©2012 mfmer | slide-0 lipid management: role of foods, lifestyle, & drugs for management steve...

©2012 MFMER | slide-1

Lipid Management: Role of Foods, Lifestyle, &

Drugs for Management

Steve Kopecky MDPreventive Cardiology

Mayo ClinicRochester MN


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


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


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”


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

/10

00

men

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


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


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 MeatBeans for Red Meat

0.4 0.6 0.8 1 1.2 1.4 1.6Hazard Ratio

Poultry for Red Meat

Less Heart Disease More Heart Disease


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

-1.5

-1

-0.5

0

0.5

1

1.51.23

-1.2

1.14

-1.23

All Cause Mortality CV Mortality

Animal Low Carb

Vegetable Low Carbp<0.001p<0.001

p=0.051 p=0.029

Low Carb Diet : Hi Animal – Increased Total/CV Mortality Hi Vegetable – Decreased Total/CV Mortality


Block cholesterol Ezetimibe

absorptionReduce hepatic Statin

cholesterol synthesisIncrease bile Cholestyramine

acid losses

Reducing Heart Disease Risk: Lowering Cholesterol

Plant Sterols/Stanols 1.6 / 3.4 gm/day

Oat b-glucan

Viscous Fiber PsylliumNuts Almonds 42 g

Annals Int Med 2005;142:793-795

DrugEffect

Source of plant sterols monounsaturated fats,vegetable protein

Diet

Soy0.8 Oz


Portfolio Diet : Per 1000 kcal of DietLower 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


Supplements to Reduce LDL: Reduce Intestinal Cholesterol Absorption

Product How much to takePlant 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™)


Product How much to takeOat 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 lovastatinNot regulated adequatelyDosage variableInstead-Use generic (low cost) statin


Product How much to takeBlonde 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™)


Lipid Management Drugs and their Effects on Lipids/Lipoprotein

NCEP/ATP III 2001

-60-50-40-30-20-10

010203040

LDL HDL TG

%

Fish Oil : EPA and DHA = 4-6 gms/day


95% ULRisk 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 benefitonce LDL reduction acheived


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


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


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 ratiosCHD=coronary heart disease

Effects on major vascular events at 1 Yr per 1·0 mmol/L reduction in LDL C

99% CI

95% CIStatin/More Better Controls/Less Better

LDL cholesterol : 1.0 mmol/L reduction = 38 mg/dl reduction


Statins for Primary Prevention of CV Disease

Study ACAPS 1994

Adult Japanese MEGA AFCAPS/TexCAPS 1998

ASPEN 2006CARDS 2004

KAPS 1995PREVEND IT 2004

WOSCOPS 1997Total (95% CI)

Statins for the primary prevention of cardiovascular disease (Review) 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Favors FavorsStatin 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 decreasein Total Mortality

©2012 MFMER | slide-20Arch 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 ?


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;150:858-8682. 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-94C4. Sewright Statin myopathy: incidence, risk factors, and pathophysiology. Curr Atheroscler Rep. 2007;9:389-96


Statin Intolerance: Definition

Unable to take statin to get to goal due to symptoms of intolerance

Most common symptom : muscle aches, weakness, cramps


Statins: Side Effects in Clinical Trials – METEOR (Rosuva 40)

Placebo12.17.1

10.32.82.12.12.81.10.73.61.1

46%

Age 57 Yrs; n=984

MM=Muscle; Ext=ExtremityCrouse et al METEOR Trial JAMA. 2007;297(12)1344-1353

Event (%) Rosuva Placebo

Musculoskeletal Side Effect or Withdrew Consent 75% 72%

Arthralgia 10.1Back Pain 8.4MM Spasms 3.7Tendinitis 3.3Ext Pain 2.9Shoulder Pain 2.0Neck Pain 1.6Arthritis 1.6Stiffness 1.1MM Weak 0.7Total 48%

Event (%) RosuvaMyalgia 12.7

Exclusion Criteria:Statin Intolerance


• 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 StudySimvastatin 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

Risk Factors for Statin Intolerance: Patient-related• Patient

Advanced age (>80)Female sexLow BMI

• Multisystem disease (particularly liver, kidney, or both)Hypothyroidism (untreated)Excess AlcoholGrapefruit or Cranberry juice consumption (_1 qt/d)Vigorous activity

• Major surgery or trauma• Intercurrent infections

History of myopathy on another lipid-lowering therapyHistory of creatine kinase elevationUnexplained crampsFamily 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

Risk Factors for Statin Intolerance: Treatment-Related

• High-dose statin therapy• Interactions with concomitant drugs (esp P450 Pathway)

Amiodarone Antifungals ( Azoles)Cyclosporine FibratesMacrolide antibiotics Nefazodone Nicotinic acidsProtease inhibitorsThiazolidinedionesVerapamilWarfarin

Differential Diagnosis of Myopathy or CreatineKinase Elevations Not Due to Lipid-Lowering Therapy

Differential Diagnosis of Myopathy or CreatineKinase 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 PermeabilityLovastatin YesPravastatin No Fluvastatin NoSimvastatin Yes Atorvastatin DisputedCerivastatin DisputedRosuvastatin No

Statin Use and Risk of DM in Postmenopausal Women in the Women's Health Initiative

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 ?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

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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

Thank you for your attention !

[email protected]

Thank you for your attention !

[email protected]

www.aspconline.org

©2012 mfmer | slide-0 lipid management: role of foods, lifestyle, & drugs for management steve...

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