Hypertriglyceridemia: A Review of Clinical Relevance and Treatment Options: Focus on Cerivastatin

SUMMARY

The triglyceride (TG) level is one of several lipid parameters that can aid prediction of coronary heart disease (CHD) risk. An elevated plasma TG level is strongly associated with an increased risk of CHD.

Hypertriglyceridemia, the second most common dyslipidemic abnormality in hypertensive subjects after increased low-density lipoprotein cholesterol (LDL-C), is defined by the National Cholesterol Education Programme (NCEP) as a fasting TG level of >2.26?mmol/l (>200?mg/dl) and is recognised as a primary indicator for treatment in type IIb dyslipidemia. Raised TG levels can be present in individuals at risk for CHD when the total cholesterol is normal. However, not all individuals with raised TG levels have increased risk of CHD. Factors such as: diet, age, lifestyle, and a range of medical conditions, drug therapy and metabolic disorders, can all affect the TG level. In some of these circumstances, other factors protect against the risk of CHD, and can minimise or negate the effect of the risk factors present.

Although TG reducing therapy has been shown to be associated with an improved clinical outcome, more research is needed to determine whether this is an independent effect of TG reduction or an effect of normalising the overall lipid profile in hypertriglyceridemic patients. Further trials are required to quantify the clinical benefits of lowering TG to ‘target’ levels and to confirm targets defined by NCEP-II (shown in Table 1).

The role of TG in CHD pathogenesis is thought to involve several direct and indirect mechanisms, such as effects on the metabolism of other lipoproteins, transport proteins, enzymes, and on coagulation and endothelial dysfunction. More research is required to fully elucidate the role of TG, the ways in which it can influence other risk factors and the mechanism of its own more direct role in the atherogenic process.

Patients with hypertriglyceridemia have been shown to respond well to dietary control and to the use of lipid lowering drugs such as 3-hydroxy-3-methylglutaryl-Coenzyme A (HMG CoA) reductase inhibitors (known as statins), fibrates and nicotinic acids. However, recent retrospective real-life clinical studies show that only 38% of patients receiving some form of lipid-lowering therapy achieved NCEP-defined LDL-C target levels, demonstrating the need for the use of more aggressive treatment.

In hypertriglyceridemic patients, the newer statins, cerivastatin and atorvastatin, have shown comparable efficacy in reducing TG compared with the older statins. Achieving NCEP target lipid levels has been shown to reduce the risk of cardiovascular disease in dyslipidemic individuals, including high-risk patient groups such as those with additional risk factors, existing heart disease, diabetes mellitus and metabolic syndrome.

Although the latest clinical studies investigating combination therapies, i.e. dual therapy with both a statin and a fibrate, have demonstrated them to be effective for overall control of lipid parameters and reducing coronary events, it is not yet clear whether this offers any significant advantage over monotherapy. Results from ongoing longer-term end-point clinical studies may provide further information in this area and consequent reviews of primary care management policies for dyslipidemia. Statin monotherapy may be a reliable option for primary care treatment of dyslipidemia (including hypertriglyceridemia).     

Myopathy during statin therapy in the daily practice of an outpatient cardiology clinic: prevalence,predictors and relation with vitamin D

Abstract

Objective:

The mechanism of statin-related myopathy is unknown, while its prevalence is probably underestimated. An association between statin-related myopathy and vitamin D deficiency has been reported. In this pilot study we assessed the prevalence of myopathy in statin users attending the outpatient clinic of the Department of Cardiology of a University Hospital from October 2009 to March 2010. We also searched for predictors of myopathy and investigated whether the myopathy was associated with vitamin D deficiency.     

Current pharmacotherapy for the treatment of dyslipidemia associated with HIV infection

ABSTRACT

Introduction: Cardiovascular disease is an important cause of morbidity and mortality in persons with human immunodeficiency virus (PWH). The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in PWH compared to uninfected persons. Dyslipidemia is a critical link in the pathogenesis of ASCVD in PWH. Chronic inflammation associated with HIV infection may drive both dyslipidemia and ASCVD.

Areas covered: The authors review the evidence for using lipid-lowering therapy in PWH and includes an overview of the utility and complexity of using statins in PWH, in particular, drug interactions, safety, and efficacy. In addition, data covering alternate therapies like omega-3 fatty acids, fibrates, niacin, ezetimibe, and PCSK-9 inhibitors are reviewed.

Expert opinion: Dyslipidemia is a common problem in PWH. The risk of ASCVD is higher in PWH. Lipid-lowering therapy reduces the risk of ASCVD, but clinical endpoint trials are lacking in PWH. Statin therapy is the mainstay of primary prevention for ASCVD. The timing of when to initiate primary prevention with statins in PWH is unclear. Beyond statins, there are limited data that other lipid-lowering agents have utility in PWH. Ongoing trials like the REPRIEVE trial will inform the community about the optimal approach to lipid-lowering therapy in PWH.     

Bavachinin inhibits cholesterol synthesis enzyme FDFT1 expression via AKT/mTOR/SREBP-2 pathway

Non-alcoholic fatty liver disease (NAFLD) is a progressive and chronic liver disease. No effective drug is currently approved for the treatment of NAFLD. Traditionally it is thought that pathogenesis of NAFLD develops from some imbalance in lipid control, thereby leading to hepatotoxicity and disease development. Squalene synthase (SQS), encoded by FDFT1, is a key regulator in cholesterol synthesis and thus a potential target for the treatment of NAFLD. Here we could identify bavachinin, a component from traditional Chinese medicine Fructus Psoraleae (FP), which apparently protects HepaRG cells from palmitic acid induced death, suppressing lipid accumulation and cholesterol synthesis through inhibition of FDFT1 through the AKT/mTOR/SREBP-2 pathway. Over-expression of FDFT1 abolished bavachinin (BVC) -induced inhibition of cholesterol synthesis. The data presented here suggest that bavachinin acts as a cholesterol synthesis enzyme inhibitor, and might serve as a drug for treating NAFLD in the future.     

Investigation of HMG-CoA reductase inhibitory and antioxidant effects of various hydroxycoumarin derivatives

Cardiovascular diseases are one of the primary causes of deaths worldwide, and the development of atherosclerosis is closely related to hypercholesterolemia. As the reduction of the low-density lipoprotein cholesterol level is critical for treating these diseases, the inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase, which is essentially responsible for cholesterol biosynthesis, stands out as a key solution to lower plasma cholesterol levels. In this study, we synthesized several dihydroxycoumarins and investigated their antioxidant and in vitro HMG-CoA reductase inhibitory effects. Furthermore, we carried out in silico studies and examined the quantum-chemical properties of the coumarin derivatives. We also performed molecular docking experiments and analyzed the binding strength of each coumarin derivative. Our results revealed that compound IV displayed the highest HMG-CoA reductase inhibitory activity (IC₅₀ = 42.0 µM) in vitro. Cupric-reducing antioxidant capacity and ferric-reducing antioxidant power assays demonstrated that coumarin derivatives exhibit potent antioxidant activities. Additionally, a close relationship was found between the lowest unoccupied molecular orbital energy levels and the antioxidant activities.     

Use of Lipid-Lowering Agents for the Prevention of Age-Related Macular Degeneration: A Meta-Analysis of Observational Studies

Purpose : To examine the effect of lipid-lowering agents in the development of age-related macular degeneration (AMD) through the techniques of meta-analysis. Methods : Case-control and cohort studies presenting relative risks and 95% confidence intervals were identified through a literature review. Inclusion was limited to studies where both the exposure of interest (lipid-lowering agents) and outcome (AMD) were explicitly defined. Pooled estimates were computed using the random effects model. To quantify heterogeneity we calculated the proportion of total variance of between study variance using the Ri statistic. The Q statistic for heterogeneity was also calculated. Results : Eight studies were identified. The pooled relative risk (RR) for all studies was 0.74 (95% CI, 0.55–1.00). When only those studies examining the use of statins were pooled (n = 7), the RR was 0.70 (95% CI, 0.48–1.03). Using the Ri statistic, the heterogeneity between studies was found to be 0.85 for all studies and 0.89 for studies examining statins. Conclusion : Lipid-lowering agents, including statins, do not appear to lower the risk of developing AMD, although clinically significant effects cannot be excluded. The use of these agents in the prevention of AMD cannot be recommended until well designed prospective studies with long follow up have demonstrated a benefit.     

Absorption and disposition of fluvastatin, an inhibitor of HMG-CoA reductase, in the rabbit.

The absorption and disposition of fluvastatin have been studied in the female rabbit. In naive rabbits receiving a single oral dose (1 mg kg-1) of [3H] fluvastatin, absorption was rapid and amounted to c. 90 per cent compared with an intravenous reference dose. The drug was subject to considerable first-pass effect, its absolute bioavailability being 46 per cent. The steady-state volume of distribution of fluvastatin was 0.29 +/- 0.04 l kg-1 while the total body clearance was 0.33 +/- 0.05 1 h-1 kg-1. The administered radioactivity was excreted predominantly in feces, with the renal pathway accounting for 28 +/- 4 per cent of the oral dose and 32 +/- 3 per cent of the intravenous dose. In pregnant rabbits on a multiple oral dosing regimen, 1 mg kg-1 day-1 beginning day 6 post-conception (p.c.), steady-state concentrations in maternal blood and tissues were achieved within 5 days. The concentrations in the reproductive organs were c. 25-50 per cent of that in maternal blood while those in the kidneys and liver were considerably higher. In contrast, radioactivity levels in the fetuses and amniotic fluid decreased significantly during repeated drug administration. The fetus: placenta and amniotic fluid: placenta concentration ratios declined from 0.92 and 0.97, respectively, on day 10 p.c. to 0.10 and 0.04, respectively, on day 18 p.c., indicating a limited transfer of fluvastatin and/or its metabolite(s) across the placenta at the later stage of pregnancy. After cessation of dosing, radioactivity levels in all tissues and fluids showed a progressive and nearly parallel decline, suggesting no tissue retention of the drug.     

Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes

TAK-475 is a squalene synthase inhibitor, rapidly metabolized to T-91485 in vivo. We investigated the myotoxicities of T-91485 and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in a human rhabdomyosarcoma cell line, RD, and in human skeletal myocytes. In differentiated RD cells, T-91485, atorvastatin (ATV) and simvastatin acid (SIM) inhibited cholesterol biosynthesis, with IC(50) values of 36, 2.8 and 3.8 nM, respectively. ATV and SIM decreased the intracellular ATP content, with IC(25) values (concentrations giving a 25% decrease in intracellular ATP content) of 0.61 and 0.44 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis in RD cells, the IC(25) value exceeded 100 microM. In human skeletal myocytes, T-91485, ATV and SIM concentration-dependently inhibited cholesterol biosynthesis, with IC(50) values of 45, 8.6 and 8.4 nM, respectively. ATV and SIM decreased intracellular ATP content, with IC(25) values of 2.1 and 0.72 microM, respectively. Although T-91485 potently inhibited cholesterol synthesis, the IC(25) value exceeded 100 microM. Myotoxicity induced by ATV was prevented by mevalonate or geranylgeranyl-PP, but not by squalene in skeletal cells. Furthermore, T-91485 attenuated the myotoxicity of ATV. These findings suggest that TAK-475 and T-91485 may not only be far from myotoxic, they may also decrease statin-induced myotoxicity in lipid-lowering therapy.     

阿托伐他汀对慢性肾衰竭大鼠外周血内皮祖细胞的影响

目的探讨阿托伐他汀对慢性肾衰竭大鼠外周血内皮祖细胞(endothelial progenitor cells,EPCs)数量和功能的影响。方法采用分阶段5/6肾切除制备大鼠慢性肾衰竭模型。实验动物随机分为4组:假手术组、慢性肾衰竭组(模型组)、8mg.kg-1.d-1阿托伐他汀干预组(小剂量组)、16mg.kg-1.d-1阿托伐他汀干预组(大剂量组)。大鼠阿托伐他汀灌胃8周后,取其外周血分离与培养EPCs,并检测EPCs数量及其增殖、黏附能力。结果与假手术组比较,慢性肾衰竭大鼠外周血EPCs数量及其增殖、黏附能力均下降(P<0.05)。应用阿托伐他汀能明显增加慢性肾衰竭大鼠外周血EPCs数量,改善外周血EPCs增殖、黏附能力(P<0.05),并且呈剂量依赖性。结论阿托伐他汀可改善慢性肾衰竭大鼠外周血EPCs的数量和功能。     

Atherosclerosis induced by arsenic in drinking water in rats through altering lipid metabolism

Arsenic in drinking water is a global environmental health problem, and the exposure may increase cardiovascular and cerebrovascular diseases mortalities, most likely through causing atherosclerosis. However, the mechanism of atherosclerosis formation after arsenic exposure is still unclear. To study the mechanism of atherosclerosis formation after arsenic exposure and explore the role of high cholesterol diet (HCD) in this process, we fed spontaneous hypertensive rats and Wistar Kyoto rats with basal diet or HCD and provided with them drinking water containing arsenic at different ages and orders for 20 consecutive weeks. We measured high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, heat shock protein 70 (HSP 70), and high sensitive C-reactive protein (hs-CRP) at predetermined intervals and determined expressions of cholesteryl ester transfer protein-1 (CETP-1) and liver X receptor β (LXRβ) in the liver. Atherosclerosis was determined by examining the aorta with hematoxylin and eosin stain. After 20 weeks, we found arsenic, alone or combined with HCD, may promote atherosclerosis formation with transient increases in HSP 70 and hs-CRP. Early combination exposure decreased the HDL-C/LDL-C ratio without changing the levels of total cholesterol and triglyceride until 30 weeks old. Both CETP-1 and LXRβ activities were suppressed, most significantly in early combination exposure. In conclusion, arsenic exposure may induce atherosclerosis through modifying reverse cholesterol transport in cholesterol metabolism and suppressing LXRβ and CEPT-1 expressions. For decreasing atherosclerosis related mortality associated with arsenic, preventing exposure from environmental sources in early life is an important element.