Statin Intolerance and Adverse Effects

Canadian Working Group Consensus

David Fitchett MD Division of CardiologySt Michael’s HospitalUniversity of Toronto

Toronto, Ontario

Robert Hegele MD Department of Medicine and Robarts Research Institute

Schulich School of MedicineLondon, Ontario

G. B. John Mancini MD Division of Cardiology

Department of MedicineUniversity of British ColumbiaVancouver, British Columbia

Disclosures

D Fitchett MDConsulting fees and CME honoraria from

Merck, Astra Zeneca, Pfizer, Novartis, Bayer, Sanofi Aventis, Valeant

R Hegele MDConsulting fees and CME honoraria from

Merck, Astra Zeneca, Pfizer, Amgen, Sunovion, Genzyme, Valeant

G. B. J. Mancini MDCME 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

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 RatesRelated to 1 mmol/l LDL Reduction

CCT Trialists. Lancet 2010;376:1670

A. More statin vs less statin (5 trials: 0.51 mmol/L LDL

difference)

Any major coronary event

Any coronary revascularization

Any stroke

5 trials: any major vascular event

B. Statin vs control (21 trials: 1.07 mmol/L LDL difference)

Any major coronary event

Any coronary revascularization

Any stroke

21 trials: any major vascular event

1725 (1.9)

2250 (2.6)

572 (0.6)

3837 (4.5)

3380 (1.3)

3103 (1.2)

1730 (0.7)

7136 (2.8)

1973 (2.2)

2741 (3.2)

663 (0.7)

4416 (5.3)

4539 (1.7)

4066 (1.6)

2017 (0.8)

8934 (3.6)

0.74 (0.65-0.85)

0.66 (0.60-0.73)

0.74 (0.59-0.92)

0.72 (0.66-0.78)

0.76 (0.73-0.79)

0.76 (0.73-0.80)

0.85 (0.80-0.90)

0.79 (0.77-0.81)

0.750.50 1.00 1.25 1.50Statin better Control better

More statin better Less statin better

Relative risk per 1 mmol/L(39 mg/dl) reduction in LDL-C

(95% CI)

0.750.50 1.00 1.25 1.50

More statin

Less statin

Statin Control

Absolute Benefit of StatinsEvents Prevented by Reducing LDL 1 mmol for 5 yrs

CTT Lancet 2005; 366:1267

Primary Prevention

Secondary Prevention25

30

20

15

10

5

0

Eve

nt r

ate

(%)

Major coronaryevent

Coronary revasc. Stroke Major vascularevent

33 37 125 20NNT

30 (24-37) 27 (20-34) 8 (4-12) 48 (39-57)Outcomes avoided per 1000 (95% CI)

Treatment

Control

25

30

20

15

10

5

0

Eve

nt r

ate

(%)

Major coronaryevent

Coronary revasc. Stroke Major vascularevent

55 83 200 40NNT

18 (14-23) 12 (9-16) 5 (1-8) 25 (19-31)Outcomes avoided per 1000 (95% CI)

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• Age• Sex• Anatomical site of cancer• Type statin

• Duration of treatment• Baseline LDL-C level• Risk of vascular event

CTT Lancet DOI:10.1016/S0140 -6736(12)60367-5

Liver Injury Associated with Statin Use

Bhardwaj SS et al. Clin Liver Dis 2007; 11:597-613

Type of liver injury

Asymptomatic elevations in aminotransferases

Clinically significant acute liver injury

Fulminant hepatic failure

Autoimmune hepatitis

Frequency

0.1%-3.0%

Very rare

Extremely rare(isolated case reports)

Case reports

Comment

Dose-dependent; class effect; clinically not significant

May be seen in combination with other medications

It was estimated that risk of fulminant liver failure is 2 per million

Statins may induce AIH in genetically susceptible individuals

Statins and Intracerebral HemorrhageMeta-analysis of 23 RCTs shows no increased risk

Hackam DG et al. Circulation 2011; 124:2233-42

Median LDL-Creduction 1.03 mmol/L

Trial

4DACAPSAFCAPSALERTALLHATASCOTASPENAURORABone et al.CARECLAPTCORONAGISSI-HFGISSI-PGREACEHPSJUPITERLIPIDMEGAMIRACLPROSPERSPARCLSSSSOverall

Weight

3.90.70.66.54.77.01.98.80.62.20.66.13.20.60.8

12.54.46.27.90.75.2

11.63.4100

RR (95% CI)

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)

1.0 10 1000.10.01

Risk ratio for intracerebral hemorrhage

Statins better Statins worse

Statins and Neuropsychiatric Effects Dementia

• Systematic review showed no increased risk of cognitive declineLaw 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 vigourWhile et al. Eur J Cardiovasc Nurs 2010

Insomnia• Initial studies suggested insomnia with lovastatin compared with

pravastatinBlack et al. JAMA 1990; 264:1105

• Study with objective measures of sleep showed no effectEhrenberg 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

Conclusions:• Statins may worsen energy and or exertional fatigue• Women appear more affected than men• 40% women complain of worse or much worse fatigue

Golomb BA et al. Arch Intern Med. 2012; 172(15):1180-2. doi:10.1001/archinternmed.2012.2171

However this is a small study of randomized subset, with uncertain reproducibility or importance of metrics used

Table. Change in Energy and Exertional Fatigue Outcome (EnergyFatigueEx) for Placebo vs Statin Groups

Placebo Statin Simvastatin Pravastatin

-0.06 ± 0.71-0.08 ± 0.72

-0.21 ± 0.87-0.39 ± 1.14

0.0050.01

-0.25 ± 0.87-0.47 ± 1.20

0.0020.004

-0.17 ± 0.86-0.31 ± 0.72

0.060.07

AllWomen

Mean ± SD P value Mean ± SD P value Mean ± SD P valueMean ± SD

Statins and New-Onset Diabetes

Absolute risk of developing DM 0.3-0.5%Note Patient reported diabetes No formal testing for diabetes

Risk factors for Statin associated DM Obesity IFG Elevated TG / HDL

Sattar N et al. Lancet 2010; 375:735-42

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

1.9%

4.6%

3.9%

4.3%

5.6%

3.0%

3.8%

4.0%

Placebo

2.8%

4.0%

3.5%

4.6%

5.0%

2.4%

3.5%

3.5%

RR, statin vsplacebo

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)

Proportion of patients with new-onset diabetes (%)

Statins and New-Onset Diabetes In Context of Reduction of CV Events: 5 Trials Comparing Intensive- to Moderate-

Dose Statin Therapy

Preiss D et al. JAMA 2011; 305:2556-64

NTT/yr 155 for CV eventsNNH/yr 498 for new-onset diabetes

Incident Diabetes

Incident CVD

PROVE-IT - TIMI 22, 2004A to Z, 2004TNT, 2005IDEAL, 2005SEARCH, 2010

Pooled odds ratio

315/1707 (18.4)212/1768 (12.0)647/3798 (17.0)776/3737 (20.8)1184/5398 (21.9)

3134/16,408 (19.1)

355/1688 (21.0)234/1736 (13.5)830/3797 (21.9)917/3724 (24.6)1214/5399 (22.5)

3550/16,344 (21.7)

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)

0.84 (0.75-0.94)

PROVE-IT - TIMI 22, 2004A to Z, 2004TNT, 2005IDEAL, 2005SEARCH, 2010

Pooled odds ratio

101/1707 (5.9)65/1768 (3.7)418/3798 (11.0)240/3737 (6.4)625/5398 (11.6)

1449/16,408 (8.8)

99/1688 (5.9)47/1736 (2.7)358/3797 (9.4)209/3724 (5.6)587/5399 (10.9)

1300/16,344 (8.0)

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)

1.12 (1.04-1.22)

0.5 1.0 2.0

0.5 1.0 2.0Odds ratio (95% CI)

Cases/Total (%)

Intensive dose Moderate dose OR (95% CI)

Statins and New-Onset Diabetes

Treatment of 255 patients with statins resultsin 1 additional case of diabetes over 4 years

Statin treatment prevented of 5.4 vascular eventsin these 255 patients

Benefit of statin treatment exceeds riskMonitor 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 IntoleranceImpact 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

dysfunctionNote CK elevation can be caused by multiple other causes Hypo or hyper thyroidism Renal dysfunction Artifactual elevation

Physical exertion Seizures 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 5.1%• Pravastatin 10.9%• Atorvastatin 14.9%• Simvastatin 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-RelatedAdverse 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 MyopathyPatient 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 MyopathyStatin 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 MyopathyDrug Interactions related to CYP Metabolism

CYP 3A4

Simvastatin

Lovastatin

Atorvastatin

Inhibitors

Protease inhibitors

Cyclosporine

Amiodarone

Fibrates

Macrolide antibiotics

Diltiazem

CYP 2C9

Fluvastatin

Rosuvastatin

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 Macrolide antibiotics HIV protease inhibitors

• Avoid lovastatin and simvastatin• Initiate atorvastatin at 10mg

Amiodarone Diltiazem

Rare cause of statin myopathy

Initiate lower doses of statin

Discontinue statin

during treatment

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 drug-induced 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 StatinsAcetate

Acetyl-CoA

Acetoacetyl-CoA

HMG-CoA

Mevalonate

Mevalonate-5-P

Mevalonate-5-PP

Isopentyl-PP

Sec-tRNA

MVK

Co-enzyme Q10

Geranylgeranyl-PP

Farnesyl-PP Squalene

Squalene-2,3-epoxide

Lanosterol

Cholestadien-3β-ol

Geranyl-PP

Dolichols

Lanosterol*3

*2

N-linked glycosylation7-Dehydrocholesterol

DHCR7DHCR24

Cholesterol Desmosterol

Protein prenylation

Statins

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 Measuresfor 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

Stefanick ML et al. N Engl J Med 1998; 339:12-20

NCEP Step 2 Diet Cholesterol < 200mg/d <30% calories from fat <7% saturated fat

8

10

6

4

2

0

-2

-4

-6

-8

-10

-12

-14

-16

Cha

nge

(%)

Women Men Women MenHDL Cholesterol LDL Cholesterol

Control groupExercise groupDiet groupDiet-plus-exercise group † ‡

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 changeMono-unsaturated diet: - 17.9%Poly-unsaturated diet: - 12.9%

Mensink RP et al. New Engl J Med 1989; 321:436-41

Diet and LDL ReductionPortfolio Diet compared to Statins

Reduced dietary fat (<30%) and cholesterol (160mg/1000kcal) Increased plant sterols: soy proteins and nuts Increased viscous fibre

Jenkins DJ et al. JAMA 2003; 290:502-10

2025

1510

50

-5-10-15-20-25-30-35-40-45

0 2 4

Cha

nge

from

bas

elin

e (%

)

Week

LDL-C

2025

151050

-5-10-15-20-25-30-35-40-45

0 2 4Week

LDL-C-HDL ratio

2025

1510

50

-5-10-15-20-25-30-35-40-45

0 2 4Week

C-reactive protein

Control Statin Dietary portfolio

Statin IntoleranceRed 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 IntoleranceReduced 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

• Two patients intolerant of atorvastatin • Changed to rosuvastatin 2.5-5mg 3x / week

Well tolerated LDL-C reduced 20-38%

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

Mackie BD et al. Am J Cardiol 2007; 99:291

Backes JM et al. Ann Phamacotherapy 2008; 42:341-46

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

Stein EA et al. Am J Cardiol 2008; 101:490-96

-15.6%

-32.8%

-46.1%80

60

100

120

140

160

180

200

0 4 8 12

LDL-

C (

mg/

dl)

Time (weeks)

Ezetimibe

Fluvastatin XL

Fluvastatin/Ezetimibe

Ezetimibe / Fluvastatin XL or Combinationin Statin Intolerant Patients

Time to Onset of Muscle Related Side Effects

Stein EA et al. Am J Cardiol 2008; 101:490-96

00

5

10

15

20

25

30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Time since randomization (weeks)

HR 0.73, 95% CI 0.35-1.55, P=0.41

HR 0.52, 95% CI 0.23-1.19, P=0.12

Ezetimibe

Fluvastatin XL

Fluvastatin/Ezetimibe

Coenzyme Q10 and Statin Myopathy

Caso et al. Am J Cardiol 2007; 99:1409

• 32 patients

• Myopathic symptoms

• Co Q10 100mg or Vit E for 30 days

• Pain severity 40% (P<0.001) Young et al. Am J Cardiol 2007; 100:1400

• 44 patients statin intolerant

• Co Q10 200 mg or placebo for 12 weeks during simvastatin titration 10 to 40 mg daily

• No difference in proportion Able to tolerate simva 40 mg Remaining on statin

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

HMG-CoA

HMG-CoAreductase

HMG-CoAReductase Inhibitors (Statins)

Mevalonate

IsopentenylPyrophosphate

FarnesylPyrophosphate

GeranylgeranylPyrophosphate

Squalene

Cholesterol UbiquinoneIsoprenylatedProteins

PrenylationPrenylation

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

Ezetimibe + Bile acid sequestrant 40-45% LDL reduction

Fibrates TG LDL little change ? Benefit when HDL low

Niacin Flushing/pruritus may limit

tolerance Lowers LDL 20% TG 40%, HDL 30%

Future Non-Statin Strategiesto 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-Adherenceto 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 Painsor Asymptomatic Elevation of CK

CK not elevated CK < 10x ULN CK >10x ULNWith significant

symptoms

Reassess CK 6-12 weekslater or if symptoms reoccur

D/C statinRestart when free of

symptoms

D/C statin

Consider precipitating ffeg thyroid, exercise, drug interactions

Follow until CK normal

Restart statin lower doseUse statin with less MRE

e.g. rosuvastatin, fluvastatin

Consider precipitating ffCheck creatinine, urine for myoglobin

Hydrate

D/C statin

Consider low dose statin, non-statin optionsUse dietary measures

ConclusionsAdverse 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 RatesRelated to 1 mmol/l LDL Reduction

CCT Trialists. Lancet 2010;376:1670

A. More statin vs less statin (5 trials: 0.51 mmol/L LDL difference)Any major coronary eventAny coronary revascularizationAny stroke5 trials: any major vascular event

B. Statin vs control (21 trials: 1.07 mmol/L LDL difference)Any major coronary eventAny coronary revascularizationAny stroke21 trials: any major vascular event

C. More statin vs less statin vs control (26 trials)Vascular events

Major vascular eventPatients with type 1 diabetesPatients with type 2 diabetesPatients without diabetes

Any vascular eventMortality

Cause-specific mortalityAll cardiacStrokeAny vascularAny non-vascular

All-cause mortality (any death)

1725 (1.9)2250 (2.6)

572 (0.6)3837 (4.5)

3380 (1.3)3103 (1.2)1730 (0.7)7136 (2.8)

145 (4.5)2494 (4.2)8272 (3.2)

10,973 (3.2)

3333 (0.9)483 (0.1)

4220 (1.2)2943 (0.8)7642 (2.1)

1973 (2.2)2741 (3.2)

663 (0.7)4416 (5.3)

4539 (1.7)4066 (1.6)2017 (0.8)8934 (3.6)

192 (6.0)2920 (5.1)

10,163 (4.0)13,350 (4.0)

3384 (1.1)501 (0.1)

4220 (1.2)2994 (0.8)8327 (2.3)

0.74 (0.65-0.85)0.66 (0.60-0.73)0.74 (0.59-0.92)0.72 (0.66-0.78)

0.76 (0.73-0.79)0.76 (0.73-0.80)0.85 (0.80-0.90)0.79 (0.77-0.81)

0.77 (0.58-1.01)0.80 (0.74-0.86)0.78 (0.75-0.81)0.78 (0.76-0.80)

0.84 (0.80-0.88)0.96 (0.84-1.09)0.86 (0.82-0.90)0.92 (0.92-1.03)0.90 (0.87-0.93)

0.750.50 1.00 1.25 1.50Statin or more statin better Control or less statin better

Statin better Control better

More statin better Less statin better

Relative risk per 1 mmol/L (39 mg/dl) reduction in LDL-C (95% CI)