Effect of thyroid hormone status and concomitant medication on statin induced adverse effects in hyperlipidemic patients.

Statins are effective treatment for the prevention of cardiovascular diseases and used extensively worldwide. However, adverse effects induced by statins are the major barrier of maximalizing cardiovascular risk reduction. Hypothyroidism and administration of drugs metabolized on the same cytochrome P450 (CYPP450) pathways where statin biotransformation occurs represent a significant risk factor for statin induced adverse effects including myopathy. Simvastatin, atorvastatin and lovastatin are metabolized by CYP3A4, fluvastatin by CYP2C9, while rosuvastatin by CYP2C9 and 2C19. We investigated the levels of the free thyroid hormones and CYP metabolism of concomitant medication in 101 hyperlipidemic patients (age 61.3 +/- 9.9 ys) with statin induced adverse effects including myopathy (56 cases; 55.4%), hepatopathy (39 cases; 38.6%) and gastrointestinal adverse effects (24 cases; 23.8%). Abnormal thyroid hormone levels were found in 5 patients (4.95%); clinical hypothyroidism in 2 and hyperthyroidism in 3 cases. 11 patients had a positive history for hypothyroidism (10.9%). Myopathy occured in one patient with hypothyroidism and two patients with hyperthyroidism. There were no significant differences in the TSH, fT4 and fT3 levels between patients with statin induced myopathy and patients with other types of adverse effects. 78 patients (77.2%) were administered drugs metabolized by CYP isoforms also used by statins (3A4: 66 cases (65.3%); 2C9: 67 cases (66.3%); 2C19: 54 cases (53.5%)). Patients with myopathy took significantly more drugs metabolized by CYP3A4 compared to patients with other types of adverse effects (p < 0.05). More myopathy cases were found in patients on simvastatin treatment (52% vs. 38%, ns.), while significantly less patients with myopathy were on fluvastatin treatment (13% vs. 33%, p < 0.05) compared to patients with other types of statin induced adverse effects. Both abnormal thyroid hormone status and administration of drugs metabolized by CYP3A4, 2C9 and 2C19 are common in our patients with statin induced adverse effects. Normalizing the thyroid hormone status and optimizing of the concomitant medication may reduce the risk of statin induced adverse effects.

The c.-133A > G polymorphism in NPC1L1 gene influences the efficacy of ezetimibe monotherapy on apolipoprotein A1 in hyperlipidemic patients.

Niemann-Pick C1-like 1 protein (NPC1L1) plays a critical role in intestinal cholesterol absorption. Previous studies found that the NPC1L1 c.-133A > G SNP, but not other NPC1L1 SNPs, was associated with response to statin treatment and statin-ezetimibe combinations. To date effect of NPC1L1 c.-133A > G SNP on ezetimibe monotherapy has not been studied. Our objective was to examine whether SNP c.-133A > G at the NPC1L1 gene has effects on lipid levels and on the efficacy of 3, 6 and 12 months of 10 mg daily ezetimibe monotherapy in hyperlipidemic patients with statin induced adverse effects. One hundred and one type IIa and IIb hyperlipidemic patients (72 females, 29 males; age: 61.23 +/- 9.87 ys; BMI: 28.18 +/- 4.29 kg/m2) were enrolled. The genotype frequencies were conformed to Hardy-Weinberg equilibrium. We could not find significant differences in initial lipid levels between AA and AG + GG patients. While plasma levels of apolipoprotein A1 (ApoA1) did not significantly decrease after ezetimibe treatment (1.96; 3.39 and 2.74%) in AA patients, a significant elevation in ApoA1 levels has been found after treatment in AG + GG patients (9.15; 8.54 and 13.58%). The effect of NPC1L1 c.-133A > G on the ApoA1 levels was found significant (p < 0.05). Efficacy of treatment with ezetimibe on other plasma lipid parameters after 3, 6 or 12 months did not differ significantly. NPC1L1-133A > G SNP influences the ApoA1 response to ezetimibe monotherapy, therefore, may alter the effect of ezetimibe on the structure and function of the high-density lipoprotein particles.

Effect of short term treatment with simvastatin and atorvastatin on lipids and paraoxonase activity in patients with hyperlipoproteinaemia.

OBJECTIVE: High-density lipoprotein (HDL)-associated paraoxonase (PON) activity may play an important role in the inhibition of low-density lipoprotein (LDL) oxidation. Previous studies have demonstrated that serum PON activity is decreased in patients with hyperlipoproteinaemia and coronary heart disease. The study presented here examined the effect of short-term treatment with simvastatin and atorvastatin on lipids and PON activity in patients with hyperlipoproteinaemia. RESEARCH DESIGN AND METHODS: A prospective, non-blinded, single-group, cross-over, comparative trial was performed. Following an 8-week dietary run-in period, 49 patients (23 men and 26 women, mean age: 59.8 +/- 7.9 years) with Fredrickson type IIa. and IIb. hyperlipoproteinaemias were randomized to receive either simvastatin 20 mg/day or atorvastatin 10 mg/day for 3 months. Following an 8-week washout period, patients were crossed-over to receive the other drug for a further 3 months. Serum lipids were measured and serum PON activity was determined spectrophotometrically using paraoxon as a substrate. RESULTS: Simvastatin treatment significantly reduced serum cholesterol, LDL-cholesterol (LDL-C) and apolipoprotein (apo) B levels (p < 0.001). Atorvastatin had a more pronounced cholesterol, LDL-C- and apo B-lowering effect (p < 0.001) compared with simvastatin. Both statins also significantly reduced serum triglyceride levels (p < 0.01). Simvastatin and atorvastatin caused no significant change in the levels of HDL-cholesterol (HDL-C) and apo A1. HDL-associated PON activity did not change significantly after simvastatin therapy, but significantly increased after atorvastatin treatment (p < 0.05). CONCLUSIONS: Short-term administration of simvastatin did not increase PON activity. Atorvastatin treatment had a favourable effect on lipid profile and increased the activity of HDL-associated PON.

The effect of micronised fenofibrate on paraoxonase activity in patients with coronary heart disease.

OBJECTIVE: To evaluate the effect of micronised fenofibrate on serum paraoxonase (PON) and lipoprotein levels in coronary heart disease patients with type IIb hyperlipidemia. PATIENTS AND METHODS: Fifty-two patients were investigated for the three-month effect of 200 mg per day micronised fenofibrate on the serum enzyme activity and concentration of PON and their relationship with serum lipids, high-density lipoprotein (HDL-C) parameters. RESULTS: Serum paraoxonase activity was lower in CHD patients with type IIb hyperlipoproteinemia. During the three-month study it was observed that following treatment with micronised fenofibrate, serum triglyceride and cholesterol levels decreased, while HDL-C increased significantly (p<0.001). Low-density lipoprotein (p<0.05) and apolipoprotein B-100 (p<0.01) decreased, while HDL constituent apolipoprotein A-I (p<0.05) increased after micronised fenofibrate treatment. The HDL-associated paraoxonase specific activity increased significantly (p<0.05). To assess whether the increased PON activity was due to elevated HDL and apoA-I level, we standardized PON activity for HDL and apoA-I concentrations. The standardized values for HDL (PON/HDL) increased (p<0.05) while the PON/apoA-I ratio did not change significantly. CONCLUSION: Three months of treatment with micronised fenofibrate is thought to normalize lipid profile and improve antioxidant status by increasing serum paraoxonase activity in these patients.

Gemfibrozil increases paraoxonase activity in type 2 diabetic patients. A new hypothesis of the beneficial action of fibrates?

OBJECTIVE: The constellation of elevated triglycerides and decreased high-density lipoprotein is recognised as a risk factor for CAD and constitutes the major dyslipidemia in type 2 diabetes. The high-density lipoprotein associated paraoxonase activity can inhibit low-density lipoprotein oxidation and has an antiatherogenic effect. To determine the effect of gemfibrozil on the dyslipidemia and serum paraoxonase activity in patients with type 2 diabetes. MATERIAL AND METHODS: Fifty-six type 2 diabetic patients with associated hypertriglyceridemia were involved. They were investigated for the effect of twice daily 600 mg of gemfibrozil on serum cholesterol, triglycerides, apolipoproteins, fibrinogen level, body mass index and glycated hemoglobin. Serum paraoxonase activity was measured spectrophotometrically. RESULTS: After three months, it was observed that under the effect of gemfibrozil, serum triglyceride level was significantly decreased (from median: 3.46 mmol/l quartiles: q1=2.92 q3=5.28 to median 2.20 mmol/l quartiles: q1=1.79 q3=3.65; p<0.001) while protective high-density lipoprotein (from 1.02 +/- 0.22 mmol/l to 1.13 +/- 0.28 mmol/l; p=0.05) and apolipoprotein A(1) (from 1.56 +/- 0.33 g/l to 1.72 +/- 0.29; p<0.01) levels were significantly increased. Serum paraoxonase activity was found to be significantly increased (from median: 100.2 U/l quartiles: q1=60.1 q3=152.7 to median 118.7 U/l quartiles: q1=80.1 q3=171.0; p<0.001) after gemfibrozil treatment. The total cholesterol, low-density lipoprotein, apolipoprotein B, lipoprotein (a), glycated hemoglobin and fibrinogen levels were not significantly changed during the three-month treatment period. The standardized paraoxonase activity for HDL and apo A(1) were not significantly changed. Paraoxonase activity did not correlate with the concentration of glycohemoglobin and the duration of diabetes. CONCLUSION: Twice daily administration of 600 mg of gemfibrozil is effective in type 2 diabetic patients with associated hypertriglyceridemia. It favorably lowers lipid levels, and improves antioxidant status by increasing serum paraoxonase activity.

[The role of HDL in the prevention of cardiovascular events]. / A HDL szerepe a cardiovascularis események megelózésében.

The Framingham and other epidemiological studies have shown HDL and triglyceride to be inversely correlated. An independent relationship between HDL cholesterol and CAD was observed in other studies and also suggested by interventional trials. Decreased HDL-C and mildly elevated LDL-C are common in patients with coronary artery disease. Identification of receptors involved in the metabolism of HDL has been the subject of intensive research. The HDL particle may be recognized by different receptors in various tissues. Niacin and fibrate have a remarkable effect on the reduction of triglyceride and elevation of HDL, while their LDL lowering effect is moderate. Statins are effective and safe drugs for CHD, and exert beneficial effects across the lipoprotein profile. Therefore, the effects of statins on HDL-C may contribute to reductions in coronary events.

[Changes in lipid profile and paraoxonase activity in obese patients as a result of orlistat treatment]. / Obes betegek lipidprofiljának és paraoxonáz aktivitásának változása orlistat kezelést követóen.

257 patients from 33 centres were involved in a six-month study, the aim of which was to assess the effect of orlistat together with a diet. The authors examined how the treatment effected the anthropometrical and lipid parameters, extending the study to the aspect of paraoxonase activity in case of 25 patients. 44 patients dropped out during the study period due to the lack of sufficient diet compliance, whereas 3 patients had to stop the therapy because of the adverse event of flatus with discharge. On the average, the body mass of the patients decreased from 100.8 +/- 18.9 to 91.3 +/- 18.6 kg, i.e. by 9.5 kgs, while their BMI was reduced from 36.1 +/- 5.6 to 32.5 +/- 5.2 kg/m2 and the circumference of the waist changing from 119.1 +/- 20 to 108.3 +/- 15.1 cm, i.e. by 10.8 cms. The blood sugar level significantly decreased from 5.7 to 5.4, while the cholesterol concentration significantly dropped from 5.9 to 5.5, the triglyceride level being reduced from 2.4 to 2.1 mmol/l and blood pressure falling significantly from 136.6/86.9 to 129.9/81.6. All the above changes showed a significant decrease. However, the HDL-cholesterol level did not change. The serum paraoxonase activity significantly increased (143 +/- 49 vs 166 +/- 43 UL) along with the standardised values for HDL (PON/HDL), even compared to the control diet group. From the above results it may be concluded that orlistat tends to have an antioxidant effect.

Relationship between serum paraoxonase and homocysteine thiolactonase activity, adipokines, and asymmetric dimethyl arginine concentrations in renal transplant patients.

Paraoxonase lactonase activity protects against homocysteinylation; therefore, it can be a potential contributing factor to prevent atherosclerosis. We aimed to determine paraoxonase and HTLase activities and to clarify the relationship between HTLase activity and some cardiovascular risk factors, such as homocysteine, cystatin C asymmetric dimethylarginine (ADMA), and adipokines both in hemo dialyzed and transplanted patients. Among 114 hemodialyzed, 80 transplanted and 64 healthy control subjects, we investigated body mass index (BMI) as well as fasting serum contents of urea, uric acid, creatinine, cystatin C, homocysteine, glucose, lipids, total protein and albumin. Serum paraoxonase (PON 1) and HTLase activities were measured spectrophotometrically. ADMA, ADPN adiponectin, leptin (LEP) levels was determined with a sandwich enzyme-linked immunosorbent assay method. Dyslipidemic patients showed hypercholesterolemia, and high low-density lipoprotein (LDL); parallel with improved renal function, they displayed decreased cystatin C and homocysteine levels (P < .001). There was a significant negative correlation between PON 1 activity and cystatin C and homocysteine concentrations (P < .05). Obese patients revealed significantly higher LDL (P < .05) and leptin concentrations (P < .01). There was a significant positive correlation between PON 1 activity and adiponectin levels (P = .0276). Both dialyzed and transplanted patients displayed significantly lower HTLase activities compared to the control group (P < .001), particularly lower HTLase and PON 1 activities in dialyzed subjects compared with the transplanted group (P < .05). HTLase activity showed significant negative correlations with ADMA levels among the whole study population (P < .001), whereas positive associations were noted between PON 1 and HTLase activities (P < .001). HTLase activity may be a new predictor of cardiovascular risk in renal failure although it is modulated by other risk factors.

Contribution of animal models to the understanding of the metabolic syndrome: a systematic overview.

The metabolic syndrome (MetS) is one of the most important challenges to public health and biomedical research. Animal models of MetS, such as leptin-deficient obese mice, obese spontaneously hypertensive rats, JCR: LA-cp rats and the Ossabaw and Göttingen minipigs, have contributed to our understanding of the pathophysiological basis and the development of novel therapies. For a complex disease syndrome, no animal model can be expected to serve all needs of research. Although each animal model has limitations and strengths, used together in a complementary fashion, they are essential for research on the MetS and for rapid progress in understanding the aetiology and pathogenesis towards a cure. The purpose of this review is to assess how current animal models contributed to our knowledge of the human MetS, and to systematically evaluate the strengths and weaknesses of the currently available 78 animal models from 11 species.

Serum paraoxonase activity changes in uremic and kidney-transplanted patients.

Serum paraoxonase (PON) is a high-density lipoprotein (HDL)-associated hydrolase, which inhibits low-density lipoprotein oxidation. Uremic and kidney-transplanted patients have an increased risk of atherosclerosis, to which an increased lipoprotein oxidation may contribute. The aim of our study was to determine whether the PON activity or phenotype is altered in uremic and kidney-transplanted patients, and to compare the values with those of healthy controls. 117 uremic patients on long-term hemodialysis treatment, 115 renal-transplanted patients, and 110 healthy controls were involved in the study. The PON activity was significantly reduced in the uremic patients compared to controls (PON 101.36+/-30. 12 vs. control 188.05+/-58.96 U/ml; p < 0.001), while in kidney-transplanted patients the values were almost identical to those of controls (PON 161.5+/-35.39 U/ml). The different immunosuppressive drug combinations did not influence PON activity. To assess whether the altered PON activity was due to a decrease HDL level, we standardized the enzyme activity for the HDL concentration (PON/HDL ratio). We found that the standardized enzyme activity was lower in the uremic (102.7+/-54.8) and kidney-transplanted patients (144.5+/-32.7) when compared to controls (194.5+/-94.5; p < 0.001). The phenotypic distribution of PON in uremic, renal transplant and control patients are as follows: AA 66.67, 56.48 and 66.67%; AB 31. 62, 33.3 and 26.67%; BB 1.71, 10.19 and 6.67%. We conclude that the decreased PON/HDL and PON/apoA-1 ratios may lead to a reduction in the antioxidant capacity of HDL, which might contribute to the accelerated development of atherosclerosis in uremic and kidney-transplanted patients.