2/23/2018. Management of Hyperlipidemia Update on Guidelines and Novel Therapies. Burden of Heart Disease in U.S.

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1 Management of Hyperlipidemia Update on Guidelines and Novel Therapies SHARATH SUBRAMANIAN, MD, FACC February 24, 2018 Disclosures : None Burden of Heart Disease in U.S /db293_fig4.png 1

2 Evolution & Cholesterol Levels O Keefe JH et al. J Am Coll Cardiol. 2004;43: Evolution of Guidelines and Landmark Trials Expanded/Modified Treatment Recommendations NCEP ATP I 1988 NCEP ATP II 1993 NCEP ATP III 2001 NCEP ATP III Update 2004 ACC/AHA, IAS, NLA 2013/2014 ACC ECDP 2016 Framingham MRFIT LRC-CPPT Coronary Drug Project Helsinki Heart CLAS Angiographic Trials (FATS, POSCH, SCORE, STARTS, Ornish, MARS) Meta-analyses (Holmes Rossouw) 4S WOSCOPS CARE LIPID AFCAPS/ TexCAPS HPS PROVE-IT ASCOT-LLA PROSPER ALLHAT-LLT TNT IDEAL ACCORD JUPITER CTT Metaanalyses ENHANCE SHARP AURORA CORONA AIM HIGH HPS2-Thrive IMPROVE-IT AFCAPS/TEXCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; CARE, Cholesterol and Current Events study; 4S, Scandinavian Simvastatin Survival Study; HPS, Heart Protection Study; LIPID, Long Term Intervention With Pravastatin in Ischaemic Disease study; PROVE IT TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22; WOSCOPS, West of Scotland Coronary Prevention Study. 2

3 ACC/AHA 2013 Guideline: Change in Focus Switch from targeting specific LDL-C levels to actual ASCVD risk reduction. Statin intensity dose decided based on ASCVD risk level. Groups most likely to benefit from statin therapy Patients with clinical ASCVD LDL-C 190 mg/dl Diabetics age years with LDL-C mg/dl and without clinical ASCVD Non-diabetics age 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 ACC/AHA 2013 Guideline: Change in Focus Evidence-based fixed dose of statins recommended as first-line treatment in all patients with elevated ASCVD risk. Non-statins reserved for when statins are contraindicated or not tolerated. Pooled Cohort Risk Assessment Equation Replaced the Framingham Risk Score (FRS) Estimates ASCVD risk based on gender, age, race, HDL-C, total cholesterol, systolic BP, presence of DM and/or HTN, smoking status Ten year risk threshold for consideration of initiation of statin therapy lowered from 10% to 7.5%. ACC/AHA 2013 Guidelines: ASCVD Risk Calculator 3

4 ACC/AHA 2013 Guideline: ASCVD Risk Calculator ACC/AHA 2013 Change: Pros and Cons Updated recommendation Pro Con Targeting ASCVD risk vs LDL-C levels Emphasis on statin therapy and avoidance of non-statin agents in most patients Use of new risk calculator Lower risk calculator cut point for statin therapy initiation -Will avoid undertreatment of high-risk patients with already low levels of LDL - Simple to implement -Avoids adverse events (AEs) associated with polypharmacy -More current and applicable to African-American and Caucasian populations - Includes stroke in risk estimation - Identifies a subset of patients not previously identified that may benefit from statin therapy - May undertreat residual risk in patients with elevated LDL-C despite recommended statin intensity - May undertreat residual risk in patients with elevated LDL-C despite recommended statin intensity - May overestimate risk in some groups - The number of patients on statin therapy, especially based on age alone, may be excessive Statin Safety Recommendations Use moderate-intensity statin therapy in patients who are predisposed to statinassociated adverse reactions. Multiple or serious comorbidities, including impaired renal or hepatic function History of previous statin intolerance or muscle disorders Unexplained ALT elevations >3 times ULN Concomitant use of drugs affecting statin metabolism >75 years of age History of hemorrhagic stroke Asian ancestry CK should not be routinely measured, although it is reasonable to measure baseline CK in individuals at increased risk for adverse muscle events 4

5 Statins and Muscle Symptoms Frequency of statin-associated muscle symptoms 1% to 5% in randomized controlled trials 11% to 29% in observational cohorts Spectrum of statin-associated muscle adverse effects Myalgia: unexplained muscle discomfort often described as flu-like 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 ARF: Clinical rhabdomyolysis Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71. Statin Intolerance A clinical syndrome characterized by the inability to tolerate at least 2 statins. Manifests as 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. Non-statin agents may be appropriate in intolerant individuals. 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 2 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 Non-statin lipid-lowering therapy in truly intolerant patients Rosenson RS, et al. J Clin Lipidol. 2014;8(3 Suppl):S58-S71. 5

6 Statins - 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 riskreduction 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 DM PCSK9 PCSK9 (proprotein convertase subtilisin kexin 9) is a secreted enzymatic protein of the subtilisin family of serine proteases Primarily synthesized in the liver; also found in the intestines and kidneys. Interferes with removal of LDL particles from circulation. Binds with the LDL-R/LDL complex Complex is degraded by the lysosome degradation of the LDL-R LDL-R can t recycle to the cell membrane LDL clearance is decreased PCSK9 Individuals with loss-of-function PCSK9 gene mutations Have LDL-C levels that are 28% lower than those without the mutation Have an 88% relative decrease in risk for atherosclerotic CV events Gain of function PCSK9 gene mutations lead to increased levels of LDL-C Gain of function mutations are associated with FH and premature CVD 6

7 PCSK9 PCSK9 PCSK9 Inhibitor Inhibitor 7

8 PCSK9 Inhibitor PCSK9 Number of LDL Receptors LDL-C PCSK9 Number of LDL Receptors LDL-C PCSK9 Inhibitor Alirocumab, Evolocumab Alirocumab: ODYSSEY Long Term Trial Robinson JG, et al. N Engl J Med. 2015;372(16):

9 Alirocumab: ODYSSEY Long Term Trial Robinson JG, et al. N Engl J Med. 2015;372(16): Evolocumab: FOURIER Trial FOURIER: Further cardiovascular Outcomes Research with PCSK9 Inhibition in subjects with Elevated Risk Sabatine MS, et al. N Engl J Med 2017; 376: Evolocumab: FOURIER Trial FOURIER: Further cardiovascular Outcomes Research with PCSK9 Inhibition in subjects with Elevated Risk Sabatine MS, et al. N Engl J Med 2017; 376:

10 Evolocumab: FOURIER Trial FOURIER: Further cardiovascular Outcomes Research with PCSK9 Inhibition in subjects with Elevated Risk Sabatine MS, et al. N Engl J Med 2017; 376: Alirocumab Fully human IgG1 mab Indications: Heterozygous FH Clinical ASCVD Dose: mg SQ q 2 weeks LDL reduction: 50% to 60% PCSK9 Inhibitors Evolocumab Fully human IgG2 mab Indications: Homozygous/heterozygous FH Clinical ASCVD Dose: 140 mg SQ q 2 weeks or 420 mg SQ q month LDL reduction: 50% to 60% Alirocumab [injection] Prescribing Information, 2015; Evolocumab Prescribing Information, 2015; Dadu RT, Ballantyne CM. Nat Rev Cardiol. 2014;11(10): ; Gumbiner B, et al. Circulation. 2012;126:a13322; Half life:17-20 days PCSK9 Inhibitors Alirocumab T max to max serum concentration: 3-7 days Metabolism: Low doses: by binding to PCSK9 Higher doses: non-saturable proteolytic pathway Dose adjustment: If LDL not optimally lowered, increase to 150 mg No adjustment for liver or kidney dysfunction or P450 drugs Drug interactions: Statins (by ing SREBP2) Alirocumab [injection] Prescribing Information, 2015; Rallidis LS, Lekakis J. Hellenic J Cardiol. 2016;57(2):

11 PCSK9 Inhibitors Evolocumab Half life: days Tmax to max serum concentration: 3-4 days Metabolism: - Low doses: by binding to PCSK9 - Higher doses: non-saturable proteolytic pathway Dose adjustment: No adjustment for liver or kidney dysfunction or P450 drugs Drug interactions: Statins (by ing SREBP2) Evolocumab Prescribing Information, 2015; Rallidis LS, Lekakis J. Hellenic J Cardiol. 2016;57(2): Alirocumab Adverse Events Alirocumab Placebo Nasopharyngitis 11% 11% Influenza 6% 5% UTI 5% 5% Injection site reaction 7% 5% LFT >3x ULN 1.7% 1.4% Myalgias 4% 3% Drug discontinuation 0.4% 0.2% Neurocognitive 0.8% 0.7% Antidrug antibodies (ADAs) 5% 0.6% Neutralizing antibody (Nab) 1.2% (of which, in 0.3% led to decreased efficacy) 0 Alirocumab [injection] Prescribing Information, Evolocumab Adverse Events Evolocumab Placebo Nasopharyngitis 11% 10% Influenza 8% 6% UTI 5% 4% Injection site reaction 6% 5% Myalgias 4% 3% Drug discontinuation 2% 1% Neurocognitive 0.2% 0.2% Antidrug antibodies 0.1% 0 (ADAs) Neutralizing antibody (Nab)

12 Barriers to PCSK9 Inhibitor Therapy Annual cost: Alirocumab $14,600; Evolocumab $14,100 Annual budget of ~$125 billion to treat intended population Only 17% initial approval rates by insurance & 26% approved after appeal 37% of patients do not pick up initial fill. Mean 30 day copay ~$ % using drug company coupon program. More likely to receive therapy if used. Icer-review.org PCSK9 Inhibitors Use Storage: Must be stored in refrigerator; Room temperature: 30 days Administration of pre filled pen: Allow injection to warm to room temp (at least min). Wash hands and use alcohol wipe to clean injection area. Medicine in window should be clear to slightly yellow Injection sites: thigh, upper arm, stomach (>2 from belly button) Pull off cap and use within 5 minutes. Firmly push auto injector on skin at 90⁰. Push start button until hear click, continue holding pen against skin. Injection takes approximately 15 seconds. Remove pen once window turns yellow. Conclusions Elevated LDL levels are a major predictor of CV events. Guidelines have changed to target ASCVD risk, rather than LDL levels. Dose of statin based on ASCVD risk. Statin therapy limited by intolerance, adverse events and noncompliance. 12

13 Conclusions PCSK9 inhibitors are currently available for reducing LDL and associated ASCVD risk. Effectively reduces LDL-C as monotherapy and in combination with statins. Well tolerated with a low rate of side effects. Limitations include high cost, lack of long-term outcomes data, logistics of storage & administration. QUESTIONS? 13