National Lipid Association - PowerPoint Presentation

Slide1

National Lipid AssociationRecommendations for Patient-Centered Management of Dyslipidemia Part 2: Women’s Health

Jacobson ta, et al

Journal of clinical

lipidology

Doi

: 10.1016/jacl.2015.09.002

Slide2

National Lipid AssociationRecommendations for Patient-Centered Management of Dyslipidemia Part 2

Women’s Health

Slide Deck

Prepared by

Merle Myerson MD, Ed D, FACC, FNLA

Slide3

National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia Part 2 - Lifespan

Writing Committee

Gender Differences Pam Morris, MD, FNLA

Unique women’s issues Robert A Wild, MD, MPH, PHD, FNLA, NCMP

Thomas Dayspring, MD, FNLA,NCMP

James A Underberg, MD, MS, FNLA

Slide4

National Lipid Association (NLA)The National Lipid Association (NLA) was created as an extension of the success established by the Southeast Lipid Association formed in 1997 by a group of pioneering lipid researchers and clinicians from the Southeastern United States. The NLA was formed in 2000 to advance the practice of clinical

lipidology

.

The NLA is a multi-disciplinary society. Members include physicians, nurse practitioners, nurses, physician assistants, PhD researchers, pharmacists, dieticians and all professionals who desire to advance improvement in the practice of clinical

lipidology

.

Slide5

Women’s Health More women than men die from cardiovascular disease (CVD)Women have traditionally been under-represented in all research designs addressing CVD findings are often generalized to women

Paucity of research age < 40 years

Unique female issues:

Polycystic ovary syndrome

Pregnancy

Breast feeding Menopause

Contraception

Slide6

Background on Development of Clinical Guidelines and Recommendations

Slide7

Cholesterol Guidelines Development2001

: National Cholesterol Education Program Adult Treatment Panel (ATP) III issued

2007

: NHLBI convened an expert panel to update the guidelines

2008

: ATP IV members appointed

June 2013

: NHLBI announced that the work of the panel would not be published as ATP IV. NHLBI asks American College of Cardiology (ACC) & American Heart Association (AHA) to complete and publish a guideline

November 12, 2013

: “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults”

Slide8

2013 ACC/AHA Guideline 4 Statin Benefit Groups:

Individuals who should engage in a risk: benefit discussion with their provider

Those with history atherosclerotic CV events

Those with LDLC

>

190 age 21 - 75Those with diabetes 1 or 2 age 40 – 75Those with no diabetes, age 40-75, 10 yr. ASCVD risk ≥ 7.5%

Depending on risk, initiate risk-benefit discussion for use of moderate or high dose statin therapy

There was insufficient evidence to support the use of LDL-C targets or goals

No studies showing adding non statin drugs (

fibric

acids, niacin, ezetimibe, bile-acid binders) to statins add preventive benefit

No LDL-C treatment targets

Slide9

2013 ACC/AHA Guideline

Risk Calculator

“This guideline recommends using the new Pooled Cohort Risk Assessment Equations developed by the Risk Assessment Work Group to estimate the 10-year ASCVD risk . . . for the identification of candidates for statin therapy.”

Web-based and includes: sex, age, race (White or African-American), total cholesterol, HDL-cholesterol, systolic blood pressure, treatment for high blood pressure (if SBP > 120), diabetes, smoking

Slide10

National Lipid Association Clinical Recommendations for Patient-Centered Management of Dyslipidemia

Part 1

Executive summary released in 2014 with the Full Report released in 2015. Document serves as a guide for clinicians for treating patients with dyslipidemia. LDL-C and non-HDL-C goals were retained for their importance in the prevention of heart attack and stroke. Evidence from randomized clinical trials (including primary, subgroup, and pooled analyses), epidemiological, metabolic, mechanistic, and genetic studies included

Part 2

Released in 2015 and serve to provide a unique set of recommendations for management of dyslipidemia in special populations.

Slide11

National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia

Target of therapy: non-HDL-cholesterol and LDL-Cholesterol

Non-HDL-C and LDL-C goals depend on absolute ASCVD risk

Apolipoprotein

B is a secondary, optional target of treatment

In selected patients with two major risk factors, any of the three risk calculators may be used to determine absolute ASCVD risk. If ≥ 3 major risk factors are present, the patient is considered at high risk and without need to calculate risk.

Statins first line therapy

Triglycerides are target of therapy when very high (≥500 mg/

dL

)

Goals:

Non-HDL-C < 130 for all risk groups except < 100 for very high risk

LDL-C < 100 for all risk groups except < 70 for very high risk

Jacobson TA, et al.

Journal of Clinical

Lipidology

.

2015;9:129-169

Slide12

Risk Calculators NLA Part 1 Recommendations: use quantitative risk scoring as an option for patients with 2 major ASCVD risk factors, in the absence of any high or very high risk conditions, to facilitate treatment decisions.

Thresholds for high risk are ≥ 10 –year risk for a hard CHD event using NCEP ATP III, ≥ 15% 10-year risk using ACC/AHA Pooled Cohort Equations, and ≥ 45% risk for CVD using Framingham long-term 30-year risk.

Slide13

CVD Risk Calculators

 

Framingham Risk Score

POOLED COHORT EQUATIONS (ACC/AHA)

REYNOLDS

RISK

Population

General population from one area. Framingham MA (USA)

Population-based cohort studies funded by NHLBI

Men and Women from USA, no known CVD (men were non-diabetic)

Age

30-74 years

 

Men 57-80?;

Women ≥45

Data collection

1968-1971 original Framingham cohort, 1971-1975 and 1984-1987

Offspring Studies

1967-1992

Men: 1995 – 2008, followed for median of 10.8 years

Women: 1992-2004, followed for a median of 10.2 years

Years risk prediction

10-year risk of CHD events

30-year risk of CHD and stroke

10-year risk of ASCVD

10-year risk for CVD

Variables

sex, age, total cholesterol, HDL-C, smoking status, systolic blood pressure (treated/not treated), diabetes

Sex, age, race (White or Black), total cholesterol, HDL-C, Systolic blood pressure, treatment for high blood pressure (if systolic > 120 mmHg), Diabetes, smoking status

Sex, age, smoking status, total cholesterol, HDL-C,

CRPhs

, parental history of MI < 60 years of age, HbA1c (if diabetic)

Guidelines using scoreNCEP ATP IIICanadian Cardiovascular SocietyInternational Atherosclerosis SocietyNational Lipid Association Recommendations2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in AdultsNational Lipid Association RecommendationsNational Lipid Association Recommendations Discrimination and Calibration c-statistic: 0.65, 0.71, 0.77O/E: 1.18, 1.51c-statistic: 0.65, 0.71O/E: 1.20; may be better than FRS at higher categories of predicted riskunknownNotes Risk scores account for White and Black RaceEliminated targets for LDL-CMen were in the Physicians Health Study and Women in the Women’s Health Study

Slide14

National Lipid Association Recommendations:Lipid Goals by Risk Category

Risk Category,

(# major ASCVD risk factors)

Criteria

LDL-C mg/

dL

Non-HDL-C mg/

dL

Apo B mg/

dL

Very High

ASCVD

DM type 1 or 2

≥2 other major

risk factors

Evidence of end organ

damage

< 70

<100

< 80

High (≥3)

DM type 1

or 2

CKD stage 3B or 4

LDL-C ≥ 190 mg/

dL

Quantitative risk score reaches highest level

< 100

<130

<90

Moderate

(2)

2 major risk factors

Consider quantitative risk scoring Consider other risk indicators <100<130<90Low(0-1)Consider other risk indicators if known <100<130<90Jacoboson, TA, et al. Journal of Clincial Lipidology. 2015:9:129

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Management Plan Initiate Lifestyle Modification TherapyTherapeutic lifestyle changes are advised for all patients regardless of level of risk

Diet: heart-healthy, Mediterranean, DASH diet

Weight reduction if indicated

Increased physical activity

Smoking cessation

Blood pressure control

Reduction of elevated fasting blood glucose

Slide16

Management Plan Pharmacologic Reduction of atherogenic cholesterol (non-HDL-C and LDL-C) is a first priority

Non-HDL-C and LDL-C are co-primary targets of therapy with non-HDL-C the primary target in patients who’s Triglycerides are < 500 mg/

dL

.

If Triglycerides ≥ 500 they are the primary target of therapy

Statin drugs are first line (if no contraindications) for atherogenic cholesterol lowering. Slide #23: Tables for degree of potency and expected lowering. Other LDL-C lowering drugs: intestine absorption inhibitor, bile acid

sequestrants

, niacin

Triglycerides: fibrates, fish oil, and niacin

HDL-C is not a target of therapy

Slide17

Primary Prevention of Atherosclerotic Cardiovascular Disease (ASCVD)

Primary prevention strategies are critical to reduce morbidity and mortality for women at risk for ASCVD

Relatively fewer women have been included in trials of primary prevention. Available data support the conclusion that women and men of comparable ASCVD risk experience similar reductions in events when treated with statin therapy

Women without ASCVD should undergo risk assessment and stratification and the intensity of lipid-lowering therapy should be matched to the level of risk as described in the NLA Recommendations for Patient-Centered Management of Dyslipidemia Part 1

Slide18

Secondary Prevention Women with manifest ASCVD benefit from statin therapy

“ . . . The NLA Expert Panel recommends consideration for the use of moderate-or high-intensity statin therapy, irrespective of baseline

atherogenic

cholesterol levels, for patients with ASCVD or diabetes mellitus . . . “

National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1

Slide19

Gender Differences in Statin Lipid-Lowering Therapy Research has shown that benefits extend similarly to both men and women

Relatively less data available for gender-specific adverse events in women

It has been estimated that women tend to be 1.5-1.7 times greater risk for clinically significant adverse drug reactions compared to men

Tran C.

J

Clin Pharmacol.

1998;38:1003

Bhardwaj S.

Clin

Interv

Aging.

2013;8:47

Wenger NK.

Heart.

2008;94:434

Mora S.

Circulation.

2010;121:1069

Recommendation

: Clinicians should be aware of the potential for elevated adverse events with taking statins, particularly glucose elevations and myalgia which may be due to differences in age, comorbidities, BMI and body fat, muscle mass, and polypharmacy

Slide20

Lipid-Lowering TherapyStatins

Most researched lipid medication in terms of efficacy, safety, morbidity and mortality

Felt to have pleiotropic effects—benefits other than LDLC-lowering: anti-inflammatory, anti-thrombotic

Lower Triglycerides, particularly in high doses

Minimal raise in HDL-C

Relatively potent vs. other LDL-C lowering medications

Slide21

Statin Drugs

Drug

Comments

Atorvastatin (Lipitor)

available as a

generic

Fluvastatin

(

Lescol

)

available

as a generic

Lovastatin (

Mevacor

)

available as a generic

Pitavastatin

(

Livalo

)

Pravastatin (

Pravachol

)

available as a generic

Rosuvastatin

(Crestor)

Simvastatin (Zocor)

Available as a generic

Avoid with doses >

40 mg/day

Slide22

Statins Doses2013 ACC/AHA Guideline

High Intensity

↓ LDL-C ≥ 50%

Rosuva

(Crestor) 20 - 40

Atorva (Lipitor) 40 – 80

Moderate Intensity

↓LDL-C 30% to < 50%

Atorva

10 – 20

Rosuva

5 - 10

Simva

20 – 40

Pitava

(

Livalo

) 2 - 4

Prava

40 - 80

Lovastatin 40

Fluva

(

Lescol

) XL 40 mg twice daily or XL 80 mg once daily

Low Intensity: any dose lower than moderate

Slide23

FDA DRUG SAFETY COMMUNICATIONStatinsFebruary 28, 2012

Liver enzyme tests

Should be performed before starting statin therapy and as clinically indicated thereafter. FDA has concluded that serious liver injury with statins is rare and unpredictable in individual patients and that routine monitoring does not appear to be effective in detecting or preventing serious liver injury.

Diabetes

FDA’s review of studies: While statin randomized controlled trials and epidemiological studies show an increase in HbA1c and incident Type 2 diabetes with statin therapy as compared to placebo, the risk for incident diabetes is low (odds ratio 1.09 95% CI 1.02-1.17) and the benefits of statin therapy in appropriate patients exceeds risk.

(Maki KC, et al.

Journal of Clinical

Lipidology

.

2014;8(3S).

Slide24

FDA DRUG SAFETY COMMUNICATIONStatins

Cognitive Adverse Events

Post-marketing adverse event reports and data from observational and clinical studies did not suggest that cognitive changes associated with statin use are common or lead to clinically significant cognitive decline

“ Patients should know that although cognitive symptoms have been reported by some statin users, information from such case reports cannot be considered to be reliable, is not conclusive, and has not been proven in a cause-and-effect manner.”

Rojas-Fernandez.

Journal of Clinical

Lipidology

.

2014;8(3S)

Lovastatin and Simvastatin

Both metabolized via CYP450, increased risk of myopathy and interaction with other medications

Slide25

Lipid-lowering TherapyStatins Myopathy

Muscle soreness is the most common side effect of statins. This may occur with or without elevation in serum

creatine

kinase.

The statin can be stopped to see if symptoms resolve and then have a retrial to see if symptoms return. Options can include reducing the dose, trial of a different statin, alternate-day dosing of a statin with a long half life or use of non-statin drugs.

Slide26

Non-statin lipid-lowering therapy There is limited gender-specific evidence for the benefit of non-statin drugs in the prevention of ASCVD events.

2013 ACC/AHA Guidelines: No studies showing adding

nonstatin

drugs (

fibric

acids, niacin, ezetimibe, bile-acid binders) to statins add preventive benefit

Slide27

Non-Statin Drugs IMPROVE-IT

Randomized double blind controlled trial: High risk secondary prevention, participants followed for 6-7 years

Simvastatin 40 mg + ezetimibe vs. Simvastatin 40 + placebo

No effect on total mortality but reduced rate of stroke and MI

LDL-C 69

 54 in intervention group

No safety signal of harm

Lower is better (maybe goals do matter)

Value of non-statins

Cannon CP. N

Engl

J Med. 2015 Jun 18;372(25):2387-97.

Slide28

Non-Statin Drugs LDL-C Lowering Triglyceride Lowering

Bile Acid

Sequestrants

Fibrates

Cholesterol Absorption Inhibitor Omega-3 fatty acids

Niacin Niacin (high dose) Mipomersen [HoFH only]

Lomitapide

[HOFH only ]

PCSK-9 Inhibitors

Slide29

Non-Statin Drugs Recommendations for use of non-statin drugs for women are the same as those outlined in the NLA Recommendations Part 1:

Non statin drug therapy may be considered for patients with contraindications for, or intolerance to, statin therapy

Non statin drug therapy can be added to statin therapy when non-HDL-C and LDL-C levels remain above goal

Note that:

Women treated with niacin and

laropiprant in the HPS2 -THRIVE study had an excess of events and trend toward harm compared to men.

HPS2-THRIVE Collaborative Group.

N

Engl

J Med.

2014;371:203.

Slide30

Lipid-lowering TherapyStatinsPregnancy

All women should have lipid testing prior to pregnancy or early in pregnancy (at least before the end of the first trimester).

For women on lipid-lowering medication prior to pregnancy, all medications except bile acid

sequestrants

should be stopped. Omega -3-FA are currently recommended to be stopped in preparation for pregnancy. Certain women with FH may also be treated with LDL apheresis

Very high triglycerides (≥ 500 mg/dL with risk for pancreatitis) may be treated with diet/lifestyle management, omega-3-fatty acids,

fenofibrate

or gemfibrozil beginning in the 2

nd

trimester based on clinical judgement.

Slide31

Lipid-lowering Therapy in Pregnancy

statin

drugs are contraindicated

Animal reproduction studies have shown adverse effects with use of

fibrates, ezetimibe, cholestyramine, and omega 3 fatty acids but there are no studies on pregnant human subjects Use of these agents should therefore be employed only after careful consideration of the risk-benefit ratio

Lomitapide

is contraindicated in pregnancy

Animal reproduction studies using

colesevelam

have shown no evidence of risk but no studies have been done on pregnant human subjects using this drug.

At present there is no definitive information on use of PCSK9 Inhibitors or

mipomersin

in pregnancy

Slide32

Lipid-lowering Therapy for Women Who are Breast Feeding Colesevelam can be used. For other bile acid

sequestrants

, use can be considered after weighing all risks and benefits

For patients with severe hypertriglyceridemia use of omega-3-fatty acids and fibrates can be considered after weighing all risks and benefits. It is advisable to avoid estrogenic oral contraception as this may increase triglyceride levels

Slide33

Lipid-lowering TherapyPregnancy: FDA Classification FDA Categories were removed from drug labeling per the new FDA labeling guidance effective June 30, 2015. Instead, drug labeling will include a summary of the risks of using a drug during pregnancy and lactation, discussion of data supporting that summary and relevant information to assist health care providers in treatment decisions.

Slide34

Lipid-lowering Therapy Pregnancy and Familial Hypercholesterolemia

Familial Hypercholesterolemia manifests as markedly elevated LDL-C levels due to genetic mutations, most commonly with the LDL receptor. Most patients are heterozygous (1/300) while the homozygous condition is very rare. Patients with FH are at increased risk for premature atherosclerosis.

Despite high circulating levels of

atherogenic

lipoproteins, data do not support an association between maternal lipid levels and maternal or perinatal outcomes. Inadequately studied

Vrijkotte

TG.

J

Clin

Endocrinol

Metab

.

2012;97:3917

No definitive data are available to guide stopping treatment but it is felt that statins and other systematically absorbed lipid drug therapy should be stopped a minimum of one month and possibly as long as 3 months prior to attempted conception.

Slide35

Lipid-lowering Therapy Lactation Patients with FH can receive bile acid sequestrants

Patients with severe hypertriglyceridemia can receive fibrates and omega-3 fatty acids and should avoid estrogenic contraception even with late breast feeding.

Slide36
Dyslipidemia in Pregnancy

Pregnancy is a metabolic stress testBest time to screen is before or during first trimesterHypertriglyceridemia associated with preeclampsia and gestational diabetes

Preeclampsia and Gestational diabetes are risk factors for later CVD as strong or stronger than smoking

Lack of awareness among Primary Care Physicians and Obstetricians

Slide37

Polycystic Ovarian Syndrome (PCOS)Diagnosis is by identifying at least two of the following criteria: androgen excess (clinical or in the blood) , ovulatory dysfunction, and/or presence of polycystic ovaries by ultrasound.

Affects 7-22% of reproductive-age women. Women with PCOs are at increased risk for metabolic syndrome, diabetes mellitus, and complications of pregnancy. Majority have insulin resistance aggravated by obesity.

Patients with PCOS should be evaluated for dyslipidemia and diabetes. The pattern seen is generally that of insulin resistance (elevated Triglycerides and low HDL-C along with a predominance of small, dense LDL particles). If baseline values are normal, testing should be repeated at least every two years.

Slide38

Polycystic Ovarian Syndrome (PCOS)The accuracy of risk assessment remains uncertain for women with PCOS but risk stratification and treatment goals should be the same as described for the general population in the NLA Recommendations Part 1

Treatment of the dyslipidemia should be focused on reversing all components of the metabolic syndrome through diet, exercise, and medication if needed. Implications for those at high risk for maternal and/or fetal complications should be considered

Combined oral contraceptives are often used to control menses, reduce endometrial and ovarian cancer risk and reduce hirsutism. Use of combined oral contraceptive may result in increase in Triglycerides and thrombotic risk and patients should be monitored.

Slide39

Oral Contraception Estrogen in combined oral contraceptives may increase Triglycerides and HDL-C and lower LDL-C. The more estrogen, the greater the TG-raising effect and may cause marked elevations (> 500 mg/

dL

) in women with high baseline TG.

Androgenic

progestins

(norgestrel and levonorgestrel) can raise LDL-C and lower HDL-C. Others are usually lipid neutral.

Transdermal contraceptive may be less prone to producing clinically important elevations in TG concentration with similar thrombotic risk as compared to oral contraceptives.

Slide40

Lipid Changes with the MenopauseBoth LDL-C and apolipoprotein B increase in the few years prior to menopausal symptoms, peak, and then plateau. HDL-C tends to decrease after menopause. These changes are related to declining ovarian production of estradiol and population average weight gain.

The absolute risk of ASCVD increases substantially during and after the menopause.

Slide41

Hormone Replacement Therapy Hormone replacement therapy is primarily indicated to control menopause-related quality of life issues.

Results from the Women’s Health Initiative suggest that women at higher risk for ASCVD events are more likely to have even higher risk when they take oral hormone replacement therapy. Risk for CVD increases with age

Wild RA.

Semin

Reprod Med. 2014;32:433

Slide42

Hormone Replacement Therapy Recommendations:Prescribe the lowest

effective

dose of HRT

Doses lower than 0.3 mg of oral conjugated estrogen or equivalent given at night will not control hot flashes for most women.

Transdermal or vaginal delivery may be associated with fewer adverse events than the oral route

Vaginal and transdermal preparations have smaller effects on clotting factors, lipid metabolism, inflammatory biomarkers, and sex hormone binding globulin synthesis.

Slide43

Recommendations for Women’s Health

In general, women should be treated according to the National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia—Part 1 with the following special considerations.

First-line cholesterol-lowering drug therapy, unless contraindicated, is moderate-to high-intensity statin. If goal levels of

atherogenic

cholesterol are not achieved, statin dose may be increased or the patient switched to a more efficacious agent. Statin therapy should be considered for patients at very high risk (known ASCVD, or diabetes with ≥ 2 major risk factors) even if pre-treatment levels are below the treatment goals.

Slide44

Recommendations for Women’s Health

Non-statin drug therapy may be considered for women with contraindications or intolerance to statin therapy, or in combination with statin therapy for patients who need additional lowering of

atherogenic

cholesterol to achieve treatment goals.

Women taking statins may be at increased risk for certain adverse events, particularly myalgia.

Slide45

Recommendations for Pregnancy to Menopause

Women should be screened for dyslipidemia before pregnancy or as part of the routine obstetrical laboratory examination

For women taking lipid-lowering medications prior to pregnancy, all except bile acid

sequestrants

should be stopped when the woman becomes pregnant, or is trying to become pregnant

Women should be educated on the importance of pregnancy avoidance when lipid-altering therapies other than bile acid

sequestrants

are used.

Slide46

Recommendations for Pregnancy to Menopause

Total cholesterol and Triglyceride levels in women with normal pregnancies should generally not exceed 250 mg/

dL

. If they do, the clinician should evaluate for preexisting or acquired secondary causes.

Hypercholesterolemia during pregnancy and breast feeding, especially in women with FH may be treated with bile acid

sequestrants

. Women with homozygous FH may be considered for treatment with LDL apheresis LDL apheresis may also be considered in heterozygous FH patients with ASCVD.

Very high Triglycerides (≥ 500 mg/

dL

) may be treated during pregnancy with diet and lifestyle plus prescription omega-3 fatty acid.

Fenofibrate

and gemfibrozil may be given starting early in the 2

nd

trimester based on clinical judgement. These agents can be used during breast feeding.

Slide47

Recommendations for Pregnancy to Menopause

PCOS is a high-risk condition for dyslipidemia, metabolic syndrome, preeclampsia, hypertension, diabetes, and premature delivery. All patients with PCOS should be screened for these and followed carefully.

Contraceptive choice impacts dyslipidemia. COC should generally not be used by women ≥ 35 years of age who smoke because of risk for stroke and MI.

Sex hormone therapy should not be used for prevention of ASCVD. Menopause sex hormone therapy is an option for treatment of significant menopause symptoms during menopause transition for women at minimal risk for ASCVD.