Lipids management and prevention of Stroke

Transcription

1 Lipids management and prevention of Stroke Dr.Vamshi Mallavarapu MD, FACC,RPVI Director CCU, Abington Hospital-Jefferson Health Diplomat of American Board of Clinical Lipidology

2 None Disclosures

3 Objectives Discuss preventative therapy for stroke- Primary and secondary Focus on lipid lowering therapy Discuss new agents for low lipid lowering therapy

4 Epidemiology An estimated 6.6 million Americans 20 years of age Prevalence of stroke is 2.6% and for silent stroke is 6-8% By 2030, an additional 3.4 million people aged 18 years will have had a stroke, a 20.5% increase in prevalence from Each year, people experience a new or recurrent stroke Medicare beneficiaries showed that the rate of first stroke among patients aged >65 years decreased by 40% over the past 2 decades ( ), a decline driven primarily by marked reductions in the incidence of ischemic stroke. The decline in stroke rates occurred over a period of significant uptake in the use of medications that attenuate stroke risk: Statin use in the general population increased from4% in 1992 to 41% in 2008, and antihypertensive drug use increased from 53% in 1992 to 74% in Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

5 TIA Prevalence 2.3%- estimated ~5 million 15% all strokes are heralded by TIA 10-year stroke risk of roughly 19% and a combined 10-year stroke, MI, or vascular death risk of 43%(4% per year). 1-year mortality rate after a TIA ~12%. Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

6 Stroke Recurrence Recurrent stroke rates -1.8% at 1 month, 5% at 6 months, 8% at 1 year, and 18.1% at 4 years 987 ARIC participants with first-ever strokes, there were 183 recurrent strokes among 147 participants. Approximately 70% of recurrent strokes were of the same subtype; however, 28% were the same when the index stroke was lacunar. One-year stroke recurrence rates by index subtype were 7.9% for thrombotic, 6.5% for cardioembolic, and 6.5% for lacunar events Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

7 Mortality 1 person dies every 4 minutes Stroke accounted for 1 of every 20 deaths in the United States. When considered separately from other CVDs, stroke ranks No. 5 among all causes of death, behind diseases of the heart, cancer, CLRD, and unintentional injuries/accidents. Approximately 59% of stroke deaths occurred outside of an acute care hospital. More women than men die of stroke each year because of the larger number of elderly women. Women accounted for 58% of US stroke deaths in From 2003 to 2013, the age-adjusted stroke death rate decreased 33.7%, and the actual number of stroke deaths declined 18.2%. Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

8 Percentage population attributable risk of main modifiable risk factors for acute myocardial infarction and stroke (ischemic and haemorrhagic stroke combined) based on the estimates from the INTERHEART study and the INTERSTROKE study. Population attributable risk (PAR) is estimating the proportion of a disease that can theoretically be attributed to a specific risk factor; estimates derived from the INTERHEART study and the INTERSTROKE study. Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

9 Hypertension- Risks - BP<120/80, 50% reduction in risk -10 mm Hg increase in levels of SBP, the increased stroke risk in whites is 8%; however, a similar 10 mm Hg increase in SBP in African Americans is associated with a 24% increase in stroke risk. Diabetes: Risk ratios In patients with TIA, impaired glucose tolerance doubles risk of recurrent stroke Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

10 Atrial fibrillation: Increases risk upto 5 fold Smoking: increases risk 2-4 fold Physical activity: decreases risk about 20-50% Family history CKD- Hazard ratio of 1.7 Sleep apnea Nutrition: Mediterranean diet: Hazard ratio of 0.54 Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

11 Exercise capacity and muscle strength and risk of vascular disease and arrhythmia in 1.1 million young Swedish men: cohort study Kasper Andersen,1 Finn Rasmussen,2 Claes Held,1 Martin Neovius,3 Per Tynelius,2 Johan Sundström1 BMJ 2015;351:h4543

12 From: Low-Risk Diet and Lifestyle Habits in the Primary Prevention of Myocardial Infarction in Men: A Population-Based Prospective Cohort Study J Am Coll Cardiol. 2014;64(13): doi: /j.jacc Figure Legend:

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14 Lipids and cerebrovascular disease The relationship between lipids and stroke is complex. Direct relationship between cholesterol levels and ischemic stroke, varies by stroke subtype, with associations strongest for atherosclerotic subtypes. Increased risk of intracerebral hemorrhage at low cholesterol levels Data strongest for total cholesterol (TC) and low-density lipoprotein-cholesterol Lipids and Cerebrovascular Disease: Research and Practice.Yaghi, Shadi MD; Elkind, Mitchell S.V. MD, MS. Issue: Volume 46(11), November 2015, p

15 HDL Decreased risk of ischemic stroke ranging from 11% to 15% for each 10-mg/dL increase in HDL-C HDL2- increased atherosclerosis HDL3- decreased atherosclerosis Lipids and Cerebrovascular Disease: Research and Practice.Yaghi, Shadi MD; Elkind, Mitchell S.V. MD, MS. Issue: Volume 46(11), November 2015, p

16 Triglycerides Association between higher triglyceride levels and relative risk (RR) of stroke (adjusted RR, 1.05; 95% CI, 1.03 to 1.07) for each 10-mg/dL increase in baseline triglycerides. Studies have also shown that triglycerides levels are inversely associated with hemorrhagic stroke risk Lipids and Cerebrovascular Disease: Research and Practice.Yaghi, Shadi MD; Elkind, Mitchell S.V. MD, MS. Issue: Volume 46(11), November 2015, p

17 Cholesterol and stroke subtype stratified for the history of prior myocardial infarction (MI) based on estimates from the MRFIT study

18 INTERSTROKE: Population-attributable risk for common risk factors Risk factor Population-attributable risk, % (99% CI) Hypertension 34.6 ( ) Smoking 18.9 ( ) Waist-to-hip ratio (tertile 2 vs tertile 1) 26.5 ( ) Dietary risk score (tertile 2 vs tertile 1) 18.8 ( ) Regular physical activity 28.5 ( ) Diabetes 5.0 ( ) Alcohol intake 3.8 ( ) Cardiac causes 6.7 ( ) Ratio of apolipoprotein B to A ( ) (tertile 2 vs tertile 1) Psychological factors Stress 4.6 ( ) Depression 5.2 ( ) *For the protective factor of physical activity, the population-attributable risks are provided for individuals who do not participate in regular physical activity. O'Donnell MJ et al. Lancet 2010; available at:

19 Meta-analysis : Statin and Stroke N total= Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

20 Meta-Analysis Stroke Death Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

21 Meta-analysis Hemorrhagic stroke Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

22 Stroke Risk and LDL Lowering Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI 6.3 to 33.5%, p<0.001) Total n=165,732 Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

23 N=17,802 LDL-c<130 mg/dl hscrp >2 mg/dl F/U 1.9 yrs JUPITER Men >50 yrs Women >60 yrs Event Rosuva * Placebo * Hazard Ratio Risk Reduction (CI) Primary endpoint 142 (1.6%) 251 (2.8%) 44% (31-54) p= Any MI 31 (0.35%) 68 (0.76%) 54% (30-70) Stroke 33 (0.37%) 64 (0.72%) 48% (21-66) p=0.002 Revascularisation or Unstable angina 76 (0.85%) 143 (1.6%) 47% (30-60) MI, Stroke, CVdeath 83 (0.93%) 157 (1.8%) 47% (30-61) * N (% randomised) Favours Rosuvastatin Favours Placebo

24 Secondary End Point: Fatal and Nonfatal Stroke 3 Atorvastatin 10 mg Number of events 89 (1.7%) Placebo Number of events 121 (2.4%) Cumulative Incidence (%) 2 1 HR = 0.73 ( ) 27% reduction p= ,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Years Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:

25 CARDS: Cumulative Hazard for Stroke Cumulative Hazard (%) Atorvastatin10 mg Placebo Placebo n=39 [31% of all first CVD events] Atorvastatin n=21 48% Risk Reduction In Stroke (P=0.016) [25% of all first CVD events] Years from Randomization Hitman GA, et al. EASD Diabetologia. 2005; Abstract 120 Data on file, Pfizer Inc.

26 Pleiotropic Effects Studied Parameter Within the Plaque Control Group n=13 Pravastatin Group n=11 P Value Lipid contain (Oil Red O) 23.9% 8.2% <0.001 Ox-LDL (NA59) 22% 13.3% <0.001 Macrophage contain 25.3% 15.3% <0.05 T-Cell count 23.4% 11.2% <0.05 SMC 16.9% 24.3% <0.05 Apoptotic Cells (TUNEL) 32% 17.7% <0.05 Crisby et al. Circulation 2001

27 Between-Group LDL Reduction and Carotid- IMT Reduction Per Year r=0.70, p= For Each 10% LDL-cholesterol IMT reduction per year = 0.76% (95%CI, ) Amarenco et al. Stroke 2004;35:2902-9

28 Stroke: Potential Mechanisms of Benefit LDL Reduction Statin 35 to 80% of the benefit Plaque stabilization: macrophages smooth muscle cells immunologic response lipid core oxidized LDL Neuroprotection. Up-regulation NO. Improves CBF. Reduces infarct size Blood pressure reduction Decrease incidence of MI and of left ventricular mural thrombus Improved endothelial function Reduced hemorheologic stress Reduced platelet aggregation Reduced thrombotic and Enhanced fibrinolytic state

29 HPS: No Reduction in Risk of Recurrent Stroke in Patients With Prior Cerebrovascular Disease Patient with Event (5) n=406 n=488 Major Vascular Events n=169 n=170 Stroke *29% RR, P=.001 Heart Protection Study Collaborative Group. Lancet. 2004;363:

30 Clinical Trial data Treat stroke to target Trial-Expected results Dec 2018

31 SPARCL: Study Design Patient Population 205 sites worldwide Double-Blind Period Atorvastatin 80 mg/day Previously documented stroke or TIA within 6 months 4,731 Patients No history of CHD LDL-C levels 100 mg/dl and 190 mg/dl Placebo 540 Primary Endpoints Primary End Point Time to the First Occurrence of a Fatal or Nonfatal Stroke Source: The SPARCL Investigators. Cerebrovasc Dis. 2003;16:

32 140 LCL-C During Follow-up Baseline LDL-C: 133 mg/dl +1% 120-7% 100 Mean (mg/d % Mean on-treatment LDL-C: Placebo = 129 mg/dl -38% 20 Atorvastatin = 73 mg/dl 0 Baseline Month 3 Year 1 Year 3 Year 5 Last Timepoint Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59

33 Primary Endpoint: Time to Fatal or Non-Fatal Stroke Fatal or Non-Fatal Stroke (%) 16% 12% 8% 4% Placebo Atorvastatin Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = % RR 0% Years Since Randomization * Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59

34 Secondary Endpoint: Time to Major Coronary Event 8% Major Coronary Event (%) 6% 4% Placebo Atorvastatin 35% RR 2% 0% Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = Years Since Randomization * Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59

35 Gender: Stroke Outcomes Gender X Treatment Interaction p-value All Stroke Women Men Non-fatal Stroke Women Men Fatal Stroke Women Men Treatment Better Placebo Better Adjusted Hazard Ratio Pre-specified adjustment for region, entry event, time since entry event and age Goldstein LB, Amarenco P, Callahan A III, al.. Stroke. 2008;39:

36 Ischemic and Hemorrhagic Stroke Post hoc analysis Ischemic or Hemorrhagic Stroke (%) Fatal and Non-fatal Stroke Placebo: Ischemic Atorvastatin: Ischemic Placebo: Hemorrhagic Atorvastatin: Hemorrhagic Ischemic: HR (95% CI) = 0.79 (0.66, 0.95) Hemorrhagic: HR (95% CI) = 1.68 (1.09, 2.59) Years Since Randomization Unadjusted HR Goldstein LB, Amarenco P, Szarek M, al. Neurology ;70:

37 Impact of Atorvastatin on Hemorrhagic stroke by Entry Event Goldstein LB, Amarenco P et al. Neurology. 2008;70: Entry Event HR (95% CI) P-value Large Vessel 1.23 (0.44, 3.39) TIA 0.97 (0.44, 2.17) Hemorrhagic 4.67 (0.96, 22.6) Small Vessel 5.07 (1.73, 14.9) Unknown 0.80 (0.30, 2.13) *Adjusted for time since entry event, gender, and age Hazard ratio* Atorvastatin better Placebo better

38 Benefit/Risk P=0.002 P= % Incidence (%) 11.2% 13.1% 14.1% Major Coronary Event Ischemic Stroke Hemorrhagic Stroke Unclassified Stroke Atorvastatin n = 2365 Placebo n = 2366 Atorvastatin n = 2365 Placebo n = 2366 Stroke Stroke and Major Coronary Events Amarenco P, et al. Exp Op Pharmacotherapy. 2007

39 Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes Percentage of Patients Free of End Points RR: 30% HR=0.70 (95% CI 0.50, 0.98), P=0.0387* Log-rank P= Atorvastatin 80 mg Placebo *Adjusted for entry event, time since entry event, gender, age, and geographic region Years since randomization Callahan A, Welch KMA, Amarenco P, et al. 6

40 Effect of Atorvastatin on CV Events In SPARCL Patients with Diabetes Percentage of Patients Free of End Points Any CHD Event RR: 51% Atorvastatin 80 mg Placebo HR=0.49 (95% CI 0.31, 0.79), P=0.0033* Log-rank P= Percentage of Patients Free of End Points Any Revascularization RR: 64% Atorvastatin 80 mg Placebo HR=0.36 (95% CI 0.21, 0.61), P=0.0001* Log-rank P= Years since randomization Years since randomization *Adjusted for entry event, time since entry event, gender, age, and geographic region Callahan A, Welch KMA, Amarenco P, et al.

41 Stroke in Patients With Carotid Stenosis Patients free of fatal or non-fatal stroke (%) RR: 33% Atorvastatin Placebo HR=0.67 (95% CI 0.47, 0.94), P=.02* Years since randomization *: adjusted for entry event, time since entry event, gender, age, and geographical region Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

42 Any Cardiovascular Event in patients With Carotid Stenosis 100 Atorvastatin Patients free of any cardiovascular event (%) RR: 42% Placebo 60 HR=0.58 (95% CI 0.46, 0.73), P< Years since randomization *: adjusted for entry event, time since entry event, gender, age, and geographical region Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

43 Stroke Risk and LDL Lowering Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI 6.3 to 33.5%, p<0.001) N total= Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

44 Time Varying LDL-C and Stroke Risk All Stroke HR (95% CI) p-value 0% Increase 1.00 <50% Decrease 50% Decrease 0.89 (0.73, 1.08) 0.69 (0.55, 0.87) Ischemic Stroke 0% Increase 1.00 <50% Decrease 50% Decrease Hemorrhagic Stroke 0% Increase 1.00 <50% Decrease 50% Decrease 0.90 (0.73, 1.12) 0.67 (0.52, 0.86) 0.84 (0.50, 1.40) 1.04 (0.61, 1.78) Note: Percent change effects from Cox proportional hazards Hazard Ratio (95% CI) models with adjustment for gender and baseline age with reference group = no change or increase Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:

45 Meta-analysis: Intensive LDL-C Lowering vs. Standard Statin Therapy Fatal and Nonfatal STROKE Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

46 Meta-analysis: Intensive Lipid-Lowering vs. Standard Statin Therapy MAJOR CARDIOVASCULAR EVENTS Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

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48 A. More statin vs less statin (5 trials: 0.51 mmol/l LDL difference) Any major coronary event Any coronary revascularization Any stroke 5 trials: any major vascular event B. Statin vs control (21 trials: 1.07 mmol/l LDL difference) Any major coronary event Any coronary revascularization Any stroke 21 trials: any major vascular event C. More statin vs less statin vs control (26 trials) Vascular events Major vascular event Patients with type 1 diabetes Patients with type 2 diabetes Patients without diabetes Any vascular event Mortality Cause-specific mortality All cardiac Stroke Any vascular Any non-vascular All-cause mortality (any death) Effect of Statins on CV Event Rates Related to 1 mmol/l LDL Reduction 1725 (1.9) 2250 (2.6) 572 (0.6) 3837 (4.5) 3380 (1.3) 3103 (1.2) 1730 (0.7) 7136 (2.8) 145 (4.5) 2494 (4.2) 8272 (3.2) 10,973 (3.2) 3333 (0.9) 483 (0.1) 4220 (1.2) 2943 (0.8) 7642 (2.1) 1973 (2.2) 2741 (3.2) 663 (0.7) 4416 (5.3) 4539 (1.7) 4066 (1.6) 2017 (0.8) 8934 (3.6) 192 (6.0) 2920 (5.1) 10,163 (4.0) 13,350 (4.0) 3384 (1.1) 501 (0.1) 4220 (1.2) 2994 (0.8) 8327 (2.3) Relative risk per 1 mmol/l (39 mg/dl) reduction in LDL-C (95% CI) More statin better Statin better 0.74 ( ) 0.66 ( ) 0.74 ( ) 0.72 ( ) 0.76 ( ) 0.76 ( ) 0.85 ( ) 0.79 ( ) 0.77 ( ) 0.80 ( ) 0.78 ( ) 0.78 ( ) 0.84 ( ) 0.96 ( ) 0.86 ( ) 0.92 ( ) 0.90 ( ) Statin or more statin better Less statin better Control better Control or less statin better CCT Trialists. Lancet 2010;376:1670

49 Reported Adverse Effects of Statins Muscle-related symptoms Elevated hepato-cellular enzymes Cancer New diabetes Hemorrhagic stroke Fatigue Neuro-psychiatric effects and insomnia Proteinuria / hematuria Erectile dysfunction Alopecia

50 Mancini GB et al. CJC 2011; 27: Muscle Adverse Effects of Statin Clinical features include Muscle aches, myalgia, weakness Stiffness, and cramps CK not increased in most patients Compromises quality of life Reduces medication adherence Major symptom limiting the use of statins

51 Risk Factors for Statin Induced Myopathy Patient Characteristics Demographics Older Age, Female gender Asian race Genetic Predisposition Transporters SLCO1B1 CYP isoenzymes Comorbidities Hypothyroidism Systemic disease Alcoholism / drugs Major surgery Myopathy Hereditary (PYGM, CTP II, AMPD) Acquired FH of statin intolerance

52 Therapeutic Options for Management of Statin Intolerant Patient Dietary and health behaviour measures Statin based strategies Alternative statin Alternative dosing Non-statin alternatives and adjuncts Ezetimibe Bile acid sequestrants Fibrates Niacin

53 Other Lipid-Lowering Drugs Niacin: A meta-analysis of 11 studies (n=9959 subjects) showed no association between the use of niacin and the risk of stroke (OR, 0.88; 95% CI, 0.50 to 1.54). Fibric acid derivatives: Veterans Affairs-HDL Intervention Trial (VA-HIT) among men with coronary artery disease and low HDL-C, benzofibrate provided a 31% reduction in stroke risk(p=0.036). A recent meta-analysis, however, included 18 trials, and > patients provided no evidence that fibrates reduce stroke risk (RR reduction, -3%; 95% CI, -16 to 9). Lipids and Cerebrovascular Disease: Research and Practice.Yaghi, Shadi MD; Elkind, Mitchell S.V. MD, MS. Issue: Volume 46(11), November 2015, p

54 Ezetimibe: Background Ezetimibe inhibits Niemann-Pick C1- like 1 (NPC1L1) protein, located primarily on the epithelial brush border of the GI tract resulting in reduced cholesterol absorption When added to statin, produces ~20% further reduction in LDL-C Two recent human genetic analyses have correlated polymorphisms in NPC1L1 with lower levels of LDL-C and lower risk of CV events* *MI Genetics Consortium Investigators NEJM 2014; online Nov 12; Ference BA et al AHA 2014

55 LDL-C and Lipid Changes 1 Yr Mean LDL-C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl Median Time avg 69.5 vs mg/dl

56 CV Death, Non-fatal MI, or Non-fatal Stroke HR 0.90 CI (0.84, 0.97) p=0.003 NNT= 56 Simva 22.2% 1704 events EZ/Simva 20.4% 1544 events 7-year event rates

57 Individual Cardiovascular Endpoints and CVD/MI/Stroke HR Simva* EZ/Simva* p-value All-cause death CVD CHD MI Stroke Ischemic stroke Cor revasc 30d UA CVD/MI/stroke Ezetimibe/Simva Better Simva Better *7-year event rates (%)

58 Dyslipidemia Recommendations 1. Statin therapy with intensive lipid-lowering effects is recommended to reduce risk of stroke and cardiovascular events among patients with ischemic stroke or TIA presumed to be of atherosclerotic origin and an LDL-C level 100 mg/dl with or without evidence for other clinical ASCVD (Class I; Level of Evidence B). (Revised recommendation) 2. Statin therapy with intensive lipid-lowering effects is recommended to reduce risk of stroke and cardiovascular events among patients with ischemic stroke or TIA presumed to be of atherosclerotic origin, an LDL-C level <100 mg/dl, and no evidence for other clinical ASCVD (Class I; Level of Evidence C). (New recommendation) 3. Patients with ischemic stroke or TIA and other comorbid ASCVD should be otherwise managed according to the 2013 ACC/AHA cholesterol guidelines, which include lifestyle modification, dietary recommendations, and medication recommendations (Class I;Level of Evidence A). (Revised recommendation) Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

59 Clinical ASCVD* LDL-C 190 mg/dl, Age 21 years Primary prevention Diabetes: Age years, LDL-C mg/dl Primary prevention - No Diabetes : 7.5% 10-year ASCVD risk, Age years, LDL-C mg/dl Circulation 2016 Jan 26;133(4): Executive Summary: Heart Disease and Stroke Statistics Update: A Report From the American Heart Association.

60 Cryptogenic stroke Retrospective study of 1008 patients with crypotgenic stroke Patients on statins, less likely to have recurrent cardiovascular events, (hazard ratio 0.23, 95% confidence interval ; p = 0.006) Statins after ischemic stroke of undetermined etiology in young adults. Putaala et.al., 2011 Aug 2;77(5):426-30

61 PCSK9 inhibitors Pharmacology: Human monoclonal antibody that inhibits PCSK9 PCSK9 is a protease that degrades LDL receptors on hepatocytes. LDL receptors clear circulating LDL

62 LDL Receptor Function and Life Cycle 62

63 The Role of PCSK9 in the Regulation of LDL Receptor Expression 63 63

64 Impact of an Anti-PCSK9 mab on LDL Receptor Expression 64 64

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67 OSLER study- Evolocumab

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72 CETP inhibitors

73 ACCELERATE ACC 2016

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77 Mipomersen Inhibits protein synthesis of apob Reduces LDL ~30% Injected weekly No outcomes trials

78 Conclusions Statins are highly effective in primary and secondary stroke prevention Lifestyle modifications are equally important in reducing stroke risk Promise for newer therapies for lipid modification

79 Questions?