascus purpureus)
2400 mg/day
• Vitamin D
supplementation if
deficient
• Coenzyme Q10
(CoQ10)
supplementation
Ahmed W, et al. Translational Research 2009;153:11–16.
Reindl EK, et al, Ann Pharmacother 2010;44:1459–1470.
Halbert SC, et al. Am J Cardiol 2010;105:198 –204)
Marcoff L, Thompson PD. J Am Coll Cardiol. 2007;49:2231–2237.
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FDA Drug Safety Communication: Important safety label
changes to cholesterol-lowering statin drugs
Safety Announcement [2-28-2012]
• Monitoring Liver Enzymes
– Labels revised to remove the need for routine periodic
monitoring of liver enzymes in patients taking statins
• Adverse Event Information
– Potential for generally non-serious and reversible
cognitive side effects (memory loss, confusion, etc.)
– Reports of increased blood sugar and glycosylated
hemoglobin (HbA1c) levels has been added
– FDA continues to believe that the cardiovascular
benefits of statins outweigh these small increased
risks
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
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Statin and Risk of Incident Diabetes
• 2010 meta-analysis of 13 trials (n=91,140)
– 4,278 developed diabetes (2,226 with statins vs.
2,052 with control) over a mean 4 yrs
• 9% increased risk
• NNH was 255 patients
(OR 1.09 [1.02–1.17])
• 2011 meta-analysis of 5 trials (n=32,752)
– 2,749 developed diabetes (1,449 with intensivedose statin vs. 1,300 with moderate-dose statin)
over a mean 1.9 yrs
• 12% increased risk (OR 1.12 [1.04-1.22])
• NNH was 498; but, NNT for CV events was 155
Lancet 2010; 375: 735–42. JAMA. 2011;305(24):2556-2564.
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Benefits and Diabetes Risk in JUPITER
• 17,603 patients, randomized to placebo or
rosuvastatin 20 mg for up to 5 years
– Stratified based on presence of major risk
factors for developing diabetes*
# of Diabetes
Risk Factors*
0
(n=6,095)
≥1
(n=11,508)
Placebo vs. Rosuvastatin
# Primary CV Endpoints
# New Diabetes Cases
91 vs. 44 (p<0.0001)
12 vs. 12 (p=0.99)
86 primary events avoided with no new cases of diabetes
157 vs. 96 (p<0.0001)
204 vs. 258 (p=0.01)
134 primary events avoided for every 54 new cases of diabetes
*BMI ≥30 kg/m², metabolic syndrome, impaired fasting glucose, glycated haemoglobin A1c ≥6%
Ridker PM, Pradhan A, MacFadyen JG, et al. Lancet. Aug 11 2012;380(9841):565-571.
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Statin Drug-Drug Interactions
• Simvastatin & lovastatin - significant CYP3A4
metabolism
– Contraindicated with strong CYP3A4 inhibitors: Azole antifungals
(ketoconazole, itraconazole, fluconazole), erythromycin,
clarithromycin, HIV protease inhibitors, and large quantities of
grapefruit or pomegranate juice
– Dose adjust with weaker CYP3A4 inhibitors
• Amiodarone , verapamil or diltiazem have maximum dose limits
that are lower than the typical maximum dose (with simvastatin
there is a maximum dose restriction with amlodipine also)
• Cyclosporine:
– Simvastatin is contraindicated
– Lovastatin should be avoided
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Rhabdomyolysis in
Combination Therapy With Statins*
No. Cases Reported
per Million Prescriptions
10
8.6
9
8
7
6
5
15-Fold Increase
4
3
2
1
0.58
0
Fenofibrate
Gemfibrozil
*Excludes cases involving cerivastatin
Jones PH et al. Am J Cardiol. 2005;95:120-122.
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Statin/Fibrate Interaction
• Facts about gemfibrozil:
– Known to  risk of rhabdomyolysis with statins
– Inhibits hepatic glucuronidation of certain statins
– When used with certain statins:
• Maximum rosuvastatin dose is 10 mg daily
• Simvastatin is contraindicated
• Lovastatin should be avoided
• Fenofibrate does not inhibit glucuronidation
Thompson PD et al. JAMA. 2003;289:1681-1690.
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Niacin (a.k.a. Nicotinic Acid)
Inhibition of lipolytic release of fatty acids from adipose
tissue resulting in reduced free fatty acid transport to liver
Apo B
VLDL
TG
synthesis
VLDL
secretion
VLDL
Serum VLDL
results in educed
lipolysis to LDL
Serum LDL
LDL
HDL
Hepatocyte
(reduced clearance,
not increased
synthesis)
Systemic Circulation
Overall decreased hepatic production of VLDL and Apo B
McKenney JM. Arch Intern Med. 2004;164:697-705.
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Niacin: Role in Therapy
• Treatment of hypertriglyceridemia, isolated low HDL-C, mixed
dyslipidemia
• CV event reduction:
– HATS trial (n=160):
• Simvastatin + SR* niacin reduced CV events versus placebo
over 3 years
– Coronary Drug Project (n=1119):
• IR* niacin (up to 3 g/day) reduced MI versus placebo in men
with CHD after 6 years; mortality benefit in 15-year extension
trial
– ARBITER-2 (n=167):
• ER* Niacin (1 g/day) added to statin therapy improved carotid
IMT versus placebo in patients with CHD
Brown BG et al. N Engl J Med 2001;345:1583-92.
Coronary Drug Project Research Group. JAMA 1975;231:360-381
Canner PL et al. J Am Coll Cardiol. 1986;8:1245-155.
Taylor AJ et al. Circulation. 2004;110:3512-3517.
*Key: SR = sustained release
IR = immediate release
ER = extended release
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Niacin Side Effects:
An Incomplete List
flushing
dyspepsia
itching
nausea & vomiting
fatigue
hepatic toxicity
hypotension
hyperglycemia
skin rash
hyperuricemia
acanthosis nigricans
macular edema
dry skin
atrial fibrillation
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Niacin Adverse Effects with Different Products
• Three Different Products
1. Immediate Release (IR)
2. Slow Release (SR)
3. Extended Release (ER)
[generic]
[Slo-Niacin®]
[Niaspan®]
• Adverse Effects per product:
– Facial flushing:
IR >> ER & SR
• All ER (prescription only) products, are enteric coated to
minimize flushing (i.e., Niaspan®, Advicor®, SIMCOR®)
– ↑ hepatic transaminases:
SR > ER & IR
– ↑ glucose & ↑ uric acid: same with all products
Guyton JR et al. Am J Cardiol. 2007;99(Suppl 6A):22C–31C.
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Blood Concentration of Niacin
Pharmacokinetic Profiles
0
4
http://www.niaspan.com/
http://www.slo-niacin.com/pi.html
8
12
16
20
Time after dosing
24
40
www.lipid.org
Flushing with Niacin
• Secondary to release of prostaglandin D2
• Frequency and intensity diminishes over weeks
or months, but can be ameliorated by:
–
–
–
–
Starting with a low dose and titrating it up
Aspirin 325 mg or ibuprofen 200 mg 30-60 min prior
Dosing ER niacin at bedtime with a small snack
Failure of flushing rates to diminish, or reappearance
of flushing, may be due to inconsistent dosing; A
niacin-free interval of ≥3 days will often necessitate
re-titration to avoid substantial flushing
– Avoid alcohol, spicy foods, hot beverages, and hot
baths or showers immediately before or after
Guyton JR et al. Am J Cardiol. 2007;99(Suppl 6A):22C–31C.
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Niacin Hepatotoxicity
O
Niacin
OH
N
Conjugated Pathway
Nonconjugated Pathway
(flushing)
(hepatotoxicity)
Nicotinuric Acid
Nicotinamide
6HN
NNO
2PY
Piepho RW. Am J Cardiol. 2000;86(Suppl 12A):35L-40L.
MNA
Nicotinamide
Adenine
Dinucleotide
4PY
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Arterial Disease Multiple Intervention Trial
(ADMIT)
• Prospective,
randomized
double-blind trial
evaluating safety
and efficacy of
niacin in patients
with diabetes
• IR niacin 3000
mg/day (or a max
tolerated dose) or
placebo for 2.5
years
Elam MB et al. JAMA. 2000;284:1263-1270.
Patients with Diabetes (n=125)
Glucose
(mg/dL)
A1C
(%)
Uric Acid
(mg/dL)
IR Niacin
(n=64)
Placebo
(n=61)
P
value
 8.1
 8.7
0.04
No
change
 0.3
0.05
0.9
No
change
<0.001
43
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Bile Acid Sequestrants
Bile Acid
Sequestrants
 Hepatic Bile Acid Pool
 Hepatic Bile Acid
Synthesis from Cholesterol
 Intrahepatic
Cholesterol
 HMG-CoA Reductase Expression
Pool
 VLDL Production /
Secretion
 LDL Production
 LDL Receptors
 LDL Clearance
 Plasma LDL-C
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Bile Acid Sequestrants:
Role in Therapy
• Combination with statin therapy for additional LDLC lowering; alternative in statin-resistant patients
• CV Event Reduction:
– LRC-Primary Prevention Trial (n=3086):
• Cholestyramine reduced fatal CHD/non-fatal MI by
19% vs. placebo (p<0.05)
– FATS Trial (n=146):
• Intense LDL-C lowering in CHD patients using
colestipol with lovastatin or niacin lowered CV events
vs. conventional therapy
LRC-CPPT. JAMA. 1984;251:351-374.
Brown G et al. N Engl J Med. 1990;323:1289-1298.
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Bile Acid Sequestrants
• Tablet and powder formulations:
– Powders must be mixed with water before use
• GI complaints are the most common side effects
(constipation, abdominal discomfort, intestinal
gas, indigestion, heartburn)
– Constipation less with colesevelam (Welchol®)
• Can bind other drugs and decrease absorption:
– With colestipol and cholestyramine interacting drugs
should be given 1 h before or 4 h after
– Interaction risk is less problematic with colesevelam
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Fibric Acid Derivatives
Fibric Acid
Derivatives
(Fibrates)
Liver
VLDL
ApoB
Activate
PPAR
HDL
LDL
TG
ApoB
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Fibrates: Role in Therapy
• For hypertriglyceridemia or mixed dyslipidemia
• CV Event Reduction:
– Helsinki Heart Study:
• Reduced in certain primary prevention patients
– VA-HIT (n=2531):
• Reduced 22% in patients with CHD (p=0.006)
– Meta-Analysis (18 trials, n=45,058)
• 10% reduction in major CV events
• no reduction in all cause mortality (p=0.048)
• No CV Event Reduction in type 2 diabetes
– FIELD Trial (n=9785) and ACCORD (n=5518)
Frick MH et al. N Engl J Med. 1987;317:1237-1245.
Rubins HB et al. N Engl J Med. 1999;341;410-418.
Keech A et al. Lancet. 2005;366:1849–1861.
Accord Study Group. N Engl J Med. 2010;362,1563-1574.
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Fibrates: Adverse Effects
• Contraindications:
– Hepatic or severe renal impairment
– Pre-existing gallbladder disease
• Minor increases in liver transaminases
• Can cause myopathy alone, but more likely
when gemfibrozil is combined with a statin
• May potentiate the action of warfarin
• May reversibly increase serum creatinine, but
does not change glomerular filtration rate (GFR)
Hardman JG et al. Goodman & Gilman‘s The Pharmacological Basis of Therapeutics.
10th ed. Columbus, Ohio: The McGraw-Hill Companies, Inc; 2001.
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Fibrates: Renal Dosing (NLA and NKF)
Fibrate
Dose based on GFR (mL/min/1.73 m2)
>90
60-90
15-59
Fenofibrate (Tricor)
145 mg daily
96 mg daily
Fenofibrate (Triglide)
160 mg daily
100 mg daily
50 mg daily
Fenofibrate
(Lofibra tablets)
160 mg daily
108 mg daily
54 mg daily
<15
48 mg daily
AVOID
Micronized fenofibrate
(Lofibra capsules)
200 mg daily
134 mg daily
67 mg daily
Micronized fenofibrate (Antara)
130 mg daily
86 mg daily
43 mg daily
Gemfibrozil
600 mg BID
600 mg BID
600 mg daily
• Fenofibric acid (TRILIPIX®), similar to fenofibrate dosing
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Cholesterol Absorption Inhibitor
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Cholesterol Absorption Inhibitor
• Ezetimibe (Zetia®) is the only available agent
• Safe and well tolerated
• Primary role is in addition to statin-based
therapy or in statin-resistant patients
• No definitive outcomes data that support lower
CV risk
Kastelein JJP et al. New Eng J Med. 2008;358:1431-1433.
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Ezetimibe: Efficacy
LDL-C
Triglyceride
HDL-C
5
3.5
Mean % Change from Baseline
*
0
-0.4
-0.2
-1.3
-5
-4.9
-10
-15
-20
-15.7
* P<0.05 vs placebo
*
Placebo
Placebo
Ezetimibe
mg(n=123)
(n=123)
Ezetimibe
1010mg
Lipka LJ et al. J Am Coll Cardiol. 2000;35(2 Suppl l):257A.
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Omega-3 Fatty Acids (FA)
• Eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) have CV benefits
• Alpha-linoleic acid, while an omega-3 FA, does
not have CV benefits
• Role in therapy:
– Prescription omega-3 FA products approved for
severe hypertriglyceridemia (≥ 500 mg/dL):
• Lovaza® both EPA and DHA
• Vascepa® EPA only
Bays HE. Am J Cardiol. 2007;99(Suppl 6A):35C–43C.
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Omega-3 Fatty Acids and “Fish Oils”
Safety Concerns
• Omega-3 fatty acids:
– No antithrombotic effects; not proven to increase
bleeding risk
– Rigorous manufacturing purification processes reduce
risk of hypervitaminosis and exposure to
environmental toxins (e.g., mercury, dioxin)
• “Fish Oils”
– USP verification not required for all products
– Not equal to prescription omega-3 fatty acids
Bays HE. Am J Cardiol. 2007;99(suppl 6A):35C–43C.
55
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www.puritan.com
www.naturesbounty.com
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Minimizing “Fish Oils” Side Effects
• Miscellaneous fish oil content can cause fishy
smelling belching/dyspepsia
• Enteric coating:
– Minimizes the fishy smelling belching/dyspepsia
– However, OTC fish oils that are enteric coated are
usually not USP verified
• Freezing uncoated OTC fish oils (not
recommended for prescription omega-3)
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Omega-3 FA and CV Benefits
Lavie CJ et al. J Am Coll Cardiol. 2009;54:585–594.
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Chapter 3
Pharmacotherapy for Specific
Dyslipidemias
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Clinical Scenarios
Dyslipidemia
Monotherapy
Options
Combination Therapies
Primary
Target:
Elevated
LDL-C
• Statin
• Niacin
• Bile Acid
Sequestrant
• Ezetimibe
•
•
•
•
Statin + Bile Acid Sequestrant
Statin + Ezetimibe
Statin + Niacin
Others
Secondary
Target:
Elevated
non-HDL-C
• Statin (high-dose)
• Niacin
•
•
•
•
Statin + Fibrate
Statin + Niacin
Statin + Omega-3 Fatty Acids
Others
Other:
Very high TG
• Fibrate
• Fibrate + Omega-3 Fatty Acids
• Omega-3 Fatty Acid • Fibrate + Niacin
• Niacin
• Niacin + Omega-3 Fatty Acids
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Reasons for Use of Combination Therapy
• To achieve the goal values:
– Primary target (LDL-C goal) when
monotherapy is not adequate
– Secondary target (non-HDL-C goal) after
LDL-C goal has been achieved and
triglycerides are 200-499 mg/dL
• In patients who experience dose related
side effects
• In patients with severe dyslipidemia
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STELLAR Trial: The “6% Rule”
• 6-week, parallel groups, open-label study (n=2431)
% LDL-C Change from Baseline .
Pravastatin
Simvastatin
Atorvastatin
Rosuvastatin
0
-10
-20
-30
-40
10mg
20mg
40mg
80mg
-50
-60
Jones PH et al. Am J Cardiol. 2003;93:152-160.
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Colesevelam added to Simvastatin
0
Mean LDL-C Change (%)
Placebo (n=33)
-4
-10
Simvastatin 10 mg/d (n=37)
-20
-30
Simvastatin 20 mg/d (n=35)
-26*
Colesevelam 2.3 g/d +
Simvastatin 20 mg/d (n=37)
-34*
-40
-42*#
-42*#
Colesevelam 3.8 g/d +
Simvastatin 10 mg/d (n=34)
-50
* P < 0.05 vs placebo
Knapp HH et al. Am J Med. 2001;110:352-360.
# P < 0.05 vs individual agents alone
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Ezetimibe/Simvastatin vs Rosuvastatin
EZ/S
EZ/S
EZ/S
10/20mg 10/40mg 10/80mg
R 10mg
R 20mg
R 40mg
Mean LDL-C Change (%)
0
-10
-20
-30
-40
-46
-50
-52
-60
-52
-55
-57
-61
-70
Catapano AL et al. Curr Med Res Opin. 2006;22:2041-2053
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Secondary Target: Non-HDL-C
• Non-HDL-C = (Total Cholesterol) – (HDL-C)
• Target of therapy only after LDL-C is lowered
and if triglycerides are 200 to 499 mg/dL
• Options to reduce non-HDL-C can target:
– More intense LDL-C lowering
– Lowering triglycerides
– Raising HDL-C
– A combination of LDL-C lowering, triglyceride
lowering, and/or HDL-C raising
Grundy S et al. Circulation. 2004;110:227-239
Smith SC, Jr. et al. J Am Coll Cardiol. 2006;47:2130 –2139.
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Niacin/Statin Combinations
• Safety of combination is well established
• Fixed combinations:
– Niaspan/Lovastatin (Advicor®)
– Niaspan/Simvastatin (Simcor®)
• Additive changes in lipoproteins
• Dosing titrations are based on the niacin
component
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Hypertriglyceridemia
• Very high TG’s ( 500 mg/dL)
– Drug therapy to  TG’s and  risk of further
TG elevations that may cause pancreatitis
(especially when >1000 mg/dL)
• Fibrates, omega-3 fatty acids, niacin
– Very low fat diet (<15% of total daily calories)
– After TG’s are < 500 mg/dL can then evaluate
if at primary target (LDL-C goal)
• Worsened by obesity, physical inactivity, or
excessive ethanol use
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Strategies for Low HDL-C
Non-Drug Therapies
• Smoking cessation
• Regular physical activity
• Dietary changes
(increased unsaturated
fat intake)
• Controlling
hypertriglyceridemia
• Controlling hyperglycemia
NCEP ATP III. JAMA. 2001;285:2486-2497.
Pharmacotherapy
• Niacin
• Fibrates
• Statins (minimal)
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New Drugs in Development
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Potential Agents
• PCSK9 Monoclonal Antibody
– Increases LDL-C removal by decreasing inhibitor of
LDL clearance receptor
• Mipomersen
– Antisense agent that inhibits ApoB systhesis
• Lomitapide
– Mitochondrial trifunctional protein enzyme inhibitor
that decreases lipoprotein production
• Anacetrapib
– Inhibits cholesteryl ester transfer protein (CETP)
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Cholesteryl Ester Transfer Protein (CETP)
Inhibition
CETP promotes transfer of cholesteryl esters (CE) from
HDL to Apo B-containing lipoproteins (VLDL, LDL)
Liver
CE
LDL-R
CE
SR-B1
CETP
FC
CE
Bile
LCAT
FC
Brousseau ME, et al. N Engl J Med. 2004;350:1505-1515.
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Determining the Efficacy and Tolerability of
CETP Inhibition with Anacetrapib (DEFINE)
– LDL-C
– HDL-C
81 mg/dL
40 mg/dL
Cannon CP, et al. N Engl J Med. 2010;363:2406-2415.
Anacetrapib
60
Change at 24 wks (mg/dL)
• 1623 patients with
CHD or high risk for
CHD on statin
therapy
• Randomized, doubleblind, to placebo or
anacetrapib 100 mg
daily for 76 wks
• Baseline lipid values:
Placebo
40
20
0
-20
P<0.001 for both
-40
LDL-C
(Primary
Endpoint)
HDL-C
(Secondary
Endpoint)
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Key Take-Away Messages
• LDL-C is the primary target and lowering it by at least 3040% is recommended as a minimum standard to reduce
cardiovascular risk when using lipid altering agents
• Statins are evidence based therapies and should be the
foundation of treatment for most patients, with several
other agents as alternatives or add-on therapies
• Fibrates and niacin are useful in addition to statin therapy
for mixed dyslipidemia (e.g., non-HDL-C lowering) as
therapy for secondary targets
• Monitoring and titration of therapy to achieve
recommended targets is needed for all lipid-lowering drug
therapies
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Key Take-Away Messages:
Lipid Treatment Assessment Project 2 (L-TAP2)
• 9955 patients on stable lipid-lowering therapy from 9 different countries
% at LDL-C Goal
100
86
74
80
67
60
40
30
20
0
Low risk
(<160)
Moderate risk
(<130)
Waters DD et al. Circulation. 2009;120:28-34.
High risk
(<100)
Very high risk
(<70)
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Case Scenario 2
• Betty is a 68-year-old woman with type 2 diabetes is treated with
simvastatin 40 mg daily. She has hypertension, but does not
smoke and does not have AVD.
• Her labs from 4 weeks ago are:
– TC = 220 mg/dL, HDL-C = 40 mg/dL, TG = 300 mg/dL and
LDL-C = 120 mg/dL; S. Creat = 1.0 mg/dL; LFTs and TSH
are normal; A1C = 7.4 mg/dL; CK = 380 U/L (normal, 0-220
U/L)
• Her provider wanted to add another drug, but decided to
continue simvastatin and have Betty increase her exercise to 3
times weekly
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Case Scenario 2
• She says she went on the Internet and found the
following warning concerned her: “If you take
simvastatin, tell your doctor about any unusual muscle
pain or weakness. This could be a sign of serious side
effects.”
• Betty says she always has some muscle aches and
pains because she is 200 lbs., but that she has had
more of them lately
How do you respond to Betty?
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Case Scenario 2, cont.
• Regardless of your conversation, Betty wants to
stop her simvastatin. Considering her current
dyslipidemia control, which of the following is a
reasonable alternative to her current simvastatin
40 mg daily?
1.
2.
3.
4.
Pravastatin 40 mg daily
Rosuvastatin 20 mg daily
Ezetimibe 10 mg daily
Colesevelam 3.75 g daily
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Case Scenario 2, cont.
• Two years later, Betty is treated with
rosuvastatin 40 mg daily. Her fasting lipid panel
is:
– TC = 178 mg/dL, HDL-C = 38 mg/dL, TG = 250 mg/dL
and LDL-C = 90 mg/dL
What is the next step in her
dyslipidemia therapy?
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Case Scenario 2, cont.
• Gemfibrozil 600 mg BID is added to Betty’s
regimen. After seven days, she calls you and
reports having severe muscle pain and
weakness, and that the color of her urine is a
funny shade of brown.
What should happen with regard to
Betty’s therapy?
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