Managing Lipid Disorders - 2017 Ann Marie Padilla, M.D. Desert View Family Medicine Gilbert, AZ CV disease is the leading cause of morbidity and mortality in the US – accounting for 1/3 of all deaths. USPSTF reviewed the evidence for benefits and harms of screening for and treating dyslipidemia in adults ages 21 to 75, and benefits and harms of treating with statins for primary prevention of CV disease

2017 USPSTF Guidelines Shift away from treating lipid targets to specific goals Treatment recommendations are statin-centric Recommend moderate to high intensity statin therapy for four groups likely to achieve maximal net benefit based on increased risk

Groups that would benefit from statin therapy 1) Adults with clinical ASCVD 2) Adults 21 and older with primary LDL-c > 190mg/dL 3) Adults 40-75 years old without ASCVD with DM and LDL-c 70-189 4) Adults 40-75 years old without ASCVD or DM but LDL-c 70-189 and estimated 10 year ASCVD risk of 7.5% or greater (using ACC/AHA Pooled Cohort Equations) Patient population under consideration – 40 yo and older primary prevention Known ASCVD use high intensity statin unless elderly or intolerant, then use moderate intensity

ACC/AHA Guidelines for Statin Therapy 1) Patients with known ASCVD 2) Patients with LDL-c > 190 (not due to secondary modifiable causes) 3) Patients 40-75 y.o. without ASCVD but with T2DM and LDL-c 70-189 4) Patients 40-75 y.o. without ASCVD or T2DM but LDL-c 70-189 and estimated 10 year ASCVD risk of 7.5% or greater (using Pooled Risk Cohort Equations) Central to ACC approach is net reduction in CV risk

Conditions That Define ASCVD Acute coronary syndrome History of myocardial infarction Stable and unstable angina Coronary or other arterial revascularization Stroke Transient ischemic attack Conditions That Define ASCVD with Comorbidities Diabetes Recent ASCVD event (< 3 months ago) ASCVD event while already taking a statin Poorly controlled other major ASCVD risk factors ACC/AHA guidelines recommend statins for

USPSTF Recommendation Adults without CVD should be treated with low to moderate dose statin if… 1) age 40-75 years old 2) one or more risk factors (dyslipidemia, diabetes, hypertension, smoking) 3) calculated 10-year risk of CV event is 10% or greater (B recommendation) or 7.5 – 10% risk (C recommendation) Liklihood that a patient will benefit depends on absolute baseline risk of having a future CVD event (although risk estimation is imprecise).

Pooled Cohort Equations Derived from prospective cohorts of volunteers from studies conducted in the 1990s May not be generalizable to a more contemporary and diverse population seen in current clinical practice Equations lack precision – use as a starting point to discuss with patient the desire for life- long statin therapy Ability to accurately identify true risk is imperfect. Best tool uses pooled cohort equations from 2013 ACC/ AHA guidelines on assessment of CV risk. May overestimate CV risk 75-150% but still more accurate than the Framingham Risk Calculator. Calculator is to date the only U.S. based CVD risk prediction tool that has published external validation studies in other U.S.-based populations. Heavily influenced by age.

USPSTF Recommendation Evidence is insufficient to assess balance of benefits and harms of initiating statin therapy for primary prevention of CVD events and mortality in adults 76 y.o. and older.

USPSTF Recommendation There is insufficient evidence that screening people 21-39 y.o. has an effect on either long or short term CV outcomes. Recommends neither for or against screening in this age group Evidence lacking in screening for familial hypercholesterolemia clinical judgement is encouraged Other relevant USPSTF recommendations – screen for HTN, abnormal blood glucose and T2 DM, interventions for smoking cessation, behavioral counseling to promote healthful diet and physical activity and screen for and manage obesity in adults.

Familial Hypercholesterolemia Autosomal dominant disorder caused by genetic mutation 1/200-500 people in North America and Europe LDL-c > 190 in the absence of other risk factors may fall below the threshold for statin use for CVD prevention Expert opinion strongly favors intervention

Screening for ASCVD Risk Factors Reasonable to assess risk factors (BP, smoking status, lipid levels) every 5 years (shorter for those with risk factors close to warranting therapy) LDL-c is the primary target of dyslipidemia management Measurement of lipoprotein (a), small LDL, HDL subspecies, apolipoprotein B, apolipoprotein A-1, oxidized LDL should NOT be used for routine CV risk screening based on lack of clinical outcome trials Elevated lipoprotein (a) could be used as an additional risk factor to justify aggressive LDL lowering in high risk patients.

Dyslipidemia and Children USPSTF – insufficient evidence in screening asymptomatic children 20 y.o. and younger Cholesterol levels vary by sex and age thorough childhood Long term effects of statin use in children and adolescents is unknown Screen for obesity over 6 y.o. with comprehensive behavioral intervention Elevated lipid levels peak before puberty and track modestly into adulthood – difficult to predict which children and adolescents will continue to have elevated cholesterol as adults. Inadequate evidence to address whether treatment with short-term pharmacotherapy leads directly to a lower incidence of premature CVD. Can treat kids with diet, physical activity, statins, bile acid sequestering agents.

Treatment Statins – inhibits the enzyme 3- hydroxy-3 methyl-glutaryl coenzyme a reductase (rate limiting step in production of cholesterol) Reduces TC, LDL-c and lesser extent TG Anti-inflammatory and plaque stabilization effects Adherence to lifestyle modification should be assessed at the time of initiating statin and during ongoing therapy. – Heart healthy diet, regular exercise, avoidance of tobacco, maintenance of healthy weight. Cochrane review – for every 1,000 treated with statin for 5 yrs, 18 avoid vascular event, (NNT = 56)

High-, Moderate-, and Low-Intensity Statin Therapy Recommended by the ACC/AHA Guideline High-Intensity Statin Therapy Moderate-Intensity Statin Therapy Low-Intensity Statin Therapy Atorvastatin (Lipitor), 40 to 80 mg Atorvastatin, 10 mg Lovastatin, 20 mg Rosuvastatin (Crestor), 20 mg Fluvastatin, 40 mg twice daily Pravastatin, 10 to 20 mg Lovastatin, 40 mg Prevastatin (Pravachol), 40 mg Rosuvastatin, 10 mg Simvastatin (Zocor), 20 to 40 mg 2013 ACC/AHA subdivided statin therapy into high and moderate intensity therapy High intensity – most patients Moderate intensity – patients over 75 Y.O. and primary prevention with 10 year ASCVD risk > 7.5% Adequate evidence low-mod dose statins decrease probability of CVD events and mortality at least moderate amount for primary prevention Degree of cholesterol reduction may be attributable in part to inter-individual variability in response, not just dosage.

Statin Intolerance Myalgia – muscle ache or weakness with normal CK – large proximal muscle groups – common Myositis – muscle symptoms with elevated CK – rare (5/100,000 patient years) Rhabdomyolysis – muscle symptoms with CK elevation > 10 times ULN with creatinine elevation – rare (1.6/100,000 patient years) Rule out other causes (hypothyroid, vit D deficiency, recent exercise), drug-drug interactions that increase statin exposure (fibrates, diltiazem, verapamil, amiodarone), alcohol and substance abuse. At risk for myopathy- over 70 Y.O., female, high-dose therapy, impaired liver / renal function, low body mass. Statin induced myopathy is dose related and may occur with all statins (esp. simvastatin)

Statin Intolerance To avoid statin induced muscle injury Use lowest effective dosage Identify patients with risk factors Monitor adverse effects and CK in symptomatic patients Avoid serious drug interactions Educate patients Baseline CK only in patient at high risk of muscle toxicity Tx approach: discontinue statin therapy and subsequently re-challenge to verify recurrence of sx. – using lower dose, alternative dosing strategies or different statin. Myopathic symptoms usually resolve within 2 months after discontinuing statin.

Statin Hepatic Risks Risk of hepatic injury cause by statins is about 1% - similar to placebo Continue statin if transaminases are no more than 3x ULN Co-existing elevations of transaminase levels from NASH, stable Hepatitis B and C are not contraindications to use Hepatologists convened by National Lipid Association – routine LFT not supported by literature but for medicolegal reasons advise check transaminase levels before initiating therapy, 12 weeks after initiating therapy or increased dose, and periodically thereafter.

Harms of Statin Use USPSTF found no clear evidence of decreased cognitive function associated with statin use HOPE-3 Trial – statin use associated with increased risk of cataract surgery JUPITER – increased risk of diabetes with high dose statin (Systematic review of RCTs found no effect on incidence of Alzheimer’s or dementia) Diabetes risk – no association in pooled analysis of RCTs vs. placebo

Before we proceed…

Statin Therapy and Pregnancy Discontinue 1-3 months before attempting to conceive Discontinue treatment immediately Counsel on lifestyle modification or bile acid sequestrants Resume after done nursing Statins will long remain cornerstone of treatment – proven benefits and cost-effectiveness

Statin use in the Elderly NICE – advise treat up to age 84 with moderate intensity statin USPSTF – insufficient evidence to balance risks and benefits of primary prevention with statin use over age 76 ACC/AHA – no recommendations for treating over age 75 unless clinical ASCVD (moderate intensity statin) Society for Post-Acute and Long Term Care Medicine (choosing wisely campaign) recommend physicians and patients question use of cholesterol lowering meds in adults with limited life expectancy (70 and older) because of increased likelihood of overall unfavorable risk – benefit ratio.

Non-Statin Therapy IMPROVE-IT trial – benefit of Ezetamibe (Zetia) Bile acid sequestrants (inadequate response to Zetia and fasting TG < 300) PCSK-9 inhibitors Niacin demonstrated significant harm – US FDA withdrew approvals No convincing evidence that routine use of Zetia, niacin, fibrates, omega-3 fatty acids are useful in primary prevention of ASCVD. Colesevelam (Welchol)- modest HgbA1C reduction

PCSK9 Inhibitors Evolocumab (Repatha) and Alirocumab (Praluent) Prevents PCSK9 protein from degrading LDL receptors, thereby increasing LDL clearance and reducing serum cholesterol For use in combination with statin for clinical ASCVD, familial hypercholesterolemia Injectable human mono-clonal antibody labeled for decreasing LDLc.

PCSK9 Inhibitors Evolocumab reduces LDL cholesterol by 50-75% Cost – (Repatha 140 mg / mL every two weeks $1127) (Praluent 75 mg SQ every two weeks $1164) NNT 81 2015 meta-analysis of 24 trials in primary and secondary prevention reported significant reductions in MI, all cause mortality in patients on PCSK9-I and max tolerated statin. To prevent one additional CV event, 81 patients must use Repatha for one year. Use of PCSK9 – I – may be limited to subspecialists seeing patients requiring significant reductions in LDLc despite max. dose statin. Caution against indiscriminate use of expensive monoclonal antibodies ($14,000/yr) – deep impact on healthcare costs

Hypertriglyceridemia Mild hypertriglyceridemia 150-199 mg / dL Moderate hypertriglyceridemia 200 - 999 mg / dL Severe hypertriglyceridemia 1,000 – 1,999 mg / dL Very severe hypertriglyceridemia > 2,000 mg / dL Severe – increase risk of pancreatitis Unclear if high TG causes atherosclerosis but may be a marker for CV disease rather than a causal factor Endocrine Society recommends screen every 5 years

Secondary Causes of Hypertriglyceridemia Excessive alcohol intake Untreated diabetes Endocrine conditions – metabolic syndrome Renal or liver disease Pregnancy Autoimmune disorders Medication (thiazides, beta blockers, estrogen, isotretinoin, corticosteroids, bile acid binding resins, anti-retroviral protease inhibitors, immunosupressants, antipsychotics

Management of Hypertriglyceridemia Dietary counseling and weight loss Severe and very severe elevation – fibrates, niacin Reduce dietary fat and simple carbs

Diving and Myalgias A 48-year old woman completed a dive to 95 feet for 25 minutes on 32 percent nitrox. Approximately 10 hours after surfacing she began to experience widespread but intense muscle pain. She could not find a comfortable position and nothing seemed to offer relief. She called EMS, and was transported to the local hospital. The ER physician found that she had begun a statin medication 3 weeks earlier… While muscle pain is a rare side-effect of statins, blood test results suggested pain most likely due to medication. However, hyperbaric physician consulted did not want to dismiss possibility of DCS and treated the diver in the chamber. Hyperbaric treatment had no effect on her symptoms which confirmed that muscle pain was probably due to medication.

Common Symptoms of DCS (Decompression Sickness) Headache Lightheadedness and/or dizziness Nausea Joint and/or muscle aches Fatigue, lethargy and/or generalized weakness Side effects of some medications can mimic DCS. Wise to recommend waiting for 30 days after starting new prescription med. before diving. DCS – challenging diagnosis – no tests to confirm or rule out. Thorough medical history including meds., inquire physical stresses associated with diving and travel (carry heavy equipment, uncomfortable travel accommodations, swimming against current) – when diving is involved, consider hyperbaric chamber treatment to be on the safe side.