Our results suggest that the APOA5 gene variants may play an important role in the pharmacogenetics of statin treatment.

Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

Statins are the most commonly used drugs in patients with dyslipidemia. Among the patients, a significant inter-individual variability with supposed strong genetic background in statin treatment efficacy has been observed. Genome wide screenings detected variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes that are among the candidates potentially modifying response to statins. Ten variants (SNPs) within these genes (rs599838, rs646776, rs16996148, rs693, rs515135, rs4420638, rs12654264, rs6511720, rs6235, rs11206510) were analyzed in 895 (46 % men, average age 60.3±13.1 years) patients with dyslipidemia treated with equipotent doses of statins (~90 % on simvastatin or atorvastatin, doses 10 or 20 mg) and selected 672 normolipidemic controls (40 % men, average age 46.5 years). Lipid parameters were available prior to the treatment and after 12 weeks of therapy. Statin treatment resulted in a significant decrease of both total cholesterol (7.00±1.53→5.15±1.17 mmol/l, P<0.0001) and triglycerides (2.03±1.01→1.65±1.23 mmol/l, P<0.0005). Rs599838 variant was not detected in first analyzed 284 patients. After adjustment for multiple testing, there was no significant association between individual SNPs and statin treatment efficacy. Only the rs4420638 (APOE/C1/C4 gene cluster) G allele carriers seem to show more profitable change of HDL cholesterol (P=0.007 without and P=0.06 after adjustment). Results demonstrated that, although associated with plasma TC and LDL cholesterol per se, variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes do not modify therapeutic response to statins.

IntroductionThe aim of study was to investigate the possibility of cardiovascular risk improvement through systematic identification of high-risk individuals and treatment in accordance with current guidelines using modern therapy in daily clinical practice.Material and methodsTwo hundred and sixty-three physicians participated in the study. The physicians were asked to screen for cardiovascular risk factors in patients presenting with unrelated problems and to re-evaluate the attainment of treatment goals in those with already known risk factors. Each physician enrolled up to 20 consecutive patients with hypertension and/or hyperlipidemia. A total of 3015 patients were included. Cardiovascular risk was assessed using the SCORE system. Risk factors were treated in accordance with current national guidelines. The therapy of hyperlipidemia and hypertension was preferentially based on rosuvastatin, amlodipine and valsartan. Further medication was at the discretion of the attending physician. Patients were examined at baseline and after 3 and 6 months.ResultsThe principal result is that global cardiovascular risk decreased by 35% (from 8.9 ±6.4 to 5.9 ±4.4, p < 0.001). Systolic and diastolic blood pressure decreased by 12.5% (from 152 ±18 to 133 ±11, p < 0.001) and 11.4% (from 88 ±11 to 78 ±7, p < 0.001). The level of total cholesterol decreased 21% (from 6.3 ±1.2 to 5.0 ±0.9, p < 0.001) and the concentration of LDL-C decreased 28% (from 3.9 ±1.1 to 2.8 ±0.8, p < 0.001). HDL-C increased by 7% (from 1.43 ±0.58 to 1.53 ±0.56, p < 0.001) and triglycerides decreased by 25% (from 2.4 ±1.3 to 1.8 ±0.9, p < 0.001). Blood pressure and LDL-C target values were reached in 68% and 34%of patients, respectively.ConclusionsThe VARO study demonstrates that in daily practice settings, both individual risk factors and global cardiovascular risk are significantly improved through the systematic identification of high-risk individuals and their treatment in accordance with current guidelines using modern pharmacotherapy.

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