Objectives. Having completed the learning activities, the participant will be able to: Dyslipidemia: The latest treatment recommendations

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1 Objectives Dyslipidemia: The latest treatment recommendations Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC President, Fitzgerald Health Education Associates, Inc. North Andover, MA Family Nurse Practitioner, Greater Lawrence (MA) Family Health Center Editorial Board, The Nurse Practitioner Journal, Medscape Nursing, The Prescriber s Letter, American Nurse Today Member, Pharmacy and Therapeutics Committee Neighborhood Health Plan, Boston, MA 1 Having completed the learning activities, the participant will be able to: Identify the most current recommendations for dyslipidemia therapy. Describe the process of arriving at a lipid lowering goal for a given patient. Discuss the role of non LDL treatment goals in contemporary dyslipidemia therapy. 2 Objectives Having completed the learning activities, the participant will be able to: (cont.) Discuss select considerations in prescribing lipid-lowering therapies. Dyslipidemia Treatment Recommendations Stone NJ, Robinson J, Lichtenstein AH, et al. ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol Available at ATP3 vs. ACC/AHA Guidelines Moderate- or high-intensity statin therapy Individuals who fall into 4 categories No specific LDL cholesterol goals Rather degree of LDL cholesterol reduction with statin therapy Measure lipids during follow-ups Not to assess achievement of given LDL goal but rather adherence to therapy Comparing the Guideline: How many adults are eligible for treatment? ATP-3=48.5 million adults ACC/AHA=56.7 million adults 5 6 1

2 ACC/AHA Dyslipidemia Guidelines High- and moderateintensity statin treatment emphasized Low-intensity statin therapy nearly eliminated ACC/AHA Dyslipidemia Guidelines Atherosclerotic cardiovascular disease (ASCVD) broadly defined Includes stroke, coronary heart disease and peripheral arterial disease 7 8 ACC/AHA Dyslipidemia Guidelines Nonstatin therapies deemphasized No guidelines provided for treating high triglyceride levels This program will cite separate recommendations on this issue later in program. Individuals From Four Major Statin Benefit Groups 1. Established ASCVD 2. Pretreatment LDL>190 mg/dl (4.9 mmol/l) 9 10 Individuals From Four Major Statin Benefit Groups 3. T1DM or T2DM, age years with LDL mg/dl ( mmol/l) and without clinical ASCVD 4. Without clinical ASCVD or DM but with LDL mg/dl ( mmol/l) and calculated estimated 10-year ASCVD risk=>7.5% Potential Limitations of ACC/AHA Guidelines Potential for overtreatment, particularly in elder Potential for undertreatment, particularly in elevated LDL-C whose 10-year ASCVD risk is less than 7.5% because of younger age

3 Potential Limitations of ACC/AHA Guidelines Does not address patients younger than age 40 or older than 75 years Family history of ASCVD, triglyceride levels not considered 13 AHA/ACC Disclaimer The results and recommendations provided by this application are intended to inform but do not replace clinical judgment. Therapeutic options should be individualized and determined after discussion between the patient and their care provider. 14 CVD Risk Estimator Calculator from ACC/AHA Guidelines Available at 15 Specific LDL C and/or Non-HDL C Treatment Goals The Expert Panel was unable to find RCT evidence to support continued use of specific LDL C and/or non- HDL C treatment targets. The appropriate intensity of statin therapy should be used to reduce ASCVD risk in those most likely to benefit. Specific LDL C and/or Non-HDL C Treatment Goals Nonstatin therapies do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. 3

4 Safety Recommendations This guideline used RCTs to identify important safety considerations in individuals receiving treatment of blood cholesterol to reduce ASCVD risk. Using RCTs to determine statin adverse effects facilitates understanding of the net benefit from statin therapy. HMG CoA Reductase Inhibitors: The Statins Simvastatin (Zocor ), atorvastatin (Lipitor ), pravastatin (Pravachol ), pitavastatin (Livalo ), others 20 Mechanism of Action HMG-CoA Reductase Inhibitor: The Statins Inhibitor of HMG-CoA reductase Enzyme responsible for conversion of HMG-CoA to mevalonate, and decreases hepatic biosynthesis of cholesterol As a result Hepatocytes compensate by increasing the number of LDL surface receptors to increase LDL reuptake from the circulation. End result is reduction of HMG CoA Reductase Inhibitor Check hepatic enzymes prior to initiation to establish baseline. No further routine hepatic enzyme monitoring warranted during statin use. Serious liver injury due to statins is usually idiosyncratic and not prevented with routine monitoring. serum LDL concentration HMG CoA Reductase Inhibitor T2DM risk is slightly increased with statin use, particularly with more potent statin in higher dose. Cardiovascular benefit outweighs small risk. Cognitive impairment while on statin rarely reported. If occurs, consider lowering dose or try another statin. Clinical Scenarios

5 59-year-old Woman of European Ancestry with HTN and T2DM Total cholesterol: 185 mg/dl (4.8 mmol/l) HDL cholesterol: 35 mg/dl (0.9 mmol/l) Systolic blood pressure: 139 mm Hg Smoker: No 10-year ASCVD risk=11.5% 25 Fitzgerald Health Education Associates, Inc. 26 High-intensity statin therapy examples LDL-C reduction approx. 50% Daily dose Atorvastatin (40 )-80 mg Rosuvastatin mg Moderate-intensity statin therapy examples LDL-C reduction approx % Daily dose Atorvastatin mg Rosuvastatin 5-10 mg Simvastatin mg Pravastatin mg Lovastatin 40 mg Fitzgerald Health Education Associates, Inc. Low-intensity statin therapy examples LDL-C reduction approx. <30% Daily dose Pravastatin mg Lovastatin 20 mg *Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. Biologic basis for a less-than-average response possible. Evidence from 1 RCT only: Down-titration if unable to tolerate atorvastatin 80 mg in IDEAL (Incremental decrease through Aggressive Lipid Lowering study) year-old Woman with HTN and DM of Other Ancestry 10-year ASCVD risk=11.5% Unchanged from white designation Might underestimate risk for persons from some race/ethnic groups, Native American, south Asian ancestry, and some Latinos (Puerto Ricans), and might overestimate risk for others, including east Asian ancestry and Mexican Americans year-old Man of European Ancestry with HTN, T2DM Race: White/other Total cholesterol: 220 mg/dl (5.7 mmol/l) HDL cholesterol: 51 mg/dl (1.3 mmol/l) Systolic blood pressure: 122 mm Hg Smoker: Yes 10-year ASCVD risk=31.8% 29 Fitzgerald Health Education Associates, Inc. 30 5

6 68-year-old African American Man, no DM, nonsmoker Total cholesterol: 180 mg/dl (4.7 mmol/l) HDL cholesterol: 28 mg/dl (0.7 mmol/l) SBP: 148 mm Hg Hypertension treatment: No 10-year ASCVD risk=16.1% High intensity statin therapy recommended With a 68-year-old African American Man Add smoking 16.1% risk becomes 26.2% risk Take away smoking, add DM 16.1% becomes 28.4% risk Add smoking and DM 16.1% becomes 43.9% risk year-old white woman with HTN, no DM, non smoker Total cholesterol: 230 mg/dl (6 mmol/l) HDL: 55 mg/dl (1.4 mmol/l) SBP: 146 mm Hg, on meds Calculated 10 yr risk of ASCVD: 4% 33 Fitzgerald Health Education Associates, Inc. 34 Additional Factors Considered in Dyslipidemia Therapy Moderate intensity statin therapy advised In individuals for whom after quantitative risk assessment a riskbased treatment decision is uncertain, additional factors may be considered to inform treatment decision making. Additional Factors Considered in Dyslipidemia Therapy LDL-C 160 mg/dl (4.1 mmol/l) Evidence of genetic hyperlipidemias Family history of premature ASCVD Onset <55 years of age in a first degree male relative or <65 years of age in a first degree female relative

7 Additional Factors Considered in Dyslipidemia Therapy hs-c-reactive protein 2 mg/l CAC score 300 Agatston units or 75 th %tile for age, sex, ethnicity CAC=Coronary Artery Calcium Ankle-brachial index<0.9 Elevated lifetime risk of ASCVD Male, GFR=84 ml/min/1.73 m2, BMI=27 kg/m2 Two 73-year-olds with Established ASCVD Female, GFR=48 ml/min/1.73 m2, BMI=22 kg/m Individuals at Risk for Statin Adverse Effects Multiple or serious comorbidities, including impaired renal or hepatic function History of previous statin intolerance or muscle disorders History of hemorrhagic stroke Fitzgerald Health Education Associates, Inc Individuals at Risk for Statin Adverse Effects Unexplained ALT elevations>3 times ULN >75 years of age Asian ancestry Drug Comparative Efficiency and Pharmacology of the Statins Reduction in LDL-C (%) Increase in HDL-C (%) Reduction Reduction in TG (%) in TC (%) T ½ (h) Metabolism Hydrophilic Atorvastatin CYP3A No Lovastatin CYP3A4 2 4 No Simvastatin CYP3A4 1 3 No Rosuvastatin CYP2C9 19 Yes Pravastatin No CYP 2 3 Yes

8 Definitions National Lipid Association (NLA) Myopathy=Symptoms of myalgia in addition to an elevation in serum creatine kinase (CK) greater than 10 times the upper limit of normal (CK >10 ULN) Also known as myositis Statin-induced Myopathy Risk >50% FDA Reported=Drug-drug Interaction Risk Statins alone Usually in higher doses in advancing age (>75 years), particularly with renal impairment Select statins and interacting medications All due to CYP450 3A4 inhibition Lova-, simva-, atorvastatin=cyp450 3A4 substrates Cyclosporine Select oral antifungals Itraconazole, ketoconazole Statin-induced Myopathy Risk >50% FDA Reported=Drug-drug Interaction Risk Select statins w interacting medications Macrolides Erythromycin, clarithromycin but not azithromycin Select HIV protease inhibitors Select calcium channel blockers Amiodarone Grapefruit juice ingestion Simvastatin: When Compared to Ingestion with Water as Control With grapefruit juice C max and AUC increased 12.0-fold (P<0.001) and 13.5-fold (P<0.001) 24 hours after last grapefruit juice C max and AUC increased 2.4-fold (P<0.01) and 2.1-fold (P<0.001) 7 days after last grapefruit juice dose No change Source: CYP450 Substrates CYP450 3A4 Atorvastatin Lovastatin Simvastatin CYP450 2C9 Pitavastatin Rosuvastatin Not metabolized by CYP450 Pravastatin Recommendations for Managing Common Difficulties During Statin Therapy Per ACC/AHA Dyslipidemia Guidelines

9 Statin Therapy During Mild to Moderate Muscle Symptoms Mild to moderate muscle symptoms develop during statin therapy In absence of clinically significant increase in serum creatine kinase Discontinue statin until the symptoms can be evaluated. Statin Therapy with Mild to Moderate Muscle Symptoms Evaluate for other conditions that increase the risk for muscle symptoms. Hypothyroidism Reduced renal or hepatic function Rheumatologic disorders such as polymyalgia rheumatica, steroid myopathy Vitamin D deficiency Primary muscle diseases Statin Therapy with Mild to Moderate Muscle Symptoms If muscle symptoms resolve off statin and no contraindication Start lower dose of same statin. Monitor for return of symptoms. Statin Therapy with Mild to Moderate Muscle Symptoms If symptoms return Discontinue current statin. Start low dose of another statin. Titrate up dose slowly to goal, monitoring for symptom recurrence Statin Therapy with Mild to Moderate Muscle Symptoms Persistent symptoms for =>2 months post discontinuation of statin therapy Myalgia and/or elevated CK levels Consider cause other than statininduced myopathy. Therapeutic Options in Statin Intolerance in the Absence of Myopathy/ Myositis An Update on Statin Alternatives and Adjuncts, Matthew J Sorrentino, Clin Lipidology. 2012;7(6):

10 Options in Statin-Intolerance Consider following options Every-other-day statin therapy Anecdotal evidence of helpfulness Aim for weekly total dose vs. getting some rather than no statin on board? Favors longer T½ statins Atorvastatin, rosuvastatin Options in Statin-Intolerance Most commonly reported Myalgia without CK rise Use of more hydrophilic/ less lipophilic statin Rosuvastatin, pravastatin most hydrophilic Simvastatin, lovastatin most lipophilic Health Education Associates, Inc Statins in liver disease? Contraindications to statin use Cholestasis, active liver disease Not been shown to worsen outcomes Chronic hepatitis B or C w/ enz elevation No specific evidence that statin use exacerbates liver disease Source: Detail-Document, Prescriber's Letter; 9(9):180924, available at Effects of Selected Drugs on Triglyceride and Cholesterol Levels Drug Triglyceride LDL Cholesterol HDL Cholesterol Alcohol Increased No effect Increased Estrogens, Increased Decreased Increased estradiol Androgens, Increased Increased Decreased testosterone Progestins Decreased Increased Decreased Alcohol, estrogens, estradiol, glucocorticoids, thiazide diuretics, beta-blockers, sertraline protease inhibitors, valproate and related drugs, and isotretinoin can cause severe hypertriglyceridemia and the chylomicronemia syndrome in patients with a familial form of hypertriglyceridemia. LDL denotes lowdensity lipoprotein, and HDL high-density lipoprotein. 57 Source: Brunzell JD. N Engl J Med 2007;357: Effects of Selected Drugs on Triglyceride and Cholesterol Levels Drug Triglyceride LDL Cholesterol HDL Cholesterol Glucocorticoids Increased No effect Increased Cyclosporines Increased Increased Increased Tacrolimus Increased Increased Increased Thiazide diuretics Increased Increased Decreased Beta-blockers Increased No effect Decreased Sertraline Possible increase Increased No effect Alcohol, estrogens, estradiol, glucocorticoids, thiazide diuretics, beta-blockers, sertraline protease inhibitors, valproate and related drugs, and isotretinoin can cause severe hypertriglyceridemia and the chylomicronemia syndrome in patients with a familial form of hypertriglyceridemia. LDL denotes low-density lipoprotein, and HDL high-density lipoprotein. Source: Brunzell JD. N Engl J Med 2007;357: Effects of Selected Drugs on Triglyceride and Cholesterol Levels Drug Triglyceride LDL Cholesterol HDL Cholesterol Protease Increased No effect No effect inhibitors Valproate and Increased No effect Decreased related drugs Isotretinoin Increased No effect Decreased Alcohol, estrogens, estradiol, glucocorticoids, thiazide diuretics, beta-blockers, sertraline protease inhibitors, valproate and related drugs, and isotretinoin can cause severe hypertriglyceridemia and the chylomicronemia syndrome in patients with a familial form of hypertriglyceridemia. LDL denotes lowdensity lipoprotein, and HDL high-density lipoprotein. Source: Brunzell JD. N Engl J Med 2007;357:

11 Niacin: AIM-HIGH The AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated lowdensity lipoprotein cholesterol rationale and study design. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: Impact on Global Health outcomes (AIM-HIGH). Am Heart J 2011; 161: PL Detail-Document, Niacin: Who needs it? Pharmacist s Letter/Prescriber s Letter. February The AIM-HIGH study goal To determine if a niacin/statin combination could further reduce the risk of cardiovascular events in patients with cardiovascular disease and wellcontrolled LDL but low HDL and high triglycerides vs a statin alone 62 AIM-HIGH Primary outcome measure Time from randomization to first CHD death, nonfatal MI, ischemic stroke, acute coronary syndrome hospitalization, or symptoms requiring coronary or cerebral revascularization (exclusive of revascularization of restenosis) AIM-HIGH Interim analysis Demonstrated lack of benefit of simva/niacin vs simva alone Small increase in ischemic stroke in the combination group (1.6% vs 0.7%) 1/3 of individuals in stroke group had DC niacin=>2 mo prior to stroke. 9 of the 28 stroke patients in the combination group had stopped taking niacin 2 months to 4 years prior to stroke What to make of AIM-HIGH results? Coronary Drug Project study Pre-statin study where most of niacin s advantage was seen AIM-HIGH Subjects with LDL well-controlled on and HPS2-THRIVE studies had well-controlled What to make of AIM-HIGH results? Statin non-ldl benefits Decreased inflammation Inability to lower CV risk further Beyond known reduction from statins HDL often have to be very low to get a benefit from niacin

12 Future Updates to the Blood Cholesterol Guideline This is a comprehensive guideline for the evidence-based treatment of blood cholesterol to reduce ASCVD risk. Future updates will build on this foundation to provide expert guidance on the management of complex lipid disorders and incorporate refinements in risk stratification based on critical review of emerging data. End of Presentation Thank you for your time and attention. Margaret A. Fitzgerald, DNP, FNP-BC, NP-C, FAANP, CSP, FAAN, DCC cs@fhea.com 68 References John F. Keaney, Jr., M.D., Gregory D. Curfman, M.D., And John A. Jarcho, M.D. A Pragmatic View Of The New Cholesterol Treatment Guidelines. N Engl J Med 2014; 370: References Stone Nj, Robinson J, Lichtenstein Ah, Bairey Merz Cn, Lioyd-jones Dm, Blum Cb, Mcbride P, eckel Rh, Schwartz Js, Goldberg Ac, Shero St, Gordon D, Smith Sc Jr, Levy D, Watson K, Wilson Pw ACC/AHA Guideline On The Treatment Of Blood Cholesterol To Reduce Atherosclerotic Cardiovascular Risk In Adults: A Report Of The American College Of Cardiology/American Heart Association Task Force On Practice Guidelines. J Am Coll Cardiol Nov 7. Pii: S All websites listed active at the time of publication

13 Fitzgerald Health Education Associates, Inc