Update on Lipid Guidelines and Intense Treatment of LDL-C with PCSK9 Inhibitors Carl J. Lavie, MD,FACC,FACP,FCCP Professor of Medicine Medical-Director, Preventive Cardiology John Ochsner Heart and Vascular Inst. Ochsner Clinical School-The UQ School of Medicine, New Orleans, LA
ATP III LDL-C and Non HDL-C Goals Risk Category CHD or equivalent (10-yr risk 20%) 2 risk factors (10-yr risk 20%) LDL-C (mg/dl) 100 130 Non HDL-C (mg/dl) 130 160 0 1 risk factors 160 190 Adapted with permission from Expert Panel. Circulation. 2002;106:3143
2004 Lipid Guidelines CAD and risk equivalent-drug TX for LDL> 100 mg/dl CAD and risk equivalent-optional goal LDL< 70 mg/dl 2 or more risk factors-optional goal LDL <100 mg/dl In high risk patients,greater emphasis on drug combinations to treat HDL and TGs. Grundy SM et al. Circulation 2004;110:227-239
New ACC/AHA 2013 Risk Assessment Guidelines Race-and Sex-Specific Pooled Cohort Equation to predict 10-year risk of first ASCVD in non- Hispanic AAs and Whites, 40-79 years Derived from ARIC,CHS,Cardia,and Framingham original and offspring Age, gender, total and HDL-C,SBP, use of anti- HTN meds, DM, and current smoking Assess 30-yr or lifetime risk of ASCVD in 20-59 yo without ASCVD or high short-term risk Goff DC et al. ACC/AHA Risk Assessment, JACC 2014;63:2935-2959
New ACC/AHA 2013 Risk Assessment Guidelines-Risk in Ethnic Groups There is not sufficient data to assess risk in Hispanics, Asians, and Indians using these same data bases The current risk assessment will OVERESTIMATE risk in Hispanics and Asian populations The current risk assessment will UNDERESTIMATE risk in American Indians Goff DC et al. ACC/AHA Risk Assessment, JACC 2014;63:2935-2959
New ACC/AHA 2013 Cholesterol Guidelines Emphasis on Clinical ASCVD ACS/MI Angina, stable or unstable Arterial Revascularization, coronary and other Stroke /TIA PAD, presumably atherosclerotic Stone NJ, et al. ACC/AHA Blood Cholesterol Guideline.JACC 2014;63:2889-2934
New ACC/AHA 2013 Cholesterol Guidelines 4 Major Statin Benefit Groups ASCVD LDL-C 190 mg/dl and higher Diabetes, age 40-75 10-year risk of major ASCVD of 7.5% and higher, age 40-75 Stone NJ, et al. ACC/AHA Blood Cholesterol Guideline.JACC 2014;63:2889-2934
New ACC/AHA 2013 Cholesterol Guidelines Keaney J. F. et al. NEJM, Nov. 27 2013
New ACC/AHA 2013 Cholesterol Guidelines Keaney J. F. et al. NEJM, Nov. 27 2013
New ACC/AHA 2013 Cholesterol Guidelines No Definitive Guidelines Age greater than 75 years w/o ASCVD or with LDL-C < 190 mg/dl DM ages 20-39 Age 20-39 w/o ASCVD and LDL-C < 190 mg/dl LDL-C and non-hdl-c goals Triglycerides, including Severe Non-Statin medications Stone NJ, et al. ACC/AHA Blood Cholesterol Guideline.JACC 2014;63:2889-2934
New ACC/AHA 2013 Cholesterol Guidelines Special Issues in > 75 yrs No drug guidelines in those w/o ASCVD and with LDL-C < 190 mg/dl In general, use moderate dose as opposed to high-dose statins Fail to definitively treat many despite very high ASCVD risk Suggest discussing pros and cons of more vs less aggressive treatments Stone NJ, et al. ACC/AHA Blood Cholesterol Guideline.JACC 2014;63:2889-2934
LDL-C Reduction Remains Fundamental to Major Cholesterol Treatment Guidelines and Recommendations Recommendations for Patients With Clinical ASCVD ASCVD = atherosclerotic cardiovascular disease; ACC = American College of Cardiology; AHA = American Heart Association; ADA = American Diabetes Association; NLA = National Lipid Association; AACE = American Association of Clinical Endocrinologists; IAS = International Atherosclerosis Society; ESC = European Society of Cardiology; EAS = European Atherosclerosis Society. *Percent LDL-C reduction defines treatment intensity and assesses adherence;1 also includes percent LDL-C reduction as an efficacy metric.7 7 1. Stone NJ, et al. J Am Coll Cardiol. 2014;63:2889-2934. 2. Keaney JF, et al. N Engl J Med. 2014;370:275-278. 3. American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S1-S94. 4. Jacobson TA, et al. J Clin Lipidol. 2014;8:473-488. 5. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78. 6. Expert Dyslipidemia Panel, Grundy SM. J Clin Lipidol. 2013;7:561-565. 7. Reiner Z, et al. Eur Heart J. 2011;32:1769-1818.
Percentage with CHD event Landmark Statin Trials: LDL-C Levels vs Events 10 9 8 7 6 WOSCOPS-S WOSCOPS-P 5 4 3 2 AFCAPS-S AFCAPS-P Primary prevention Pravastatin Lovastatin 1 0 2.3 (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190) LDL-C, mmol/l (mg/dl) 5.4 (210) S = statin treated; P = placebo treated Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21
Percentage with CHD event Landmark Statin Trials: LDL-C Levels vs Events 10 9 8 7 6 WOSCOPS-S WOSCOPS-P 5 4 3 2 1 AFCAPS-S ASCOT-S ASCOT-P AFCAPS-P Primary prevention Pravastatin Lovastatin Atorvastatin 0 2.3 (90) 2.8 (110) 3.4 (130) 3.9 (150) 4.4 (170) 4.9 (190) 5.4 (210) LDL-C, mmol/l (mg/dl) S = statin treated; P = placebo treated Modified from Kastelein JJP. Atherosclerosis. 1999;143(suppl 1):S17-S21
REVERSAL Baseline Values Prava (n=249) Atorva (n=253) Age 57 56 T Cholesterol 233 232 LDL 150 150 HDL 43 42 Triglyceride 200 197 CRP 3.0 2.8 Nissen S. E., et. al., JAMA. 2004;291:1071-1080
REVERSAL Follow-up Labs Prava (n=249) Atorva (n=253) P-Value mean % mean % TC 188-18 151-34 <0.001 LDL 110-25 79-46 <0.001 HDL 45 +5.6 +43 +2.9 =0.06 Trig 166-7 148-20 <0.001 CRP 2.9-5 1.8-36 <0.001 Nissen S. E., et. al., JAMA. 2004;291:1071-1080
REVERSAL Change in Atheroma Nissen S. E., et. al., JAMA. 2004;291:1071-1080
After ASTEROID 1.8 1.2 CAMELOT plasebo REVERSAL pravastatin Change in Percent Atheroma Volume (%) 0.6 0 REVERSAL atorvastatin A-Plus placebo ACTIVATE plasebo -0.6 ASTEROID rosuvastatin -1.2 50 60 70 80 90 100 110 120 LDL-C
SATURN Trial A 2 year, randomized, double-blind, parallel group study comparing the effects of treatment with rosuvastatin 40 mg and atorvastatin 80mg on atherosclerotic disease burden as measured by IVUS in patients with CAD (n=1,300). Primary Outcome Measure: Comparison of the effects of rosuvastatin with atorvastatin on PAV, as measured by IVUS Nicholls SJ et al. NEJM;Nov 15,2011
SATURN Trial LDL lower on Rosuva vs Atorva( 62.6 vs 70.2; p< 0.0001) HDL higher on Rosuva vs Atorva( 50.4 vs 48.6; p= 0.01) Primary End-point-PAV( NS) Secondary End-point-TAV reduced slightly more with Rosuva vs Atorva( p=0.01) Nicholls SJ et al. NEJM; Nov 15,2011
TIMI 22: Study Design Double-blind, randomized trial in 4,162 patients with Acute Coronary Syndrome <10 days and Total Cholesterol < 240 mg/dl ASA + Standard Medical Therapy Pravastatin 40 mg, qhs Atorvastatin 80 mg, qhs Gatifloxacin Placebo Gatifloxacin Placebo Duration: Mean 2 year follow-up (1001 events) Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
TIMI 22 RESULTS: All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg 537/2063 (26.3%) % with Event 25 20 15 10 5 0 Atorvastatin 80mg 464/2099 (22.4%) 16% RRR at 2 years (p = 0.005) 0 3 6 9 12 15 18 21 24 27 30 Months of Follow-up Cannon, C, et al. NEJM 2004;35
Cumulative Rate of Recurrent MI or Death from Coronary Causes CRP Levels and Outcome after Statin Therapy 0.10 LDL cholesterol 70 mg/dl 0.10 CRP 2 (mg/l) 0.08 0.08 0.06 0.06 0.04 LDL cholesterol < 70 mg/dl 0.04 CRP < 2 (mg/l) 0.02 0.02 0.00 0.00 0.0 0.5 1.0 1.5 2.0 2.5 0.0 0.5 1.0 1.5 2.0 2.5 Follow-up (Years) Follow-up (Years) Ridker PM, et al. NEJM 2005;352:20-8
TNT: Design Screening: CHD patients LDL-C: 130-250mg/dL after washout Open-label Atorvastatin 10 mg/day Target LDL: <130mg/dL Randomized 10,000 men and women aged 35-75 Atorvastatin 10mg/day Target LDL: 100mg/dL Atorvastatin 80mg/day Target LDL: 75mg/dL Objective: To assess whether reducing LDL-C aggressively to 75mg/dL will provide a greater reduction in CHD events than lowering LDL-C more moderately to 100mg/dL Primary Endpoint: Occurrence of major coronary event (i.e., CHD death or nonfatal MI) 5 year follow-up period and completion of study end of 2004
TNT: Baseline and final LDL cholesterol levels LDL cholesterol level Atorvastatin 10 (n=5006) Atorvastatin 80 (n=4995) Mean baseline LDL cholesterol levels (mg/dl) Final LDL cholesterol levels (mg/dl) 98 97 101 77 LaRosa JC et al. N Engl J Med 2005;352:1425-35
TNT: Primary efficacy outcomes Outcome Total major cardiovascular events (%) Death from coronary heart disease (%) Atorvastatin 10 mg (n=5006) Atorvastatin 80 mg (n=4995) Hazard ratio (95% CI) 10.9 8.7 0.78 (0.69-0.89) 2.5 2.0 0.80 (0.61-1.03) Nonfatal MI (%) 6.2 4.9 0.78 (0.66-0.93) Resuscitation after cardiac arrest (%) Fatal or nonfatal stroke (%) 0.5 0.5 0.96 (0.56-1.67) 3.1 2.3 0.75 (0.59-0.96) p <0.001 0.09 0.004 0.89 0.02 LaRosa JC et al. N Engl J Med 2005;352:1425-35
JUPITER URANUS EARTH Will Jupiter Change the Course of Earth?
hscrp (mg/l) LDL (mg/dl) JUPITER Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hscrp 140 60 120 50 100 80 60 40 40 30 20 20 0 LDL decrease 50 percent at 12 months 10 0 HDL increase 4 percent at 12 months 5 4 3 2 1 0 hscrp decrease 37 percent at 12 months 0 12 24 36 48 Months TG (mg/dl) HDL (mg/dl) 140 120 100 80 60 40 20 0 TG decrease 17 percent at 12 months 0 12 24 36 48 Months Ridker et al NEJM 2008
JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death 0.00 0.02 0.04 0.06 0.08 Cumulative Incidence Number at Risk Rosuvastatin Placebo HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 0 1 2 3 4 Follow-up (years) Placebo 251 / 8901-44 % Rosuvastatin 142 / 8901 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174 Ridker et al NEJM 2008
High Dose Atorvastatin After CVA/TIA(SPARCL Trial) 4731 pts after CVA/TIA with LDL 100-190 mg/dl;80 mg atorva vs placeo 4.9 yrs;ldl 73 atorva,129 placebo Atorva reducedstroke16%(p=.03),cva/tia 2 3%(p<.001),major CAD 35%(P=.003),major CVD 20%(p=.002),and any CVD event 26%(p<.001) SPARCL;NEJM 2006;355:549-559
Do Statins Cause Diabetes Statins increase the prevalence of T2DM(Sattar N et al;lancet 2010;375:735-742) High-dose or Intense statin therapy increases T2DM more so than lower doses(preiss D et al;jama 2011;304:2556-2564.) Statins, more so higher dose or Intense doses, reduce clinical events in MetS and T2DM, as much or more so than in other patients.
Limitations of Statins Muscle Side Effects-consider Coenzyme Q 10 Many patients do not obtain all lipid goals despite intensive doses Considerable Residual Risk Concern about other Adverse Effects- Liver,Diabetes,Memory, etc Most effective in patients with higher CHD risk
Ezetimibe Therapy Implications of IMPROVE-IT Produces 15-20% reductions in LDL-C added to statins Negative results and publicity from ENHANCE IMPROVE-IT AHA Nov,2014 Over 18,000 post-acs;7 years;median LDL-C 69.9 to 53.2 md/dl Significant event reduction, absolute 2% and relative 6.4%;NNT 50 for 7 yr ( or 350 per year) DiNicolantonio J, Lavie CJ et al. Am J Med, on-line 2/27/15
10 PCSK9 Inhibitors Lowers LDL-C by Binding to PCSK9
PCSK9 Inhibition Indications ASCVD and Heterozygous FH in addition to maximally tolerated statin and nonpharmacologic therapy in those who need additional LDL-C Lowering Evolocumab also indicated for Homozygous FH
LDL Particles Are Cleared From the Plasma by Binding to LDL Receptors and Being Internalized by the Hepatocyte1-3 1 LDL binds to LDL receptor Intravascular LDL/LDL receptor 2 complex internalized by hepatocyte LDL degraded in 3 lysosome 4 LDL receptor recycled to cell surface Hepatocyte Recycled LDL receptors continue to clear plasma LDL 1. Brown MS, et al. Proc Natl Acad Sci U S A. 1979;76:3330-3337. 2. Brown MS, et al. Science. 1986;232:34-47. 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547. 11
PCSK9 Binds to the LDL Receptor and Targets the LDL Receptor for Degradation1-3 Intravascular PCSK9: 1 made in hepatocyte, secreted 2 PCSK9 binds to LDL receptor 3 Internalization of entire complex 4 LDL receptor as part of entire complex is degraded 5 LDL receptor not recycled Hepatocyte Fewer LDL receptors on hepatocyte surface result in increased plasma LDL 1. Abifadel M, et al. Hum Mutat. 2009;30:520-529. 2.Seidah NG, et al. Circ Res. 2014;114:1022-1036. 3. Steinberg D, et al. Proc Natl Acad Sci U S A. 2009;106:9546-9547. 12
PCSK9 Inhibitors Binds to PCSK9, Preventing PCSK9 From Binding to the LDL Receptor1,2 Intravascular 1 PCSK9I binds to PCSK9 X 2 Inhibits PCSK9 from binding to LDL receptor 3 LDL receptor recycled, not degraded Hepatocyte LDL receptors can recycle to hepatocyte surface to clear more plasma LDL
ODYSSEY and LDL Cholesterol with Alirocumab Robinson JG et al, NEJM March 15, 2015
ODYSSEY and LDL-Cholesterol with Alirocumab Robinson JG et al. NEJM, March 15, 2015.
OSLER and LDL-Cholesterol with Evolocumab Sabatine MS et al. NEJM, March 15, 2015.
OSLER and LDL-Cholesterol with Evolocumab Sabatine MS et al. NEJM March 15, 2015
Nicholls, S. JAMA. doi:10.1001/jama.2016.16951
Evolucomab, LDL-C and Coronary Atheroma Progression Nicholls, S. JAMA. doi:10.1001/jama.2016.16951
Sabatine MS et al. NEJM 2017; 376: 1713-1722
Evolocumab and Major CVD Events Sabatine MS et al. NEJM 2017; 376: 1713-1722
Evolocumab and Major CVD Events Primary Efficacy End Point Sabatine MS et al. NEJM 2017; 376: 1713-1722
Evolocumab and Major CVD Events Key Secondary Efficacy End Point Sabatine MS et al. NEJM 2017; 376: 1713-1722
Evolocumab Reduced Risk of Composite CV Events by 20% in a Median of Only 2.2 Years 1,2 Evolocumab + statin (N=13,784)
Post-hoc exploratory analysis Risk Reduction with Evolocumab Changes Between Months 0-12 and Months 13-36 Evolocumab + statin (N=13,784) Evolocumab + statin (N=13,784)
Efficacy of Evolocumab Was Generally Consistent Across Major Demographic and Disease Subgroups: Key Secondary Endpoint Favors Evolocumab Favors Evolocumab
Post-hoc analysis Patients With a More Recent MI Are at Higher Risk of a Subsequent Event Evolocumab Evolocumab
Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
Benefits of Evolocumab in PAD Bonaca MP et al. Circulation 2017:137: 338-350
EBBINGHAUS: A Cognitive Study of Patients Enrolled in the FOURIER Trial RP Giugliano, F Mach, K Zavitz, AC Keech, TR Pedersen, MS Sabatine, P Sever, C Kurtz, N Honarpour, BR Ott, on behalf of the EBBINGHAUS Investigators American College of Cardiology 66th Annual Scientific Session Late-Breaking Clinical Trial March 18, 2017
Cognition and Statins Case series and 2 small, 6-month RCTs with statins raised concern regarding cognitive deficits In 2012 FDA added risk of adverse cognitive effects to label of all statins However analyses from large scale RCTs do not support these findings and 2014 Statin Cognitive Safety Task Force* concluded that statins are not associated with cognitive side effects. *The National Lipid Task Force. Rojas-Fernandez CH, et al. J Clin.Lipidol. 2014;8(3 Suppl):S5-16.
Cognition and PCSK9 Inhibitors Brain synthesizes cholesterol locally mab (e.g., evolocumab) are too large to cross the intact bloodbrain barrier Nevertheless meta-analysis* of adverse events from 6 trials in 9581 pts suggested an increased risk with PCSK9 inhibitors: HR 2.3 [1.1, 4.9] Event rates low (<1%) Unadjudicated, diverse AE terms reported Not correlated with LDL-C achieved *Lipinski MJ, et al. Eur Heart J. 2016;37(6):536-545.
FOURIER: Summary Results FOURIER Study Population: 27,564 stable patients with CV disease, age 40-85 years; additional CV risk factor(s), LDL 70 mg/dl (or non-hdl 100) Placebo SC Q2W or QM RANDOMIZED DOUBLE BLIND 26 mos. mean f/u Evolocumab SC 140 mg Q2W or 420 mg QM Evolocumab on background of statin c/w placebo: LDL-C by 59% CV outcomes on background of statin therapy Safe and well-tolerated Sabatine, MS et al. New Eng J Med 2017 (NEJMoa1615664 on-line)
EBBINGHAUS: Hypothesis The addition of evolocumab to statin therapy in patients with clinically evident vascular disease does not adversely affect cognitive function. Giugliano RP et al. Clin Card 2017;40:59 65
Secondary Endpoints
Secondary Endpoint Results
Cognitive Assessments by Nadir Achieved LDL-C and Treatment (Full Pop)
Investigator Reported Cognitive Adverse Events
Selecting Combination Therapy Statin Therapy LDL not at goal HDL not at goal TG not at goal Increase statin* Add niacin* Add fenofibrate* Add ezetimibe Add BAR PCSK9I Add niacin* Add fibrate* *Increased risk of myopathy Add niacin* Add fibrate* Add fish oils Grundy S. Am J Cardiol. 2002;90:1135
Summary and Conclusions The New Cholesterol Guidelines have many pros and cons These Guidelines have potential for over- and under-treatment The Guidelines emphasize evidence based therapy, especially with statins Statins have tremendous evidence in primary and especially secondary prevention The Guidelines may lead to under-treatment in the young elderly and in high-risk Combined Dyslipidemia and do not emphasize non-statin therapies (including Ezetimibe and PCSK9Is), but the latter 2 receive attention in recent updates.
Update on Lipid Guidelines and Intense Treatment of LDL-C with PCSK9 Inhibitors Carl J. Lavie, MD,FACC,FACP,FCCP Professor of Medicine Medical-Director, Preventive Cardiology John Ochsner Heart and Vascular Inst. Ochsner Clinical School-The UQ School of Medicine, New Orleans, LA