Reducing LDL-C with Non- Statin Therapies

Reducing LDL-C with Non- Statin Therapies Michael Miller, MD, FACC, FAHA, FNLA University of Maryland School of Medicine Baltimore, Maryland www.drmichaelmiller.org

Disclosures SPIRE (Pfizer): U.S. National Coordinator REDUCE IT (Amarin): Steering Committee DalGene (Dalcor): U.S. National Coordinator 2

Stone NJ et al. Circulation. 2014;129:S1-45.

Non-Statin Agents with Efficacy in Reducing LDL-C Levels Drug Class Bile Acid Sequestrants (BAS) Cholesterol absorption inhibitors Fibric acids Examples of Agents Colestipol, Colesevelam, Cholestyramine Ezetimibe Fenofibric Acid* Microsomal Tg transfer protein inh Lomitapide + Nicotinic Acid Niacin* Oligonucleotide inh apo B-100 syn Mipomersen + PCSK9 Inhibitors Alirocumab, Evolocumab *In April 2016, the FDA withdrew approval of fenofibric acid delayed-release capsules and Niacin extended-release tables in combination with statins due to lack of evidence that coadministration Further reduced CV risk. +FDA-approved as an adjunct to lipid-lowering treatments and diet for people with HoFH. 4

2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-C Lowering in the Management of ASCVD Risk Assumptions and Definitions Thresholds for consideration of net benefit Maximally-tolerated statin therapy Achievement of 50% LDL-C reduction on highintensity statin, or 30% to <50% reduction for moderate-intensity statin May consider absolute LDL-C levels (or non-hdl-c in patients with DM) as factors in treatment decisions ( LDL-C or non-hdl-c treatment thresholds ) Writing Committee emphasizes that these are not firm triggers for adding medication but factors that may be considered within the broader context of an individual patient s clinical situation Lloyd-Jones D et al. J Am Coll Cardiol. 2016;68:92-125.

2016 ACC Expert Consensus Decision Pathway: Patient with Stable Clinical ASCVD without Comorbidities (one of several settings for potential use of non-statin therapies for additional LDL-C lowering) Treat with maximal tolerated statin Achieve at least 50% LDL-C reduction If this reduction is not achieved, initiate patient clinician discussion and consider non-statins: LDL-C treatment threshold 100 mg/dl Try ezetimibe first; consider BAS if TG <300 mg/dl PCSK9 inhibitor next If treatment objective achieved, follow lipids If not, reassess medication adherence and lifestyle Lloyd-Jones D et al. J Am Coll Cardiol. 2016;68:92-125.

Ezetimibe Lipid / lipoprotein effects LDL-C: Decrease 13-20% Non-HDL-C: Decrease 14-19% HDL-C: Increase 3-5% TG: Decrease 5-11% Jacobson T. 20147 J Clin Lipidol. 8:473-88.

Mean LDL-C (mg/dl) IMPROVE IT Trial: Effect on LDL-C Ezetimibe (EZ) + Simvastatin vs Simvastatin Alone 100 90 80 70 60 50 40 1 yr mean LDL-C TC TG HDL-C hs-crp Simvastatin 69.9 145.1 137.1 48.1 3.8 EZ/Simvastatin 53.2 125.8 120.4 48.7 3.3 Δ in mg/dl -16.7-19.3-16.7 +0.6-0.5 Simvastatin Time since randomization (months) EZ/Simvastatin QE R 1 4 8 12 16 24 36 48 60 72 84 96 Median Time avg 69.5 vs 53.7 mg/dl Cannon CP et al. Am Heart J. 2008;156:826-832. 8 Study drug is administered once daily in the evening.

Primary Endpoint Event Rate (%) IMPROVE IT Trial Ezetimibe + Simvastatin vs Simvastatin Alone Primary Endpoint: death from cardiovascular disease, a major coronary event, or nonfatal stroke 40 30 HR 0.936 CI (0.887, 0.988) P=0.016 Simvastatin 34.7% 2742 events NNT = 50 20 10 Ezetimibe/Simvastatin 32.7% 2572 events 7-year event rates 0 0 1 2 3 4 5 6 Time Since Randomization (years) 7 Cannon CP et al. N Engl J Med. 2015;371:2387-2397.

ARS Question? Major statin trials have consistently shown a direct relationship between LDL-C reduction and reduced rates of adverse clinical events. Reducing LDL-C by approximately 40% generally reduces risk of adverse events by about: 1.1) 5% 2.2) 10% 3.3) 15% 4.4) 20% 5.5) 25%

Reduction in Rate of Major Vascular Events (%) IMPROVE-IT: Ezetimibe vs Statin Benefit Change in LDL-C vs Clinical Benefit 0.5 (19.3) 1.0 (38.6) 1.5 (57.9) Reduction in LDL Cholesterol: mmol/l (mg/dl) 2.0 (77.2) Cannon CP et al. CTT Collaboration. Lancet. 2005;366:1267-1278. CCT Collaboration. Lancet. 2010;376:1670-1681. Cannon CP et al. N Engl J Med. 2015;372:2387-2397.

Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) Secreted serine protease Chaperones LDL-R to destruction circulating LDL-C PCSK9 inhibitor Gain of function mutation: Higher LDL-C Loss of function mutation: Lower LDL-C Lambert et al. Atherosclerosis. 2009; 203: 1-7 Soutar AK. Curr Op 12 Lipidol. 2011;22:192-96

FDA-Approved PCSK9 Inhibitors (fully human monoclonal antibodies) Alirocumab: Indicated as adjunct to diet and 1) maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD), who require additional lowering of LDL- C. Dose: Initiate 75 mg SQ every 2 weeks (The majority of patients achieve sufficient LDL-C redution with this dosage.) If LDL-C response is inadequate may be increased to 150 mg every 2 weeks. Evolocumab: Indicated as as an adjunct to diet and: 1) Maximally tolerated statin therapy for treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C 2) Other LDL-C-loweing therapies (e.g., statins, ezetimibe, LDL apheresis) in patients with homozygous familial hypercholesterolemia (HoFH) who require additional lowering of LDL-C Dose: ASCVD or HeFH:; 140 mg every 2 weeks or 420 mg once monthly. For HoFH: 420 hg once monthly Note: The 420 mg dose can be administered: 1) over 9 minutes by using the single-use on-body infusor with prefilled cartridge, or 2) by SQ

PCSK9 Inhibitors and Lipid / Lipoprotein Effects LDL-C is reduced about 50-60% with alirocumab or evolocumab Same % reduction in LDL-C is seen with appropriate dosing when added to diet alone, low and maximal dose statin or statin plus ezetimibe Patients with HeFH and nonfh respond the same HoFH patients respond about half as well, with mean reductions in LDL-C of 31% to evolocumab Other blood lipids: Decreases in Lp(a), Apo B, Non-HDL-C, Total cholesterol, triglycerides. Increase in HDL-C.

Safety Data from Studies Prior to FOURIER (ODYSSEY LONG TERM and OSLER 1/2) Alirocumab: Nasopharyngitis, injection site reactions, influenza Evolocumab: Nasopharyngitis, URI, influenza, back pain, and injection site reactions Self-reported neuro-cognitive AE * Alirocumab vs placebo: 1.2% vs 0.5% (Odyssey Long- Term) Evolocumab vs placebo: 0.9% vs 0.3% (OSLER 1/2) *Deliria, confusion; cognitive and attention disorders and disturbances; dementia and amnestic conditions; disturbances in thinking and perception; mental impairment disorders No diabetes signal in short-term trials. Robinson et al, NEJM 2015; Sabatine et al, NEJM, 2015; Lipinski et al, EHJ 2015; Colhoun et al. EHJ 2016

GLAGOV Trial Question: Does treatment with a PCSK9 inhibitor modify coronary atherosclerosis disease progression? Trial Summary: 968 patients with coronary disease treated with statins. Treated with evolocumab or placebo monthly for 76 wks and underwent IVUS determination of coronary atheroma volume. LDL-C levels reduced significantly in evolocumab group from 93 to 36 mg/dl vs from no change in placebo group. Significant reduction in percent atheroma volume with evolocumab vs placebo Significantly greater percentage of patients demonstated plaque regression Conclusion: Addition of PCSK9 inhibitor evolocumab to statin therapy produced greater LDL-C lowering and atheroma regression. Nicholls S et al. JAMA. 2016;316:2373-84.

PCSK9 Inhibitors Cardiovascular Outcomes Trials Alirocumab Evolocumab Bococizumab Sponsor Sanofi/Regeneron Amgen Pfizer Trial ODYSSEY Outcomes FOURIER SPIRE I & 2 Sample Size 18,000 28,000 27,000 Patients 4-16 weeks post-acs MI, stroke, or PAD High risk of CV event Statin Evidence-based Rx Atorvastatin 20 mg or equivalent Lipid-lowering Rx LDL-C 70 mg/dl 70 mg/dl 70-99, >100 mg/dl Dosing (sc) Every 2 weeks Every 2 or Every 4 weeks Every 2 weeks Endpoint CHD death, MI, ischemic stroke, or UA hospitalization Primary: CV death, MI, stroke, UA hospitalization or coronary revascularization Key Secondary: CV death, MI, or stroke CV death, MI, stroke, or urgent revascularization Completion February 2018 November 2016 Discontinued 11/2016 Available at: Clinicaltrials.gov.

FOURIER Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk MS Sabatine, RP Giugliano, AC Keech, N Honarpour, SM Wasserman, PS Sever, and TR Pedersen, for the FOURIER Steering Committee & Investigators American College of Cardiology 66 th Annual Scientific Session Late-Breaking Clinical Trial March 17, 2017 An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

Trial Design 27,564 high-risk, stable patients with established CV disease (prior MI, prior stroke, or symptomatic PAD) Screening, Lipid Stabilization, and Placebo Run-in High or moderate intensity statin therapy (± ezetimibe) LDL-C 70 mg/dl or non-hdl-c 100 mg/dl Evolocumab SC 140 mg Q2W or 420 mg QM RANDOMIZED DOUBLE BLIND Placebo SC Q2W or QM Follow-up Q 12 weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Sabatine MS et al. Am Heart J 2016;173:94-101

Baseline Characteristics Characteristic Value Age, years, mean (SD) 63 (9) Male sex (%) 75 Type of cardiovascular disease (%) Myocardial infarction 81 Stroke (non-hemorrhagic) 19 Symptomatic PAD 13 Cardiovascular risk factor (%) Hypertension 80 Diabetes mellitus 37 Current cigarette use 28 Median time from most recent event ~3 yrs An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Pooled data; no differences between treatment arms

Lipid Lowering Therapy & Lipid Levels at Baseline Characteristic Statin use (%)* Value High-intensity 69 Moderate-intensity 30 Ezetimibe use (%) 5 Median lipid measures (IQR) mg/dl LDL-C 92 (80-109) Total cholesterol 168 (151-189) HDL-C 44 (37-53) Triglycerides 133 (100-182) *Per protocol, patients were to be on atorva 20 mg/d or equivalent. 1% were on low intensity or intensity data were missing. Statin intensity defined per ACC/AHA 2013 Cholesterol Guidelines. An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School Pooled data; no differences between treatment arms

LDL Cholesterol (mg/dl) LDL Cholesterol 100 90 Placebo 80 70 60 50 40 30 20 10 59% mean reduction (95%CI 58-60), P<0.00001 Absolute reduction: 56 mg/dl (95%CI 55-57) Evolocumab (median 30 mg/dl, IQR 19-46 mg/dl) 0 0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 Weeks An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

CV Death, MI, Stroke, Hosp for UA, or Cor Revasc Primary Endpoint 16% 14% 12% Hazard ratio 0.85 14.6% (95% CI, 0.79-0.92) P<0.0001 Placebo 12.6% 10% 8% 6% Evolocumab 4% 2% 0% 0 6 12 18 24 30 36 Months from Randomization An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

CV Death, MI, Stroke Landmark Analysis 8% 16% RRR 8% 25% RRR 6% HR 0.84 (95%CI 0.74-0.96) P=0.008 6% HR 0.75 (95%CI 0.66-0.85) P<0.00001 4% 4% Placebo 2% 2% Evolocumab 0% An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School 0% 0 3 6 9 12 12 18 24 30 36 Months from Randomization

Safety Evolocumab (N=13,769) Placebo (N=13,756) Adverse events (%) Any 77.4 77.4 Serious 24.8 24.7 Allergic reaction 3.1 2.9 Injection-site reaction 2.1 1.6 Treatment-related and led to d/c of study drug 1.6 1.5 Muscle-related 5.0 4.8 Cataract 1.7 1.8 Diabetes (new-onset) 8.1 7.7 Neurocognitive 1.6 1.5 Laboratory results (%) Binding Ab 0.3 n/a Neutralizing Ab none n/a New-onset diabetes assessed in patients without diabetes at baseline; adjudicated by CEC An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

Summary for Evolocumab LDL-C by 59% Consistent throughout duration of trial Median achieved LDL-C of 30 mg/dl (IQR 19-46 mg/dl) CV outcomes in patients already on statin therapy 15% broad primary endpoint; 20% CV death, MI, or stroke Consistent benefit, incl. in those on high-intensity statin, low LDL-C 25% reduction in CV death, MI, or stroke after 1 st year Long-term benefits consistent w/ statins per mmol/l LDL-C Safe and well-tolerated Similar rates of AEs, incl DM & neurocog events w/ EvoMab & pbo Rates of EvoMab discontinuation low and no greater than pbo No neutralizing antibodies developed An Academic Research Organization of Brigham and Women s Hospital and Harvard Medical School

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Confidential

Available online NEJM March 17, 2017

Percent Reduction in LDLC The SPIRE Bococizumab Lipid Lowering Trials: Unanticipated Attenuation of LDL-C Reductions at 52 weeks 55.2 % reduction in LDLC at 12 weeks 42.5 % reduction in LDLC at 52 weeks 12 weeks, 150 mg 12 weeks, 75 mg 52 weeks, 150 mg 26 weeks, 150 mg Ridker ACC 2017

Cumulative proportion with MACE + UARUR 0.00 0.02 0.04 0.06 0.08 The SPIRE-2 Cardiovascular Outcomes Trial: Baseline LDL-C > 100 mg/dl Primary Pre-Specified Endpoint* Placebo: 224 events Bococizumab 150 mg: 179 events (referent) HR 0.79 95%CI 0.65-0.97 P = 0.021 Baseline LDLC 133 mg/dl Placebo Event Rate 4.19 / 100-person years Median follow-up 12 months 0 13 26 39 52 65 78 91 104 117 130 143 5309 5312 5211 5213 5096 5123 4173 4209 2285 2307 1143 1173 Weeks 403 421 209 211 113 117 48 46 13 13 4 2 *Nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death Ridker ACC 2017

Percent Change in LDLC The SPIRE Bococizumab Lipid Lowering Trials : Wide Individual Variation in Percent Change in LDLC at 52 Weeks with Bococizumab, Even Among Those Who Are Antidrug Antibody Negative* 100 80 60 40 20 0-20 9% 31% 60% 52 weeks ADA negative (N=780) -40-60 -80-100 No reduction Reduction<50% Reduction 50% * Analysis excludes non-compliant participants Ridker ACC 2017

Conclusions (1) Selection of Non-Statin Therapies: clinician-patient discussion (shared decision-making) is important CV outcome benefit with ezetimibe in addition to statin therapy (IMPROVE-IT) PCSK9 inhibitors have been evaluated in: Patients with FH Patients with high ASCVD risk and not at desirable LDL-C with maximally tolerated statin Patients intolerant to statin therapy

Conclusions (2) FOURIER / EBBINGHAUS: In pts with known CV disease: PCSK9 inhibition with evolocumab significantly & safely major CV events when added to statin therapy Benefit was achieved with lowering LDL-C well below current targets Are all agents in this class the same? No Discontinuation of bococizimab; awaiting CV outcome results with alirocumab in ODYSSEY OUTCOMES For LDL-Lowering, lower is better (lower than traditional goals)

In your patients with clinical ASCVD who require additional lowering of LDL- C and are on maximally tolerated statin therapy, how often WILL YOU NOW recommend adding a non-statin agent such as ezetimibe or a PCSK9 inhibitor?? 1.1) 100% of the time 2.2) 75% of the time 3.3) 50% of the time 4.4) 25% of the time 5.5) Never

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Disclosures None related to this presentation UpToDate: Author and Advisory Board 2

Objectives Discuss recommendations for the use of statin therapy in cholesterol guidelines. Recognize and describe patient populations who may benefit from further reductions in LDL-C despite statin therapy. Explain best practices in diagnosis and treatment of patients with familial hypercholesterolemia and statin intolerance. Describe clinical profiles of key non-statin therapies. (and emerging clinical data from ACC including FOURIER and EBBINGHAUS) Identify recommendations for the use of non-statin therapies in the ACC Expert Consensus Decision Pathway. 3

Age-Adjusted Death Rates for 10 Leading Causes of Death: 2014, 2015 Heart disease deaths increased in 2015 for the first time since 1993. Xu J, et al. NCHS Data Brief No. 267. December 2016

Cardiovascular Disease Mortality Trends 1979-2014 Statins

Case Example: Mr. E.M. 75 years old PMHx CVA 1998 carotid artery disease with left ICA stent 1999 CAD with stent 2006 type 2 DM, HTN colon cancer with resection 2011 85-90% stenosis of right ICA Retired teamster Lives with wife and 2 dogs; wife has MS Rarely drinks ETOH; smokes 1-1.5 ppd since teenage years 6

Case continued Patient takes usual secondary prevention medications ASA 81 mg Atorvastatin 40 mg Valsartan, amlodipine, metoprolol Glipizide Lipid panel Total chol 131 mg/dl TG 132 mg/dl HDL 47 mg/dl LDL 48 mg/dl 7

ARS Question Mr. E.M. is treated according to the ACC/AHA Cholesterol Guideline for which of the following reasons? A. LDL-C is at < 100 mg/dl goal. B. LDL-C is at < 70 mg/dl goal. C. He takes a high intensity statin. D. His treatment and/or LDL-C goal is not in accordance with the ACC/AHA guideline.

Stone NJ et al., Circulation 2013, DOI: 10.1161/01.cir.0000437738.63853.7a 9

ACC/AHA 2013 Guideline: Paradigm Shift Goal is ASCVD risk reduction rather than targeting specific LDL-C levels Statin intensity matched to ASCVD risk level, with less dependence on LDL-C levels Groups most likely to benefit from statin therapy Patients with clinical ASCVD LDL-C 190 mg/dl Diabetics age 40-75 years with LDL-C 70-189 mg/dl and without clinical ASCVD Non-diabetics age 40-75 years with an estimated 10-year ASCVD risk of 7.5% Recommended statin intensity High intensity High intensity 7.5% 10-year ASCVD risk = high intensity <7.5% 10-year ASCVD risk = moderate intensity Moderate to high intensity if appropriate after clinician-patient discussion Finkel JB, Duffy D. Trends Cardiovasc Med. 2015;25(4):340-347. Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

Use of Statins Statins have an acceptable margin of safety when used in properly selected individuals and appropriately monitored. Statin therapy recommended for secondary and primary prevention of ASCVD Based on RCTs, statins reduce morbidity and mortality associated with ASCVD Cost-effective: most statins are now generic 11

From Cholesterol Treatment Trialists (CTT) Collaboration. Lancet. 2015;385(9976):1397-1405; with permission. Efficacy and Safety of LDL-Lowering Therapy Meta-analysis of Individual Data from 174,000 Participants in 27 Randomized Trials Every 2 mg/dl in LDL 1% in CHD deaths

Managing Insufficient Response Intensity of Statin Therapy Reasonable Expectation for Treatment Response High-intensity statin therapy Average LDL-C reduction of 50% from the untreated baseline Moderate-intensity statin therapy Average LDL-C reduction of 30% to <50% from the untreated baseline Non-statin cholesterol-lowering drug(s) may be considered if the ASCVD risk-reduction benefits outweigh the potential for AEs. High-risk individuals include: Clinical ASCVD in those <75 years of age Baseline LDL 190 mg/dl Age 40 to 70 years with diabetes mellitus Preference should be given to agents shown to reduce ASCVD events in RCTs RCTs = randomized controlled trials Stone NJ, et al. Circulation. 2014;129(25 Suppl 2):S1-45.

Jacobson TA et al., Journal of Clinical Lipidology 2014; doi:10.1016/j.jacl.2014.07.007

NLA Recommendations for Patient-Centered Management of Dyslipidemia Used evidence from more than randomized controlled trials for recommendations. Evidence that has accumulated since the 2004 update of the ATP III guidelines warrants a modest refinement of previous lipid-related risk management strategies. Importance of lifestyle therapies Jacobson TA et al., Journal of Clinical Lipidology 2014; doi:10.1016/j.jacl.2014.07.007 15

Risk Assessment and Treatment Goals for Atherogenic Cholesterol Jacobson TA et al., Journal of Clinical Lipidology 2014; doi:10.1016/j.jacl.2014.07.007

Case Example: K.C. 28 year old with FH 2014 total chol was 418 mg/dl; age 2 250 mg/dl Family history: Father: age 53, hypercholesterolemia, treated with atorvastatin 80 mg, ezetimibe 10 mg; total chol 200-250 mg/dl; otherwise healthy Paternal grandmother: CABG x 4, a second CABG years later Paternal uncle: died of MI at age 35 Paternal uncle: hypercholesterolemia Mother: no health problems Maternal grandmother: MI Patient s brother: normal cholesterol Patient is otherwise in good health; BMI 21.8 kg/m 2

Case Continued 2015 Lipid panel Total chol 455, HDL 55, TG 103, LDL > 350 mg/dl Left carotid bruit Ultrasound: no intimal thickness or plaque seen 2016 Lipid panel on atorvastatin 80 mg Total chol 187, HDL 44, TG 151, LDL 113 mg/dl Added ezetimibe 10 mg Total chol 202, HDL 46, TG 164, LDL 123 mg/dl

ARS Question If you were K.C. s provider, what should you do next? A. Change the statin. B. Assess adherence to lipid lowering therapies. C. Prescribe a PCSK9 inhibitor. D. Nothing the patient had an excellent response to lipid lowering therapies.

Familial Hypercholesterolemia Group of inherited genetic defects resulting in severely elevated cholesterol Prevalence HeFH: 1 in 300-500 HoFH: 1 in a million Mutations in LDLR, ApoB, PCSK9 genes ~1600 known mutations of the LDLR gene (85-90% of FH cases) LDL-C 190 mg/dl (adults), 160 mg/dl (children and adolescents) FHx of high cholesterol and premature CHD in first degree relatives Think about FH with: Tendon xanthomas Arcus corneae in patient < 45 years Tuberous xanthomas or xanthelasma in patient < 20-25 years Goldberg et al., J Clin Lipidol 2011;5:S1-S8.

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Case Example: D.S. 54-year-old female with CAD History includes hyperlipidemia, obesity, former smoker Family history of premature CAD (mother MI at age 55) Medications: Nebivolol 5 mg daily Furosemide 20 mg daily NTG 0.4 mg SL Rosuvastatin 2.5 mg twice a week Statin intolerance: pravastatin (mental cloudiness), atorvastatin (muscle aches), pitavastatin (muscle aches), rosuvastatin (muscle/joint pain) Lipid panel: Total cholesterol 187 mg/dl Triglycerides 87 mg/dl HDL-C 49 mg/dl LDL-C 121 mg/dl

Case continued Evolocumab 140 mg subcutaneously every 2 weeks 6-week lipid panel: Total cholesterol 140 mg/dl Triglycerides 85 mg/dl HDL-C 53 mg/dl LDL-C 70 mg/dl Mild nasopharyngitis; fatigue for 2 days after injection

ARS Question Your patient reports muscle pain in her upper arms 3 months after starting atorvastatin 40 mg. Which of the following is related to statin intolerance and should be checked? A. Low serum potassium B. Low vitamin D level C. Iron deficiency anemia D. Your patient must have injured herself. Statins don t cause muscle pain.

Statins and Muscle Symptoms Frequency of statin-associated muscle symptoms: 1-5% in randomized controlled trials 11-29% in observational cohorts Spectrum of statin-associated muscle adverse events: Myalgia: unexplained muscle discomfort often described as flulike symptoms with normal CK level Myopathy: muscle weakness (not attributed to pain or elevated CK) Myositis: muscle inflammation Myonecrosis: muscle enzyme elevations or elevated CK Myonecrosis with myoglobinuria or acute renal failure (clinical rhabdomyolysis) CK = creatinine kinase Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Statins and Adherence The most common non-genetic factor contributing to reduced statin response is poor medication adherence 40-70% of patients discontinue statin therapy one year after initiation The most common patient-reported reason for statin discontinuation or noncompliance is adverse effects >90% of statin-associated adverse events are musclerelated Fear of symptoms and adverse effects also contributes to non-adherence Banach M, et al. Int J Cardiol. 2016;225:184-196.

Statin Intolerance Definition: A clinical syndrome characterized by the inability to tolerate at least 2 statins Due to either objectionable symptoms (real or perceived) or abnormal lab determinations, which are temporally related to statin treatment Reversible upon discontinuation Reproducible by re-challenge Approximately 1 in 10 patients taking statins will report intolerance Novel non-statin agents may be appropriate in intolerant individuals Guyton JR, et al. J Clin Lipidol. 2014;8(3 Suppl):S72-S81. Jacobson TA, et al. J Clin Lipidol. 2015;9(6):S1-S122.

Approaches to Statin Intolerance Use a systematic approach to evaluate statin intolerance Careful history of symptoms Describe Timing Rule out other causes (hypothyroidism, vitamin D deficiency, recent exercise) Evaluate for drug-drug interactions Discontinue statin therapy and then rechallenge to verify recurrrence of muscle symptoms Rechallenge on at least 2-3 statins; use statins with different metabolic pathways and different lipophilicity 28

Managing Muscle Symptoms Switch to an alternate statin 92% of patients are able to tolerate a second statin after discontinuing their initial statin due to AEs 72.5% of patients who are intolerant to two statins due to myalgia can successfully tolerate a third statin Use an alternate dosing strategy Lower dose of the same statin Less-than-daily dosing Once-weekly dosing of a long-acting statin Switch to nonstatin lipid-lowering therapy in truly intolerant patients Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71.

Assess Adherence During Each Visit In the past 2 weeks, what percent of your cholesterol medicine would you say you have taken? (If less than 100%).. What is the main reason you might miss your medication? Discuss potential solutions with the patient.

Summary Statins are the class of medications with proven outcomes. If a patient is in a statin benefit group, several attempts should be made to find a medication regimen that is tolerated. High intensity statins are recommended for: Patients with clinical ASCVD Patients with LDL 190 mg/dl Patients with diabetes and a 10-year ASCVD risk 7.5% It s important to assess adherence in all patients but especially those who have a suboptimal response to statin therapy. Clinicians should thoroughly assess muscle symptoms in patients taking statins. Patients should be engaged in a discussion while initiating treatment and when making decisions about treatment options. 31