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

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 ≥ 1.7 + HDL-Ch<1.3 mmol/L ♀ <1.0 mmol/L ♂

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)

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

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

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

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

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

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 4.7-6.8 AFCAPS/TexCAPS lova HPS, JUPITER

Statins are safe and well tolerated BUT !!! Statins increase risk of T2DM development Meta-analysis (atorva, simva, rosuva, prava, lova) n = 91 140; OR 1.09 (1.02 – 1.17) Rosuvastatin OR 1.18 (1.04-1.33) Sattar N et al.: Lancet 2010; www.lancet.com; DOI:10.1016/S0140-6736(09)61965-6.

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.

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

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

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;

Aterogennic index of plasma M. Dobiasova = log (TG/HDL-C) CV risk low middle high -0.3 – 0.1 0.1 – 0.24 >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

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

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, 2010. Epub.

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)

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;1:195-202. 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

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)

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

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)