Statin intolerance: A pain in the ........
Natural Products Derived from the
Cholesterol Synthesis Pathway
Mevalonic Acid
HMGCoAR - Statins
Acetyl CoA
Statins: LDL Receptor Upregulation
LDL Receptor
Gene
Sterol regulatory element
binding proteins (SREBPs),
which are nuclear transcription
factors that regulate the LDL
receptor gene, are up-regulated
Statins reduce
cholesterol
synthesis leading
to intracellular
cholesterol
depletion
Statins block the
compensatory
stimulation of
HMGCoAR by
SREBP
LDL Receptors are upregulated and LDL
particles are removed
Cholesterol Synthesis Pathway
However, the molecular mechanisms are not
well understood that lead to these musclespecific side effects. Here, we show that
statins cause apoptosis in differentiated
human skeletal muscle cells. Consecutive
activation of caspase 9 and 3 execute
apoptotic cell death that was in part reversed
by the coadministration of mevalonic acid.
Conversely, the simvastatin-induced
activation of calpain was not prevented by
mevalonic acid.
“Delineation of Myotoxicity Induced by 3-Hydroxy-3methylglutaryl CoA Reductase Inhibitors in Human Skeletal
Muscle Cells” Sacher J et al, JPET 314: 1032-1041
Potential Mechanisms of Statin-Induced
Myopathy and Rhabdomyolysis
THEORY 1:
Blocking cholesterol synthesis reduces cholesterol content of
skeletal muscle membranes, making them unstable
THEORY 2:
Statins lead to a reduced synthesis of ubiquinone (coenzyme Q10),
an essential element of mitochondria, thereby disturbing normal cell respiration
THEORY 3:
Reduction of small GTP-binding proteins leads to muscle apoptosis
Pasternak RC et al. J Am Coll Cardiol. 2002;40:567-572
Thompson PD et al. JAMA. 2003;289:1681-1690
Non-Statins: LDL Receptor Upregulation
LDL Receptor
Gene
Sterol regulatory element
binding proteins (SREBPs),
which are nuclear transcription
factors that regulate the LDL
receptor gene, are up-regulated
Non-statins deplete
intracellular
cholesterol by
other means.
Non-statins do
NOT block the
compensatory
stimulation of
HMGCoAR by
SREBP
LDL Receptors are upregulated and LDL
particles are removed
Cholesterol Biosynthesis Pathway:
Sites of Enzyme Inhibition
Acetoacetyl-CoA + acetyl-CoA + H2O
Statins
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
HMG-CoA reductase
Mevalonic acid
Mevalonate-5-phosphate
Dimethylallyl-PP
Lapaquistat
acetate
Isopentenyl-5-pyrophosphate (PP)
Geranyl-PP
Prenylation of proteins
Farnesyl-PP
Geranylgeranyl-PP
Dolichols
Squalene synthase
Squalene
GTPases
biosynthesis of biologically
important N-linked
glycoproteins
Ubiquinones
Lanosterol
Cholesterol
a component of the mitochondrial respiratory chain,
ubiquinone has in recent years acquired increasing
attention with regard to its function in the reduced form
(ubiquinol) as an antioxidant
Rate of Reports of Serious Rhabdomyolysis
for Ezetimibe Similar to Newer Statins
Category
All
Statins
Atorva
Fluva
Lova
Prava
Rosuva
Simva
US Spontaneous
Serious
Rhabdomyolysis
1362
348
56
45
75
103
760
2
68
Total Prescriptions
(Millions)
383.9
209.5
16.3
16.7
46.0
7.61
87.74
0.80
15.2
Reporting Rate (Per
Million
Prescriptions)
3.55
1.66
3.50
2.65
1.63
12.88
8.64
2.00
4.53
Total AE Reports
10842
3713
517
251
965
2562
3072
35
920
Proportion
Reporting Rate
0.13
0.09
0.11
0.18
0.08
0.04
0.25
0.06
0.07
Davidson MH et al. Am J Cardiol. 2006;97:32C-43C
Vytorin Ezet
Justification of FDA recommendation that serial
monitoring of LFTs is no longer indicated
(180,000 Patients in 21 Major Statin Trials for avg of 3 yrs)
Elevated ALT >3
x ULN/100,000
Treatment Placebo
Net Risk
person-yrs
Single Measure
300
200
100 cases
2 Consecutive
Measures
110
40
70 cases
Thus, one would have to monitor the ALT in 100,000 patients each year for an average
of 3 yrs to detect 110 patients who have consecutive elevations in ALT to identify the
statistical 0.1 person who may progress to liver failure, assuming that statins can cause
liver failure in the first place.
Law M, Rudnicka AR. Am J Cardiol. 2006;97:52C-60C
Association between statins
and development of diabetes
Statin
Odds ratio (95% CI)
Overall (n=91 140)
1.09 (1.02–1.17)
Atorvastatin only (n=7773)
1.14 (0.89–1.46)
Simvastatin only (n=18 815)
1.11 (0.97–1.26)
Rosuvastatin only (n=24 714)
1.18 (1.04–1.33)
Pravastatin (n=33 627)
1.03 (0.90–1.19)
Lovastatin (n=6211)
0.98 (0.70–1.38)
NNH ie to cause 1 excess case of diabetes in Jupiter: 250
NNT to prevent 1 major acute coronary event in Jupiter: 25
Sattar N et al. Lancet 2010; available at:
http://www.lancet.com.
Inhibition of
Albumin Uptake (%)
Inhibition of Tubular Albumin Uptake
(a non-pathological form of proteinuria?)
100
Rosuvastatin
Simvastatin
Pravastatin
80
60
40
20
0
0
10 20 30 40 50 60 70 80 90 100
Inhibition of Cholesterol Synthesis (%)
Preclinical data: proximal tubule-derived opossum kidney cell line
Sidaway JE et al. Poster presented at: 41st Congress of the European Societies of Toxicology,
September 28-October 1, 2003; Florence, Italy
Creatinine and GFR Changes:
(Glomerular function stable or improved)
Treatment
371
Creatinine
% Change
0.8
Change in
GFR
-0.3
N
Placebo
Rosuvastatin
5 mg
10 mg
20 mg
40 mg
637
2909
1432
2107
-1.6
-1.4
-1.6
-1.3
1.5
1.6
1.9
1.6
Atorvastatin
10 mg
20 mg
40 mg
80 mg
1394
1562
221
535
-1.5
-1.4
-2.0
-3.8
1.6
1.5
1.9
3.4
Simvastatin
10 mg
20 mg
40 mg
80 mg
161
1217
506
500
-0.4
-1.4
-1.6
-1.2
0.5
1.4
1.7
1.5
Pravastatin
10 mg
20 mg
40 mg
159
342
745
-1.8
-2.1
-0.7
1.8
1.9
0.8
Median duration of therapy ~ 8 weeks
GFR in mL/min/1.73 m2
Data on file, (DA-CRS-07) AstraZeneca Pharmaceuticals LP. Wilmington, DE
Statins and Peripheral
Neuropathy: Cohort Studies
Anderson JL et al. Am J Cardiol. 2005;95:1097-1099
Corrao G et al. J Epidemiol Community Health. 2004;58:1047-1051
Gaist D et al. Neurology. 2002;58:1333-1337
Gaist D et al. Eur J Clin Pharmacol. 2001;56:931-933
ALL COHORT STUDIES
1.8 (1.1-3.4)
0
1 2 3
4 5
Odds Ratio (95% confidence interval)
Based on these 4 cohort studies and placebo cases in HPS;
estimated incidence of idiopathic peripheral neuropathy with
statins is 12 cases/100,000 person-years
Law M, Rudnicka AR. Am J Cardiol. 2006;97:52C-60C
Statins and Cognitive Function:
Non-RCT observations favour statin use
Results of 7 observational studies
Hajjar I et al. J Gerontol A Biol Sci Med Sci. 2002;57:408-414
Green RC et al. Neurobiol Aging. 2002;23:S273-S274
Jick H et al. Lancet. 2000;356:1627-1631
Rockwood K et al. Arch Neurol. 2002;59:223-227
Rodriquez EG et al. J Am Geriatr Soc. 2002;50:1852-1856
Wolozin B et al. Arch Neurol. 2000;57:1439-1443
Yaffe K et al. Arch Neurol. 2002;59:378-384
0.43 (0.31-0.62)
ALL COHORT STUDIES
0
Etminan et al. Pharmacotherapy. 2003;23:726-730
1
2
HPS – Results of Testing for
Neuropsychiatric Disorders
Measure
Simvastatin
Placebo
Cognitively Impaired*
23.7%
24.2%
Dementia
0.3%
0.3%
Psychiatric Disorder
0.7%
0.7%
Suicide
0.1%
0.1%
* Telephone Interview for Cognitive Status Questionnaire
Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22
PROSPER – Results of Testing
for Cognitive Function
Measure
Pravastatin - Placebo
Number of correct
letter digits recalled
-0.01 (-0.24-0.23) p=0.95
Number of words
Remembered
+0.02 (-0.12-0.16) p=0.80
Time needed to
complete Stroop test
MMSE score
Shepherd J et al. Lancet. 2002;360:1623-1630
+0.8 s (-0.4-2.0) p=0.19
+0.06 (-0.04-0.16) p=0.26
Cataract: Disparity between pre-marketing
and post-marketing data Heart doi:10.1136/hrt.2010. 199034
Risk factor
Female HR
Male HR
No statin use
Statin use
1.00
1.30
1.00
1.30
Ethincity
up to 4.32
up to 3.52
Smoking
heavy 1.11
heavy 1.11
Comorbidities :
CVD
Diabetes T2
Rh Arthritis
Corticosteroids
Atrial Fib
1.11
10.02
1.16
1.47
1.16
1.13
9.77
NS
1.58
1.23
Factors That Increase the Risk of
Statin-Induced Myopathy
Patient
Characteristics
Increasing age
Female sex
Renal insufficiency
Hepatic dysfunction
Hypothyroidism
Diet (i.e. grapefruit juice)
Polypharmacy
Adapted from Rosenson RS. Am J Med. 2004;116:408-416
Statin Properties
High systemic exposure
Lipophilicity
High bioavailability
Limited protein binding
Potential for drug-drug
interactions metabolized
by CYP pathways
(particularly CYP450 3A4)
Human Cytochrome P450 Isoenzymes
Known to Oxidize Clinically Used Drugs
CYP2C9
CYP2C19
Alprenolol
Diazepan
Amitriptyline
Diclofenac
Ibobrufen
Codeine
Fluvastatin
Mephenytoin
Hexobarbital
Methylphenobarbital
Flecainide
Imipramine
Erythromycin
Itraconazole
Ndesmethyldiazepa
n
Omeprazol
Metoprolol
Mibefradil
Ketoconazole
Lovastatin
Rosuvastatin
Proguanyl
Nortriptyline
Mibefradil
Midazolam
Tolbutamide
Phenytoin
Perphenazine
Warfarin
CYP2D6
Dextromethorphan
Propanolol
Thioridazine
Bufaralol
Debrisoquine
Encainide
Perhexiline
Propafenone
CYP3A4
Amlodipine
Cerivastatin
Cyclosporine A
Atorvastatin
Clarithromycin
Diltiazem
Nefazodone
Nifedipine
Sparteine
Protease
inhibitors
Quinidine
Timolol
Sildefanil
Simvastatin
Terbinafine
Verapamil
Warfarin
Adapted from Brower et al. In: Evans WE et al., eds. Applied Pharmacokinetics: Principles of Therapeutic
Drug Monitoring. 3rd ed. Philadelphia PA: Lippincott Williams & Wilkins; 1992
Ethnicity is a risk factor for statininduced myopathy Heart doi:10.1136/hrt.2010. 199034
Ethnicity
White or N/A
Indian
Pakisani
Bangladeshi
Other Asian ?
Caribbean
Black African
Chinese
Other
Female adjusted HR Male adjusted HR
1.00
1.42
1.41
NA
NA
3.94
4.47
1.44
2.54
1.00
1.96
1.68
1.61
0.48
6.57
7.87
2.10
2.84
Statin/Fibrate Combination Therapy:
Pharmacokinetic Interactions
GEMFIBROZIL
FENOFIBRATE
Atorvastatin
 in Cmax (expected)
No effect
Simvastatin
 in Cmax by 2-fold
No effect
Pravastatin
 in Cmax by 2-fold
No effect
Rosuvastatin
 in Cmax by 2-fold
No effect
Fluvastatin
No effect
No effect
Lovastatin
 in Cmax by 2.8-fold
Not available
Cerivastatin
 in Cmax by 2-3–fold
No effect
TriCor [package insert]. Abbott Laboratories. 2004; Kyrklund C et al. Clin Pharmacol Ther. 2001;69:340-345;
Pan WJ et al. J Clin Pharmacol. 2000;40:316-323; Backman JT et al. Clin Pharmacol Ther. 2000;68:122-129;
Backman JT et al. Clin Pharmacol Ther. 2002;72:685-691; Abbott Laboratories. Data on file. 2005;
Davidson MH. Am J Cardiol. 2002;90:50K-60K; Prueksaritanont T et al. Drug Metab Dispos. 2002;30:1280-1287;
Martin PD et al. Clin Ther. 2003;25:459-471; Bergman AJ et al. J Clin Pharmacol. 2004;44:1054-1062
Summary and link to cases
Major site affected
Symptoms
Prevalence
practice)
MSS syndromes







Aches & pains
Cramps
Stiffness
Tenderness
Weakness
Fatigue
Muscle atrophy (rare)


CNS
Headache
Visual disturbance
Memory loss
Dyspepsia
Bowel disturbance
Bloating
Abdominal discomfort
jaundice (rare)
Uncommon (<1%)
<1%
GIT syndromes








<1%
<1%
Skin
Rash
Rare
Rare
Hair & nails
Alopecia
Rare
Rare
Very rare
Very rare
Rare
Rare
Autoimmune syndromes Vasculitis
Genitourinary
Erectile dysfunction
Endocrine
Hyperglycemia
increased
diabetes
(clinical Prevalence
trials)
2-5% (low doses)
5-10.5% (high doses)
and Unknown
new-onset
(randomized
1-2%
~9% (meta-analysis
12 trials)
STATIN -ASSOCIATED MYOPATHY
(SAM)
The Achilles’ Heel of Statin
Therapy?
SAM: THE ISSUES
1. It’s common but confounding factors:
• Similar symptoms to SAM are common
• Many drugs cause myopathy
2. Mechanisms unknown but probably multi-factorial
3. Lots of pseudoscience
4. Significant cause of poor compliance
5. Can be conquered with patience and reassurance
and specific techniques
6. Treatment: ?
SAM: CK Classification
•
•
•
•
Myalgia: normal CK
Myositis: CK 3-10 ULN
Myopathy: CK>10x ULN
Rhabdomyolysis: definitions vary
• CK>10x ULN with renal impairment and need for redydration
• CK>10xULN with
myoglobinaemia, myoglobinuria
• FDA, ADRAC
• reports unreliable
SAM prevalence
• RPCCT (but lead-in period: withdrawal if SAM)
•
•
•
•
Myalgia <3%
Myositis <0.1%
Myopathy < 0.01%
Rhabdo very rare (placebo = statin)
• Clinical practice: COMMON
• PRIMO trial of French GPs (Bruckert et al)
• High dose statins
• up to 17% SAM
Bruckert E et al. Cardiovasc Drugs 2005;19:403-14
PRIMO Study: factors predicting SAM
• Factor
Odds ratio
• Unexplained muscle pain
with other lipid therapy
• Unexplained cramps
• History of elevated CK
• Family history of muscle symptoms
• Family history of muscle symptoms
• with lipid therapy
• Hypothyroid
• >3mo statin therapy
• Antidepressant therapy
*** P< 0.0001 ** P< 0.01 * P< 0.05
10.1***
4.1***
2.0***
1.9*
1.9*
1.7*
0.28***
0.51**
Factors increasing risk of statin-associated
myopathy
•
•Age (>80 years; especially in F)
• Small muscle mass
Hypothyroidism
• Infections
• Carbon monoxide poisoning
• Polymyositis
• Dermatomyositis
• Illicit drug abuse (cocaine,
amphetamines, heroin,
phencyclidine hydrochloride)
• Vit D deficiency
• Genetic myopathies
• Hypothyroidism
• Asian ethnicity
•
•
•
•
•
•
•
•
•
•
Multisystem diseases
(especially diabetic
chronic kidney disease)
Multiple medications
Acute
illness/surgery/trauma
Alcohol abuse
Grapefruit juice >1
quart/day (SV, AV)
Exercise
Trauma
Falls
Accidents
Seizures
Shaking chills
Muscle symptoms of SAM
•
•
•
•
•
•
Aches & pains
Cramps
Stiffness
Fatigue
Tenderness
Atrophy: rare, may indicate autoimmune myopathy
SEARCH NEJM 2008;359:789-799
300,000 SNPs in 85 subjects with definite or incipient
myopathy with SV 80mg and 90 controls
SAM with normal CK
• P Phillips, JF England (Scripps Mercy, La Jolla)
• Uncommon
• TREAT SYMPTOMS NOT CK
Statin withdrawal with SAM
• “Gold standard” diagnosis of SAM: statin withdrawal
and re-challenge at same dose produces same
symptoms
• Cease statin
• CK >10x ULN (?? or at lower CK levels)
• Intolerable symptoms
Stein E et al Am J Cardiol 2008 ; 101: 490-496
Case 1
H.D
• Moderately overweight 57 year old man with
mixed hyperlipidaemia, typically cholesterol 6 to
8 mmol/l and fasting TG 3.0 to 4.0 mmol/l.
• You start rosuvastatin 20 mg nocte
• Follow- up blood tests reveal TC 4.5, TG 2.5,
HDL 0.9, LDL 2.5 mmol
• Soon after this he develops polyuria and is
diagnosed with Type 2 DM.
• He blames the statin.
Questions regarding Mr H.D
• He asks if the diabetes could be due to the statin. You reply:
Yes / No / Yes but / No but
• He asks if he should stop the statin. You reply:
Yes / No / Yes but / No but
• Despite appropriate diet, exercise and diabetic control, TG
remains raised (2.5 – 3.0 mmol/l) and HDL remains low (0.8 –
1.0 mmol/l). Additional therapy should include:
• A) Gemfibrozil B) Niacin C) Fish oil D) Fenofibrate E) Increase
Rosuvastatin to 40 mg
• Mr H.D is a moderately overweight 57 year old man with mixed
hyperlipidaemia, typically cholesterol 6 to 8 mmol/l and fasting
triglycerde 3.0 to 4.0 mmol/l. You start him on rosuvastatin 20
mg nocte. Follow- up blood tests reveal TC 4.5 mmol/l, TG 2.5
mmol/l, HDL 0.9 mmol/l LDL 2.5 mmol/l. Soon after this he
develops polyuria and is diagnosed with Type 2 diabetes.
diabetic and blames it.
• He asks if the diabetes could be due to the statin. You reply:
Yes / No / Yes but / No but
• He asks if he should stop the statin. You reply: Yes / No / Yes
but / No but
• Despite appropriate diet, exercise and diabetic control, TG
remains raised (2.5 – 3.0 mmol/l) and HDL remains low (0.8 –
1.0 mmol/l). Additional therapy should include:
• A) Gemfibrozil B) Niacin C) Fish oil D) Fenofibrate E) Increase
Rosuvastatin to 40 mg
• He asks if the diabetes could be due to the
statin. You reply:
• Yes
• No
• Yes, but...
• No, but...
He asks if the diabetes could be due to the
statin. You reply:
• The case for “Yes, but...” or “No, but....”
Statin
Odds ratio (95% CI)
Overall (n=91 140)
1.09 (1.02–1.17)
Atorvastatin only (n=7773)
1.14 (0.89–1.46)
Simvastatin only (n=18 815)
1.11 (0.97–1.26)
Rosuvastatin only (n=24 714)
1.18 (1.04–1.33)
Pravastatin (n=33 627)
1.03 (0.90–1.19)
Lovastatin (n=6211)
0.98 (0.70–1.38)
Metanalysis of 33,000 patients in five clinical trials high-dose statin :
NNH for 4 years to result in 1 additional case of type II diabetes was
approx 500
NNT for 4 years to prevent 1 major cardiovascular event (such as heart
attack or stroke) was
approx 150
Journal of the American Medical Association in June, 2011
• He asks if he should stop the statin.
You reply:
• Yes
• No
• Yes, but...
• No, but...
• He asks if he should stop the statin.
You reply: The case for “No”
NNH ie to cause 1 excess case of diabetes in Jupiter:
250
NNT to prevent 1 major acute coronary event in Jupiter:
25
• Despite appropriate diet, exercise and
diabetic control, TG remains raised (2.5 – 3.0
mmol/l) and HDL remains low (0.8 – 1.0
mmol/l). Additional therapy should include:
• A) Gemfibrozil
• B) Niacin
• C) Fish oil
• D) Fenofibrate
• E) Increase Rosuvastatin to 40 mg
• Additional therapy should include:
The case for “D”
(but “C” & “E” are reasonable)
Number of cases reported
per million prescriptions
Number of reports of rhabdomyolysis per million prescriptions (excluding cerivastatin)
9.7
10
9
8
7
6
5
4.0
4
3
3.1
2.6
2.1
2
1
0
Fenofibrate
Gemfibrozil
Simva
Atorva
Rosuva
Holoshitz N et al. Am J Cardiol 2008;101:95–97
Case 2
Case 2 – Ms D.M.
• 63 year old woman non-diabetic, nonsmoker who has been aware of
hypercholesterolaemia since menopause
• Family history is negative
• BP 143/92
• TC=9.6, TG=0.6, HDL=3.2
LDL=6.1mmol/l.
• She has seen a naturopath who has
warned her of associated liver, muscle
and memory problems.
Questions concerning Ms D.M.
• Should she be treated?
• Which of her fears is best founded in terms of evidence?
•
• Which of the naturopath’s recommendations is most likely to
lower LDL?
• A) Bergamot B) Garlic C) Fish Oil
• D) Red rice yeast E) Basikol
• The Naturopath’s remedies are unsuccessful so she starts a
statin. Within weeks she complains of musculoskeletal
discomfort: Is there any supplement you would recommend to
alleviate her symptom?
• A) Carnitine B) Magnesium C) Co-Enzyme Q 10
• D) Vitamin D E) Something else
• The myalgia does not resolve. Does this exclude statins as a
cause. Yes / No
• This 63 year old lady is a non-diabetic, non-smoker who has
been aware of hypercholesterolaemia since menopause.
Family history is negative, BP 143/92 and current results
include TC=9.6, TG=0.6, HDL=3.2 LDL=6.1mmol/l. She has
seen a naturopath who has warned her of associated liver,
muscle and memory problems
• Should she be treated?
• Which of her fears is best founded in terms of evidence?
• Which of the naturopath’s recommendations is most likely to
lower LDL? A) Bergamul B) Garlic C) Fish Oil D) Red rice
yeast E)
• The Naturopath’s remedies are unsuccessful so she starts a
statin. Within weeks she complains of musculoskeletal
discomfort: Is there any supplement you would recommend to
alleviate her symptom? A) Carnitine B) Magnesium C) CoEnzyme Q 10 D) Vitamin D E) Something else
• The myalgia does not resolve. Does this exclude statins as a
cause. Yes / No
Ms D.M. Should she be treated?
Yes
No
Ms D.M. Should she be treated?
Calculated risk 4%
Invalidated by TC > 7.5 mmol/l
BP > ideal
Case 3 – Ms D.M. Which of her fears is best
founded in terms of evidence?
A)Liver problems
B) Muscle problems
C) Memory problems
Case 3 – Ms D.M. Which of her fears is best
founded in terms of evidence?
The case for “B”
Incidence above
placebo (per
100,000)
Muscle AE
Myalgias
1,500 to 3,000
Myopathy (Sx + CK)
5
Rhabdomyolysis
Variable
Law M, Rudnicka
AR. Am J Cardiol.
2006;97:52C-60C
1.6
Lova
Prava
Simva
Fluva
Atorva
Total
Fatal cases of
rhabdomyolysis
19
3
14
0
6
73
Number of
prescriptions
(millions†)
99
81
116
37
140
484
Reporting rate
(per 1 million
prescriptions)
0.19
0.04
0.12
0
0.04
0.15
Which of the naturopath’s recommendations
is most likely to lower LDL-C?
• ? A) Bergamot
• B) Garlic
• C) Fish Oil
• D) Red rice yeast
• E) Basikol
Which of the naturopath’s recommendations
is most likely to lower LDL-C?
The case for “D” (“E” also possible)
Lipid
parameter
Red yeast rice 12 wk
(n=31), baseline
24 wk
Placebo (n=31), 12 wk
baseline
24 wk
LDL
cholesterol
(mg/dL)
163.3
120.0
128.3
165.1
154.2
149.8
Total
cholesterol
(mg/dL)
245.2
194.1
208.7
246.0
232.2
230.4
HDL
cholesterol
(mg/dL)
52.8
51.4
56.4
51.5
48.3
54.0
Triglycerides
(mg/dL)
145.5
113.3
119.9
147.7
148.1
133.7
Becker DJ, Gordon RY, Halbert SC, et al. Red yeast rice for dyslipidemia
in statin-intolerant patients. Ann Internal Med 2009; 150:830-839.
The Naturopath’s remedies are unsuccessful
so she starts a statin. Within weeks she
complains of musculoskeletal discomfort: Is
there any supplement you would recommend
to alleviate her symptom?
• A) Carnitine
• B) Magnesium
• C) Co-Enzyme Q 10
• D) Vitamin D
• E) Something else
The Naturopath’s remedies are unsuccessful
so she starts a statin. Within weeks she
complains of musculoskeletal discomfort: Is
there any supplement you would recommend
to alleviate her symptom?
A survey - some evidence for “C” and “D”
On vitamin D supplementation plus re-instituted statins for a median of
8.1 months, 131 of the 150 patients (87%) were free of myositis-myalgia
and tolerated the statins well. Serum 25 (OH) vitamin D increased from
median 21 to 40 ng/ml (p < 0.001), and normalized (≥32 ng/ml) in 117
(78%) of 150 previously vitamin D deficient, statin-intolerant patients.
Median LDLC decreased from 146 mg/dl to 95 mg/dl, p < 0.001
Curr Med Res Opin. 2011 Sep;27(9):1683-90.
Vitamin D deficiency, myositis-myalgia, and reversible statin
intolerance. Glueck CJ et al
The myalgia does not resolve. Does this
exclude statins as a cause?
Yes
No
The myalgia does not resolve. Does this
exclude statins as a cause?
The case for “No”
Arthritis Rheum. 2012 Aug 29.
Antibody levels correlate with creatine kinase levels and strength in
anti-HMG-CoA reductase-associated autoimmune myopathy.
Werner JL et al
Anti-HMGCR antibodies are found in patients with statin-associated
immune-mediated necrotizing myopathy and, less commonly, in statinunexposed subjects with autoimmune myopathy
Case 3 B.L.
• 27 year-old test level West Indian fast bowler
• recently been found to have severe
hypercholesterolaemia (LDL=7.4 mmol/l)
• history is consistent with Familial
Hypercholesterolaemia.
• You plan to start statin therapy.
• His baseline CK levels often exceed 500 IU/l,
but it has not been possible to avoid exercise
before collection.
• He is 198 cm tall and weighs 103 kg.
Questions concerning Mr B.L.
• Will you proceed with the plan to commence statin?
Yes / No
• If you proceed, what dosage level will you use?
A) Less than average B) Average C) More than average
• Discuss his long-term management
• This 27 year-old test level West Indian fast bowler has
recently been found to have severe hypercholesterolaemia
(LDL=7.4 mmol/l) and his history is consistent with Familial
Hypercholesterolaemia. You plan to start statin therapy. His
baseline CK levels often exceed 500 IU/l, but it has not been
possible to avoid exercise before collection. He is 198 cm tall
and weighs 103 kg.
• Will you proceed with the plan to commence statin? Yes / No
• If you proceed, what dosage level will you use? A) Less than
average B) Average C) More than average
• Discuss his long-term management
Will you proceed with the plan to
commence statin?
• Yes
• No
Will you proceed with the plan to commence
statin? Considerations:
Br J Clin Pharmacol. 2004 April; 57(4): 525–528.
Professional athletes suffering from familial hypercholesterolaemia
rarely tolerate statin treatment because of muscular problems
H Sinzinger and J O'Grady*
Muscular problems are the major group of side-effects during statin treatment. They are
known to occur much more frequently during and after exercise.
For the last 8 years we have monitored 22 professional athletes in whom, because of
familial hypercholesterolaemia, treatment with different statins was attempted. Only six
out of the 22 finally tolerated at least one member of this family of drugs. In three of
these six the first statin prescribed allowed training performance without any limitation.
Changing the drug demonstrated that only two tolerated all the four or five statins
examined (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin). Cerivastatin
was not among the statins prescribed.
These findings indicate that in top sports performers only about 20% tolerate statin
treatment without side-effects. Clinical decision making as to lipid lowering therapy
thus becomes a critical issue in this small subgroup of patients
Discuss Mr B.L’s long-term
management.
Muscle function
Risk of dehydration / renal impairment
Interpretation of CK levels
Risk of an acute coronary episode
Questions regarding M.S.
• Is there any risk that statins will reduce steroid hormone
levels or have a negative impact on growth or maturation?
Yes/No
• Is there evidence to support long term benefit in this setting?
Yes/No
• Which clinical parameters would you monitor regularly during
therapy in adolescence?
• A) LFT’s B) Serum testosterone C) Growth & maturation
D) CK
E) Plasma glucose
Case M.S.
• You are reviewing the children of a patient with familial
hypercholesterolaemia who had an AMI at age 43 years. The
oldest child, Sam, who is known to have inherited FH, has
reached age 10. The Australian model of care for FH
suggests that he should commence statin treatment.
• You are reviewing the children of a patient with familial
hypercholesterolaemia who had an AMI at age 43 years. The
oldest child, Sam, who is known to have inherited FH, has
reached age 10. The Australian model of care for FH
suggests that he should commence statin treatment.
• Is there any risk that statins will reduce steroid hormone
levels or have a negative impact on growth or maturation?
Yes/No
• Is there evidence to support long term benefit in this setting?
Yes/No
• Which clinical parameters would you monitor regularly during
therapy in adolescence?
• A) LFT’s B) Serum testosterone C) Growth & maturation
D) CK
E) Plasma glucose
• Is there any risk that statins will reduce steroid
hormone levels or have a negative impact on
growth or maturation?
•
Yes
• No
• Is there any risk that statins will reduce steroid
hormone levels or have a negative impact on
growth or maturation? The case for “No”
• Which clinical parameters would you
monitor regularly during therapy in
adolescence? The preference for “C”
Familial Hypercholesterolemia: Screening, diagnosis and
management of pediatric and adult patients
Clinical guidance from the National Lipid Association Expert Panel
on Familial Hypercholesterolemia
3.5.3 Clinical trials with medium term follow up suggest safety and
efficacy of statins in children
Journal of Clinical Lipidology (2011) 5, S1–S8
• Is there evidence to support long term
benefit in this setting?
• Yes
• No
• Is there evidence to support long term
benefit in this setting? The case for “Yes”
Overall: Treatment associated with a CAD risk reduction of 76%:
HR 0.24 (95%CI 0.18-0.30), p<0.001
Versmissen J, et al BMJ 2008;337:a2423
• Which clinical parameters would you
monitor regularly during therapy in
adolescence?
• A) LFT’s
• B) Serum testosterone
• C) Growth & maturation
• D) CK
• E) Plasma glucose