Recommendations for PatientCentered Management of Dyslipidemia Part 2 Womens Health Jacobson ta et al Journal of clinical lipidology Doi 101016jacl201509002 National Lipid Association ID: 916671
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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
Slide2National Lipid AssociationRecommendations for Patient-Centered Management of Dyslipidemia Part 2
Women’s Health
Slide Deck
Prepared by
Merle Myerson MD, Ed D, FACC, FNLA
Slide3National 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
Slide4National 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
.
Slide5Women’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
Slide6Background on Development of Clinical Guidelines and Recommendations
Slide7Cholesterol 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: NHLBI announced that the work of the panel would not be published as ATP IV.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”
Slide82013 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
Slide92013 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
Slide10National 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.
Slide11National 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
Slide12Risk 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.
Slide13CVD 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
Slide14National 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
Slide15Management 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
Slide16Management 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
Slide17Primary 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
Slide18Secondary 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
Slide19Gender 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
Slide20Lipid-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
Slide21Statin 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
Slide22Statins 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
Slide23FDA 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).
Slide24FDA 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
Slide25Lipid-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.
Slide26Non-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
Slide27Non-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.
Slide28Non-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
Slide29Non-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.
Slide30Lipid-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.
Slide31Lipid-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
Slide32Lipid-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
Slide33Lipid-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.
Slide34Lipid-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.
Slide35Lipid-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.
Slide36Dyslipidemia in PregnancyPregnancy 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
Slide37Polycystic 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.
Slide38Polycystic 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.
Slide39Oral 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.
Slide40Lipid 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.
Slide41Hormone 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
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.
Slide43Recommendations 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.
Slide44Recommendations 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.
Slide45Recommendations 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.
Slide46Recommendations 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.
Slide47Recommendations 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.