Intensivierte Cholesterin-Senkung: Wie und für wen?

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1 Intensivierte Cholesterin-Senkung: Wie und für wen?

2 Senkung des LDL-Cholesterin-Spiegels mit Statinen bei Patienten mit oder ohne vorige KHK verbessert die kardiovaskuläre Prognose 1,2 : je niedriger desto besser CHD Events (%) TNT (80mg atorvastatin) CARE HPS LIPID 4S TNT (10mg atorvastatin) HPS CARE WOSCOPS LIPID WOSCOPS 5 ASCOT AFCAPS AFCAPS 0 ASCOT LDL Cholesterol 4S Secondary prevention trials 1 Active treatment/statin Placebo Primary prevention trials 2 Active treatment/statin Placebo (mg/dl) (mmol/l) 1. LaRosa JC, et al. N Engl J Med. 2005;352: O Keefe J, et al. J Am Coll Cardiol. 2004;43:

3 Senkung des LDL-Cholesterin ist primäres Behandlungsziel bei Patienten mit Hypercholesterinämie und hohem KHK-Risiko Die Empfehlungen der European Society of Cardiology (ESC) und European Atherosclerosis Society (EAS) sowie des National Cholesterol Education Program (NCEP)-Adult Treatment Panel (ATP) III empfehlen die Senkung des LDL-C auf <100 mg/dl (< 2.6 mmol/l) bei Hochrisikopatienten und. < 70 mg/dl (< 1.8 mmol/l) bei Patienten mit höchstem KHK-Risiko 1,2 Diese Ziele werden bei vielen Patienten mit den derzeitig verfügbaren Therapien nicht erreicht 3-6 High CV risk LDL-C Target <100 mg/dl 2.5 mmol/l Very High CV risk LDL-C Target <70 mg/dl 1.8 mmol/l 1. Reiner Z, et al. ESC/EAS Guidelines. Eur Heart J. 2011;32: Grundy SM, et al. Circulation. 2004;110: Go AS, et al. Circulation. 2013;127:e6-e Jones PH, et al. J Am Heart Assoc. 2012;1:e doi: /JAHA Stein EA, et al. Am J Cardiol. 2003;92: Pijlman AH, et al. Atherosclerosis. 2010;209:

4 Percentage reduction of LDL cholesterol to achieve goals according to starting levels and efficacy of different statins at different dosages Catapano et al. EHJ 2016 in press

5 Patientengruppen die einer weiteren LDL-C senkenden Therapie bedürfen Hoch-Risiko-Patienten mit unzureichend gesenktem LDL-C trotz maximaler Statin-Behandlung Höchstrisikopatienten (Zielwert LDL-C < 1.8 mmol/l): 76% 1 Hochrisikopatienten (Zielwert LDL-C < 2.6 mmol/l): 23% 2,3 Fam. Hypercholesterinämie (Zielwert LDL-C < 2.6 mmol/l): 80% 2,3 Patienten, die wegen Nebenwirkungen keine Statine einnehmen können oder wollen (ca. 60% der Patienten, die eine Statintherapie abbrechen (12%) 4 1. Jones PH, et al. J Am Heart Assoc. 2012;1:e Stein EA, et al. Am J Cardiol. 2003;92: Pijlman AH, et al. Atherosclerosis. 2010;209: Cohen JD, et al. J Clin Lipidol. 2012;6:

6 IMPROVE IT: Study Design Patients stabilized post ACS 10 days: LDL-C *mg/dL (or **mg/dL if prior lipid-lowering Rx) *3.2mM **2.6mM N=18,144 Standard Medical & Interventional Therapy Simvastatin 40 mg Uptitrated to Simva 80 mg if LDL C > 79 (adapted per FDA label 2011) Ezetimibe / Simvastatin 10 / 40 mg Follow-up Visit Day 30, every 4 months 90% power to detect ~9% difference Duration: Minimum 2 ½-year follow-up (at least 5250 events) Primary Endpoint: CV death, MI, hospital admission for UA, coronary revascularization ( 30 days after randomization), or stroke Cannon CP AHJ 2008;156:826 32; Califf RM NEJM 2009;361:712 7; Blazing MA AHJ 2014;168:205 12

7 IMPROVE IT: LDL C Levels 1 Yr Mean LDL C TC TG HDL hscrp Simva EZ/Simva Δ in mg/dl Median Time avg 69.5 vs mg/dl Cannon CP, et al. N Engl J Med. 2015;372(25):

8 IMPROVE IT: 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 Cannon CP, et al. N Engl J Med. 2015;372(25):

9 Safety No statistically significant differences in cancer or muscle or gallbladder related events Simva n=9077 % EZ/Simva n=9067 % p ALT and/or AST 3x ULN Cholecystectomy Gallbladder related AEs Rhabdomyolysis* Myopathy* Rhabdo, myopathy, myalgia with CK elevation* Cancer* (7 yr KM %) % = n/n for the trial duration Cannon CP, et al. N Engl J Med. 2015;372(25):

10 Log-Linear Association Between Genetically and Pharmacologically Mediated Lower Low-Density Lipoprotein Cholesterol and Risk of Coronary Heart Disease Up to 63,746 Cases of CHD and 130,681 Control Subjects Ference et al. J Am Coll Cardiol 2015;65:

11 PCSK9 Mutationen und LDL-Cholesterin LDL-C gain of function Mutationen LDL-C loss of function Mutationen S127R F216L D374Y N425S R496W SP Prodomain Catalytic domain C terminal R46L DR97G106RY142X L253F A443T C679X Wildtyp D35Y L108R S127R F216L R218S D374Y R46L DR97 G106R Y142X C679X C679X/C679X DR97/Y142X PCSK9* gain of function Mutationen PCSK9* loss of function Mutationen LDL-C LDL-C LDL-C (mg/dl) *PCSK9 = Protein Convertase Subtilisin/Kexin Typ 9 S. Poirier and G. Mayer, Drug Des Devel. Ther. 7, 1135 (2013).

12 Loss of function (LOF) Mutationen in PCSK9 sind mit niedrigem LDL-Cholesterin und verringertem Risiko für kardiovaskulärer Erkrankungen assoziiert Frequenz (%) Frequenz (%) Afroamerikanische Probanden Wildtyp (n=3.278) Kaukasische Probanden Wildtyp (n=9.223) (mg/dl) LDL-Cholesterin Afroamerikanische Probanden mit LOF*-Mutation (n=85) Kaukasische Probanden mit LOF*-Mutation (n=301) (mg/dl) LDL-Cholesterin Koronare Herzerkrankung (%) Afroamerikaner 88% Reduktion (p=0,008) Amerikaner europäischer Abstammung 47% Reduktion (p=0,003) Nein Ja loss of function Mutation J. C. Cohen et al., N. Engl. J. Med. 354, 1264 (2006).

13 PCSK9 verringert die zelluläre Aufnahme von LDL durch LDL- Rezeptoren 23 % nicht auf Zielwert Krähenbühl., Pavlik, von Eckardstein (2016): Drugs 76:

14 Statin-Effekte auf PCSK9, LDL-Rezeptor und LDL-Cholesterin Berthold HK, et al. PLoS One. 2013;8(3). Krähenbühl., Pavlik, von Eckardstein (2016): Drugs 76:

15 Hemmung von PCSK9 durch Antikörper erhöht die Verfügbarkeit von LDL- Rezeptoren und die zelluläre Aufnahme von LDL Krähenbühl., Pavlik, von Eckardstein (2016): Drugs 76:

16 Phase I Studien zu verschiedenen PCSK9 Inhibitoren Dadu, R. T. & Ballantyne, C. M. Nat. Rev. Cardiol. 11, (2014)

17 Plasmakinetiken von Alirocumab, PCSK9 und LDL-C Freies/Gesamt PCSK9 Konz. (ng/ml) Gesamt Alirocumab (ng/ml) x 0, Freies PCSK9, Gesamt-Alirocumab- Konz. und Mean % Änderung LDL-C vs Zeit LDL C % Änderung (mean) Alirocumab (total) Zeit (Stunden) free PCSK9 LDL c *Alirocumab=SAR236553/REGN727 Stein EA et al. NEJM. 2012; 366:

18 LAPLACE-2: LDL-C Response at Mean of Weeks 10 and 12 Evolocumab Q2W & QM: 63 to 75% reductions in LDL-C versus placebo Ezetimibe: 19 to 32% reductions in LDL-C versus placebo Mean Percent Change from Baseline in LDL-C and 95% CI Atorvastatin 80 mg Rosuvastatin 40 mg Atorvastatin 10 mg Rosuvastatin 5 mg Simvastatin 40 mg Placebo Q2W Placebo QM Ezetimibe QD + Placebo Q2W Ezetimibe QD + Placebo QM Evolocumab Q2W Evolocumab QM All treatment differences versus placebo and ezetimibe were statistically significant (P < 0.001). Vertical lines represent 95% CIs. No notable differences were observed between the mean of weeks 10 and 12 and week 12 alone. LDL-C, low-density lipoprotein cholesterol; Q2W, biweekly; QM, monthly. 18

19 Der PCSK9-Hemmer Evolocumab senkt den LDL-C Spiegel um ca. 60% unabhängig von der parallelen lipidsenkenden Therapie (Diät, tief- oder hochdosiertes Statin, Ezetimib) 901 patients were started on background lipid-lowering therapy with diet alone or diet plus atorvastatin at a dose of 10 mg daily, atorvastatin at a dose of 80 mg daily, or atorvastatin at a dose of 80 mg daily plus ezetimibe at a dose of 10 mg daily, for a runin period of 4 to 12 weeks. Patients with an LDL cholesterol level of 75 mg per deciliter (1.9 mmol per liter) or higher were then randomly assigned in a 2:1 ratio to receive either evolocumab (420 mg) or placebo every 4 weeks. Blom and DESCARTES investigators N Engl J Med 2014;370:

20 Alirocumab Maintained Consistent LDL-C Reductions Over 52 Weeks Achieved LDL-C Over Time on Background of Maximally-Tolerated Statin ±Other LLT LDL-C, LS mean (SE), mmol/l Placebo: FH I Alirocumab: FH I FH II FH II 4.0 mmol/l 4.0 mmol/l 3.7 mmol/l 3.5 mmol/l 1.8 mmol/l 1.9 mmol/l 1.8 mmol/l 1.7 mmol/l mg/dl 20 Dose if LDL-C >70 mg/dl at W8 Week Intent-to-treat (ITT) Analysis LLT = lipid-lowering therapy

21 Most hefh Patients Receiving Alirocumab on Background Statin Other LLT Achieved LDL-C Goals % patients Proportion of patients reaching LDL-C goal at Week 24 FH I 81.4% FH II 72.2% Alirocumab Placebo % % 0 P< Very high-risk: <1.81 mmol/l (70 mg/dl); high-risk: <2.59 mmol/l (100 mg/dl). LLT = lipid-lowering therapy. 21 Intent-to-treat (ITT) Analysis

22 ODYSSEY ALTERNATIVE Study Design Statin intolerant patients* (by medical history) with LDL-C 70 mg/dl (very-high CV risk) or 100 mg/dl (moderate/ high risk) Placebo PO QD + Placebo SC Q2W R N=100 Double-Blind Treatment Period (24 Weeks) Alirocumab 75/150 mg SC Q2W + placebo PO QD administered via single 1 ml injection using prefilled pen for self-administration N=100 N=50 Per-protocol dose possible depending on W8 LDL-C Ezetimibe 10 mg PO QD + placebo SC Q2W Atorvastatin 20 mg PO QD + placebo SC Q2W OLTP/8 week FU Assessments W -4 W0 W4 W8 W12 W16 W24 Patients discontinued if muscle-related AEs reported with placebos during run-in Per-protocol dose increase if Week 8 LDL-C 70 or 100 mg/dl (depending on CV risk) Primary endpoint (LDL-C % change from baseline, ALI and EZE only) Safety analysis (all groups) *Unable *Unable to tolerate tolerate least at two least different two different statins, statins, including including one at one the lowest at the lowest dose, due dose, to due muscle-related to muscle-related symptoms symptoms 22 4-week single-blind placebo run-in follows 2-week washout of statins, ezetimibe and red yeast rice. OLTP: Alirocumab open-label treatment period; W, Week.

23 23 LS mean (SE) % change from baseline to Week 24 Alirocumab Significantly Reduced LDL-C from Baseline to Week 24 versus Ezetimibe % change from baseline to Week 24 in LDL-C ITT (primary endpoint) On-treatment (key secondary endpoint) n= % received 150 mg Q2W at W % n= % Absolute change of -33 (4.2) mg/dl n= % n= % Absolute change of -38 (4.2) mg/dl Alirocumab Ezetimibe Absolute Absolute change of change of -84 (4.1) mg/dl -96 (3.9) mg/dl LS mean difference (SE) vs ezetimibe: (3.1); P< LS mean difference (SE) vs ezetimibe: (2.8); P< % of 109 patients who received at least one injection after Week 12 had dose increase.

24 Fewer Skeletal Muscle AEs with Alirocumab than with Atorvastatin Kaplan-Meier estimates for time to first skeletal muscle event Cumulative probability of event Atorvastatin Ezetimibe Alirocumab Cox model analysis: HR ALI vs ATV = 0.61 (95% CI: 0.38 to 0.99), nominal P=0.042 HR ALI vs EZE = 0.71 (95% CI: 0.47 to 1.06), nominal P= Week 24 Pre-defined category including myalgia, muscle spasms, muscular weakness, musculoskeletal stiffness, muscle fatigue. ALI, alirocumab; ATV, atorvastatin, EZE, ezetimibe.

25 Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events Randomized trial involving 2341 patients at high risk for cardiovascular events who had LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or more and were receiving treatment with statins at the maximum tolerated dose (the highest dose associated with an acceptable sideeffect profile), with or without other lipidlowering therapy. Patients were randomly assigned in a 2:1 ratio to receive alirocumab (150 mg) or placebo as a 1-ml subcutaneous injection every 2 weeks for 78 weeks. The primary efficacy end point was the percentage change in calculated LDL cholesterol level from baseline to week 24. Robinson et al. N Engl J Med 2015;372:

26 Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events Two open-label, randomized trials, enrolling 4465 patients who had completed 1 of 12 phase 2 or 3 studies ( parent trials ) of evolocumab. Eligible patients were randomly assigned in a 2:1 ratio to receive either evolocumab (140 mg every 2 weeks or 420 mg monthly) plus standard therapy or standard therapy alone. Follow up for a median of 11.1 months Data from the two trials were combined Sabatine et al. N Engl J Med 2015;372:1500-9

27 Meta-Analysis on Effects of PCSK9 Antibodies in Adults With Hypercholesterolemia on Total and Cardiovascular Mortality and Myocardial Infarction Total Mortality: OR 0.45 [CI, 0.23 to 0.86]; P = CV Mortality: OR, 0.50 [CI, 0.23 to 1.10]; P = AMI : OR 0.49 [CI, 0.26 to 0.93]; P = Navarese et al. Ann Intern Med. 2015;163:40-51

28 Meta-Analysis on Serious Adverse Events (SAE) and CK-Activity Elevation Caused by Treatment with PCSK9 Antibodies in Adults With Hypercholesterolemia CK elevation: OR 0.72 [CI, 0.54 to 0.96]; P = SAE: OR 1.01 [CI, ]; n.s. Navarese et al. Ann Intern Med. 2015;163:40-51

29 Zusammenfassung Epidemiologische, genetische und klinische Studien sprechen für die kausale Bedeutung von LDL-Cholesterin in der Atherogenese. Statine oder Ezitimibe senken LDL-Cholesterin durch Hochregulation der LDL-Rezeptor-Expression und reduzieren das Risiko kardiovaskulärer Erkrankungen. Gain-of-function oder loss-of-function Mutationen in PCSK9 verursachen erhöhte bzw. erniedrigte LDL Cholesterin Spiegel. Statine erhöhen die Genexpression und die Plasmaspiegel von PCSK9 und wirken dadurch der Hochregulation des LDLR durch Statine entgegen. PCSK9 Inhibitoren bewirken eine 65 70% Senkung des LDL-C zusätzlich zur Statintherapie Derzeit werden mehrere monoklonale Antikörper gegen PCSK9 in Phase III Studien evaluiert. Bisherige Auswertungen und Meta-Analysen weisen auf eine Senkung der Mortalität und Herzinfarktrate sowie auf Sicherheit

30 EAS/ESC Recommendations for the pharmacological treatment of hypercholesterolaemia Schettler et al. für Deutsche Gesellschaft für Nephrologie (DGfN) Verband Deutsche Nierenzentren (DN) Internist :

31 Diagnostisches und therapeutisches Vorgehen bei vermuteter Statin-Intoleranz AGLA, modifiziert nach ESC/EAS-Empfehlungen : Stroes et al. Eur Heart J 2015; 36:

32 Treatment algorithm for severe familial hypercholesterolemia 23 % nicht auf Zielwert Santos et al. for International Atherosclerosis Society in Lancet Diabetes Endocrinol 2016 in press

33 Therapiealgorithmus zur Lipoprotein- Apherese und PCSK9- Inhibition bei schwerer Hypercholesterinämie oder isolierter Lipoprotein(a)- Hyperlipoproteinämie Schettler et al. für Deutsche Gesellschaft für Nephrologie (DGfN) Verband Deutsche Nierenzentren (DN) Internist :

34 Effect of PCSK9 Inhibitors on Total Health Care Spending Over 5 Years Adding PCSK9 inhibitors to statins in heterozygous FH was estimated to prevent MACE at a cost of $ per QALY gained compared with adding ezetimibe to statins (80% uncertainty interval [UI], $ $ ). In ASCVD, adding PCSK9 inhibitors to statins was estimated to prevent 4.3 million MACE compared with adding ezetimibe at $ per QALY (80% UI, $ $ ). Kazi et al. JAMA. 2016;316(7):

35 Incremental Cost-effectiveness Ratio (ICER) of PCSK9 Inhibitor Therapy Among Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease 23 % nicht auf Zielwert 4536 USD 2261 USD 6810 USD Kazi et al. JAMA. 2016;316(7): In the base case, status quo statin plus PCSK9 inhibitor therapy is compared with status quo statin plus ezetimibe (black line). When PCSK9 inhibitor therapy costs less than $7049 per year (inflection in the graph), ezetimibe is eliminated by extended dominance and status quo statin plus PCSK9 inhibitory therapy is compared directly with status quo statin therapy (gray line).