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Lipid Management:
Role of Foods, Lifestyle, &
Drugs for Management
Steve Kopecky MD
Preventive Cardiology
Mayo Clinic
Rochester MN
©2012 MFMER | slide-0
Disclosure : Conflict of Interest
Stephen L Kopecky
Research Grants:
NIH/NHLBI, Mayo Clinic, Genzyme, Sanofi,
Genetech, Regeneron
Consultant:
•Amer Soc for Prev Card- President
(2012-2014)
•Acad of Clin Research Professionals:
Chair, Global Certification Exam Committee
•Applied Clinical Intelligence:
DSMB Chair
•Prime Therapeutics – Formulary Committee
©2012 MFMER | slide-1
Learning Objectives
1. Appreciate the different lipid biomarkers and
their role in assessing risk from
hyperlipidemia
2. Understand lifestyle issues involved with
hyperlipidemia
3. Learn the beneficial effects and side effects
of drug therapy for hyperlipidemia
©2012 MFMER | slide-2
Secondary CV Prevention: US 2011
“Million Hearts Campaign”
In patients with Hyperlipidemia:
1/3 have adequate treatment
Frieden and Berwick N Engl J Med 2011; 365:e27 September 29, 2011
©2012 MFMER | slide-3
Seven Countries Study:
Relationship of Serum Cholesterol to Mortality
Death rate from CHD/1000 men
35
Northern Europe
30
25
United States
20
15
Southern Europe, inland
10
5
Serbia
Southern Europe, Mediterranean
Japan
0
2.60
3.25
3.90
4.50
5.15
5.80
6.45
7.10
7.75
8.40
9.05
Serum total cholesterol (mmol/L)
Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136
©2012 MFMER | slide-4
What Diet Components Decrease Risk for MI ?
INTERHEART Study:
55 countries
All inhabited continents of the world
Association
w/ MI
Western Diet:
Fried foods, salty snacks, and meat
Increases
Oriental Diet:
Tofu, pickled foods, soy and other sauces
Prudent Diet:
Dairy, fruits, vegetables, nuts
Neutral
Decreases
Iqbal et al INTERHEART Study:Dietary patterns and risk of MI AHA Epi Conf Orlando 2007
©2012 MFMER | slide-5
CAD Associated with Daily Replacement
(1 serving) of Protein Source
Replacing 1 serving per day of red meat with 1 serving per day of fish was
associated with a 24% (95% CI, 6% to 39%) lower risk
Less Heart Disease
More Heart Disease
High Fat Dairy for Fish
Poultry for Red Meat
Fish for Red Meat
Nuts for Red Meat
Beans for Red Meat
0.4
Nurse’s Health Study
27 Year Follow-up
0.6
Bernstein Circulation. 2010;122:876-883
0.8
1
Hazard Ratio
1.2
1.4
RRs and 95% CIs
1.6
©2012 MFMER | slide-6
Low Carbohydrate Diets : Mortality Effect ?
Health Professional’s Follow Up Study n=51,529 : 20 Yr follow-up
All Cause Mortality (HR)
Any Low Carb Diet
1.12 ( 95% CI 1.01-1.24)
1.5
1.23
1.14
All Cause Mortality
CV Mortality
1
Vegetable Low Carb
0.5
p<0.001
p<0.001
0
p=0.051
-0.5
p=0.029
Animal Low Carb
-1
-1.2 -1.23
-1.5
Low Carb Diet : Hi Animal – Increased Total/CV Mortality
Hi Vegetable – Decreased Total/CV Mortality
Fung Low Carbohydrate Diets and All-Cause and Cause-Specific Mortality Ann Int Med 2010;153:289-298
©2012 MFMER | slide-7
Reducing Heart Disease Risk:
Lowering Cholesterol
Diet
Effect
Drug
Plant Sterols/Stanols Block cholesterol Ezetimibe
1.6 / 3.4 gm/day
absorption
Reduce hepatic Statin
Oat b-glucan
cholesterol synthesis
Increase
bile
Cholestyramine
Viscous Fiber
acid losses
Psyllium
Nuts
Almonds 42 g
Soy
Source of plant sterols
monounsaturated fats,
vegetable protein
0.8 Oz
Annals Int Med 2005;142:793-795
©2012 MFMER | slide-8
Portfolio Diet : Per 1000 kcal of Diet
Lower LDL ~15% over 6 months
•Plant sterols- 0.94 g in margarine;
•Viscous fibers- 9.8 g from oats, barley, and psyllium;
•Soy protein-22.5 g as soy milk, tofu, and soy meat ;
•Nuts - 22.5 g (including tree nuts and peanuts)
¾ of an ounce
• Consumption of peas, beans, and lentils encouraged.
1.
2.
Jenkins et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum Lipids and
C-reactive protein. JAMA. 2003;290(4):502–510
Jenkins et al JAMA.2011;306(8):831-839. doi: 10.1001/jama.2011.1202
©2012 MFMER | slide-9
Supplements to Reduce LDL:
Reduce Intestinal Cholesterol Absorption
Product
Plant stanols
(sitostanol, such as
Benecol Light™
Spreads, Smart
Chews)
How much to take
800 - 4,000 mg/day divided and taken
with meals (2 to 3 tsps Benecol Light™
Spreads or 2 to 4 Smart Chews)
Plant sterols
800 mg to 6 gms/day, divided and taken
(Promise activ™
with meals (= 2 tsps Promise activ™
Spreads, SuperShots™) Spread or -2 servings of SuperShots™)
Plant stanol,
900 mg (usually found in 450 mg caplets)
sterol supplements two times per day with a meal
(CholestOff™ and
Centrum Cardio™)
©2012 MFMER | slide-10
Supplements to Reduce LDL:
Reduce Cholesterol Production in Liver
Product
Oat bran
(oatmeal,oat bran
products; look for
oat bran or whole
oats as ingredient
on label)
How much to take
Up to 150 g of whole oat
products per day (about
equal to eating 1½ cups of
cooked oatmeal)
Do not use Red Yeast Rice –
Contains lovastatin
Not regulated adequately
Dosage variable
Instead-Use generic (low cost) statin
©2012 MFMER | slide-11
Supplements to Reduce LDL:
Increase Loss of Cholesterol via Bile Acid into
Intestine
Product
Blonde psyllium
(seed husks and
products such as
Metamucil™)
How much to take
5 g seed husk twice per
day, or 1 serving of
product such as
Metamucil™
©2012 MFMER | slide-12
Lipid Management Drugs and their
Effects on Lipids/Lipoprotein
LDL
%
HDL
TG
40
30
20
10
0
-10
-20
-30
-40
-50
-60
sh
Fi
O
il
ib
im
et
Ez
es
at
br
Fi
e
d
ci
A
s
n
ci
ia
N
ile
B
in
at
St
NCEP/ATP III 2001
Fish Oil : EPA and DHA = 4-6 gms/day
©2012 MFMER | slide-13
Effect of Different Anti-lipidemic Agents and
Diets on Overall Mortality
95% UL
(%)
RR (95% CI
P
I2
Statins (n=35)
0.87 (0.81-0.94)
0.05
30
0-54
Fibrates (n=17)
1.00 (0.91-1.11)
0.01
33
0-63
Resins (n=8)
0.84 (0.66-1.08)
0.86
0
0-68
Niacin (n=2)
0.96 (0.86-1.08)
0.81
0
n-3 FA (n=14)
0.77 (0.63-0.94)
0.01
53
14-75
Diet (n=18)
0.97 (0.91-1.04)
0.19
23
0-56
Risk ratio
0.5
0.8 1.0 1.25
Favors Tx
2.0
Favors ctrl
AIM-HIGH : Niacin no benefit
once LDL reduction acheived
Effect of Different Antilipidemic Agents and Diets on Mortality: A Systematic Review
Studer et al Arch Intern Med. 2005;165:725-730.
©2012 MFMER | slide-14
Normalization of Serum Triglycerides by
Exercise
• 7 Men – Sedentary then 4 days of exercise,
3 to 4 miles in approximately 40 minutes.
Ask about :
•“White” –bread,
rice, pasta
•Soft drinks
•Juices
•Sports drinks
•Alcohol
Oscai et al AJC 1972; 30:775-780
©2012 MFMER | slide-15
Statins : LDL Reduction From Starting to Max
Dose
Fluva
20-80
Prava
20-40
Lova Simva
20-80 20-80
Atorva Rosuva
10-80
5-40
0
-10
-19
-27
-28
-20
-30
-12
-6
% -40
-50
-35
-45
-12
-12
Start Dose
-37
-18
-18
Max Dose
-60
-70
Dose Increase : 4x
2x
4x4x
8x
Illingworth Medical Clinics of North America- Volume 84, Issue 1(January 2000);23-42
8x
©2012 MFMER | slide-16
Are Statins of Benefit in Primary Prevention ?
Effects on major vascular events at 1 Yr per 1·0 mmol/L reduction in LDL C
LDL cholesterol : 1.0 mmol/L reduction = 38 mg/dl reduction
99% CI
95% CI
Statin/More Better
Controls/Less Better
RR= Rate ratios
CHD=coronary heart disease
Efficacy and safety of more intensive lowering of LDL cholesterol : meta-analysis of 170 000 participants in 26
randomised trials Lancet 2010; 376: 1670–81
©2012 MFMER | slide-17
Statins for Primary Prevention of CV Disease
Study
ACAPS 1994
Adult Japanese MEGA
AFCAPS/TexCAPS 1998
ASPEN 2006
CARDS 2004
KAPS 1995
PREVEND IT 2004
WOSCOPS 1997
Total (95% CI)
Total Statin Placebo
n
14,058 14,103
Risk Ratio
Total
Mortality
Does not include
JUPITER, which
also showed decrease
in Total Mortality
0.84 [0.73,0.96]
.2 .5 1 2 5
Favors
Statin
Favors
Control
Statins for the primary prevention of cardiovascular disease (Review)
2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
©2012 MFMER | slide-18
Statins and All-Cause Mortality in High-Risk
Primary Prevention: Benefit by Baseline Age
Age explained ~70%
of variation in events
between groups
11 Trials
p<.001
Would you send this patient to the cath lab if they
had a STEMI tomorrow ?
Arch Intern Med. 2010;170(12):1024-1031
©2012 MFMER | slide-19
Proposed Definitions for Statin-Related
Myopathy
Clinical Entity
Myopathy
Myalgia
Myositis
Rhabdomyolysis
1.
2.
3.
4.
ACC/AHA 1
General term- any
disease of muscles
Muscle
ache/weakness w/o
Hi CK
Muscle Sx w/ Hi CK
NLA 2
Sx of myalgia &
CK > 10x ULN
NA
FDA 3
CK > 10x ULN
NA
NA
Muscle Sx w/ CK >
10x ULN & Hi Creat
(Us w brown urine)
CK > 10,000IU/L
or CK> 10x ULN
& Hi Creat or IV
Hydration
CK> 50x ULN &
organ damage
NA
Joy Ann Intern Med 2009;150:858-868
ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-72.
NLA Am J Cardiol. 2006;97:89C-94C
Sewright Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep. 2007;9:389-96
©2012 MFMER | slide-20
Statin Intolerance: Definition
Unable to take statin to get to goal
due to symptoms of intolerance
Most common symptom : muscle aches,
weakness,
cramps
©2012 MFMER | slide-21
Statins:
Side Effects in Clinical Trials – METEOR (Rosuva 40)
Event (%)
Myalgia
Arthralgia
Back Pain
MM Spasms
Tendinitis
Ext Pain
Shoulder Pain
Neck Pain
Arthritis
Stiffness
MM Weak
Total
Rosuva
12.7
10.1
8.4
3.7
3.3
2.9
2.0
1.6
1.6
1.1
0.7
48%
Placebo
12.1
7.1
10.3
2.8
2.1
2.1
2.8
1.1
0.7
3.6
1.1
46%
Age 57 Yrs; n=984
Exclusion Criteria:
Statin Intolerance
Event (%)
Musculoskeletal Side Effect or Withdrew Consent
Rosuva
75%
Placebo
72%
MM=Muscle; Ext=Extremity
Crouse et al METEOR Trial JAMA. 2007;297(12)1344-1353
©2012 MFMER | slide-22
Heart Protection Study
Simvastatin 40 mg vs Placebo
n=20,536 patients randomized
•At 25 months - no difference in myalgias.
81% still on simvastatin or placebo
• How was the study performed ?
• 63,603 attended study screening clinics
• 32,145 pre-randomization run-in phase
• Run-in (10 weeks), if side-effects to
treatment - then do not randomize
• 32% of original patient pool randomized
Heart Protection Study Collaborative Group European Heart Journal (1999) 20, 725–741
©2012 MFMER | slide-23
Prevalence of Statin Use on Self Reported
Musculoskeletal Pain: NHANES
Body Region
Any region
W/O Arthritis (n=5170) W/ Arthritis (n=3058)
1.33 (1.06-1.67)
0.96 (0.81-1.15)
Neck/upper back 0.88 (0.53-1.45)
Upper extremities 0.82 (0.49-1.35)
0.81 (0.61-1.08)
0.84 (0.62-1.15)
Lower back
1.47 (1.02-2.13)
Lower extremities 1.59 (1.12-2.22)
1.05 (0.81-1.37)
0.96 (0.76-1.22)
Statin use was associated with a higher prevalence of
musculoskeletal pain in the lower extremities, among individuals
without arthritis
*Adjusted :age, sex, race, smoking, self-reported health, CHD, DM, cancer, Sys BP, BMI, TC,ABI
Buettner et al American Journal of Medicine (2012) 125, 176-182
Risk Factors for Statin Intolerance:
Patient-related
•Patient
Advanced age (>80)
Female sex
Low BMI
•Multisystem disease (particularly liver, kidney, or both)
Hypothyroidism (untreated)
Excess Alcohol
Grapefruit or Cranberry juice consumption (_1 qt/d)
Vigorous activity
•Major surgery or trauma
•Intercurrent infections
History of myopathy on another lipid-lowering therapy
History of creatine kinase elevation
Unexplained cramps
Family history of myopathy on lipid-lowering therapy
•Family history of myopathy
(polymorphisms of P450 isoenzymes or drug
transporters, inherited defects of muscle metabolism, traits
that affect oxidative metabolism of fatty acids)
Risk Factors for Statin Intolerance:
Treatment-Related
•High-dose statin therapy
•Interactions with concomitant drugs (esp P450 Pathway)
Amiodarone
Antifungals ( Azoles)
Cyclosporine
Fibrates
Macrolide antibiotics
Nefazodone
Nicotinic acids
Protease inhibitors
Thiazolidinediones
Verapamil
Warfarin
Differential Diagnosis of Myopathy or Creatine
Kinase Elevations Not Due to Lipid-Lowering Therapy
Muscle symptoms
Creatine kinase elevations
•Physical exertion (deconditioned)
•Viral illness
•Vitamin D deficiency
•Hypo- or hyperthyroidism
•Cushing syndrome or adrenal insuffic
•Hypoparathyroidism
•Fibromyalgia
•Polymyalgia rheumatica
•Polymyositis
•Systemic lupus erythematosus
•Tendon or joint disorder
•Trauma
•Seizures or severe chills
•Peripheral arterial disease†
•Medications
•Glucocorticoids
•Antipsychotics
•Antiretroviral drugs
•Illicit drugs (cocaine or amphetamines)
•Physical exertion
•Hypothyroidism
•Metabolic or inflammatory myopathies
•Alcoholism
•Neuropathy or radiculopathy
•Ethnicity (black Americans may have elevated
baseline creatine kinase levels)
•Idiopathic hyperCKemia‡
•Seizure or severe chills
•Trauma
•Medications
•Illicit drugs (cocaine or amphetamines)
•Antipsychotics
† For patients who present with cramping
in their calves or thighs.
‡ Refers to elevated creatine kinase level
without another cause identified
FDA Advisory : Statins Feb 28, 2012
• Routine monitoring of liver enzymes in the blood
is no longer needed
• Cognitive impairment ( memory loss,
forgetfulness and confusion) has been
reported by some statin users
• People being treated with statins may have an
increased risk of raised blood sugar levels and
the development of Type 2 diabetes
• Some medications interact with lovastatin and
can increase the risk of muscle damage.
Blood-Brain Barrier Permeability of Major
Statins
Name
Lovastatin
Pravastatin
Fluvastatin
Simvastatin
Atorvastatin
Cerivastatin
Rosuvastatin
Permeability
Yes
No
No
Yes
Disputed
Disputed
No
Shepardson et al Arch Neurol. 2011 Nov;68(11):1385-92. Cholesterol level and statin use in Alzheimer disease
Statin Use and Risk of DM in Postmenopausal
Women in the Women's Health Initiative
Culver et al Statin Use and Risk of Diabetes Mellitus in Postmenopausal Women in the Women's
Health Initiative Arch Intern Med. 2012;172(2):144-152.
Dementia-free survival probability
Are Statins Associated with Dementia ?
Statin Ever User
Statin Never User
Beydoun et al J Epidemiol Community Health 2011;65:949-957 doi:10.1136/jech.2009.100826 Ageing Research report
Statins and serum cholesterol's associations with incident dementia and mild cognitive impairment
Take Home Messages:
• Integrating lifestyle and diet changes with
medical Rx key to lipid management
• Dietary changes and exercise are best initial
steps to treating hypertriglyceridemia
• Statins and fish oil are the only medical Rx
shown to consistently lower CV mortality
• For primary prevention, elderly patients derive
most benefit from statin therapy.
• Statin intolerance is more common than
previously thought and must be addressed
©2012 MFMER | slide-32
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your attention !
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