Cholesterol verlaging (om cardiovasculair risico te verlagen) Toen, - PowerPoint PPT Presentation

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 No diabetes mellitus and age Diabetes mellitus (type 1 or 2) LDL-C Clinical ASCVD of 40 – 75 yr and and age of 40 – 75 yr and LDL-C ≥190 mg/dL 70 – 189 mg/dL LDL-C 70 – 189 mg/dL Calculate 10-year risk* of Calculate 10-year risk* of ASCVD ASCVD If risk <7.5%*, moderate- High-intensity High-intensity statin If risk ≥7.5, moderate -to-high- intensity statin therapy statin therapy therapy intensity statin therapy If risk ≥7.5%*, 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, J ACC 2013 ePub Nov 12.; Stone et al. J ACC 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

Genetic versus Pharmacologic LDLc decrease From LDL- c concentration to ‘life -long LDL- c exposure’ 2 x 2 Factorial Mendelian Randomisation Study 69.5% reduction in CHD risk for each 1mmol/L 30% in CHD risk (log scale) (38.6mg/dL) lower LDL-C Proportional reduction Genetically lower LDL-C 20% NPC1L1 LDL-C score ~20% reduction GISSI- A to HMGCR LDL-C score in CHD risk for P Z LDLR Pharmacologically each 1mmol/L rs2228671 LDLR lower LDL-C ABCG5/8 (38.6mg/dL) rs6511720 10% PCSK9 46L Combined rs4299376 rs11206510 lower LDL-C NPC1L1 & ALLHAT-LLT HMGCR rs12916 HMGCR LDL-C HMGCR IMPROVE-IT score LDL-C score NPC1L1 LDL-C NPC1L1 rs217386 SEARCH score 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 Lower LDL-C (mg/dL) Ference BA, et al. J Am Coll Cardiol 2015;65:1552 – 61.

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

Concept change II: use combination therapy Ezetimibe induced LDL-c lowering reduces CV-risk Proportional Reduction in Event 50% 40% Rate (SE) 30% CTT-meta-analysis 20% 10% IMPROVE-IT 0% 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 RANDOMIZED Evolocumab SC Placebo SC DOUBLE BLIND 140 mg Q2W or 420 mg QM Q2W or QM Follow-up Q 12 weeks 10 Sabatine MS et al. Am Heart J 2016;173:94-101

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 Placebo HR 0.85 (0.79-0.92) Evolocumab P<0.0001 2,5 Placebo 14,6 HR 0.80 15 (0.73-0.88) 2,0 12,6 59% mean decline KM Rate (%) at 3 Years P<0.00001 P<0.00001 LDL-C (mM) 9,9 1,5 Absolute↓1.45 mM 10 7,9 (1.42-1.47) 1,0 Evolocumab 5 0,5 Median 0.78 mM IQR [0.49-1.27] 0,0 0 4 12 24 48 72 96 120 144 168 0 Weeks after randomization CV death, MI, stroke, CV death, MI, stroke Sabatine MS et al. New Engl J Med 2017;376:1713-22 UA, cor revasc

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 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. MG Silverman et al - JAMA. 2016;316(12):1289 1297.

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 – < 75 75 – < 100 100 – < 125 125 – < 150 150 – < 175 ≥ 175 < 50 (1.29 – < 1.94) (1.94 – < 2.58) (2.58 – < 3.23) 3.23 – <3.88 (3.88 – < 4.52) (≥ 4.52) (< 1.29) (n = 4375) (n = 10,395) (n = 10,091) (n = 8953) (n = 3128) (n = 836) (n = 375) Major CV events 194 (4.4) 1185 (11.4) 1664 (16.5) 1480 (16.5) 557 (17.8) 184 (22.0) 123 (32.8) 0.20 (0.16 – 0.25) 0.40 (0.33 – 0.48) 0.50 (0.42 – 0.60) 0.48 (0.40 – 0.58) 0.51 (0.42 – 0.62) 0.64 (0.51 – 0.81) Unadjusted HR (95% CI) 1.00 (ref) Adjusted HR (95% CI)* 0.44 0.51 0.56 0.58 0.64 0.71 1.00 (0.35 – 0.55) (0.42 – 0.62) (0.46 – 0.67) (0.48 – 0.69) (0.53 – 0.79) (0.56 – 0.89) (ref) Major coronary events 129 (2.9) 918 (8.8) 1431 (14.2) 1336 (14.9) 492 (15.7) 170 (20.3) 107 (28.5) 0.15 (0.12 – 0.20) 0.36 (0.29 – 0.43) 0.50 (0.41 – 0.61) 0.51 (0.42 – 0.62) 0.53 (0.43 – 0.65) 0.69 (0.54 – 0.88) Unadjusted HR (95% CI) 1.00 (ref) 0.47 (0.36 – 0.61) 0.53 (0.43 – 0.65) 0.58 (0.48 – 0.71) 0.62 (0.51 – 0.75) 0.67 (0.55 – 0.83) 0.78 (0.61 – 0.99) Adjusted HR (95% CI)* 1.00 (ref) Major cerebrovascular events 72 (1.6) 315 (3.0) 302 (3.0) 205 (2.3) 91 (2.9) 21 (2.5) 23 (6.1) 0.47 (0.29 – 0.74) 0.62 (0.41 – 0.95) 0.52 (0.34 – 0.79) 0.38 (0.25 – 0.58) 0.47 (0.30 – 0.75) 0.41 (0.23 – 0.74) Unadjusted HR (95% CI) 1.00 (ref) 0.36 (0.22 – 0.59) 0.46 (0.30 – 0.71) 0.49 (0.32 – 0.75) 0.45 (0.29 – 0.69) 0.58 (0.36 – 0.91) 0.43 (0.24 – 0.78) Adjusted HR (95% CI)* 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.