Personalised treatment Personalised treatment of dyslipidemiaof dyslipidemia

Professor Hana Rosolova, M.D., DrSc.,FESCProfessor Hana Rosolova, M.D., DrSc.,FESCCenter of Preventive CardiologyCenter of Preventive Cardiology

2nd Medical Department 2nd Medical Department

Charles University Prague – Medical Faculty in PilsenCharles University Prague – Medical Faculty in Pilsen

DyslipidemiaDyslipidemia

The most common metabolic disorderThe most common metabolic disorder

1. Isolated hypercholesterolemia:

T-ch ≥ 5.0, LDL-ch ≥ 3.0 mmol/L

2. Isolated hypertriglyceridemia:

TG ≥ 1.7 mmol/L + normal ch

3. Combined (Mixed) dyslipidemia:

a) LDL-ch ≥3.0 + TG ≥ 1.7 mmol/L

b) TG ≥ 1.7 + HDL-Ch<1.3 mmol/L ♀

<1.0 mmol/L ♂

DyslipidemiaDyslipidemia

PrimaryPrimary – – genetic disordergenetic disorder + + life stylelife style

MED-PED – FH – Pilsen Regional CenterMED-PED – FH – Pilsen Regional Center

SecondarySecondary – in the frame of other diseases + – in the frame of other diseases + life stylelife style

(LDL-ch(LDL-ch>6 mmol/L)>6 mmol/L)

High-risk patients High-risk patients

Manifested CV diseaseManifested CV disease Type 1 DM + AUR, Type 2 DMType 1 DM + AUR, Type 2 DM Degenerative valvular diseasesDegenerative valvular diseases• Chronic renal diseaseChronic renal disease• Preclinical atherosclerosis Preclinical atherosclerosis

Subjects in primary preventionSubjects in primary prevention Subjects ≥ 18 y. + dyslipidemia in the personal Subjects ≥ 18 y. + dyslipidemia in the personal

historyhistory Primary prevention of atherosclerosis Primary prevention of atherosclerosis

in men in men >>40 y., in women 40 y., in women >>50 y. ( 50 y. ( àà 5 y.) 5 y.) Patients with arterial hypertensionPatients with arterial hypertension Subjects with abdominal obesitySubjects with abdominal obesity Serious dyslipidemia in a family memberSerious dyslipidemia in a family member Positive family history of early CVD Positive family history of early CVD

We are treated the patient We are treated the patient

not the lipid levels!not the lipid levels!

We have to assess the global cardiovascular risk and We have to assess the global cardiovascular risk and also individual association between dyslipidemia also individual association between dyslipidemia

and other risk factors and diseasesand other risk factors and diseases

Pharmacotherapy of dyslipidemiasPharmacotherapy of dyslipidemias

Recommended lipid valuesRecommended lipid values

General General populationpopulation

No CVDNo CVD

CV riskCV risk≥5% ≥5% T2 DM T2 DM T1DM +MAUT1DM +MAU**

ManifestedManifested

CVDCVD

Total ChTotal Ch <<5 mmol/L5 mmol/L <<4.5 mmol/L4.5 mmol/L <<4.0 mmol/L4.0 mmol/L

LDL-ChLDL-Ch <<3 mmol/L3 mmol/L <<2.5 mmol/L2.5 mmol/L <<2.0 2.0 mmol/Lmmol/L****

**** Patients with very high risk Patients with very high risk - - LDL-Ch 1.5 mmol/L LDL-Ch 1.5 mmol/L

Optimal values of HDL-Ch and TGOptimal values of HDL-Ch and TG

HDL-ChHDL-Ch

menmen

>> 1 mmol/L 1 mmol/L

womenwomen

>> 1. 3 mmol/L 1. 3 mmol/L

TriglyceridesTriglycerides

menmen

<< 1.7 mmol/L 1.7 mmol/L

womenwomen

<< 1.7 mmol/L 1.7 mmol/L

STATIN STUDIES – the 90thSTATIN STUDIES – the 90th

4S

simva

LIPID prava

CARE

prava

4 S simva

LIPID prava CARE

WOSCOPS prava

AFCAPS/TexCAPS lova

CHD secondary prevention

CHD primary prevention

chol 5.5-8

chol 4-7

chol 6.5

HDL-ch1,2 .chol

4.7-6.8

chol 6.2

HPS, JUPITERHPS, JUPITER

Statins increase risk of T2DM development Statins increase risk of T2DM development

Meta-analysis (atorva, simva, rosuva, prava, lova) Meta-analysis (atorva, simva, rosuva, prava, lova)

n = 91 140; n = 91 140; OR 1.09 (1.02 – 1.17)OR 1.09 (1.02 – 1.17)

RosuvastatinRosuvastatin OR 1.18 (1.04-1.33)OR 1.18 (1.04-1.33)

Statins are safe and well toleratedStatins are safe and well tolerated

BUT !!!BUT !!!

Sattar N et al.: Lancet 2010; Sattar N et al.: Lancet 2010; www.lancet.com; DOI:10.1016/S0140-6736(09)61965-6.; DOI:10.1016/S0140-6736(09)61965-6.

A panel aimed at 184 different variants on 34 genes (VeraCode ADME Core Panel, Illumina, San Diego, CA) will be used to identify patients at increased simvastatin-

related myopathyOne or two copies of a variant of SLCO1B1, a gene

involved in the regulation of statin uptake in the liver and associated with increased myopathy risk.

Patients with two copies of the variant have an almost 20-fold increased risk of simvastatin-related myopathy.

Pharmacogenomic Resource for Enhanced Pharmacogenomic Resource for Enhanced Decisions in Care and Treatment Decisions in Care and Treatment (PREDICT)(PREDICT)

Vanderbilt University Medical Center (VUMC)Vanderbilt University Medical Center (VUMC)

Vanderbilt University Medical Center. Vanderbilt doctors to screen patients taking cholesterol-lowering drugs

for harmful genetic variation [press release]. October 28, 2011.

Residual vascular risk Residual vascular risk in patients treated by statinsin patients treated by statins

34,9

24,8

29,6

19,4

0

5

10

15

20

25

30

35

40

DM nonDM

MA

CE

% control

treatment

CTT Collab Group: Lancet 2008;371:117-25

100% 78%

RRR 22%

100% 85%

RRR 15%

Residual Residual riskrisk

Residual Risk Reduction Initiative

International Project

Prof. MUDr. R. Češka, CSc. ČIMS, o.p.s.ČSAT Prof. MUDr. Hana Rosolová, DrSc.

Aterogennic dyslipidemiaAterogennic dyslipidemia

American Diabetes Association. Diabetes Care 2003;26 (Suppl. 1):S83-86

SmallSmalldensedenseLDLLDL

SmallSmalldensedenseLDLLDL

TGTG TGTG

HDL-cHDL-chh HDL-cHDL-chh

• Increased postprandialIncreased postprandial lipemialipemia• Increased apo-BIncreased apo-B

apo-B/apo-Aapo-B/apo-A• Increased non-HDL-chIncreased non-HDL-ch

T2DM MS

Prediabetes

Aterogennic index of plasmaM. Dobiasova = log (TG/HDL-C)

-0.3 – 0.1 0.1 – 0.24 >0.24

low low middlemiddle highhighlow low middlemiddle highhigh

CV riskCV risk

Dobiasova M, Frohlich J: Clin Biochem 2001;34: 5Dobiasova M, Frohlich J: Clin Biochem 2001;34: 5

AIP evaluation SCORE

High CV risk AIP > 0,21

Low CV risk AIP < 0,1

Middle CV risk AIP 0,1- 0,21

Calculator- http://www.biomed.cas.cz/fgu/aip - http://www.athero.cz

Fenofibrate reduces residual risk Fenofibrate reduces residual risk associatedassociated with high TG and low HDL-C in patients with high TG and low HDL-C in patients with T2DMwith T2DM

0

2

4

6

8

10

12

14

16

18

TG <204 mg/ dL, HDL >34 mg/ dL(n=4,548)

TG ≥204 mg/ dL + HDL-C ≤34 mg/ dL(n=941)

Pro

port

ion w

ith E

vent

Simvastatin

Simvastatin + Fenofibrate

ACCORD LipidACCORD Lipid

4.95% ARR

ACCORD Study Group. N Engl J Med March 14, 2010. Epub.

17.32%

12.37%

10.11% 10.11%

TG TG < < 2.3 mmol/L, HD 2.3 mmol/L, HD >>0.9 mmol/L0.9 mmol/L(n= 4 548)(n= 4 548)

TG ≥ 2.3 mmol/L TG ≥ 2.3 mmol/L + + HDL-C≤0.9 mmol/LHDL-C≤0.9 mmol/L(n= 941)(n= 941)

CV

eve

nts

(%

)C

V e

ven

ts (

%)

31% RRR

Fibrates indicationFibrates indication

• Atherogennic dyslipidemia - monotherapy or combination with statin (metabolic syndrome, T2DM) residual risk reduction (macro and microangiopathy) • Mixed dyslipidemia (LDL-ch + TG) – statin non-tolerance esp. in the secondary CVD prevention

• Serious hypertriglyceridemia (≥7 mmol/L – prevention of pancreatitis)

Complex effect on mixed Complex effect on mixed dyslipidemia:dyslipidemia: Increase of Increase of HDL-CHDL-C Reduction ofReduction of TG TG about about

20%20% Reduction ofReduction of LDL-C LDL-C

Reduction of LpReduction of Lp((a)a) about about 30 % 30 %

Nicotinic acid (niacin)Nicotinic acid (niacin) improves lipid profileimproves lipid profile

1 – Morgan JM et al. J Cardiovasc Pharmacol Ther 1996;1:195-202.

2 – Goldberg A. et al. Am J Cardiol 2008;85:1100-5.3 – McCormack PL, Keating JM. Drugs 2005;65:2719-40.4 – MORGAN JM et al. Am J Cardiol 2003;91:1432-4.5 – Pan J et al. Diiabetes Obes Metab 2002;4:255-61.

19

Niacin indications Niacin indications

Mixed dyslipidemia (Mixed dyslipidemia (↑ LDL-ch, ↑ TG, ↑ LDL-ch, ↑ TG, HDL-ch) HDL-ch)

The most effective for the increase of HDL-chOnly one drug for the reduction of Lp(a)

Niacin + statin – significant CV risk reduction (A)

General schedule of dyslipidemia treatmentGeneral schedule of dyslipidemia treatment

Life styleLife styleLife styleLife style

PharmacotherapyPharmacotherapyPharmacotherapyPharmacotherapy

LDL-LDL-chch 11

HDL-ch, TGHDL-ch, TGnnon-HDL-on-HDL-ch, apo-Bch, apo-B22

+ niacin + niacin

+fibrates, (+fibrates, (++ωω3 FA)3 FA)

statins

statins

Lipid modifying Lipid modifying drugs combinationdrugs combination

+ezetimibe+ezetimibe

+ resins+ resins

Dyslipidemia are different Dyslipidemia are different Dyslipidemia treatment has to be personalizedDyslipidemia treatment has to be personalized

• type of dyslipidemia, other risk factors and diseases (CV risk)type of dyslipidemia, other risk factors and diseases (CV risk)

• individual disorder of lipid metabolism (manifestation + individual disorder of lipid metabolism (manifestation + genomics)genomics)

• individual sensitivity to the specific drug or to its side effectindividual sensitivity to the specific drug or to its side effect (pharmacogenomics)(pharmacogenomics)