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 GbRPriv. Doz. Dr. med. V. Schettler

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

Familial Hyperlipidaemia (FH) with heterozygous expressions (he) (FHhe)

- burden of high LDL-C levels

Nordestgaard et al., Eur Heart J 2013;34:3478-90a.

Neil et al., Eur Heart J 2008;29:2625–33.

LDL-C-lowering studies and reduction of coronary events

50 70 110 130 150 170 19090 210

Cor

onar

y Ev

ents

(%)

LDL Cholesterol (mg/dl)

25

20

15

10

5

0?

LRC-PL

AFCAPS-Rx

WOSCOPS-RxWOSCOPS-PL

AFCAPS-PLASCOT-PL

ASCOT-RxLRC-Rx

Primary Prevention

CARE-Rx

4S-Rx

LIPID-PL

4S-PL

CARE-PL

LIPID-Rx

POSCH-PL

POSCH-Rx

Secondary Prevention

HPS-Rx

HPS-PL

HPS

Non-Statin Studies

Statin Studies

based on Kastelein, Atherosclerosis 1999;143:S17-S21*Heart Protection Study Collaborative Group. Lancet 2002;360:7-22.

…but EUROSPIRE IV says….

Reiner et al., Atherosclerosis 2016;246:243-50.

6648 CHD patients' data from centres in 24 European countries

• Too many CHD patients with dyslipidaemia are still inadequately treated• Most of these patients on statin therapy are not achieving the treatment

targets.

(<70 mg/dl)

based on Gotto & Moon, Nat Rev Cardiol 2013;10:560-70.

LDL-RiPCSK9

Overview – lipid lowering/ modifying strategies

HMG-ReductaseStatins

PCSK9PCSK9i

Specific PCSK9 mutations induce low LDL-C levels:low incidence for cardiovascular events

- 88% events

PCSK9 mutation: LDL-C levels: 138 mg/dl vs. 100 mg/dl (black American inhabitants)

Cohen et al., N Engl J Med 2006;354:1264-72.

New drugs on the block…

• PSCK9-Inhibitiors• MTP-Inhibitors• Antisense therapy targeting Lp(a): ISIS 144367• …

Results of new drugs in lowering lipids/ lipoproteins may be convincing, but we have to wait on results from cardiovascular outcome studies!

Drug therapy

1) Statin: Maximal tolerable dosage (optimal 80 mg atorvastatin or maximal permitted dosages of other statins) per day

in combination with

2a) Ezetimibe (!): 10 mg per day

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!

The first major chapter: Before the initiation of lipoprotein apheresis – LDL-Cholesterol lowering concept: Drugs

German Working Group for Therapeutic Apheresis

Metabolism of Proprotein convertasesubtilisin/kexin type 9 (PCSK9)

Lambert et al., J Lipid Res. 2012;53:2515-24.Weinreich & Frishman, Cardiol Rev 2014;22:140-46.

Antibodies target: PCSK9

Lambert et al., J Lipid Res. 2012;53:2515-24.Weinreich & Frishman, Cardiol Rev 2014;22:140-46.

Cellmembrane

81%

<1.8 mmol/L (70 mg/dL) regardless of risk

P<0.0001 79%

Alirocumab

9% 8%

0

10

50

40

30

20

60

70

80

90 P<0.0001

%pa

tient

s

Very high-risk: LDL-C <1.8 mmol/L (70 mg/dL) High-risk: <2.6 mmol/L (100 mg/dL)

Placebo

Intent-to-treat (ITT) analysis; LLT = lipid-lowering therapy

Most of the patients achieved the LDL-C goal: combination of Alirocumab and

“Background Statin ± Other LLT”

Patient exampleLA + (statin) + PCSK9i

58y patientLDL-R frame shift mutation in exon 18

since 1989 LA - prior:3 vessel CHD2 myocardial infarctionsCABGrotablator atherectomy (RIVA)

Start of PCSK9i Statins paused

time [months]

chol

este

rola

ndLD

L-ch

oles

tero

l(m

g/dl

)

Schettler VJ et al., Cardiovasc 2016 in press

Success of PCSK9i therapies ?

Navarese et al., Ann Intern Med 2015;163:40-51.

Total mortality Cardiovascular mortality

Threshold level for lipoprotein apheresis indication

Patients suffering from cardiovascular, cerebrovascular or peripheral arterial disease or extended atherosclerosis

The second major chapter: Initiation of lipoprotein apheresis

– LDL-Cholesterol lowering concept

German Working Group for Therapeutic Apheresis

• 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).

Can Lp(a) levels reduced by PCSK9i (e.g. Evolocumab)?

Desai et al., Circulation 2013;128:962-9.

Reduction rates mean up to xy %!No outcome studies!

A look in details…

Desai et al., Circulation 2013;128:962-9.Raal et al, Lancet 2015;385:341-50.McConnell et al., J Clin Lipidol 2014;8:550-3.Schettler et al., Cardiovasc 2015;15:41-3.

nmol/l in mg/dl – x* 0,4167 – z.B. 41 nmol/l = 17,1 mg/dl

TESLA Part B)

Meta-analysis of 20 Studies:Lp(a) decrease induced by PCSK9i

Li et al., J Am Heart Assoc. 2015;4: e001937.

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.

Threshold level for lipoprotein apheresis indication

Patients suffering from cardiovascular, cerebrovascular or peripheral arterial disease or extended atherosclerosis

The third major chapter: Initiation of lipoprotein apheresis

– Lp(a)-Cholesterol lowering concept

• 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

Now, can we create a new lipid loweringalgorithm for patients at very high risk?

Potential treatment algorithm inrelation to the use of PCSK9-AB and LA

Neumann et al., Blood Purif 2016;41:270-276.

Therapeutic Algorithm PCSK9i and LDL-Apheresis – or both?

Schettler VJ et al., Internist 2016; ;57:511-6.

…for theGerman Societyof Nephrology(DGfN)

and

Foundation ofGerman Centresof Nephrology(VDN)

Therapeutic Algorithm – PCSK9i, LA

Schettler VJ et al., Internist 2016; ;57:511-6.

Patients example: intolerance of statins – use of PCSK9i – approved?

58J. patient with2 vessel CHDStatin intolerance

PCSK9i application induce a decrease of 57% LDL-C

Last tryof statins

PCSK9i-application

Cho

lest

erol

and

LDL-

Cho

lest

erol

(mg/

dl)

Time (months)Schettler VJ et al., Cardiovasc 2016 in press

Summary – describing the current statein 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…