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)