Nephrologisches Zentrum Göttingen GbR Priv. Doz. Dr. med. V. Schettler

Transcription

1 Therapeutic algorithm for Patients with severe Hypercholesterolemia or isolated Lipoprotein(a)-Hyperlipoproteinemia with progressive cardiovascular disease: PCSK9- Inhibitors, Lipoprotein Apheresis or both? Nephrologisches Zentrum Göttingen GbR Priv. Doz. Dr. med. V. Schettler

2 Disclosures The speaker declares, that he had held lectures for: Amgen GmbH B.Braun Avitum AG DIAMED Medizintechnik GmbH Fresenius Medical Care AG & Co. KGaA Genzyme GmbH Kaneka Pharma Europe N.V. German Branch KWHC Health Consulting GmbH MSD SHARP & DOHME GMBH Novartis Pharma GmbH Pfizer Consumer Healthcare GmbH Sanofi-Aventis GmbH

3 Familial Hyperlipidaemia (FH) with heterozygous expressions (he) (FH he ) - burden of high LDL-C levels Nordestgaard et al., Eur Heart J 2013;34: a. Neil et al., Eur Heart J 2008;29:

4 LDL-C-lowering studies and reduction of coronary events POSCH-PL 4S-PL Coronary Events (%) ? CARE-Rx ASCOT-Rx POSCH-Rx HPS-Rx 4S-Rx LIPID-PL HPS-PL LIPID-Rx WOSCOPS-Rx ASCOT-PL AFCAPS-Rx CARE-PL LDL Cholesterol (mg/dl) WOSCOPS-PL LRC-Rx AFCAPS-PL LRC-PL Secondary Prevention Primary Prevention HPS Statin Studies Non-Statin Studies based on Kastelein, Atherosclerosis 1999;143:S17-S21 *Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.

5 but EUROSPIRE IV says CHD patients' data from centres in 24 European countries (<70 mg/dl) Too many CHD patients with dyslipidaemia are still inadequately treated Most of these patients on statin therapy are not achieving the treatment targets. Reiner et al., Atherosclerosis 2016;246:

6 Overview lipid lowering/ modifying strategies PCSK9i ipcsk9 PCSK9LDL-R Statins HMG-Reductase based on Gotto & Moon, Nat Rev Cardiol 2013;10:

7 Specific PCSK9 mutations induce low LDL-C levels: low incidence for cardiovascular events PCSK9 mutation: LDL-C levels: 138 mg/dl vs. 100 mg/dl (black American inhabitants) - 88% events Cohen et al., N Engl J Med 2006;354:

8 New drugs on the block PSCK9-Inhibitiors MTP-Inhibitors Antisense therapy targeting Lp(a): ISIS Results of new drugs in lowering lipids/ lipoproteins may be convincing, but we have to wait on results from cardiovascular outcome studies!

9 The first major chapter: Before the initiation of lipoprotein apheresis LDL-Cholesterol lowering concept: Drugs Drug therapy 1) Statin: Maximal tolerable dosage (optimal 80 mg atorvastatin or maximal permitted dosages of other statins) per day 2a) Ezetimibe (!): 10 mg per day in combination with or/ and 2b) Bile acid sequestrants (BAS): Maximal tolerable dosages, to meals (optimal 24 g cholestyramine, 30 g colestipol oder 3,75 g colesevelam per day) or/ and in combination with 3) (Mipomersen), PCSK-9 Antibodies (!), CETP-Inhibitors(?), etc.? When these therapeutic concepts fail, indication of lipoprotein apheresis should be considered by cardiologist, angiologist, endocrinologist, but not nephrologist! German Working Group for Therapeutic Apheresis

10 Metabolism of Proprotein convertase subtilisin/kexin type 9 (PCSK9) Lambert et al., J Lipid Res. 2012;53: Weinreich & Frishman, Cardiol Rev 2014;22:

11 Antibodies target: PCSK9 Cell membrane Lambert et al., J Lipid Res. 2012;53: Weinreich & Frishman, Cardiol Rev 2014;22:

12 Most of the patients achieved the LDL-C goal: combination of Alirocumab and Background Statin ± Other LLT % patients 90 P< % Very high-risk: LDL-C <1.8 mmol/l (70 mg/dl) High-risk: <2.6 mmol/l (100 mg/dl) <1.8 mmol/l (70 mg/dl) regardless of risk 79% P< Alirocumab Placebo % 8% 0 Intent-to-treat (ITT) analysis; LLT = lipid-lowering therapy

13 Patient example LA + (statin) + PCSK9i cholesterol and LDL-cholesterol (mg/dl) Start of PCSK9i Statins paused 58y patient LDL-R frame shift mutation in exon 18 since 1989 LA - prior: 3 vessel CHD 2 myocardial infarctions CABG rotablator atherectomy (RIVA) time [months] Schettler VJ et al., Cardiovasc 2016 in press

14 Success of PCSK9i therapies? Total mortality Cardiovascular mortality Navarese et al., Ann Intern Med 2015;163:40-51.

15 The second major chapter: Initiation of lipoprotein apheresis LDL-Cholesterol lowering concept Threshold level for lipoprotein apheresis indication Patients suffering from cardiovascular, cerebrovascular or peripheral arterial disease or extended atherosclerosis With respect to the given actual ESC guidelines if LDL-cholesterol levels remain increased (>~100 mg/dl (2.6 mmol/l) for risk patients; > ~70 mg/dl (1.8 mmol/l) for high risk patients) although lipid-lowering diet and drug regimens were proved to be ineffective, lipoprotein apheresis should be initiated. During LA all known cardiovascular risk factors should be treated with respect to the given guidelines (AHA, ESC ). A decrease of more than 60% from of LDL-Cholesterol initial levels should be achieved by lipoprotein apheresis. The optimal mean goal level is <70 mg/dl (1.8 mmol/l). German Working Group for Therapeutic Apheresis

16 Can Lp(a) levels reduced by PCSK9i (e.g. Evolocumab)? Reduction rates mean up to xy %! No outcome studies! Desai et al., Circulation 2013;128:962-9.

17 A look in details TESLA Part B) nmol/l in mg/dl x* 0,4167 z.b. 41 nmol/l = 17,1 mg/dl Desai et al., Circulation 2013;128: Raal et al, Lancet 2015;385: McConnell et al., J Clin Lipidol2014;8: Schettler et al., Cardiovasc 2015;15:41-3.

18 Meta-analysis of 20 Studies: Lp(a) decrease induced by PCSK9i Figure 9. Forest plots depicting the effect of proprotein convertase subtilisin/kexin9 monoclonal antibodies on lipoprotein(a). For high risk Lp(a) patients these reduction rates induced by PCSK9i are unimportant. Li et al., J Am Heart Assoc. 2015;4: e

19 The third major chapter: Initiation of lipoprotein apheresis Lp(a)-Cholesterol lowering concept Threshold level for lipoprotein apheresis indication Patients suffering from cardiovascular, cerebrovascular or peripheral arterial disease or extended atherosclerosis If the Lp(a) levels are increased (> 60 mg/dl (~ > 120 nmol/l)), lipoprotein apheresis should be initiated. All known cardiovascular risk factors should be treated with respect to the given guidelines (AHA, ESC ). A decrease of more than 50% from of Lp(a) initial levels should be achieved by lipoprotein apheresis. The optimal goal level is <30 mg/dl (<70 nmol/l). German Working Group for Therapeutic Apheresis

20 Now, can we create a new lipid lowering algorithm for patients at very high risk?

21 Potential treatment algorithm in relation to the use of PCSK9-AB and LA Neumann et al., Blood Purif 2016;41:

22 Therapeutic Algorithm PCSK9i and LDL-Apheresis or both? for the German Society of Nephrology (DGfN) and Foundation of German Centres of Nephrology (VDN) Schettler VJ et al., Internist 2016; ;57:511-6.

23 Therapeutic Algorithm PCSK9i, LA Schettler VJ et al., Internist 2016; ;57:511-6.

24 Patients example: intolerance of statins use of PCSK9i approved? Cholesterol and LDL-Cholesterol (mg/dl) Last try of statins PCSK9iapplication 58J. patient with 2 vessel CHD Statin intolerance PCSK9i application induce a decrease of 57% LDL-C Time (months) Schettler VJ et al., Cardiovasc 2016 in press

25 Summary describing the current state in LDL-C and Lp(a) lowering stratgies Diet (LDL-C), not for Lp(a) Statins and further LLT are necessary (LDL-C), not for Lp(a) Only LDL-C increase may justify the use of PCSK9i...but CV outcome studies are essential for a general use Lp(a) can only decreased with lipoprotein apheresis

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