Lipid Management: Role of Foods, Lifestyle, & Drugs … · Drugs for Management ... Would you send...
Transcript of Lipid Management: Role of Foods, Lifestyle, & Drugs … · Drugs for Management ... Would you send...
©2012 MFMER | slide-0
Lipid Management: Role of Foods, Lifestyle, &
Drugs for Management
Steve Kopecky MD
Preventive Cardiology
Mayo Clinic
Rochester MN
©2012 MFMER | slide-1
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-2
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-3
Secondary CV Prevention: US 2011
Frieden and Berwick N Engl J Med 2011; 365:e27 September 29, 2011
In patients with Hyperlipidemia:
1/3 have adequate treatment
“Million Hearts Campaign”
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35
Seven Countries Study: Relationship of Serum Cholesterol to Mortality
Adapted from Verschuren WM et al. J Am Med Assoc 1995;274(2):131–136
Serum total cholesterol (mmol/L)
30
25
20
15
10
5
0
Death
rate
fro
m C
HD
/1
00
0 m
en
2.60 3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05
Northern Europe
United States
Southern Europe, inland
Southern Europe, Mediterranean
Japan
Serbia
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What Diet Components Decrease Risk for MI ?
Iqbal et al INTERHEART Study:Dietary patterns and risk of MI AHA Epi Conf Orlando 2007
Western Diet:
Fried foods, salty snacks, and meat
Association
w/ MI
Increases
Oriental Diet:
Tofu, pickled foods, soy and other sauces
Prudent Diet:
Dairy, fruits, vegetables, nuts
Neutral
Decreases
INTERHEART Study:
55 countries
All inhabited continents of the world
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CAD Associated with Daily Replacement (1 serving) of Protein Source
Bernstein Circulation. 2010;122:876-883
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
High Fat Dairy for Fish
Nurse’s Health Study
27 Year Follow-up
RRs and 95% CIs
Fish for Red Meat
Nuts for Red Meat
Beans for Red Meat 0.4 0.6 0.8 1 1.2 1.4 1.6
Hazard Ratio
Poultry for Red Meat
Less Heart Disease More Heart Disease
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Low Carbohydrate Diets : Mortality Effect ?
Fung Low Carbohydrate Diets and All-Cause and Cause-Specific Mortality Ann Int Med 2010;153:289-298
All Cause Mortality (HR)
Any Low Carb Diet 1.12 ( 95% CI 1.01-1.24)
Health Professional’s Follow Up Study n=51,529 : 20 Yr follow-up
1.23
-1.2
1.14
-1.23 -1.5
-1
-0.5
0
0.5
1
1.5All Cause Mortality CV Mortality
Animal Low Carb
Vegetable Low Carb
p<0.001 p<0.001
p=0.051 p=0.029
Low Carb Diet : Hi Animal – Increased Total/CV Mortality
Hi Vegetable – Decreased Total/CV Mortality
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Block cholesterol Ezetimibe
absorption
Reduce hepatic Statin
cholesterol synthesis
Increase bile Cholestyramine
acid losses
Reducing Heart Disease Risk: Lowering Cholesterol
Plant Sterols/Stanols
1.6 / 3.4 gm/day
Oat b-glucan
Viscous Fiber
Psyllium
Nuts
Almonds 42 g
Annals Int Med 2005;142:793-795
Drug Effect
Source of plant sterols
monounsaturated fats,
vegetable protein
Diet
Soy
0.8 Oz
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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. 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
2. Jenkins et al JAMA.2011;306(8):831-839. doi: 10.1001/jama.2011.1202
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Supplements to Reduce LDL: Reduce Intestinal Cholesterol Absorption
Product How much to take
Plant stanols 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
with meals (= 2 tsps Promise activ™
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
(sitostanol, such as
Benecol Light™
Spreads, Smart
Chews)
(Promise activ™
Spreads, SuperShots™)
(CholestOff™ and
Centrum Cardio™)
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Product How much to take
Oat bran Up to 150 g of whole oat
products per day (about
equal to eating 1½ cups of
cooked oatmeal)
Supplements to Reduce LDL:
Reduce Cholesterol Production in Liver
(oatmeal,oat bran
products; look for
oat bran or whole
oats as ingredient
on label)
Do not use Red Yeast Rice –
Contains lovastatin
Not regulated adequately
Dosage variable
Instead-Use generic (low cost) statin
©2012 MFMER | slide-12
Product How much to take
Blonde psyllium 5 g seed husk twice per
day, or 1 serving of
product such as
Metamucil™
Supplements to Reduce LDL: Increase Loss of Cholesterol via Bile Acid into
Intestine
(seed husks and
products such as
Metamucil™)
©2012 MFMER | slide-13
Lipid Management Drugs and their Effects on Lipids/Lipoprotein
NCEP/ATP III 2001
-60-50-40-30-20-10
010203040
Statins
Bile A
cid
Niacin
Fibrates
Ezetimibe
Fish Oil
LDL HDL TG
%
Fish Oil : EPA and DHA = 4-6 gms/day
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95% UL Risk ratio 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
Favors Tx Favors ctrl
0.5 0.8 1.0 1.25 2.0
Effect of Different Anti-lipidemic Agents and
Diets on Overall Mortality
Effect of Different Antilipidemic Agents and Diets on Mortality: A Systematic Review Studer et al Arch Intern Med. 2005;165:725-730.
AIM-HIGH : Niacin no benefit
once LDL reduction acheived
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Oscai et al AJC 1972; 30:775-780
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
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Statins : LDL Reduction From Starting to Max Dose
Illingworth Medical Clinics of North America- Volume 84, Issue 1(January 2000);23-42
Fluva Prava Lova Simva Atorva Rosuva
20-80 20-40 20-80 20-80 10-80 5-40
-19-27 -28
-35 -37-45
-12-6
-12
-12-18
-18
-70
-60
-50
-40
-30
-20
-10
0
%
Start Dose Max Dose
Dose Increase : 4x 2x 4x 4x 8x 8x
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Are Statins of Benefit in Primary Prevention ?
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
RR= Rate ratios
CHD=coronary heart disease
Effects on major vascular events at 1 Yr per 1·0 mmol/L reduction in LDL C
99% CI
95% CI Statin/More Better Controls/Less Better
LDL cholesterol : 1.0 mmol/L reduction = 38 mg/dl reduction
©2012 MFMER | slide-18
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)
Statins for the primary prevention of cardiovascular disease (Review)
2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Favors Favors Statin Control
.2 .5 1 2 5
Total Statin Placebo n 14,058 14,103
Risk Ratio
0.84 [0.73,0.96]
Total Mortality
Does not include JUPITER, which
also showed decrease in Total Mortality
©2012 MFMER | slide-19 Arch Intern Med. 2010;170(12):1024-1031
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 ?
©2012 MFMER | slide-20
Proposed Definitions for Statin-Related Myopathy
Clinical Entity ACC/AHA 1 NLA 2 FDA 3
Myopathy General term- any disease of muscles
Sx of myalgia & CK > 10x ULN
CK > 10x ULN
Myalgia Muscle ache/weakness w/o Hi CK
NA NA
Myositis Muscle Sx w/ Hi CK NA NA
Rhabdomyolysis 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
1. Joy Ann Intern Med 2009;150:858-868
2. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. J Am Coll Cardiol. 2002;40:567-72.
3. NLA Am J Cardiol. 2006;97:89C-94C
4. Sewright Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep. 2007;9:389-96
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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-22
Statins: Side Effects in Clinical Trials – METEOR (Rosuva 40)
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
MM=Muscle; Ext=Extremity Crouse et al METEOR Trial JAMA. 2007;297(12)1344-1353
Event (%) Rosuva Placebo
Musculoskeletal Side Effect or Withdrew Consent 75% 72%
Arthralgia 10.1
Back Pain 8.4
MM Spasms 3.7
Tendinitis 3.3
Ext Pain 2.9
Shoulder Pain 2.0
Neck Pain 1.6
Arthritis 1.6
Stiffness 1.1
MM Weak 0.7
Total 48%
Event (%) Rosuva
Myalgia 12.7
Exclusion Criteria:
Statin Intolerance
©2012 MFMER | slide-23
• Run-in (10 weeks), if side-effects to
treatment - then do not randomize
Heart Protection Study Collaborative Group European Heart Journal (1999) 20, 725–741
•At 25 months - no difference in myalgias.
81% still on simvastatin or placebo
Heart Protection Study
Simvastatin 40 mg vs Placebo n=20,536 patients randomized
• 32,145 pre-randomization run-in phase
• 63,603 attended study screening clinics
• 32% of original patient pool randomized
• How was the study performed ?
Any region 1.33 (1.06-1.67) 0.96 (0.81-1.15)
Neck/upper back 0.88 (0.53-1.45) 0.81 (0.61-1.08)
Upper extremities 0.82 (0.49-1.35) 0.84 (0.62-1.15)
Lower back 1.47 (1.02-2.13) 1.05 (0.81-1.37)
Lower extremities 1.59 (1.12-2.22) 0.96 (0.76-1.22)
*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
Statin use was associated with a higher prevalence of
musculoskeletal pain in the lower extremities, among individuals
without arthritis
Body Region W/O Arthritis (n=5170) W/ Arthritis (n=3058)
Prevalence of Statin Use on Self Reported
Musculoskeletal Pain: NHANES
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 •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)
Creatine kinase elevations •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
• Routine monitoring of liver enzymes in the blood
is no longer needed
FDA Advisory : Statins Feb 28, 2012
• 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.
• Cognitive impairment ( memory loss,
forgetfulness and confusion) has been
reported by some statin users
Shepardson et al Arch Neurol. 2011 Nov;68(11):1385-92. Cholesterol level and statin use in Alzheimer disease
Blood-Brain Barrier Permeability of Major
Statins
Name Permeability
Lovastatin Yes
Pravastatin No
Fluvastatin No
Simvastatin Yes
Atorvastatin Disputed
Cerivastatin Disputed
Rosuvastatin No
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.
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
Dem
en
tia
-fre
e s
urv
ival p
rob
ab
ilit
y
©2012 MFMER | slide-32
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
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