Transcript 2012 Dyslipidemia Guidelines: Statin Intolerance and Adverse Effects

Statin Intolerance and
Adverse Effects
Canadian Working Group Consensus
David Fitchett MD
Division of Cardiology
St Michael’s Hospital
University of Toronto
Toronto, Ontario
G. B. John Mancini MD
Division of Cardiology
Department of Medicine
University of British Columbia
Vancouver, British Columbia
Robert Hegele MD
Department of Medicine and
Robarts Research Institute
Schulich School of Medicine
London, Ontario
Disclosures
D Fitchett MD
Consulting fees and CME honoraria from
Merck, Astra Zeneca, Pfizer, Novartis, Bayer, Sanofi Aventis, Valeant
R Hegele MD
Consulting fees and CME honoraria from
Merck, Astra Zeneca, Pfizer, Amgen, Sunovion, Genzyme, Valeant
G. B. J. Mancini MD
CME Honoraria from Merck, Astra Zeneca
Secondary Review Panel
Dominic Ng
University of Toronto
Milan Gupta
McMaster University
Jiri Frohlich
University of British Columbia
Jean Bergeron
Laval University
Jacques Genest
McGill University
Janet Pope
University Western Ontario
Steven Baker
McMaster University
54 Year Old Male
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No prior illness / medications
STEMI 5 weeks ago
Discharged from hospital on atorvastatin 80mg daily
Other medications: ASA, clopidogrel, perindopril, bisoprolol
Within a few days, complained of back and lower limb
pains and lower limb weakness
 Also complains of insomnia, and poor memory
 Biochemistry (on treatment)
• CK 200 U/L
• ALT 95 U/L
How would you manage ?
TC 3.5, HDL 1.1, TG 1.4, LDL 1.8 mMol/l,
Creatinine 95 μm/l
Canadian Journal of Cardiology 2011; 27:635-662
Prospective meta-analysis: 90,056 participants
in 14 randomized statin trials
For each 1 mmol/L LDL-C lowering
 12% reduction in all-cause mortality (P<0.0001)
 19% reduction in coronary mortality (P<0.0001)
 23% reduction in MI and coronary death (P<0.0001)
 24% reduction in revascularizations (P<0.0001)
 17% reduction in fatal or non-fatal stroke (P<0.0001)
 21% reduction in any major vascular event (P<0.0001)
 No increase in non-vascular mortality or cancers
Adapted from Baigent C et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Lancet 2005; 366:1267-78
Benefits of More vs Less Intensive
Statin Therapy: (5 RCTs, N=39,612)
 Intensive therapy statin therapy resulted in a further
reduction of LDL-C of 0.51mmol/L
 After 1 year:
• 15% reduction in major vascular events
• 13% reduction of coronary death or non-fatal MI
• 16% reduction in ischaemic stroke
CTT Lancet 2010; 376: 1670-81
Effect of Statins on CV Event Rates
Related to 1 mmol/l LDL Reduction
More
statin
Less
statin
A. More statin vs less statin (5 trials: 0.51 mmol/L LDL difference)
Any major coronary event
1725 (1.9)
Any coronary revascularization
2250 (2.6)
Any stroke
572 (0.6)
5 trials: any major vascular event
3837 (4.5)
Relative risk per 1 mmol/L
(39 mg/dl) reduction in LDL-C
(95% CI)
1973
0.74(2.2)
(0.65-0.85)
2741
0.66(3.2)
(0.60-0.73)
663
0.74(0.7)
(0.59-0.92)
4416
0.72(5.3)
(0.66-0.78)
0.50 0.75 1.00 1.25 1.50
More statin better Less statin better
Statin
Control
B. Statin vs control (21 trials: 1.07 mmol/L LDL difference)
Any major coronary event
3380 (1.3)
Any coronary revascularization
3103 (1.2)
Any stroke
1730 (0.7)
21 trials: any major vascular event
7136 (2.8)
4539
0.76(1.7)
(0.73-0.79)
4066
0.76(1.6)
(0.73-0.80)
2017
0.85(0.8)
(0.80-0.90)
8934
0.79(3.6)
(0.77-0.81)
0.50 0.75 1.00 1.25 1.50
Statin better Control better
CCT Trialists. Lancet 2010;376:1670
Absolute Benefit of Statins
Event rate (%)
Events Prevented by Reducing LDL 1 mmol for 5 yrs
30
25
20
NNT
33
Secondary Prevention
15
10
5
0
Major coronary Coronary revasc.
event
Outcomes avoided per 1000 30 (24-37)
(95% CI)
Event rate (%)
37
30
25
20
15
10
5
0
27 (20-34)
125
20
Treatment
Control
Stroke
Major vascular
event
8 (4-12)
48 (39-57)
200
40
Stroke
Major vascular
event
5 (1-8)
25 (19-31)
Primary Prevention
NNT
55
83
Major coronary Coronary revasc.
event
Outcomes avoided per 1000 18 (14-23)
(95% CI)
12 (9-16)
CTT Lancet 2005; 366:1267
Reported Adverse Effects of Statins
 Muscle-related symptoms
 Elevated hepato-cellular enzymes
 Cancer
 New diabetes
 Hemorrhagic stroke
 Fatigue
 Neuro-psychiatric effects and insomnia
 Proteinuria / hematuria
 Erectile dysfunction
 Alopecia
Lack of Risk of Cancer with Statins
 Meta-analysis of 175,000 subjects in 27 trials
5 years of statin therapy had no effect on the
incidence of, or mortality from cancer
 Incidence of or mortality from cancer not related to
• Duration of treatment
• Age
• Baseline LDL-C level
• Sex
• Anatomical site of cancer • Risk of vascular event
• Type statin
CTT Lancet DOI:10.1016/S0140 -6736(12)60367-5
Liver Injury Associated with Statin Use
Type of liver injury
Frequency
Comment
Asymptomatic elevations
in aminotransferases
0.1%-3.0%
Dose-dependent; class effect;
clinically not significant
Clinically significant acute
liver injury
Very rare
May be seen in combination with
other medications
Fulminant hepatic failure
Extremely rare
(isolated case reports)
It was estimated that risk of fulminant
liver failure is 2 per million
Autoimmune hepatitis
Case reports
Statins may induce AIH in genetically
susceptible individuals
Bhardwaj SS et al. Clin Liver Dis 2007; 11:597-613
Statins and Intracerebral Hemorrhage
Meta-analysis of 23 RCTs shows no increased risk
Trial
4D
ACAPS
AFCAPS
ALERT
ALLHAT
ASCOT
ASPEN
AURORA
Bone et al.
CARE
CLAPT
CORONA
GISSI-HF
GISSI-P
GREACE
HPS
JUPITER
LIPID
MEGA
MIRACL
PROSPER
SPARCL
SSSS
Overall
RR (95% CI)
Weight
0.64 (0.21-1.96)
0.14 (0.01-2.75)
3.00 (0.12-3.62)
0.59 (0.27-1.28)
3.42 (1.26-9.27)
0.55 (0.26-1.14)
1.98 (0.36-10.9)
1.04 (0.57-1.91)
0.74 (0.03-18.3)
0.33 (0.07-1.65)
0.34 (0.01-8.34)
1.66 (0.72-3.80)
3.69 (1.03-13.2)
2.99 (0.12-73.6)
1.00 (0.06-16.0)
0.96 (0.65-1.41)
0.67 (0.24-1.87)
1.89 (0.84-4.24)
1.09 (0.56-2.11)
0.14 (0.01-2.78)
0.81 (0.32-2.04)
1.68 (1.09-2.60)
1.75 (0.51-6.00)
1.10 (0.86-1.42)
3.9
0.7
0.6
6.5
4.7
7.0
1.9
8.8
0.6
2.2
0.6
6.1
3.2
0.6
0.8
12.5
4.4
6.2
7.9
0.7
5.2
11.6
3.4
100
Median LDL-C
reduction 1.03 mmol/L
Risk ratio for intracerebral hemorrhage
0.01
0.1
1.0
10
100
Statins better
Statins worse
Hackam DG et al. Circulation 2011; 124:2233-42
Statins and Neuropsychiatric Effects
 Dementia
• Systematic review showed no increased risk of cognitive decline
Law et al. Am J Cardiol 2006; 97:52C
 Suicide / violent death
• Conflicting evidence on relationship between statin use mood
states: depression, anxiety, fatigue, confusion and vigour
While et al. Eur J Cardiovasc Nurs 2010
 Insomnia
• Initial studies suggested insomnia with lovastatin compared with
pravastatin
Black et al. JAMA 1990; 264:1105
• Study with objective measures of sleep showed no effect
Ehrenberg et al. Sleep 1999; 22:117
Statins and Cognitive Impairment
FDA review of case reports, observational data and
randomized clinical trials
FDA concluded:
 Some individuals over 50 years old suffer notable,
but ill-defined memory loss / impairment
 Reversible on discontinuation of statin
 Variable time of onset (1 day to years)
 No fixed or progressive dementia
 Not related to specific statin
FDA Safety Communication http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm
Statins and Fatigue
 Randomised subset of a controlled trial (397 of 1016 subjects)
 Equal randomisation to simvastatin 20mg, pravastatin, or placebo
 6 month follow-up
Table. Change in Energy and Exertional Fatigue Outcome (EnergyFatigueEx) for Placebo vs Statin Groups
Placebo
All
Women
Statin
Simvastatin
Mean ± SD
Mean ± SD
P value
Mean ± SD
P value
-0.06 ± 0.71
-0.08 ± 0.72
-0.21 ± 0.87
-0.39 ± 1.14
0.005
0.01
-0.25 ± 0.87
-0.47 ± 1.20
0.002
0.004
Pravastatin
Mean ± SD P value
-0.17 ± 0.86
-0.31 ± 0.72
0.06
0.07
 Conclusions:
• Statins may worsen energy and or exertional fatigue
• Women appear more affected than men
• 40% women complain of worse or much worse fatigue
However this is a small study of randomized subset,
with uncertain reproducibility or importance of metrics used
Golomb BA et al. Arch Intern Med. 2012; 172(15):1180-2. doi:10.1001/archinternmed.2012.2171
Statins and New-Onset Diabetes
Proportion of patients with
new-onset diabetes (%)
Study
WOSCOPS (N=5974)
HPS (N=14,543)
ASCOT (N=7773)
LIPID (N=7937)
CORONA (N=3534)
JUPITER (N=17,802)
Combined all above (N=57,593)
Combined all above except
WOSCOPS (N=51,619)
Statins
Placebo
1.9%
4.6%
3.9%
4.3%
5.6%
3.0%
3.8%
4.0%
2.8%
4.0%
3.5%
4.6%
5.0%
2.4%
3.5%
3.5%
Absolute risk of developing DM 0.3-0.5%
Note
 Patient reported diabetes
 No formal testing for diabetes
RR, statin vs
placebo
0.69
1.14
1.14
0.95
1.13
1.25
1.06
1.13
95% CI
0.49-0.96
0.98-1.33
0.90-1.43
0.77-1.16
0.86-1.49
1.05-1.49
0.93-1.22 (P=0.38)
1.03-1.23 (P=0.008)
Risk factors for Statin associated DM
 Obesity
 IFG
 Elevated TG / HDL
Sattar N et al. Lancet 2010; 375:735-42
Statins and New-Onset Diabetes In Context of Reduction
of CV Events: 5 Trials Comparing Intensive- to ModerateDose Statin Therapy
Cases/Total (%)
Incident Diabetes
Intensive dose
PROVE-IT - TIMI 22, 2004 101/1707 (5.9)
A to Z, 2004
65/1768 (3.7)
TNT, 2005
418/3798 (11.0)
IDEAL, 2005
240/3737 (6.4)
SEARCH, 2010
625/5398 (11.6)
Moderate dose
99/1688 (5.9)
47/1736 (2.7)
358/3797 (9.4)
209/3724 (5.6)
587/5399 (10.9)
Pooled odds ratio
1300/16,344 (8.0) 1.12 (1.04-1.22)
1449/16,408 (8.8)
OR (95% CI)
1.01 (0.76-1.34)
1.37 (0.94-2.01)
1.19 (1.02-1.38)
1.15 (0.95-1.40)
1.07 (0.95-1.21)
0.5
1.0
2.0
1.0
Odds ratio (95% CI)
2.0
Incident CVD
PROVE-IT - TIMI 22, 2004
A to Z, 2004
TNT, 2005
IDEAL, 2005
SEARCH, 2010
315/1707 (18.4)
212/1768 (12.0)
647/3798 (17.0)
776/3737 (20.8)
1184/5398 (21.9)
355/1688 (21.0)
234/1736 (13.5)
830/3797 (21.9)
917/3724 (24.6)
1214/5399 (22.5)
0.85 (0.72-1.01)
0.87 (0.72-1.07)
0.73 (0.65-0.82)
0.80 (0.72-0.89)
0.97 (0.88-1.06)
Pooled odds ratio
3134/16,408 (19.1) 3550/16,344 (21.7) 0.84 (0.75-0.94)
0.5
NTT/yr
NNH/yr
155 for CV events
498 for new-onset diabetes
Preiss D et al. JAMA 2011; 305:2556-64
Statins and New-Onset Diabetes
 Treatment of 255 patients with statins results
in 1 additional case of diabetes over 4 years
 Statin treatment prevented of 5.4 vascular events
in these 255 patients
Benefit of statin treatment exceeds risk
Monitor fasting glucose and A1C
Muscle Adverse Effects of Statin
 Major symptom limiting the use of statins
 Clinical features include
• Muscle aches, myalgia, weakness
• Stiffness, and cramps
• CK not increased in most patients
 Compromises quality of life
 Reduces medication adherence
Mancini GB et al. CJC 2011; 27:635-662
Statin Intolerance
Impact of Adverse Effects on Adherence
 Survey of 10,138 current or former statin users
 Muscle related side effects reported in
• 60% former users
• 25% current users
 Primary reason for discontinuation was side effects
(62%)
Cohen JD et al. J Clin Lipid 2012; 6 (3):208-15
Muscle Disease Nomenclature
 Myalgia
• Muscle aches or weakness in absence of CK rise
 Myositis
• Elevated CK in presence of muscle symptoms
• No absolute CK cut-off to define elevated
 Rhabdomyolysis
• Pronounced CK elevation (> 10x ULN) with muscle
symptoms
• May be associated with urine myoglobin and renal
dysfunction
Note CK elevation can be caused by multiple other causes
 Hypo or hyper thyroidism
 Physical exertion
 Renal dysfunction
 Seizures
 Artifactual elevation
 Trauma
Mancini GB et al. CJC 2011; 27:635-662
Rhabdomyolysis and Statins



Very rare: 0.7 cases / 100,000 person-years
Can also occur in absence of statin therapy
Incidence for individual statins (AERS)
(1 reported case per number of prescriptions)
• Lovastatin
5.2 million
• Atorvastatin 23.4 million
• Pravastatin
27.1 million
• Simvastatin
8.3 million
• Cerivastatin 320,000
FDA Adverse Reporting System
• Rosuvastatin incidence similar to other statins
FDA Advisory 2005

Statin dose-related incidence of rhabdomyolysis
• Compared to Atorvastatin 10mg
 40 mg HR 3.8 (95% CI 2.3-6.6)
 80mg HR 11.3 (95% CI 6.4-20.4)
Holbrook A et al. Can J Cardiol 2011; 27:146-51
Incidence of Muscle-Related Symptoms
during High-dose Statin Treatment
 7924 subjects with hypercholesterolemia
 Received high dose statins for > 3 months
• Atorvastatin 40-80mg
● Fluvastatin ER 80mg
• Pravastatin 40mg
● Simvastatin 40-80mg
 Men : Women 2:1
 832 (10.5%) reported muscle related symptoms
 Incidence related to statin type
• Fluvastatin
• Pravastatin
• Atorvastatin
• Simvastatin
5.1%
10.9%
14.9%
18.2%
PRIMO Bruckert E et al. Cardiovascular Drugs and Therapy 2005; 19:403-14
Incidence of Muscle-Related Symptoms
during High-dose Statin Treatment
 Onset <1 month to 12 months after start
 Triggers for muscle related symptoms
• Unusual physical exertion
• Starting new medication
 Muscle Pain Location
• Widespread 60.1%
• “All over” 24.2%
• Lower extremities > upper body or trunk
 Muscle pain
• Continuous in 25%
• Intermittent in 75% duration minutes – hours
PRIMO Bruckert E et al. Cardiovascular Drugs and Therapy 2005; 19:403-14
Clinical Trials and Muscle Related Adverse Effects
 Meta-analysis of statins vs. placebo studies
 18 Studies with 71,108 patients and 301,374 patient-years
 Muscle related events:
• Statin Rx: 316 patients; Placebo 253 patients (P<0.001)
 CK elevation:
• Statin Rx: 81 patients; Placebo 64 (P=0.001)
 Rhabdomyolysis:
• Statin Rx: 10 patients; Placebo 5 patients (NS)
 NNT = 27 (All cause mortality, MI, CVA, revascularisation)
 NNH = 3400 (Rhabdomyolysis or CK > 10xULN)
Silva M et al. Clin Ther 2006; 29 (2):253-60
Clinical Trials and Muscle-Related
Adverse Effects
Why the low incidence in clinical trials?
 Patients highly selected
 Often have pre-randomisation “run-in”
 Definition of muscle adverse effects differ
 Motivated trial patients may minimize symptoms
 Muscle aches and pains are common in placebo group
Mancini GB et al. CJC 2011; 27:635-662
Mechanisms of Statin Myopathy
 Excess exposure to statins
• Increased plasma levels
• Increased transmembrane flux of statins
 Pre-existing neuromuscular disease
• May be previously undiagnosed
 Impaired calcium handling in skeletal muscle
 Statin induced myocellular metabolic dysfunction
 Immune mediated inflammatory myopathy
• Idiopathic inflammatory myopathy (polymyositis)
• Immune mediated necrotizing myopathy
Mancini GB et al. CJC 2011; 27:635-662
Risk Factors for Statin Induced Myopathy
Patient Characteristics
 Demographics
 Older Age,
 Female gender
 Asian race
 Genetic Predisposition
 Transporters SLCO1B1
 CYP isoenzymes
 FH of statin intolerance
 Comorbidities
 Hypothyroidism
 Systemic disease
 Alcoholism / drugs
 Major surgery
 Myopathy
• Hereditary (PYGM,
CTP II, AMPD)
• Acquired
Risk Factors for Statin-Induced Myopathy
Statin Dose and Pharmacodynamics
Statin dose
 Muscle-related side effects not related to lipid lowering potency
 Dose threshold generally above approved doses
 High vs low statin dose
• 7 RCT meta analysis N= 29,395
• No increase in myopathy
Properties of statin
 Bioavailabity
 Lipophilicity
 Potential for drug interactions
• CYP450 inhibitors
• Inhibition of glucuronidation (eg. gemfibrozil)
Josan K et al. CMAJ 2008; 178:576-84
Risk Factors for Statin-Induced Myopathy
Drug Interactions related to CYP Metabolism
CYP 3A4
Simvastatin
Lovastatin
Atorvastatin
CYP 2C9
Fluvastatin
Rosuvastatin
Inhibitors
Protease inhibitors
Cyclosporine
Amiodarone
Fibrates
Macrolide antibiotics
Diltiazem
Inhibitors
Cyclosporine
No CYP Metabolism
Pravastatin
Medication Interactions as Cause of
Statin-Induced Muscle-Related Side Effects
 Fibrates • Avoid statin + gemfibrozil
• Statin + fenofibrate or bezafibrate can be used cautiously
 Anti-rejection drugs
• Cyclosporine, tacrolimus, sirolimus mycophenylate, rapamycin, 3T3
• Limit statin doses to rosuvastatin 5 mg, atorvastatin 10 mg
 Antifungals
Discontinue statin
 Macrolide antibiotics
during treatment
 HIV protease inhibitors
• Avoid lovastatin and simvastatin
• Initiate atorvastatin at 10mg
Rare cause of statin myopathy
 Amiodarone
Initiate lower doses of statin
 Diltiazem
Genetics and Statin-Induced
Muscle Pains
 SNP polymorphism rs4149056 of SLCO1B1 gene
 Encodes transporter for hepatic uptake of statins
• For the less common C allele, ORs for simvastatin-induced
myopathy (mainly at the 80 mg dose)
• heterozygous 4.5 homozygous 16.9
 C variant could account for ~60% of statin MRSE
 Not all C homozygotes develop MRSE
 Need additional genetic factor
• e.g. partial carnitine palmitoyl transferase II (CPTII)
deficiency
 Or medication e.g. fibrate
 May be most specific for high-dose simvastatin
 No indication for testing currently
Search Collaborative Group. NEJM 2008; 359:789-99
Genetic Risk Factors Associated with
Statin-Induced Myopathies
 Cross sectional study of 136 patients with druginduced myopathies
 Mutations for metabolic myopathies
• Symptomatic 10% vs. control 3%, P=0.04
 Increased frequency of carriers vs control
• CMT II 13 fold
• McArdle disease 20 fold
• Myoadenylate deaminase deficiency 3.25 fold
 Biopsies abnormal in 52%
Vladutiu GD et al. Muscle Nerve 2006; 34:153-62
Biochemical Effects of Statins
Acetate
Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA
Statins
Mevalonate
Mevalonate-5-P
Mevalonate-5-PP
 Co-enzyme Q10
MVK
Protein
prenylation
Geranylgeranyl-PP
 Geranyl-PP  Farnesyl-PP
Squalene
Isopentyl-PP
Dolichols
Squalene-2,3-epoxide
Sec-tRNA
Lanosterol
N-linked glycosylation
7-Dehydrocholesterol
Cholestadien-3β-ol
Lanosterol
DHCR7
DHCR24
*2
Cholesterol
Desmosterol
*3
Statin Myopathy
A Metabolic Muscle Disease ?
Proposed Mechanisms
 Depletion of isoprenoids
• Results in reduced protein prenylation
• Disruption of small G protein function
• Alterations in protein handling
• Alterations of gene expression
 Depletion of coenzyme Q
 Mitochondrial dysfunction
 Impaired calcium handling
 Unmasking pre-existing metabolic myopathies
• McArdle disease, CPT II deficiency
Prevention of Statin Intolerance
 Pre-treatment assessment
• Assess risk (e.g. elderly, prior muscle pains, FH of myopathy,
renal disease, DM, hypothyroidism)
• Consider exogenous factors (e.g. statin dose, alcohol use,
drug-drug interactions, excessive grapefruit juice use)
• Measure baseline CK, ALT, TSH, creatinine
 Counseling
• Inform that statins are very well tolerated in most people
• Inform about muscular symptoms and when to discontinue
 Monitoring
• Check CK / ALT when monitoring lipid lowering efficacy
 At 6-8 weeks after starting or with dose increase and then
every 6-12 m
 Avoid severe exercise for several days prior to testing
Therapeutic Options for Management of
Statin “Intolerant” Patient
 Dietary and health behaviour measures
 Statin based strategies
• Alternative statin
• Alternative dosing
 Non-statin alternatives and adjuncts
• Ezetimibe
• Bile acid sequestrants
 Fibrates
 Niacin
Dietary and Health Behaviour Measures
for Reduction of LDL Cholesterol
 Reduced dietary fat
• Low cholesterol, saturated fat, trans-fats
• Low saturated fat
• Low trans-fat
 Replacement diets
• Saturated fat replaced with mono or
polyunsaturated fats
 Plant sterols
 Viscous fibre
 Red yeast rice – A “LOVASTATIN-LIKE” PRODUCT
NCEP Diet Lowers LDL-C Only when
Combined with Exercise
10
NCEP Step 2 Diet
 Cholesterol < 200mg/d
 <30% calories from fat
 <7% saturated fat
8
6
4
Change (%)
2
0
-2
-4
-6
-8
-10
-12
-14
Control group
Exercise group
Diet group
Diet-plus-exercise group
†
‡
-16
Women
Men
HDL Cholesterol
Women
Men
LDL Cholesterol
Stefanick ML et al. N Engl J Med 1998; 339:12-20
Poly-unsaturated or Mono-unsaturated Fats
to Lower LDL-C
 Baseline mixed natural diet
• 19.3% saturated, 11.5 % mono-unsaturated, 4.6% poly-unsaturated
 Mono-unsaturated Fat Diet (Olive oil + sunflower oil enriched)
• 12.9% saturated, 15.1% mono-unsaturated, 7.9% poly-unsaturated
 Poly-unsaturated Fat Diet (Sunflower oil alone)
• 12.6% saturated, 10.8% mono-unsaturated, 12.7% poly-unsaturated
LDL-C change
Mono-unsaturated diet:
Poly-unsaturated diet:
- 17.9%
- 12.9%
Mensink RP et al. New Engl J Med 1989; 321:436-41
Diet and LDL Reduction
Portfolio Diet compared to Statins
Control
Change from baseline (%)
LDL-C
25
20
15
10
5
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
0
2
Week
Statin
Dietary portfolio
LDL-C-HDL ratio
4
25
20
15
10
5
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
0
2
Week
4
C-reactive protein
25
20
15
10
5
0
-5
-10
-15
-20
-25
-30
-35
-40
-45
0
2
Week
 Reduced dietary fat (<30%) and cholesterol (160mg/1000kcal)
 Increased plant sterols: soy proteins and nuts
 Increased viscous fibre
4
Jenkins DJ et al. JAMA 2003; 290:502-10
Statin Intolerance
Red Rice Yeast
 Red rice yeast 2400 mg bid vs pravastatin 20 mg bid
 LDL-C reduction
• Red rice yeast 27%, pravastatin 30%
NS
 Myalgia
• Red rice yeast 5%, pravastatin 9%
NS
Halbert et al. Am J Cardiol 2010; 105:198
 Variable potency in different preparations,
• Not well regulated or standardized
 Not recommended as replacement for statin
Statin based Options for LDL-Cholesterol
Lowering in Statin “Intolerant” Patient
 Lower statin dose
 Switch to alternative statin
 Altered dosing regimens
• Rosuvastatin 2.5-10 mg 3 x weekly or alternate days
• Rosuvastatin 5-20 mg once weekly
 Low dose / alternative statin /alternating day rosuvastatin
+
• Ezetimibe
• Bile acid binding resin
Statin Intolerance
Treatment with Low Dose Statins
Degreef et al. Eur J Int Med 2010; 21:293
 Simvastatin 0.825-8.75mg daily
 57% able to tolerate, 30% recurrent muscle pains
 LDL-C  26%
 20% able to tolerate statin achieved LDL-C < 2.5
Glueck et al. Clin Ther 2006; 6:933
 61 patients 38-80 years – 50 with myalgia
 Moderate risk Rx rosuvastatin 5 mg High risk Rx 10mg
 LDL-C reduction 5 mg -42 + 18 % 10mg -42 + 24%
 Only 1 /61 unable to tolerate statin
Statin Intolerance
Reduced Frequency Dosing
 Alternate day
• Retrospective analysis 51 patients (76% myalgia)
• Alternate day rosuvastatin (mean dose 5.6mg)
 72.5% able to tolerate
 LDL-C reduced 34.5% P<0.001 in patients tolerating statin
Backes JM et al. Ann Phamacotherapy 2008; 42:341-46
• Two patients intolerant of atorvastatin
• Changed to rosuvastatin 2.5-5mg 3x / week
 Well tolerated
 LDL-C reduced 20-38%
Mackie BD et al. Am J Cardiol 2007; 99:291
 Once weekly
• 10 patients (7 myalgias; 3 GI complaint on prior statin)
• Weekly rosuvastatin 5-20 mg
• LDL-C reduced 29% (range 6-62%)
• 2 patients discontinued because of similar symptoms
Backes JM et al. Am J Cardiol 2007; 100:554-55
Fluvastatin, Ezetimibe or Both in the
Management of Statin Intolerance
 199 patients with statin Intolerance
 Received either Fluvastatin XL 80mg or Ezetimibe 10mg or
Fluvastatin + Ezetimibe
 97% tolerated treatment
 17% develop tolerable muscle symptoms
200
LDL-C (mg/dl)
180
160
Ezetimibe
-15.6%
140
120
Fluvastatin XL
-32.8%
100
-46.1%
Fluvastatin/Ezetimibe
80
60
0
4
8
Time (weeks)
12
Stein EA et al. Am J Cardiol 2008; 101:490-96
Ezetimibe / Fluvastatin XL or Combination
in Statin Intolerant Patients
Time to Onset of Muscle Related Side Effects
30
Ezetimibe
25
20
HR 0.73, 95% CI 0.35-1.55, P=0.41
Fluvastatin XL
HR 0.52, 95% CI 0.23-1.19, P=0.12
15
Fluvastatin/Ezetimibe
10
5
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Time since randomization (weeks)
Stein EA et al. Am J Cardiol 2008; 101:490-96
Coenzyme Q10 and Statin Myopathy
HMG-CoA
Reductase
Inhibitors
(Statins)
Squalene
Cholesterol
 Caso et al. Am J Cardiol 2007; 99:1409
• 32 patients
HMG-CoA
reductase
• Myopathic symptoms
Mevalonate
• Co Q10 100mg or Vit E for 30 days
• Pain severity  40% (P<0.001)
Isopentenyl
 Young et al. Am J Cardiol 2007; 100:1400
Pyrophosphate
• 44 patients statin intolerant
• Co Q10 200 mg or placebo for 12 weeks
Farnesyl
Pyrophosphate
during simvastatin titration 10 to 40 mg
daily
Geranylgeranyl • No difference in proportion
Pyrophosphate
 Able to tolerate simva 40 mg
Prenylation Prenylation
 Remaining on statin
HMG-CoA
Isoprenylated
Proteins
Ubiquinone
Systematic Review: Insufficient evidence to support any role for Coenzyme
Q10 in the management or prevention of statin related myopathy
Marcoff L and Thompson PB. JACC 2007; 49:2231-7
Non-Statin Lipid Lowering Strategies
Ezetimibe
 Lowers LDL 15-20%
 Well tolerated
 May be added to
low dose statin
Bile acid sequestrants
 Lowers LDL 15%
 May prevent diabetes
 Colesevalam better
tolerated
Fibrates
  TG LDL little change
 ? Benefit when HDL low
Niacin
 Flushing/pruritus may limit
tolerance
 Lowers LDL 20%
 TG 40%, HDL 30%
Ezetimibe + Bile acid sequestrant
 40-45% LDL reduction
Future Non-Statin Strategies
to Reduce LDL Cholesterol
 CETP inhibitor
• Torcetrapib (increased mortality) and Dalcetrapib (no benefit)
• Anacetrapib results awaited ( HDL 138%,  LDL 40%)
• Evacetrapib Phase 2 study presented 2010
 Mipomersen
• Inhibits protein synthesis of apoB
• Reduces LDL ~30%
• Injected weekly
• No outcomes trials
 PCSK9 inhibitors
• Reduce LDL 50-60 %,
• Injected q 2 weeks
• No outcomes trials
Adherence to Lipid Lowering Therapy
and Outcomes
 Adherence rates at 1 year 26-85%
 Muscle related symptoms more frequent in
non-adherent patients
 Patient perception of short-term disadvantages
outweighs any long-term benefits
 Outcomes worse in non-adherent patients
 RRR for CV event according to adherence
RRR %
• Fully adherent
39.3%
• 50% adherent
26.1%
• 25% adherent
10.9%
Lipid Research Clinic. Miller NH Am J Med 1997; 102 Suppl 1:43-49
Determinants of Non-Adherence
to Statin Therapy
 Younger patient age
 Primary vs. secondary prevention
 Cost (copayment by patient)
 Not taking other medication
 Male gender
 No diabetes nor hypertension
 No recent acute MI (vs. chronic CAD)
 Infrequent physician visits
 Adverse effects of medication
Algorithm for Statin-Induced Myopathy
Symptoms of Muscle Pains
or Asymptomatic Elevation of CK
CK not elevated
CK < 10x ULN
CK >10x ULN
With significant
symptoms
D/C statin
D/C statin
D/C statin
Restart when free of
symptoms
Consider precipitating ff
Consider precipitating ff
eg thyroid, exercise, drug interactions
Check creatinine, urine for myoglobin
Follow until CK normal
Hydrate
Reassess CK 6-12 weeks
later or if symptoms reoccur
Restart statin lower dose
Use statin with less MRE
e.g. rosuvastatin, fluvastatin
Consider low dose statin, non-statin options
Use dietary measures
Conclusions
Adverse Effects of Statin Treatment
 More common than clinical trials suggest
 Probably more frequent at higher doses
 Important cause of poor adherence to treatment
 Prevent statin induced muscle adverse events
 Manage adverse events
• Use alternative statin
• Reduce frequency of statin
• Use non-statin agents as monotherapy or together
with reduced dose or frequency statin
Back-up Slide
Effect of Statins on CV Event Rates
Related to 1 mmol/l LDL Reduction
A. More statin vs less statin (5 trials: 0.51 mmol/L LDL difference)
Any major coronary event
1725 (1.9)
Any coronary revascularization
2250 (2.6)
Any stroke
572 (0.6)
5 trials: any major vascular event
3837 (4.5)
B. Statin vs control (21 trials: 1.07 mmol/L LDL difference)
Any major coronary event
3380 (1.3)
Any coronary revascularization
3103 (1.2)
Any stroke
1730 (0.7)
21 trials: any major vascular event
7136 (2.8)
C. More statin vs less statin vs control (26 trials)
Vascular events
Major vascular event
Patients with type 1 diabetes
145 (4.5)
Patients with type 2 diabetes
2494 (4.2)
Patients without diabetes
8272 (3.2)
Any vascular event
10,973 (3.2)
Mortality
Cause-specific mortality
All cardiac
3333 (0.9)
Stroke
483 (0.1)
Any vascular
4220 (1.2)
Any non-vascular
2943 (0.8)
All-cause mortality (any death)
7642 (2.1)
Relative risk per 1 mmol/L (39 mg/dl)
reduction in LDL-C (95% CI)
0.74 1973
(0.65-0.85)
(2.2)
0.66 2741
(0.60-0.73)
(3.2)
0.74 (0.59-0.92)
663 (0.7)
0.72 4416
(0.66-0.78)
(5.3)
More statin better
Less statin better
0.76 4539
(0.73-0.79)
(1.7)
0.76 4066
(0.73-0.80)
(1.6)
0.85 2017
(0.80-0.90)
(0.8)
0.79 8934
(0.77-0.81)
(3.6)
Statin better
Control better
0.77 (0.58-1.01)
192 (6.0)
0.80 2920
(0.74-0.86)
(5.1)
0.78
10,163
(0.75-0.81)
(4.0)
0.78
13,350
(0.76-0.80)
(4.0)
0.84 3384
(0.80-0.88)
(1.1)
0.96 (0.84-1.09)
501 (0.1)
0.86 4220
(0.82-0.90)
(1.2)
0.92 2994
(0.92-1.03)
(0.8)
0.90 8327
(0.87-0.93)
(2.3)
0.50 0.75 1.00 1.25 1.50
Statin or more statin better
Control or less statin better
CCT Trialists. Lancet 2010;376:1670