Possible Mechanism and Treatment of o,p'DDD-induced Hypercholesterolaemia

Ortho, para, dichlorodiphenyl dichloroethane (o,p'DDD, Mitotane(Roussell)) is used as an adrenolytic drug to reduce adrenocorticalmass and circulating cortisol levels in Cushing's syndrome buthas the unwanted side-effect of inducing hypercholesterolaemia.This paper examined the mechanism of that effect in 30 patientswith Cushing's syndrome treated with o,p'DDD during the past10 years. o,p'DDD increased serum cholesterol by 68 per cent, mainly byincreasing LDL-cholesterol. The latter effect was not due toimpaired binding of LDL to its receptor, as shown in vitro usingcultured fibroblasts. Increases in plasma mevalonic acid duringo,p'DDD administration were suggestive of increased cholesterolsynthesis, this effect being reversed by simvastatin. These findings suggest that o,p'DDD causes hypercholesterolaemiaby increasing cholesterol synthesis. It is proposed that thiseffect is due to the drug's known ability to block cytochromeP450-mediated reactions, thus impairing the formation of oxysterolsresponsible for down-regulating hepatic cholesterol synthesis.Treatment with simvastatin, an inhibitor of cholesterol synthesis,reverses the hyperlipidaemia and enables o,p'DDD therapy tobe maintained without increasing cardiovascular risk.     

HMG CoA reductase inhibitors as lipid-lowering agents: five years experience with lovastatin and an appraisal of simvastatin and pravastatin

The HMG CoA reductase inhibitors are the most effective drugs for treating hypercholesterolaemia currently available. They inhibit cholesterol synthesis and thus stimulate receptor-mediated uptake and degradation of low-density lipoprotein cholesterol by the liver. In 30 patients with severe hypercholesterolaemia administration of lovastatin alone or in combination with other lipid-lowering manoeuvres maintained reductions of 25 to 31 per cent in serum cholesterol over five years. The drug was easy to take and well tolerated, the only significant side effect being a reversible myopathy. Two similar compounds, simvastatin and pravastatin, exert comparable effects on serum lipids, including modest reductions in triglycerides and increases in high-density lipoprotein cholesterol. The use of these drugs seems likely to exert a beneficial effect on atherosclerosis.     

Simvastatin decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: pathophysiological and therapeutic implications

Abstract. We studied six patients with heterozygous familial hypercholesterolaemia (FH) before and after 8 weeks of treatment with simvastatin (40 mg day^-1), an inhibitor of 3-hydroxy-3-methyl-glutaryl-Coenzyme A. Simvastatin decreased plasma low-density lipoprotein (LDL) cholesterol by 43% ( P = 0.002), triglycerides by 27% ( P = 0.05) and mevalonic acid (a measure of in vivo cholesterol synthesis) by 20% ( P = 0.002); high-density lipoprotein cholesterol increased by 17% ( P = 0.02). The hepatic secretion rate of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) was measured directly using a primed, constant intravenous infusion of l-[¹³C]-leucine with monitoring of the isotopic enrichment of apoB by gas chromatography-mass spectrometry; fractional secretion rate (FSR) was derived using a mono-exponential function. Simvastatin decreased the FSR, ASR and pool size of VLDL apoB by 17% (14.3 (SEM 3.6)) vs. (11.9 (SEM 3.5) pools day^-1, P = 0.10), 83% (51.4 (SEM 17.9) vs. (8.6 (SEM 1.4), P = 0.007mgkg^-1day^-1) and 65% (234.2 (SEM 30.4) vs. 82.6 (SEM 24.0)mg, P = 0.02), respectively. The change in the ASR of VLDL apoB was significantly correlated with the change in plasma LDL cholesterol concentration ( P = 0.04), but not with the change of triglyceride or mevalonic acid. We conclude that the hepatic secretion of VLDL apoB in FH is decreased by simvastatin, which may partly explain the fall in plasma cholesterol. This effect does not appear to be directly related to the inhibition of cholesterol synthesis and may be due to decreased hepatic delivery of cholesterol esters via the LDL receptor-independent pathway, but these mechanisms require further investigation.     

Use of an indirect effect model to describe the LDL cholesterol-lowering effect by statins in hypercholesterolaemic patients

Statins are the most commonly prescribed agents for the treatment of hypercholesterolaemia. This is due to their efficacy in reducing low-density lipoprotein cholesterol (LDL) level which is the primary goal of the treatment especially for patients with multiple risk factors or with established coronary heart diseases. The purpose of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the LDL-lowering process in patients with hypercholesterolaemia treated with atorvastatin, fluvastatin or simvastatin. A total of 100 patients were studied retrospectively. They received atorvastatin (n = 57), fluvastatin (n = 26) or simvastatin (n = 17). As no pharmacokinetic data were available, the absorption rate was fixed to 1/h and atorvastatin, simvastatin and fluvastatin elimination half-lives were fixed to 14, 2 and 2.5 h respectively. A total of 309 LDL levels were measured and the data were analysed by nonmem v. The time course of the LDL-lowering effect of statins was described by an indirect-response model with precursor (LDL synthesis, input rate K(in)) and response (circulating LDL, input and output rates K) compartments. The following parameters were estimated: LDL input rate (K(in)) 0.14 +/- 0.015 g/L/day (mean +/- SD); inhibition fraction of K(in) (INH) 0.21 +/- 0.017; and dose producing 50% increase of LDL removal (D50), 26 +/- 7.8, 1.3 +/- 0.48 and 15 +/- 5.25 mg for atorvastatin, simvastatin and fluvastatin, respectively. Gender, bodyweight, age, calories/day, sugar/day, lipids/day, hyperlipidaemia types and waist/hip circumference, renal and hepatic functions had no effect on the pharmacodynamic parameters. The pharmacodynamic parameters for the three statins were accurately estimated. The PK/PD model developed successfully predicted the time course of the LDL-lowering effect of statins.     

Enhanced cellular metabolism of very low density lipoprotein by simvastatin. A novel mechanism of action of HMG-CoA reductase inhibitors

Abstract. To test the possibility that HMG-CoA reductase inhibitors reduce LDL mass by an increased VLDL catabolism, we determined the effect of simvastatin therapy on cellular metabolism of VLDL in 18 patients with primary hypercholesterolaemia. Six months of simvastatin therapy was followed by 26%, 31% and 21% reduction of plasma total cholesterol, LDL-cholesterol and plasma triglyceride levels, respectively. Before therapy, patients' VLDL metabolism in cultured human normal skin fibroblasts was similar to control VLDL. Six months after therapy was initiated, a remarkable 2–5-fold increase in VLDL cell metabolism was found. These effects were even more marked when the VLDL was enriched with exogenous recombinant apo E-3. A comparison of the metabolism of the patients' VLDL to control VLDL and LDL, revealed that simvastatin increased metabolic ratios of 60–70% and 45–95%, respectively. Simvastatin therapy was associated with a decrease of VLDL cholesteryl ester content of 19% and increase of the phospholipid content of 13%. The data strongly indicate that simvastatin therapy stimulates VLDL: cell interactions and catabolism, possibly reflecting alterations of the physico-chemical properties of the particle. It is proposed that in addition to other previously described pathways, HMG-CoA reductase inhibitors decrease LDL mass through a novel mechanism of enhanced VLDL catabolism prior to the conversion to LDL.     

Effect of simvastatin on plasma lipid and lipoprotein concentrations and low-density lipoprotein metabolism in the nephrotic syndrome.

1. The effect of inhibiting the rate-limiting enzyme (3-hydroxy-3-methylglutaryl-CoA reductase, EC 1.1.1.88) in cholesterol synthesis on plasma lipid and lipoprotein concentrations was investigated in 16 patients with primary glomerular disease, heavy proteinuria, well-preserved renal function and hypercholesterolaemia. 2. Detailed studies of low-density lipoprotein metabolism were performed on eight patients before and after 12 weeks of simvastatin therapy. Radioiodinated tracers were used to quantify the fractional catabolic rate of low-density lipoprotein by apolipoprotein B/E receptors and alternative pathways. 3. Simvastatin produced consistent reductions in total plasma cholesterol concentration (median 36.9%), plasma low-density lipoprotein-cholesterol concentration (43.6%) and apolipoprotein B pool size (29.9%). 4. In contrast, the changes in kinetic parameters of low-density lipoprotein metabolism showed no clear pattern. Although an increase in the receptor-mediated catabolism of low-density lipoprotein was demonstrated in five patients, no change or a slight decrease was seen in three patients. Production rates were not significantly altered, although there was a slight decrease in the median value (from 12.4 to 9.7 mg day-1 kg-1). Plasma lathosterol concentration was reduced in all eight patients (range 34-71%), indirectly confirming significant inhibition of cholesterol synthesis. 5. These results suggest that, as in patients with primary moderate hyperlipidaemia, the significant cholesterol-lowering effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in the nephrotic syndrome is accompanied by variable changes in lipoprotein metabolism. The reasons for this heterogeneous response are unclear. This reflects our limited understanding of the metabolic basis of nephrotic hyperlipidaemia and the relationship between hepatic sterol synthesis and plasma lipoprotein kinetics.     

The effects of simvastatin on plasma lipoproteins and cholesterol homeostasis in patients with heterozygous familial hypercholesterolaemia

We have examined the influence of simvastatin, a competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase on plasma concentrations of lipids and lipoproteins, the rates of cholesterol biosynthesis and degradation of 125I-labelled LDL by freshly isolated mononuclear leucocytes and the 24 h urinary excretion of mevalonic acid in patients with heterozygous familial hypercholesterolaemia. Patients were treated with progressively increasing doses of simvastatin (20, 40, and 80 mg day-1) taken in a twice-daily dosage for a period of 6 weeks on each dose. Plasma concentrations of LDL cholesterol decreased by 36.6%, 45.6% and 47.1% respectively on the three doses. High-affinity degradation of 125I-LDL by freshly isolated mononuclear leucocytes increased significantly on the 20 mg day-1 dosage but no further increase was observed on doses of 40 and 80 mg of simvastatin per day. Rates of 2-14C acetate incorporation into cholesterol by freshly isolated mononuclear leucocytes (obtained 12-15 h after the last dose of simvastatin) increased by 62%, 71% and 29% in cells isolated from patients on 20, 40, and 80 mg day-1 of simvastatin compared with values at baseline. In contrast, the 24 h excretion of mevalonic acid in the urine fell by 16.9%, 31.4% and 31.9% respectively on these three doses. Our results indicate that the potent hypocholesterolaemic effects of simvastatin are accompanied by increases in high-affinity LDL receptor-mediated degradation of LDL and a compensatory increase in cholesterol biosynthesis in freshly isolated mononuclear leucocytes but that rates of mevalonic acid excretion in the urine decrease.     

Serum noncholesterol sterols during inhibition of cholesterol synthesis by statins

We studied changes in serum cholestanol and plant sterols (indexes of cholesterol absorption) and cholesterol precursors (indexes of cholesterol synthesis) in response to cholesterol reduction by way of 1 year's treatment with atorvastatin (n = 102) and simvastatin (n = 105) treatments in patients with coronary heart disease. Serum cholesterol levels and ratios of the precursor sterols to cholesterol after 1 year of treatment were reduced in proportion to the pretreatment values (33% +/- 1% by simvastatin and 36% +/- 1% by atorvastatin; P <.01 for difference between groups) for cholesterol; the respective reductions in the precursor sterol:cholesterol ratios were also higher with atorvastatin (50% +/- 2% for lathosterol) than with simvastatin (42% +/- 1%; P <.01 between groups), but the ratio of squalene to cholesterol was increased (17% +/- 5%, P <.001) by atorvastatin. Plant sterol concentrations were gradually increased by atorvastatin but decreased initially by simvastatin. However, their ratios with respect to cholesterol were increased by as much as 82% with atorvastatin and by as much as 39% with simvastatin. In conclusion, effective inhibition of cholesterol synthesis and subsequent reduction in serum cholesterol levels by statins lead to increases in serum plant-sterol levels, probably as a result of reduced biliary secretion and enhanced absorption of these sterols. Because serum plant sterols have been claimed to be involved in the early development of atherosclerosis, the question arises whether continuously increasing serum plant sterols during long-term statin treatment should be prevented by cholesterol malabsorption (eg, by plant stanol ester consumption), especially in subjects with high baseline plant sterol values and effective sterol absorption.     

Ezetimibe plus simvastatin cardiovascular outcomes study program

Ezetimibe is a drug that impairs intestinal cholesterol absorption and decreases blood cholesterol levels. It has been shown that added to statins it can achieve a further reduction of low-density lipoprotein-cholesterol of 18-20%, overcoming the increase in absorption that follow the reduction in cholesterol synthesis by statins. Four major outcome trials are underway to study the effect of ezetimibe plus simvastatin in different subsets of high-risk patients: familiar hypercholesterolemia, degenerative aortic stenosis, chronic kidney disease and acute coronary syndrome. Hopefully, in the next few years the information provided by these trials will allow us to further reduce the increasing burden of cardiovascular disease.     

Residual effects of lovastatin and simvastatin on urinary mevalonate excretions in patients with familial hypercholesterolemia

3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitors are widely used to decrease plasma cholesterol levels in patients with heterozygous familial hypercholesterolemia (FH) who are at increased risk of premature coronary artery disease. Tissue-culture and animal studies have indicated that administration of HMG CoA reductase inhibitors (eg, lovastatin, simvastatin, etc) induces a compensatory increase in the activity of HMG CoA reductase, both by increasing its synthesis and decreasing catabolism. To determine in human subjects whether cessation of therapy with this class of drugs leads to induction of HMG CoA reductase activity and above-normal rates of cholesterol biosynthesis, we measured urinary concentrations of mevalonic acid (an indicator of cholesterol biosynthesis) after the cessation of therapy with lovastatin and simvastatin (80 mg/day) in patients with heterozygous FH. Plasma concentrations of LDL increased promptly on discontinuation of reductase inhibitor therapy but did not increase above pretreatment levels at any point after drug discontinuation. Similarly, the 24-hour urinary excretion of mevalonic acid was reduced during treatment with lovastatin or simvastatin and increased promptly on discontinuation of drug but did not increase to levels exceeding those found at baseline when the patients were receiving dietary therapy only. We conclude that cessation of treatment with HMG CoA reductase inhibitors in patients with FH does not result in a rebound increase in cholesterol biosynthesis and that no rebound overshoot occurs in plasma concentrations of low-density-lipoprotein cholesterol.     

International multicentre comparison of cerivastatin with placebo and simvastatin for the treatment of patients with primary hypercholesterolaemia. International Cerivastatin Study Group

An international multicentre double-blind randomised trial compared the efficacy and safety of cerivastatin (0.025, 0.05, 0.1 and 0.2 mg once daily) with placebo and simvastatin (20 mg) over a period of 12 weeks, with study extensions to 52 and 100 weeks. The primary efficacy parameter was the percentage change in low density lipoprotein cholesterol (LDL-C). This was reduced from the baseline by 12.5% (0.025 mg) to 30.6% (0.2 mg) compared with falls of 2.0% on placebo and 40.3% on simvastatin. All four cerivastatin doses and simvastatin (20 mg) produced significantly greater falls than placebo (p < 0.0001) and the decrease in LDL-C was dose-dependent for cerivastatin. Simvastatin produced significantly greater falls than any cerivastatin dose or placebo (p < 0.0001). The effect was maintained at 1 year but somewhat attenuated at 100 weeks. Significant falls were also seen in serum total cholesterol and triglycerides. High density lipoprotein cholesterol (HDL-C) levels were significantly increased by cerivastatin (0.1 and 0.2 mg) and simvastatin (20 mg) at 12 weeks and increased further by 100 weeks. Mean fasting apolipoprotein A1 and lipoprotein A1 were increased and apolipoprotein B decreased by cerivastatin and simvastatin therapy. All doses of cerivastatin produced significant falls in the total cholesterol/HDL-C ratio at 12 weeks (0.5-1.6) compared with a fall of 2.1 for simvastatin (20 mg). Cerivastatin was well tolerated. Elevations in creatine phosphokinase, aspartate aminotransferase and alanine aminotransferase were mostly minor and transitory. Vital signs, electrocardiogram determinations, urinalysis and ophthalmic assessment showed similar results for both drugs. Cerivastatin, at doses of 0.1 mg and 0.2 mg daily, is considered to be of therapeutic value in the treatment of patients with primary hypercholesterolaemia, with 0.2 mg cerivastatin achieving reductions of LDL-C and total cholesterol similar to those achieved in the WOSCOP and CARE studies.     

辛伐他汀对急性冠脉综合征患者颈动脉粥样硬化的影响

目的：探讨辛伐他汀对急性冠脉综合征患者颈动脉粥样硬化的影响及其机制。方法：80例急性冠脉综合征患者随机分成辛伐他汀20 mg组（40例）和辛伐他汀40 mg组（40例）,于治疗前及治疗6个月后分别测定血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）及高密度脂蛋白胆固醇（HDL-C）水平,并超声检测颈动脉内-中膜厚度（IMT）及颈动脉斑块面积。结果：两组治疗后TC、TG、LDL-C水平均明显降低（P〈0.01）,HDL-C明显升高（P〈0.01）;而辛伐他汀40 mg组较20 mg组作用更为明显（P〈0.05）。治疗6个月后IMT及颈动脉斑块面积明显缩小（P〈0.01）,且辛伐他汀40 mg组作用更显著（P〈0.01）。结论：辛伐他汀对急性冠脉综合征患者颈动脉粥样硬化斑块具有延缓和稳定作用。     

丹红注射液联合小剂量辛伐他汀对急性冠脉综合征的降脂效果

目的探讨丹红注射液联合小剂量辛伐他汀对急性冠脉综合征的降脂效果。方法将急性冠脉综合征患者70例按随机数字表法分为2组:对照组35例给予辛伐他汀降脂,观察组35例给予丹红注射液联合小剂量辛伐他汀降脂,评估两者降脂效果。结果治疗后观察组患者TC、TG、LDL-C及hs-CRP明显低于对照组(P<0.05),观察组患者血脂达标率明显高于对照组(97.14%比77.14%,P<0.05)。结论丹红注射液联合小剂量辛伐他汀在急性冠脉综合征中降脂的临床效果明确,值得应用。     

Heterozygous familial hypercholesterolaemia is associated with pathological exercise-induced leakage of muscle proteins, which is not aggravated by simvastatin therapy

Abstract. The objective of this study was to assess the relationship between therapy with the HMG-CoA reductase inhibitor simvastatin and muscle damage and the possible causal role of hypercholesterolaemia. The exercise-induced release of muscle proteins as a parameter of muscle damage was studied in two equicholesterolaemic groups of male patients with heterozygous familial hypercholesterolaemia (FH); one group without treatment, the second group on simvastatin. To assess the role of cholesterol, a third group of healthy male volunteers was studied as well. The study took place at the Lipid Clinic of an 800-bed University Hospital. One group of 21 male patients with heterozygous FH did not receive treatment, except for a lipid-lowering diet. A second group of 13 male FH patients were treated with 40 mg simvastatin day^-1 for at least 1 year and matched for cholesterol levels with the first group. A third group consisted of 25 normocholesterolaemic male controls. All subjects underwent a 45 min lean body mass (LBM) standardized ergometer muscle provocation test (2 Watt/kg LBM). Levels of creatine kinase (CK) and myoglobin (Mb) were assessed before and 1 and 8 h after exercise and compared with baseline levels. The exercise-induced release of muscle proteins is reflected by peak CK and Mb levels expressed as a percentage of baseline levels. The exercise-induced increase in Mb and CK levels did not differ between untreated and simvastatin-treated FH patients. However, the increase in Mb 1 h after exercise in untreated FH patients (181% of baseline level) and in simvastatin-treated patients (144% of baseline level) differed significantly from controls (107% of baseline level, P < 0.025, Mann-Whitney test). We conclude that hypercholesterolaemia may be associated with muscle damage, and the CK rises observed under therapy with HMG-CoA reductase inhibitors might be attributed to hypercholesterolaemia per se .     

Efficacy, safety and LDL-C goal attainment of ezetimibe 10 mg-simvastatin 20 mg vs. placebo-simvastatin 20 mg in UK-based adults with coronary heart disease and hypercholesterolaemia

It is increasingly accepted that more intensive lipid‐lowering treatment is associated with greater cardiovascular risk reductions in patients with coronary heart disease (CHD), thus providing a rationale for more aggressive LDL‐cholesterol (LDL‐C) targets. Ezetimibe in combination with statin therapy provides an additional approach to lipid management by utilising the additive action of two different mechanisms of LDL‐C reduction. In this multicentre, randomised, double‐blind, placebo‐controlled study, a total of 98 men and 55 women with CHD and primary hypercholesterolaemia, naïve to statin therapy, were randomised to receive treatment for 6 weeks with either ezetimibe 10 mg–simvastatin 20 mg (n = 77) or placebo–simvastatin 20 mg (n = 75). At 6 weeks, ezetimibe 10 mg–simvastatin 20 mg provided a mean additional LDL‐C reduction of 14.6% (95% CI 10.1–19.1) compared with simvastatin monotherapy (p < 0.0001). Moreover, a higher proportion of patients on ezetimibe/simvastatin achieved the National Standard Framework LDL‐C standard (<3.0 mmol/l; 93% vs. 75%, p < 0.001) or the new Joint British Societies (JBS 2) goal of LDL‐C < 2.0 mmol/l (49.3% vs. 11.1%, p < 0.001). On logistic regression analysis, the odds ratio of achieving target LDL‐C with ezetimibe 10 mg–simvastatin 20 mg was 5.1 (95% CI 1.8–15.0) times higher than with simvastatin monotherapy (p = 0.003). Clinical chemistry profiles and proportions of adverse events were similar in both groups at baseline and follow‐up. In conclusion, ezetimibe 10 mg–simvastatin 20 mg is a practical, effective and safe option for the treatment of primary hypercholesterolaemia in CHD patients, and brings more patients to new aggressive cholesterol targets compared with simvastatin 20 mg monotherapy.     

Review of efficacy of rosuvastatin 5 mg

The prevalence of coronary heart disease (CHD) has been increasing in the past few decades in Japan, as it has in industrialised countries worldwide. CHD risk can be substantially reduced by lowering low-density lipoprotein cholesterol (LDL-C) in patients with dyslipidaemia. Statins are highly effective for this indication, but many patients treated with these drugs still do not meet their treatment goals, often because clinicians fail to titrate these patients to a higher, potentially more effective, dose. Thus, there is a need for more effective agents that can help patients reach their goals at starting doses. This paper reviews key clinical results for a new agent, rosuvastatin. The data show that rosuvastatin 5 mg is highly effective in lowering LDL-C to recommended levels for most patients (mean reductions ranging from 42 to 52%). In addition, rosuvastatin 5 mg effectively lowers triglycerides (-16%), total cholesterol (-30%), non-high-density lipoprotein cholesterol (non-HDL-C; -38%) and apolipoprotein (apo) B levels (-33%) and increases HDL-C (+8.2-13%) in a wide range of patients with hypercholesterolaemia, including the elderly, obese patients, postmenopausal women and patients with hypertension, CHD, diabetes and metabolic syndrome. The 5-mg dose of rosuvastatin dose also produces greater reductions in LDL-C and larger increases in HDL-C than recommended initial doses of atorvastatin, simvastatin or pravastatin (for LDL-C reductions, p <0.001 vs. atorvastatin 10 mg, simvastatin 20 mg and pravastatin 20 mg; for HDL-C elevations, p <0.01 vs. atorvastatin 10 mg). These results demonstrate that rosuvastatin 5 mg produces favourable effects on the lipid profile and helps more patients achieve LDL-C goals than comparator statins.     

Effect of simvastatin on the antihypertensive activity of losartan in hypertensive hypercholesterolemic animals and patients: Role of nitric oxide,oxidative stress,and high‐sensitivity C‐reactive protein

This study investigated whether simvastatin has antihypertensive activity and can enhance the antihypertensive effect of losartan in hypertensive hypercholesterolemic animals and patients. Hypertension and hypercholesterolemia were induced in rats by L‐NAME and cholesterol‐enriched diet, respectively . In these animals, repeated administration of simvastatin decreased the systolic blood pressure, enhanced its progressive reductions induced by repeated administration of losartan, and corrected the compromised lipid profile. Concomitantly, repeated administration of simvastatin, losartan, or simvastatin in combination with losartan to these animals increased nitric oxide (NO) production and decreased the elevated serum malondialdehyde (MDA) and high‐sensitivity C‐reactive protein (hs‐CRP) levels. Effects of combined treatment were greater than those of simvastatin or losartan alone. In hypertensive hypercholesterolemic patients, repeated administration of losartan decreased systolic and diastolic blood pressure, increased NO production, and decreased the elevated serum MDA and hs‐CRP levels. Addition of simvastatin to losartan therapy enhanced these effects and corrected the compromised lipid profile. Simvastatin inhibited the contractile responses of isolated aortic rings induced by angiotensin II and enhanced the inhibitory effect of losartan on this preparation. l ‐arginine and acetylcholine enhanced, while L‐NAME inhibited the effects of simvastatin, losartan, and their combination on these contractile responses. Thus, simvastatin exerts antihypertensive effect in hypertensive hypercholesterolemic animals and enhances the antihypertensive effect of losartan in hypertensive hypercholesterolemic animals and patients . Besides, its cholesterol‐lowering effect, the ability of simvastatin to ameliorate endothelial dysfunction through increasing NO bioavailability and through suppression of oxidative stress and vascular inflammation may play an important role in these effects.     

Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia

Combination therapy is routinely used to achieve improved cholesterol reduction in familial hypercholesterolaemia. We compared the standard simvastatin plus bile-acid sequestrant (cholestyramine) therapy with simvastatin plus fenofibrate in 29 patients with severe familial hypercholesterolaemia. The fibrate regimen resulted in an 35.1 +/- 10.7% reduction in total cholesterol, a 40.6 +/- 20.5% in LDL cholesterol, 17.2 +/- 56.5% reduction in triglycerides and a 20.3 +/- 52.0% increase in HDL cholesterol. The cholestyramine regimen produced reductions of 29.3 +/- 13.2% in cholesterol, 37.1 +/- 21.9% in LDL cholesterol, and 12.5 +/- 48.9% in triglycerides, and a 5.0 +/- 25.4% rise in HDL cholesterol. The fibrate regimen was significantly more effective in reducing total cholesterol (p < 0.001) and LDL-cholesterol (p = 0.004), and also reduced triglycerides significantly (p = 0.05), compared to the cholestyramine regimen. There were significant improvements in the LDL:HDL cholesterol ratio (3.62 +/- 1.54 vs. 4.00 +/- 1.36; p = 0.05) and in the apolipoprotein B:A1 ratio (1.13 +/- 0.036 vs. 1.20 +/- 0.34; p = 0.05). Gastrointestinal side-effects occurred in 10 patients on cholestyramine therapy, and four patients on fibrate therapy had myalgia. There were no cases of rhabdomyolysis with either regime. No significant differences in liver biochemistry or creatine kinase were seen with either regimen.      

Differences among hyperlipoproteinaemic subjects in the response of lipoprotein lipids to resin therapy.

Ih has been reported that cholesterol turnover is raised when hypercholesterolaemia occurs in association with elevated levels of very low density lipoprotein, but normal when hypercholesterolaemia reflects an increase in the concentration of low density lipoprotein alone. The relationship of plasma lipoprotein levels to cholesterol metabolism has been further investigated in the present experiments, in which the acute effects on lipoprotein lipids of stimulating cholesterol turnover with a bile acid-sequestering resin, colestipol, have been compared in normal subjects and in patientw with four types of hyperlipoproteinaemia. Very low density lipoprotein (VLDL) lipids increased in every subject. The increase was greatest in patients with type IV or type V hyperlipoproteinaemia, least in normal subjects and in those with type IIa hyperlipoproteinaemia, and intermediate in patients with type IIb hyperlipoproteinaemia. The induced increments in VLDL cholesterol and triglyceride mass were accordingly positively correlated with the pre-treatment concentrations. Low density lipoprotein (LDL) lipids decreased during resin therapy in all subjects, except those with type IV or type V hyperlipoproteinaemia in whom there was a transient rise. The reductions in LDL cholesterol were significantly greater in patients with type II hyperlipoproteinaemia than in the normal volunteers, and in both groups of subjects were proportionately greater than those in LDL triglyceride. These findings demonstrated clear differences among the hyperlipoproteinaemias in the response of lipoprotein lipids to resin therapy, and profide further evidence for the heterogeneity of cholesterol metabolism in these conditions. The colestipol-induced changes in type UV and type V patients could be partially reproduced in normal subjects during the consumption of high carbohydrate diets, which might be expected to increase VLDL synthesis. It is suggested, therefore, that the synthesis of VLDL cholesterol may be enhanced in such patients, and that any rise in LDL cholesterol observed during resin therapy reflected subsequent metabolism of VLDL to LDL rather than diminished LDL cholesterol clearance.