1. Personalised treatment of dyslipidemia
Professor Hana Rosolova, M.D., DrSc.,FESC
Center of Preventive Cardiology
2nd Medical Department
Charles University Prague – Medical Faculty in Pilsen

2. The most common metabolic disorder
Dyslipidemia
The 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 ≥ HDL-Ch<1.3 mmol/L ♀
<1.0 mmol/L ♂

3. Dyslipidemia Primary – genetic disorder + life style
MED-PED – FH – Pilsen Regional Center
Secondary – in the frame of other diseases + life style
(LDL-ch>6 mmol/L)

4. High-risk patients Manifested CV disease Type 1 DM + AUR, Type 2 DM
Degenerative valvular diseases
Chronic renal disease
Preclinical atherosclerosis

5. Subjects in primary prevention
Subjects ≥ 18 y. + dyslipidemia in the personal history
Primary prevention of atherosclerosis
in men >40 y., in women >50 y. ( à 5 y.)
Patients with arterial hypertension
Subjects with abdominal obesity
Serious dyslipidemia in a family member
Positive family history of early CVD

6. Pharmacotherapy of dyslipidemias
We are treated the patient
not the lipid levels!
We have to assess the global cardiovascular risk and also individual association between dyslipidemia and other risk factors and diseases

7. Recommended lipid values
General population
No CVD
CV risk≥5% T2 DM
T1DM +MAU*
Manifested
CVD
Total Ch
<5 mmol/L
<4.5 mmol/L
<4.0 mmol/L
LDL-Ch
<3 mmol/L
<2.5 mmol/L
<2.0 mmol/L**
** Patients with very high risk - LDL-Ch 1.5 mmol/L

8. Optimal values of HDL-Ch and TG
men
> 1 mmol/L
women
> 1. 3 mmol/L
Triglycerides
< 1.7 mmol/L

9. CHD secondary prevention CHD primary prevention
STATIN STUDIES – the 90th 4S
simva
4 S simva
chol 5.5-8
CHD secondary prevention
LIPID prava
CARE
prava
chol 4-7
LIPID prava CARE
chol  6.2
WOSCOPS prava
chol 6.5
CHD primary prevention
HDL-ch1,2 .chol
AFCAPS/TexCAPS lova
HPS, JUPITER

10. Statins are safe and well tolerated
BUT !!!
Statins increase risk of T2DM development
Meta-analysis (atorva, simva, rosuva, prava, lova)
n = ; OR 1.09 (1.02 – 1.17)
Rosuvastatin OR 1.18 ( )
Sattar N et al.: Lancet 2010; DOI: /S (09)

11. Pharmacogenomic Resource for Enhanced
Decisions in Care and Treatment (PREDICT)
Vanderbilt University Medical Center (VUMC)
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 myopathy One 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.
Vanderbilt University Medical Center. Vanderbilt doctors to screen patients taking cholesterol-lowering drugs
for harmful genetic variation [press release]. October 28, 2011.

12. Residual vascular risk in patients treated by statins
100%
85%
100%
78%
RRR 15%
RRR 22%
Residual
risk
CTT Collab Group: Lancet 2008;371:117-25

13. Residual Risk Reduction Initiative
International Project
Prof. MUDr. R. Češka, CSc ČIMS, o.p.s.
ČSAT Prof. MUDr. Hana Rosolová, DrSc.

14. Aterogennic dyslipidemia
Type 2 diabetes: Macrovascular complications
Diabetes and the metabolic syndrome:
a typical atherogenic lipoprotein profile (ALP)
Small
dense
LDL
 TG
T2DM MS
Prediabetes
Increased postprandial
lipemia
Increased apo-B
apo-B/apo-A
Increased non-HDL-ch
 The lipid profile in people with type 2 diabetes is characterized by hypertriglyceridemia and low levels of HDL-cholesterol. LDL- cholesterol levels in diabetic patients are not usually significantly increased compared with those in nondiabetic patients. However, there are important differences in the types of LDL particles seen: people with diabetes tend to have LDL particles that are small and dense compared with those in nondiabetic individuals.
 This pattern, characterized by high triglycerides, low HDL-cholesterol and small, dense LDL particles, is a typical atherogenic lipid profile (ALP).
 HDL-ch
American Diabetes Association. Diabetes Care 2003;26 (Suppl. 1):S83-86
References :
American Diabetes Association. Diabetes Care 2003;26 (Suppl. 1):S83-6;

15. Aterogennic index of plasma M. Dobiasova = log (TG/HDL-C)
CV risk
low middle high
-0.3 – – >0.24
We have limited data from clinical studies about the specific risk of increased TGs in patients achieving optimal LDL-C. Tgs are dependent on concomitant low HDL-C or elevated LDL/HDL-ratio.
Dobiasova M, Frohlich J: Clin Biochem 2001;34: 5

16. Calculator- http://www.biomed.cas.cz/fgu/aip
AIP evaluation
SCORE
High CV risk
AIP > 0,21
Middle CV risk
AIP 0,1- 0,21
Low CV risk
AIP < 0,1
Calculator- -

17. ACCORD Lipid
Fenofibrate reduces residual risk associated with high TG and low HDL-C in patients with T2DM
31% RRR
17.32%
CV events (%)
4.95% ARR
12.37%
10.11%
10.11%
TG < 2.3 mmol/L, HD >0.9 mmol/L
(n= 4 548)
TG ≥ 2.3 mmol/L + HDL-C≤0.9 mmol/L
(n= 941)
ACCORD Study Group. N Engl J Med March 14, Epub.

18. Fibrates 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)

19. Nicotinic acid (niacin) improves lipid profile
Complex effect on mixed dyslipidemia:
Increase of HDL-C
Reduction of TG about 20%
Reduction of LDL-C
Reduction of Lp(a) about 30 %
Niacin is considered the most potent agent available for raising HDL-C, with an average increase of 20% to 25%. Niacin also lowers triglycerides by 15 to 25 percent and LDL-C by 10 to 15 percent.
1 – Morgan JM et al. J Cardiovasc Pharmacol Ther 1996;1:
2 – Goldberg A. et al. Am J Cardiol 2008;85:
3 – McCormack PL, Keating JM. Drugs 2005;65:
4 – MORGAN JM et al. Am J Cardiol 2003;91:
5 – Pan J et al. Diiabetes Obes Metab 2002;4: 19

20. Mixed dyslipidemia (↑ LDL-ch, ↑ TG,  HDL-ch)
Niacin indications
Mixed dyslipidemia (↑ LDL-ch, ↑ TG,  HDL-ch)
The most effective for the increase of HDL-ch
Only one drug for the reduction of Lp(a)
Niacin + statin – significant CV risk reduction (A)

21. General schedule of dyslipidemia treatment
Life style
Pharmacotherapy
statins 1
LDL-ch
statins
HDL-ch, TG
non-HDL-ch, apo-B
+ezetimibe 2
The management of the patient with mixed hyperlipidemia starts with TLC and progresses to LDL-C reduction to the LDL-C goal. If patients require additional treatment to achieve their secondary treatment goal defined by non-HDL-C, several approaches can be chosen. Statin therapy (or other LDL-C–lowering regimens) may be intensified, or triglyceride-lowering drugs may be added to the regimen. Niacin raises HDL.C independently of TG, Fenofibrate requires TG to be high to rase HDL-C!
+ resins
+ niacin
+fibrates, (+ω3 FA)
Lipid modifying drugs combination 21

22. Dyslipidemia are different
Dyslipidemia treatment has to be personalized
type of dyslipidemia, other risk factors and diseases (CV risk)
individual disorder of lipid metabolism (manifestation + genomics)
individual sensitivity to the specific drug or to its side effect
(pharmacogenomics)