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2/27/2013
TAKING A STATIN CAN
REALLY BE A PAIN
PREVENTION AND MANAGEMENT OF
STATIN INTOLERANCE
Randy W. Burden, PharmD, MDiv, PhC, FNLA
Presbyterian Medical Group
Belen, NM
Diplomate, Accreditation Council for Clinical Lipidolgy
1
2/27/2013
Prevention of Statin Muscle
Related Symptoms
 Verify
y need for statin therapy
py
 Identify patients at high risk for statin
intolerance and modify risk if possible
before starting statin
 Avoid high doses of statins
 Minimize potential for statin food or drug
i t
interactions
ti
2
2/27/2013
Case Study
• DC is a 68 year old petite Asian female (BMI 18) with a
history of 1 ppd tobacco use for 40 years and
hypertension (BP 145/90).
• Her sister has had muscle related side effects with statin
use
• Labs:Total cholesterol 280 mg/dL, HDL 30 mg/dL,
Triglyceride 250 mg/dL, LDL 200 mg/dL, TSH 7.4 mIU/L.
• Meds: lisinopril 20 mg daily and verapamil 240 mg daily.
• Framingham
F
i h
risk
i k score – 26%
• Referred for lipid management – would you start her on
a statin? If yes, which one and at what dose?
3
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Comorbidities and Other Conditions that May
Increase the Risk of Statin-Induced Myopathy
•
•
•
•
•
•
Reduced renal function (creatinine > 1.5 ULN)
Active or unexplained
p
hepatic
p
disease
Untreated hypothyroidism
Diabetes mellitus
Hypertension
Intercurrent illness, surgery or trauma
Vandenberg et al. Curr Atrheroscler Rep. 2010;12:48‐57. Shannon J et al. US Pharm. 2012;37(2):55‐59.
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2/27/2013
Factors That Increase the Risk of
Statin-Induced Myopathy
•
•
•
•
•
•
•
Advancing age
Use with caution if small bodyy frame,, especially
p
y if female
Race/ethnicity: rosuvastatin clearance ↓ in Asians
Grapefruit juice > 1 quart/day
Alcoholism
Illicit drugs (eg, cocaine, amphetamines)
G
Genetics
ti
Vandenberg et al. Curr Atrheroscler Rep. 2010;12:48‐57
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SEARCH Trial
• 12,000 myocardial infarction survivors
• Double blind, randomized to 80 or 20 mg of
simvastatin
• Average follow-up 6 years
• 53 cases of myopathy in the 80 mg and 3 in the
20 mg group
• Risks: older age, female, 2x if on diltiazem
Search Collaborative Group . Lancet, 2010;(376) 1658-1669,
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Genetic Risk Factors
SEARCH T
Trial
i l -SLC01B1
SLC01B1 (OATP)
• In a subgroup analysis 85 subjects with
myopathy
th (including
(i l di iincipient
i i t myopathy),
th ) allll on
80 mg simvastatin, underwent a genome wide
scan
• More than 60% of simvastatin induced myopathy
cases were attributed to at least one common
variant in the SLC01B1 gene
• SLC01B1 encodes for an organic anion
transporter known as OATP1
p
uptake
p
of statins
• OATP1 mediates the hepatic
Search Collaborative Group. N Engl J Med. 2008;359:789-99
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Factors That Increase the Risk of
Statin-Induced Myopathy
Statin
St
ti Properties
P
ti
• High systemic exposure (statin dose)
• Potential
P
i l ffor d
drug-drug
d
iinteractions
i
metabolized
b li d
by CYP pathways
– particularly CYP450 3A4
• P-Glycoprotein (pGp) interactions also assoicated primarily
with 3A4 metabolized drugs
• Lipophilicity (theoretical)
• High bioavailability
• Limited protein binding
Kellick KA. LipidSpin. 2012;10(3): 9-12.
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The Prediction of Muscular Risk in
Observational Conditions Study (PRIMO)
• Prospective observational design
PCP s
• 7924 French patients from 2752 PCP’s
• Patients included if on high dose statin for 3
months or statin had been ↓ or stopped
pp in last 3
months
g ((atorvastatin 40-80 mg,
g fluvastatin
• Statin dosing
XL 80mg, pravastatin 40mg or simvastatin 4080mg)
Bruckert. Cardiovasc Drug Ther. 2005;19:403-14
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PRIMO: Risk of Muscular Symptoms with
Individual Statins
Percentage of
patients with
muscular
symptoms*
symptoms
Odds Ratio†
[95% CI]
P value‡
Statin
Dosage
(n=832)
Pravastatin
40 mg/day
10.9%
Atorvastatin
40–80 mg/day
14.9%
1.28 [1.02–1.60]
0.035
Simvastatin
40–80 mg/day
18.2%
1.78 [1.39–2.29]
<0.0001
Fluvastatin
80 mg/day
5.1%
0.33 [0.26–0.42]
<0.0001
*% values relative to the total number of patients with or without muscular symptoms.
† Odds ratios were calculated using pravastatin as the reference.
reference
‡ P values were determined by Pearson’s Chi-squared test.
Bruckert E et al. Cardiovascular Drugs and Therapy. 2005 ;19: 403–414.
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Distribution of the time of onset of muscular
symptoms after initiation of statin therapy or
titration to higher doses
Bruckert. Cardiovasc Drug Ther. 2005;19:403-14.
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CK >10 X ULN Frequency by
% LDL-C
LDL C Reduction
3.0
CK > 10  UL
LN
2.5
Cerivastatin (0.2
(0 2 - 0.8
0 8 mg)
Pravastatin (40 - 80 mg)
Simvastatin (40 - 80 mg)
Atorvastatin (10 - 80 mg)
Rosuvastatin (5 - 80 mg)
Fluvastatin (40-80 mg)
20
2.0
1.5
1.0
0.5
0.0
20
30
40
50
60
70
% LDL-C Reduction
Jacobson T. Am J Cardiol 2006;97[suppl]:44C–51C
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Drug Drug Interactions
Drug-Drug
CYP3A4
• Simvastatin**
Simvastatin
• Atorvastatin**
• Lovastatin
Lovastatin**
CYP2C9/other pathways
# DDI
77
65
58
**significant interaction with
grapefruit juice
#DDI
•
•
•
•
Fluvastatin
Rosuvastatin+
Pravastatin+
Pitavastatin
31
30
27
10
+ hydrophilic - greater
hepatoselectivity
Micromedex 2012. Accessed December 27, 2012.
Neuvonan et al. Clin Pharmacol Ther 2006;80:565-81...
Kellick KA. LipidSpin. 2012;10(3): 9-12.
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2/27/2013
FDA Safety Announcement 6/8/11:
Simvastatin
 Maintain 80 mg dose only if taking for > 12 months
without muscle symptoms
 Do not start new patients on 80 mg
 If not at LDL goal on 40 mg change to another statin
 Do not exceed 10 mg daily with verapamil or
diltiazem
 Do not exceed 20 mg daily with amlodipine,
ranolazine, or *amiodarone.
 Contraindicated (new): posaconazole,
posaconazole gemfibrozil,
gemfibrozil
cyclosporine, danazole
 Avoid > 1 qt/day grapefruit juice
http://www.fda.gov/Drugs/DrugSafety/ucm256561.htm
*originally was 10 mg but redacted in Dec 2011 due to lack of supportive evidence
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FDA Safety Announcement 2/28/12:
Lovastatin
• Do not exceed 20 mg with danazol, diltiazem,
verapamil
• Do not exceed 40 mg with amiodarone
• Contraindicated
C t i di t d (new):
(
) posaconazole,
l
boceprevir, telaprevir
• Avoid: clyclosporin and gemfibrozil and > 1
quart/day of grapefruit juice
http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
15
2/27/2013
Back to the Case Study
• DC is a 68 year old petite Asian female (BMI 18) with a
history of 1 ppd tobacco use for 40 years and
hypertension (BP 145/90).
• Her sister has had muscle related side effects with statin
use
• Labs:Total cholesterol 280 mg/dL, HDL 30 mg/dL,
Triglyceride 250 mg/dL, LDL 200 mg/dL, TSH 7.4 mIU/L.
• Meds: lisinopril 20 mg daily and verapamil 240 mg daily.
• Framingham
F
i h
risk
i k score – 26%
• Referred for lipid management – would you start her on
a statin? If yes, which one and at what dose?
16
2/27/2013
National Lipid Association (NLA)
Statin Safety Assessment Task Force
• Definitions of muscle findings:
– Myalgia (1.5%*)
• muscle ache or weakness without creatine kinase (CK)
elevation
– Myopathy (5/100,000*)
• myalgia, plus elevation in CK >10 x ULN
– Rhabdomyolysis (1.6/100,000*)
• CK 10,000 > IU/L, or
plus an elevation in serum creatinine or medical
• CK >10 x ULN p
intervention with IV hydration
* 180,000 patients in 21 major statin trials for an ave of 3 years
Law M et al. Am J Cardiol. 2006; 97 (suppl 8A): 52C-61C.
McKenney et al. Am J Cardiol 2006;97(suppl 8A):89C–94C.
17
2/27/2013
Case Study
•
•
•
•
•
DP is a 56 year old Hispanic male
M di l problems
Medical
bl
iinclude:
l d MI iin 1996
1996, h
hypertension,
t
i
asthma,
th
diabetes, GERD, hypovitaminosis D, history of statin intolerance
Lipids: T Cholesterol 245 mg/dL, Triglyceride 160 mg/dL, HDL 37
mg/dL,
/dL LDL 176 mg/dL,
/dL non-HDL
HDL 208 mg/dL
/dL
Meds: metformin 500 mg BID, ranitidine 150 mg BID, vitamin D3
1000 IU daily, lisinopril 20 mg daily, hydrochlorothiazide 12.5 mg
d il albuterol
daily,
lb t l MDI prn, metoprolol
t
l l 50 mg BID
BID, clonidine
l idi 0
0.2
2 mg
daily, fish oil capsules 2 caps daily.
Over the past 11 years he has tried atorvastatin, simvastatin,
sim astatin/e etimibe and lo
simvastatin/ezetimibe,
lovastatin
astatin all ca
causing
sing weakness
eakness and
muscle pain. He had flushing with niacin and a rash with
fenofibrate.
18
2/27/2013
Recommendations from the NLA Statin Safety
Task Force for Muscle Issues
PATIENT MONITORING
• Obtain baseline CK levels in high risk patients ( renal dysfunction,
transplants, polypharmacy), optional for others
• Monitoring with CK measurement only in symptomatic patients
• Rule out other etiologies of muscle symptoms or asymptomatic
CK elevations
• Exacerbating factors should be considered (grapefruit juice
consumption concomitant medications
consumption,
medications, herbal remedies
remedies,
infection, sepsis, alcohol abuse)
McKenney JM et al. Am J Cardiol. 2006;97:89C-94C
Thompson PD et al. Am J Cardiol. 2006;97:69C-76C
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Etiologies of Muscle Symptoms
or Increased CK Level
o Exercise or increased physical activity (particularly in
unaccustomed individuals)
y
p
,
o Medication: colchicine,, amiodarone,, clyclosporin,
glucocorticoids, cimetidine
o Trauma, falls, accidents
o Seizures, shaking chills
o Hypothyroidism
H
th idi
o Infections
o Carbon monoxide poisoning
o Inherited metabolic muscle disease
• Carnitine PalmitoylTransferase II deficiency (1/270 carrier)
• McArdle disease - myophosphorylase deficiency (1/170)
• Myoadenylate deaminase deficiency
Kellick KA. LipidSpin. 2012;10(3): 9-12.
Vandenberg et al. Curr Atrheroscler Rep. 2010;12:48-57.
Mc Kenney et al. Am J Cardiol. 2006;97(suppl 8A): 89C -94c
Eckel RH. J Clin Enocrinol Metab. 2010;95(5):2015-22.
Del Grande M et al. Int J Clin Rhematol. 2012;7(3):243-246.
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Triggering Factors for
Muscular Symptoms
• Of the PRIMO patients who reported muscular
symptoms with statin therapy (n=832), 41% noted a
potential triggering factor:
– 53% reported unusual physical exertion
– 30% reported taking a new medication
Bruckert E et al. Cardiovascular Drugs and Therapy. 2005 ;19: 403–414.
21
2/27/2013
Understanding Statin Use in America and
Gaps in Patient Education (USAGE)
OBJECTIVE: to assess the attitudes,
attitudes beliefs,
beliefs practices,
practices
and behavior of 8918 current and 1220 former statin
users.
 Muscle–related side effects while taking a statin reported
by 29% of all participants
• 25% among current users
• 60% among former users
 On average, respondents reported using 3 medications
or supplements with the potential for statin interaction
Cohen et al. J Clin Lipidol. 2012;6:208-215.
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Recommendations from the NLA Statin Safety
Task Force for Muscle Issues
MANAGEMENT OF MUSCLE SYMPTOMS
• Intolerable muscle symptoms:
– Discontinue statin regardless
g
of CK levels and
rechallenge only after patient becomes asymptomatic
• Tolerable muscle symptoms
y p
and:
– Mild CK elevation < 5x UL: May continue statin and use
symptoms as guide to stop or continue treatment
– Moderate to severe CK elevation: Discontinue statin therapy
py
and weigh risks and benefits
– CK elevation with elevated creatinine or need for IV hydration:
Discontinue statin therapy
McKenney JM et al. Am J Cardiol. 2006;97:89C-94C
Thompson PD et al. Am J Cardiol. 2006;97:69C-76C
23
2/27/2013
Approaches to Patients with History of
Statin Related Muscle Pain
 Restart
R
statin
i therapy
h
when
h patient
i
iis
asymptomatic
– Try up to 2-3
2 3 different low dose statins and
titrate to highest tolerated dose (1/2 max
dose)
• Add non
non-statin
statin therapy if LDL not at goal
– Red Yeast Rice?
– Alternate day
day, 2-3x
2 3x week,
week or weekly dosing
– After vitamin D replenishment
24
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Fluvastatin XL
• 199 moderate
d t or high
hi h risk
i kd
dyslipidemic
li id i patients
ti t
• Prior history of statin induced muscle related
side effects
• 3 treatment arms for 12 weeks – double blinded
– Ezetimibe 10mg/d (n= 66)
– Fluvastatin XL 80mg/d (n= 69)
– Fluvastatin XL 80mg/d + ezetimibe 10mg/d (n=
(n 64)
Stein EA et al. Am J Cardiol 2008;101:490–496
25
2/27/2013
Incidence of and time
to first muscle-related side effect
Number of Patients
Median Time to
(Incidence Rate)
First Event (wks)
Ezetimibe (n= 66)
16 (24%)
3.07
Fluvastatin XL (n=69)
12 (17%)
1.36
9 (14%)
2.14
5 (8%)
2.57
3 (4%)
0.43
2 (3%)
1.57
Treatment Group
Any MRSE recurrence
Fluvastatin XL/ezetimibe (n=64)
MRSE recurrence leading to
discontinuation
Ezetimibe (n=66)
Fluvastatin XL ( n=69)
Fluvastatin XL/ezetimibe (n=64)
Stein EA et al. Am J Cardiol 2008;101:490–496
.
26
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Red Yeast Rice
Monascus purpureus
•
•
•
•
Rice fermented with a red mold
mold. Also known as Hong Qu
Contains 14 active compounds called monacolins
Used in China since 800 AD
FDA regulations prohibit inclusion of monacolin K (lovastatin)
above a certain level in RYR
• To avoid being an unapproved drug, RYR products typically
do not disclose levels of monacolins nor do they have a
standardized monacolin K content
• Some RYR products contain citrinin, a mycotoxin that is
nephrotoxic in animals.
Gordon RY et al. Arch Inter Med. 2010;170(19);1722-27.
Kaolpakchi AL et al. Ann Intern Med. 2010;152(2):133-134.
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Red Yeast Rice Trials
Study
Intervention
Duration
Becker
RYR 1800mg BID
(lovastatin 6mg/d)
vs.
Placebo
24 weeks
RYR 2400mg BID
(lovastatin 10mg/d)
vs.
Pravastatin 20mg BID
12 weeks
Halbert
Population
62 dyslipidemic patients
with history of statin intolerance
due to myalgia
Results
No difference in pain severity
scores between groups.
7% of RYR group and 3% of
placebo discontinued therapy
due to myalgia. RYR reduced
LDL-C
LDL
C by 21%
21%.
43 dyslipidemic patients with
history of statin intolerance due
to myalgia
No difference in treatment
discontinuation rates.
Discontinuation due to myalgia
was 5% for RYR and 9% for
P
Prava
(p=0.99).
( 0 99) LDL
LDL-C
C
reduction was 30% for RYR and
27% for Pravastatin.
Becker. Ann Intern Med. 2009;150:830.
Halbert. Am J Cardiol. 2010;105:198.
Adapted from Abd and Jacobson. Expert Opin Drug Safety 2011:10(3):1-15
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Alternative Statin Dosing in Statin Intolerant Patients
Investigator
Reddy
2009
Retrospective
chart review
N
23
Intervention
rosuvastatin 5-40 mg
or
atorvastatin 20-40 mg
twice-weekly
+
ezetmibe
t ib 10 mg twice
t i weekly
kl
and
colesevelam 625 mg twice daily
Duration
mean, 4.5 months
Results
87% patients tolerated
therapy. Mean LDL-C
reduction from baseline
not statistically significant
as 78% were already at
ATP II goals
l before
b f
starting therapy.
Ruisinger
2009
Retrospective
chart review
50
rosuvastatin 2.5 to 20mg
once weekly
4 months
74% of patients tolerated
therapy. Mean LDL-C
reduction 23%
Gadalara
2008
Retrospective
chart review
40
rosuvastatin 5 or 10 mg
twice-weekly
2-12 months
(3 months ave)
Backes
2008
Retrospective
chart review
51
rosuvastatin
(mean=5.6mg)
every-other-day
4 months
72% of patients tolerated
therapy. Mean LDL-C
reduction 35%
Athyros
2008
Interventional,
noncontrolled
56
atorvastatin 10mg
Twice weekly
+
ezetimibe 10mg/d
3months
91% of patients tolerated
therapy. Mean LDL-C
reduction 37%
80% tolerated therapy.
Mean LDL-C reduction
43%.
Adapted from Reinhart et al. Am J Health-System Pharmacy. 2012;69(4):291-300.
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Limitations of Alternative Day
Statin Dosing Trials
•
•
•
•
Retrospective designs
placebo control g
groups
p
Lack of p
Small study populations
Some trials allowed p
patients to continue other
lipid lowering drugs
• Event reduction- unknown
30
2/27/2013
The High
High-Dose
Dose Rosuvastatin
Once Weekly Study
• R
Randomized
d i d tto rosuvastatin
t ti 80 mg once weekly
kl
(n=10) or atorvastatin 10 mg daily (n=10)
• Double-blind
Double blind
• Parallel group
• 8 week
k pilot
il t study
t d
• Overall mean LDL-C reduction of 29% in both
groups.
groups
• No statin related muscle symptoms reported
Backes JM et al. JCL. 2012:6;362-367.
31
2/27/2013
Vitamin D
• Low vitamin D levels associated with myalgia
• Low vitamin D levels associated with reduced
muscle function
• A specific nuclear receptor for vitamin D has
been isolated in myocytes
Lips P. Prog Biophys Mol Biol.2006;92:4-8.
Bischoff-Ferrari. Am J Clin Nutr.2004;80-752-8.
Bischoff Ferrari. Histochem J . 2001;33:19-24
32
2/27/2013
Vitamin D and Myalgias
• Vitamin D deficiency is common among patients
with statin-associated myalgias
• Vitamin D deficiency might be a risk factor in
developing statin-intolerance
statin intolerance in patients with
certain polymorphisms
• Anecdotally,
y, manyy patients
p
with vitamin D
deficiency that developed myalgias once starting
a statin have noted resolution of myalgias and
/or greater tolerance for statins in retreatment
after vitamin D repletion.
Linde et al. Dermato-Endocrinology. 2010; 2:2, 77-84.
Bittner V et al. J Am Coll Card. 2010;55:A177.E1659..
Duell PB et al. Circulation. 2008;118:S_470.
Lee JH et al. J Am Coll Card. 2008; 52(24): 1949-1953.
33
2/27/2013
Vitamin D Repletion
• 21 vitamin D deficient patients (< 30ng/mL)
complained of intolerable myalgias while on
statins
• After 2-3 months of vitamin D repletion, 15
patients were rechallenged with statin therapy
• 14 (93%) remained symptom free, 1 with mild
and tolerable symptoms able to continue statin
Linde et al. Dermato-Endocrinology. 2010; 2:2, 77-84.
34
2/27/2013
Vitamin D Repletion
• 128 statin
t ti myalgia
l i patients
ti t
• 82 of 128 (patients with Vitamin D below 32
ng/ml)
• 38 of 82 continued statins + agreed to therapy
with 50,000
50 000 units ergocalciferol a week for 3
months
• 35 of 38 patients (92%) became myalgia free
Ahmed W. Translational Research. 2009;153:11-16
35
2/27/2013
Vitamin D
• Study
St d Limitations
Li it ti
–
–
–
–
Not randomized
No placebo group
Not blinded
Myalgia reports were subjective, no objective
questionnaire
– Small number of participants
Ahmed W. Translational Research. 2009;153:11-16
36
2/27/2013
Non-Statin Approaches to Patients with
Statin Related Muscle Pain
• If still unable to tolerate statin
therapy then:
– start on non-statin therapy
(ezetimibe niacin
(ezetimibe,
niacin, BAS) or
combinations
– consider
id more aggressive
i
dietary interventions
37
2/27/2013
Ezetimibe + Colesevelam
• R
Retrospective
t
ti review
i
off 16 patients
ti t with
ith statin
t ti
intolerance and diabetes mellitus
• Treated with ezetimibe 10mg/day and
colesevelam 1.875mg BID for 3 months
• LDL-C
LDL C was reduced 42% from baseline
• 50% achieved LDL-C goal of < 100 mg/dL
• No reports of myalgia
Rivers. Endocrin Pract. 2007;13:11
38
2/27/2013
Diet Change
• Plant stanols and sterols
– found naturally in many nuts, seeds grains, fruits, vegetable oils
and legumes
– Inhibit cholesterol absorption
– 2-3 gm/day decreases LDL by 6-15%
• Portfolio diet
–
–
–
–
–
Soy based foods instead of meat
High in viscous fiber
Replace butter/margarine with plant sterol enriched margarine
Increase nut intake, especially almonds
5-25% LDL reduction
Houston MC, et al. Progress in Cardiovascular Diseases. 2009;52:61-94
;
Jenkins DJ,, et al. Am J Clin Nutr. 2005;81:380-387
39
2/27/2013
Back to the Case Study
•
•
•
•
•
DP is a 56 year old Hispanic male
M di l problems
Medical
bl
iinclude:
l d MI iin 1996
1996, h
hypertension,
t
i
asthma,
th
diabetes, GERD, hypovitaminosis D, history of statin intolerance
Lipids: T Cholesterol 245 mg/dL, Triglyceride 160 mg/dL, HDL 37
mg/dL,
/dL LDL 176 mg/dL,
/dL non-HDL
HDL 208 mg/dL
/dL
Meds: metformin 500 mg BID, ranitidine 150 mg BID, vitamin D3
1000 IU daily, lisinopril 20 mg daily, hydrochlorothiazide 12.5 mg
d il albuterol
daily,
lb t l MDI prn, metoprolol
t
l l 50 mg BID
BID, clonidine
l idi 0
0.2
2 mg
daily, fish oil capsules 2 caps daily.
Over the past 11 years he has tried atorvastatin, simvastatin,
sim astatin/e etimibe and lo
simvastatin/ezetimibe,
lovastatin
astatin all ca
causing
sing weakness
eakness and
muscle pain. He had flushing with niacin and a rash with
fenofibrate.
40
2/27/2013
Prevention of Statin Muscle
Related Symptoms
Verify
y need for statin therapy
py
Identify patients at high risk for statin
intolerance and modify risk if possible
before starting statin
Avoid high doses of statins
Minimize potential for statin food or drug
i t
interactions
ti
41
2/27/2013
Approaches to Patients with History of
Statin Related Muscle Pain
 Restart
R
statin
i therapy
h
when
h patient
i
iis
asymptomatic
– Try up to 2-3
2 3 different low dose statins and
titrate to highest tolerated dose (1/2 max
dose)
• Add non
non-statin
statin therapy if LDL not at goal
– Red Yeast Rice: not recommended
– Alternate day
day, 2-3x
2 3x week,
week or weekly dosing
– After vitamin D replenishment
42
2/27/2013
Non-Statin Approaches to Patients with
Statin Related Muscle Pain
If still unable to tolerate statin therapy
py then
 Start on non-statin therapy/combos
• Ezetimibe
• Niacin
• Bile acid sequestrants
q
 Consider more aggressive dietary
interventions
 Add plant stanols and sterols
 Portfolio diet
43
2/27/2013
Acknowledgements
Terry A. Jacobson, MD, FNLA
Professor of Medicine
Director, Office of Health Promotion and Disease Prevention
Emory University
Atlanta, GA
Diplomate American Board of Clinical Lipidology
Diplomate,
44