Cholesterol verlaging (om cardiovasculair risico te verlagen)

Cholesterol verlaging (om cardiovasculair risico te verlagen) Toen, nu en straks Erik Stroes AMC, The Netherlands

Outline Cholesterol verlaging: toen, nu en straks Cholesterol verlaging toen Fire and Forget Statins only Cholesterol verlaging nu Cholesterol verlaging toekomst

The central role of arterial retention of apob-containing lipoproteins in the pathogenesis of atherosclerosis Boren J, Williams KJ. Curr Opin Lipidol 2016;27:473 83

Causative, excacerbating factors vs bystanders Boren, Cur Op Lip 2016

ACC/AHA Guidelines Recommend Lowering LDL-C to Reduce the Risk of a CVD Event Patients >21 yr of age without heart failure or ESRD Screen for ASCVD risk factors Measure LDL-C Clinical ASCVD Diabetes mellitus (type 1 or 2) and age of 40 75 yr and LDL-C 70 189 mg/dl No diabetes mellitus and age of 40 75 yr and LDL-C 70 189 mg/dl LDL-C 190 mg/dl Calculate 10-year risk* of ASCVD Calculate 10-year risk* of ASCVD High-intensity statin therapy If risk <7.5%*, moderateintensity statin therapy If risk 7.5%*, high-intensity statin therapy If risk 7.5, moderate-to-highintensity statin therapy High-intensity statin therapy 2013 ACC/AHA guidelines state that reduction of CVD events according to risk should be achieved with statin treatment in 4 groups with increased CV risk ACC=American College of Cardiologists; AHA=American Heart Association; ASCVD= atherosclerotic cardiovascular disease; ESRD=end-stage renal disease; LDL-C=low-density lipoprotein cholesterol; RCT=randomized controlled trials. Goff et al, JACC 2013 epub Nov 12.; Stone et al. JACC 2014; 63:2889-934; Keaney et al. NEJM 2013; epub Nov 27.

LDL-C Lowering Therapies Reduce CV-Risk 2013 ACC/AHA guidelines state that lowering LDL-C lowers ASCVD risk, but since no RCTs have been done to specifically treat to goals, an optimal goal is not supported 2013 ACC/AHA guidelines do not routinely allow for non-statin therapy to treat high-risk patients who: Have a less-than-anticipated response to statins Are unable to tolerate a less-than-recommended intensity of a statin Are completely statin intolerant ACC=American College of Cardiologists; AHA=American Heart Association; ASCVD= atherosclerotic cardiovascular disease; HDL-C=high-density lipoprotein cholesterol; LDL-C=low-density lipoprotein cholesterol; RCT=randomized controlled trials. Stone et al. JACC 2014; 63:2889-934; Keaney et al. NEJM 2013; epub Nov 27

Outline Cholesterol verlaging: toen, nu en straks Cholesterol verlaging toen Fire and Forget Statins only Cholesterol verlaging nu Van LDL-c target naar LDL-c eradicatie Van statines naar combinatie therapie Cholesterol verlaging toekomst Low-frequency injectables Tailored therapy

Proportional reduction in CHD risk (log scale) Genetic versus Pharmacologic LDLc decrease From LDL-c concentration to life-long LDL-c exposure 30% 20% 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 Ference BA, et al. J Am Coll Cardiol 2015;65:1552 61. 2 x 2 Factorial Mendelian Randomisation Study Genetically lower LDL-C NPC1L1 LDL-C score HMGCR LDL-C score LDLR rs2228671 LDLR 10% ABCG5/8PCSK9 46L rs6511720 rs4299376 Combined rs11206510 NPC1L1 & HMGCR rs12916 HMGCR HMGCR LDL-C LDL-C score score NPC1L1 rs217386 NPC1L1 LDL-C score A to Z GISSI- P SEARCH Lower LDL-C (mg/dl) Pharmacologically lower LDL-C IMPROVE-IT 69.5% reduction in CHD risk for each 1mmol/L (38.6mg/dL) lower LDL-C ALLHAT-LLT ~20% reduction in CHD risk for each 1mmol/L (38.6mg/dL) lower LDL-C

Concept change I: Start Early Less LDL-exposure years leads to prevention of disease formation Development of early atherosclerotic vascular disease in familial hypercholesterolaemia showing the potential impact of early recognition and treatment on evolution of the condition Wiegman et al. European Heart Journal doi:10.1093/eurheartj/ehv157

Proportional Reduction in Event Rate (SE) Concept change II: use combination therapy Ezetimibe induced LDL-c lowering reduces CV-risk 50% 40% 30% 20% CTT-meta-analysis 10% 0% IMPROVE-IT 0.5 1.0 1.5 2.0 Reduction in LDL-C (mmol/l) CTTC. Lancet 2005;366:1267 1278. CTTC. Lancet 2010;376:1670 1681. Cannon et al. N Engl J Med 2015;372:2387 2397.

PCSK9-antibody on top of statins Fourier study 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 Sabatine MS et al. Am Heart J 2016;173:94-101 Follow-up Q 12 weeks 10

LDL-C (mm) KM Rate (%) at 3 Years LDL-c reduction and CV-benefit LDL-C by 59% (from 2.4 -> 0.8 [0.5, 1.2] mm) CV outcomes in patients already on statin therapy Evolocumab was safe and well-tolerated 2,5 2,0 1,5 1,0 Placebo 59% mean decline P<0.00001 Absolute 1.45 mm (1.42-1.47) 15 10 HR 0.85 (0.79-0.92) P<0.0001 14,6 12,6 Placebo Evolocumab HR 0.80 (0.73-0.88) P<0.00001 9,9 7,9 0,5 0,0 Evolocumab Median 0.78 mm IQR [0.49-1.27] 0 4 12 24 48 72 96 120 144 168 Weeks after randomization Sabatine MS et al. New Engl J Med 2017;376:1713-22 5 0 CV death, MI, stroke, UA, cor revasc CV death, MI, stroke

CV-benefit dependent upon LDL-c reduction Independent from pathway Hazard Ratio (95% CI) per 1 mmol/l reduction in LDL-C Median follow-up of 2.2 years in FOURIER vs. 4.9 years on average in CTTC meta-analysis Supplement to Sabatine, et al. N Engl J Med 2017; March 17: online 12 CTTC data from Lancet 2010;376:1670-81

Association Between Lowering LDL-C and Cardiovascular Risk Reduction Among Different Therapeutic Interventions Weighted Between-Group Difference in Achieved Low-Density Lipoprotein Cholesterol (LDL-C) Level and Relative Risk for Major Vascular Events for Each Class of Intervention MG Silverman et al - JAMA. 2016;316(12):1289 1297. The RR for major vascular events per 1- mmol/l reduction in LDL-C was: 0.77 (95%CI, 0.71-0.84; P <.001) for statins 0.75 (95%CI, 0.66-0.86; P =.002) for established non-statin interventions that work primarily via up-regulation of LDL receptor expression (ie, diet, bile acid sequestrants, ileal bypass, and ezetimibe) 0.61 (95%CI, 0.58-0.65) for PCSK9i (P =.25). The use of statin and non-statin therapies that act via up-regulation of LDL receptor expression to reduce LDL-C were associated with similar RRs of major vascular events per change in LDL-C.

CETPi + HMG-CoA SNPs: LDL-c less predictive than apob due to discordance 21 genetic variants with naturally occurring discordance between LDL-C and apob similar in magnitude to what occurs when CETP & HMGCR inhibition are combined Odds Ratio Ference, JAMA 2017 aug.

Concept change III: Treat (much more) aggressive From threshold to eradication Achieved on-trial LDL-C concentration, mg/dl (mmol/l) < 50 (< 1.29) (n = 4375) 50 < 75 (1.29 < 1.94) (n = 10,395) 75 < 100 (1.94 < 2.58) (n = 10,091) 100 < 125 (2.58 < 3.23) (n = 8953) 125 < 150 3.23 <3.88 (n = 3128) 150 < 175 (3.88 < 4.52) (n = 836) 175 ( 4.52) (n = 375) Major CV events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 194 (4.4) 0.20 (0.16 0.25) 0.44 (0.35 0.55) 1185 (11.4) 0.40 (0.33 0.48) 0.51 (0.42 0.62) 1664 (16.5) 0.50 (0.42 0.60) 0.56 (0.46 0.67) 1480 (16.5) 0.48 (0.40 0.58) 0.58 (0.48 0.69) 557 (17.8) 0.51 (0.42 0.62) 0.64 (0.53 0.79) 184 (22.0) 0.64 (0.51 0.81) 0.71 (0.56 0.89) 123 (32.8) 1.00 (ref) 1.00 (ref) Major coronary events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 129 (2.9) 0.15 (0.12 0.20) 0.47 (0.36 0.61) 918 (8.8) 0.36 (0.29 0.43) 0.53 (0.43 0.65) 1431 (14.2) 0.50 (0.41 0.61) 0.58 (0.48 0.71) 1336 (14.9) 0.51 (0.42 0.62) 0.62 (0.51 0.75) 492 (15.7) 0.53 (0.43 0.65) 0.67 (0.55 0.83) 170 (20.3) 0.69 (0.54 0.88) 0.78 (0.61 0.99) 107 (28.5) 1.00 (ref) 1.00 (ref) Major cerebrovascular events Unadjusted HR (95% CI) Adjusted HR (95% CI)* 72 (1.6) 0.47 (0.29 0.74) 0.36 (0.22 0.59) 315 (3.0) 0.62 (0.41 0.95) 0.46 (0.30 0.71) 302 (3.0) 0.52 (0.34 0.79) 0.49 (0.32 0.75) 205 (2.3) 0.38 (0.25 0.58) 0.45 (0.29 0.69) 91 (2.9) 0.47 (0.30 0.75) 0.58 (0.36 0.91) 21 (2.5) 0.41 (0.23 0.74) 0.43 (0.24 0.78) 23 (6.1) 1.00 (ref) 1.00 (ref) Data taken from 8 randomized statin trials. Values are n (%) unless otherwise indicated. The highest LDL-C category was used as the reference category. *Adjusted for sex, age, smoking status, presence of diabetes mellitus, systolic blood pressure, HDL-C concentration and trial. HDL-C, high-density lipoprotein cholesterol; Boekholdt SM, et al. J Am Coll Cardiol 2014;64:485 94.

Very low LDL-c levels achieved beyond any target defined in guidelines Achieved LDL-C in mm at 4 Weeks At Randomization <0.5 (N=2669) 0.5-1.3 (N=8003) 1.3-1.8 (N=3444) 1.8-2.6 (N=7471) >2.6 (N=4395) Median Lipid values LDL-C, mm 2.1 2.4 2.2 2.3 3.0 Total cholesterol, mm 4.0 4.3 4.2 4.2 5.0 Triglycerides, mm 1.5 1.5 1.6 1.4 1.6 HDL-C, mm 1.1 1.1 1.1 1.1 1.2 Lipoprotein (a), nm 22 43 32 37 48 High potency statin, % (> Atorvastatin 40 mg/d) 63 69 70 70 72 Ezetimibe, % 4.1 5.0 5.4 4.6 7.4 Giugliano RP, Lancet 2017

Progressive CV-risk reduction with very-low LDLc achieved CV Death, MI, or Stroke LDL-C (mm) Adj HR (95% CI) <0.5 0.69 (0.56-0.85) 0.5-1.3 0.75 (0.64-0.86) P = 0.0001 1.3-1.8 0.87 (0.73-1.04) 1.8-2.6 0.90 (0.78-1.04) > 2.6 referent Giugliano RP, Lancet 2017 LDL-C (mm) at 4 weeks

Exploratory Analysis Pts with LDL-C <0.26 mm at 4 wks N=504: Median [IQR] LDL-C 0.18 [0.13-0.23] mm = 7 [5-9] mg/dl Cardiovascular Efficacy Safety 15 10 5 HR 0.69 (0.49-0.97) P=0.03 11,9 7,3 7,8 2.6 mm <0.26 mm HR 0.59 (0.37-0.92) P=0.02 4,4 30 25 20 15 10 HR 0.94 (0.74-1.20) P=0.61 23,3 22,8 2.6 mm <0.26 mm HR 1.08 (0.63-1.85) P=0.78 5 3,4 3,4 0 CVD, MI, Stroke, UA, Cor Revasc CVD, MI, Stroke 0 Serious adverse event AE -> drug discontinued Giugliano RP, Lancet 2017

Caveat for combining: cost-efficacy Determined by absolute CV-risk and [LDL-c] >30% 10-year ASCVD risk Clinical ASCVD + diabetes Clinical ASCVD + chronic kidney disease Recent acute coronary syndrome (<3 months) Clinical ASCVD with multiple recurrent events* Percent LDL-C reduction Add ezetimibe Combination therapy PCK9 mab PCSK9 mab maximum dose Initial LDL-C 20% 35% 50% 65% 190 mg/dl 32 18 13 10 160 mg/dl 38 22 15 12 130 mg/dl 47 27 19 15 100 mg/dl 61 35 25 19 70 mg/dl 88 50 35 27 Possible NNTs with PCKS9i for the recommended populations from the ESC/EAS consensus statement (PCSK9i recommended by the ESC/EAS for rapid progression of ASCVD and LDL-C>100 mg/dl on maximally tolerated efficacious statin and ezetimibe) Robinson JG et al. JACC. 2016.

Outline Cholesterol verlaging: toen, nu en straks Cholesterol verlaging toen Fire and Forget Statins only Cholesterol verlaging nu Van LDL-c target naar LDL-c eradicatie Van statines naar combinatie therapie, Cholesterol verlaging toekomst

Opportunities and Challenges for the future LDL-c: Improving adherance Other lipid moieties Lp(a) Remnant cholesterol Personalized medicine Cantos / COMPASS / FOURIER

Chowdhury et al., EHJ 2013;34:2940 8 Relative Risk of Death for Adherence > 80% versus < 80% Meta-analysis of 44 studies, n= 1 978 919; 135 627 CVD events; 94 126 cases of all-cause mortality 9% of all CVD events in Europe could be attributed to poor adherence to vascular medications alone

Novel therapeutic modalities: RNAi is an intrinsic process for inhibiting mrna Synthetic sirna dsrna Targeted gene silencing RISC dicer Cleavage Strand separation Complementary pairing mrna Natural process of RNA interference mrna degradation Cleavage

Mean percent change (±95% CI) Single dose results in > 3 months 50% LDL-c lowering 20 0-20 -40-60 P-value for all comparisons to placebo <0.0001 End of study if LDL-C back to baseline Placebo 200 mg 300 mg 500 mg -80 0 30 60 90 120 150 180 210 240 270 Days from first injection Ray KK, N Engl J Med 2017

Mean percent change (±95% CI) Future: twice a year injection = whole year >50 LDLc reduction 20 0-20 -40-60 P-value for all comparisons to placebo <0.0001 End of study if LDL-C back to baseline Placebo 100 mg 200 mg 300 mg -80 0 30 60 90 120 150 180 210 240 270 Days from first injection Ray KK, N Engl J Med 2017

Opportunities and Challenges for the future LDL-c: Improving adherance Other lipid moieties Lp(a) Remnant cholesterol Personalized medicine Cantos / COMPASS / FOURIER

Lp(a) is a causal factor in atherogenesis

Lp(a) (q4 vs q1) and Residual CV-Risk in Primary and Secondary prevention Tsimikas Curr Opin Endocrinol Diabetes Obes 2016;23:157 164 Q4 LDL-C: AIM-HIGH 54, JUPITER 62 and LIPID 112 mg/dl Q4 of Lp(a): 50-73.7 mg/dl

Novel therapeutic options in Lp(a) patients Antisense for apo(a) Prakash TP, Nucleic Acids Res 2014

Reduction in Lp(a) and OxPL following 2nd generation apo(a)-antisense Viney, Stroes, Tsimikas S, Lancet 2016 Injection site reactions: >80 %

Effect of gal-nac apo(a) antisense of Lp(a) *** *** *** * * *** * *** *** *** *** *** Weekly dose ED 50 of 3.9 mg (0.05 ml) Viney, Stroes, Tsimikas, Lancet 2016 Injection site reactions: 0 %

Varbo JACC 2013 Remnant cholesterol causally related to CVD-risk Mendelian Randomisation studies

Remnant cholesterol is next on the list Apo-CIII antisense potently reduces TG levels and remant chol. Gaudet et al. NEJM 2015

Opportunities and Challenges for the future LDL-c: Improving adherance Other lipid moieties Lp(a) Remnant cholesterol Personalized medicine CANTOS / COMPASS / FOURIER

The need for Personalized medicine Multiple effective therapeutic regimens Differential benefits within target population

Benefit of anti-inflammatory intervention Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) Stable CAD (post MI) On Statin, ACE/ARB, BB, ASA Persistent Elevation of hscrp (> 2 mg/l) N = 10,061 39 Countries April 2011 - June 2017 1490 Primary Events Randomized Canakinumab 50 mg SC q 3 months Randomized Canakinumab 150 mg SC q 3 months Randomized Canakinumab 300 mg SC q 3 months* Randomized Placebo SC q 3 months Primary CV Endpoint: Nonfatal MI, Nonfatal Stroke, Cardiovascular Death (MACE) Key Secondary CV Endpoint: MACE + Unstable Angina Requiring Unplanned Revascularization (MACE+) Critical Non-Cardiovascular Safety Endpoints: Cancer and Cancer Mortality, Infection and Infection Mortality Ridker N Engl J Med 2017

Cumulative Cumulative Incidence Incidence (%) 0.00 0.05 0.10 0.15 0.20 0.25 IL1 beta antibodies MACE reduce CV-MACE (CANTOS) Placebo 150/300mg Placebo SC q 3 months Canakinumab 150/300 SC q 3 months HR 0.85 95%CI 0.76-0.96 P = 0.007 39% reduction in hscrp No change in LDLC 15% reduction in MACE Differential benefits: > median CRP reduction? HR 0.73 0 1 2 3 4 5 Follow-up Years Ridker PM et al, NEJM 2017

CANTOS: Additional Outcomes (per 100 person years of exposure) Adverse Event Placebo (N=3347) Canakinumab SC q 3 months 50 mg (N=2170) 150 mg (N=2284) 300 mg (N=2263) P-trend Any SAE 12.0 11.4 11.7 12.3 0.43 Leukopenia 0.24 0.30 0.37 0.52 0.002 Any infection 2.86 3.03 3.13 3.25 0.12 Fatal infection 0.18 0.31 0.28 0.34 0.09/0.02* Injection site reaction 0.23 0.27 0.28 0.30 0.49 Any Malignancy 1.88 1.85 1.69 1.72 0.31 Fatal Malignancy 0.64 0.55 0.50 0.31 0.0007 Arthritis 3.32 2.15 2.17 2.47 0.002 Osteoarthritis 1.67 1.21 1.12 1.30 0.04 Gout 0.80 0.43 0.35 0.37 0.0001 ALT > 3x normal 1.4 1.9 1.9 2.0 0.19 Ridker N Enlg J Med 2017

Eikelboom J, N Engl J Med 2017 Rivaroxaban reduces CV-risk in patients with stable CV-disease (COMPASS)

At the expense of higher bleeding rate (COMPASS) Eikelboom J, N Engl J Med 2017

Landrey M, N Engl J Med 2017 Effects of CETPi (anacetrapib) on lipids

Landrey M, N Engl J Med 2017 Anacetrapib (CETPi) decreases CV-risk in stable CVD patients (REVEAL)

Proportional reduction in CHD/MI vs absolute reduction in non-hdl c Landrey M, N Engl J Med 2017; Ference B, JAMA 2017.

Future CV-treatment: Personalized algorithms High CV-risk High Intensity Statin Residual Lipid Risk Residual Inflamm Risk Residual Thromb. Risk Application of a readily LDL 70 applicable mg/dl (1.8 mmol/l) marker of benefit/harm : LDL 92 mg/dl (2.4 mmol/l) Prior to initiating personalized therapy LDL 130 mg/dl (3.3 mmol/l) CRP 1.8 mg/l CRP 3.8 mg/l CRP 1.9 mg/l Further lipid modulation Ezetimibe 6% RRR PCSK9-ab: (15-) 30% RRR CETPi: 9% RRR Inflammation Reduction IL1B-ab: (15-) 27% RRR Coagulation Reduction Rivaroxa: 24% RRR

Nahrendorf, Stroes, et al J Am Coll Cardiol 2015;65(15)1583-91. Ganz, P. et al..jama 2016;315:2532-41 Future selection for personalized medicine: Most effective drug for most suitable patient Multimodal imaging: Active pathway analysis using proteomics

Opportunities and Challenges for the future LDL-c: Improving adherance Other lipid moieties Lp(a) Remnant cholesterol Personalized medicine CANTOS / COMPASS / FOURIER

AMC: John Kastelein Bert Groen Kees Hovingh Max Nieuwdorp Europe: Alberico Catapano Wolfgang Koenig Borge Nordestgaard Acknowledgements US: Matthias Nahrendorf Sam Tsimikas Zahi Fayad PhDs: Renate Hoogeveen Lotte Stiekema Rens Reeskamp Rutger Verbeek Fleur vd Valk Simone Verweij Funding: HORIZON2020 REPROGRAM; CVON-GENIUS; FP7-Nano-Athero; FP7-TRANSCARD