Combined bezafibrate and simvastatin treatment for mixed hyperlipidaemia

A. Kehely et al., Q J Med 1995; 88:421–7     

Ezetimibe/simvastatin (INEGY) in the treatment of hyperlipidaemia

Ezetimibe/simvastatin (INEGY), a dual inhibitor of both cholesterol production and absorption, is a new approach to the management of hyperlipidaemia. Recent studies have shown that it produces greater reductions in low-density lipoprotein (LDL) cholesterol than the single inhibition of statin therapy, enabling many more patients to achieve their LDL cholesterol treatment goals. With ezetimibe/simvastatin therapy, reductions of up to 61% from baseline have been seen in LDL cholesterol, with clear improvements in other associated lipid fractions. It has been well tolerated across all studies, with a safety profile similar to that of statin therapy. This article will review clinical experience to date with ezetimibe/simvastatin, commenting upon its place and potential value in the prevention of cardiovascular disease.     

Anti-sense oligonucleotide therapies for the treatment of hyperlipidaemia

ABSTRACT

Introduction: Anti-sense oligonucleotide (ASO) therapies are a new development in clinical pharmacology offering greater specificity compared to small molecule inhibitors and the ability to target intracellular process’ not susceptible to antibody-based therapies.

Areas covered: This article reviews the chemical biology of ASOs and related RNA therapeutics. It then reviews the data on their use to treat hyperlipidaemia. Data on mipomersen – an ASO to apolipoprotein B-100(apoB) licensed for treatment of homozygous familial hypercholesterolaemia (FH) is presented. Few effective therapies are available to reduce atehrogenic lipoprotein (a) levels. An ASO therapy to apolipoprotein(a) (ISIS Apo(a)_Rx) specifically reduced lipoprotein (a) levels by up to 78%. Treatment options for patients with familial chylomicronaemia syndrome (lipoprotein lipase deficiency; LPLD) or lipodystrophies are highly limited and often inadequate. Volanesorsen, an ASO to apolipoprotein C-3, shows promise in the treatment of LPLD and severe hypertriglyceridaemia as it increases clearance of triglyceride-rich lipoproteins and can normalise triglycerides in these patients.

Expert opinion: The uptake of the novel ASO therapies is likely to be limited to selected niche groups or orphan diseases. These will include homozygous FH, severe heterozygous FH for mipomersen; LPLD deficiency and lipodystrophy syndromes for volanesorsen and treatment of patients with high elevated Lp(a) levels.     

Blood rheology changes during bezafibrate treatment

To evaluate the effect of bezafibrate on the haemorheological pattern, 30 atherosclerotic non-diabetic patients were enlisted in a double-blind, comparative, parallel group trial with bezafibrate (600 mg daily) or placebo being randomly assigned. The 45-day treatment period was preceded by a three week pharmacological wash-out. Haemorheological parameters such as whole-blood, plasma and serum viscosity, haematocrit, fibrinogen, fibrinogen/albumin ratio and erythrocyte filterability were evaluated before and at the end of treatment. The results showed no change in haemorheological determinants in the placebo-treated group but a significant reduction in whole-blood viscosity, in haematocrit, in fibrinogen and fibrinogen/albumin ratio was observed in the bezafibrate treated patients. No variation was present in the plasma and serum viscosity and in the erythrocyte filterability.     

阿托伐他汀与常用调脂药物治疗老年混合型高脂血症的疗效比较分析

目的 比较他汀类经物阿托伐他汀、辛伐他汀、洛伐他汀单独应用及与不饱和脂肪酸（Omega-3)联用，治疗老年混合型高脂血症患者的疗效与安全性。方法 104例混合型高脂血症患者随机分为3组，即阿托伐他汀组、辛伐他汀组、洛伐他汀＋Omega-3组，治疗8周，观察降脂疗效、不良反应。结果 阿托伐他汀降甘油三酯（TG）、低密度脂蛋白（LDL－C）优于辛伐他汀、洛伐他汀与Omega-3联用；升高高密度脂蛋白（HDL－C）则是辛伐他汀、洛伐他汀与Omega-3联用优于阿托伐他汀；降总胆固醇（TC）、动脉硬化指数（TC－HDL－C）／HDL－C），三组无显著差别。TC、TG、LDL－C三项指标达标率三组也极为相近。结论 综合考虑各种因素，建议治疗混合型高脂血症患者可首选他汀类药物，必要时与不饱和脂肪酸联用，全面调节血脂的效果最好。     

治疗老年原发性混合性高脂血症的临床观察

目的探讨在老年混合性高脂血症中调脂药物小剂量联合应用的有效性和安全性.方法选择原发性混合性高脂血症患者(年龄≥65岁),给予辛伐他汀20 mg/d治疗,疗程4周;复查血脂指标,选择参数未全面达标者100例,分别进入辛伐他汀治疗组(55例)、辛伐他汀与吉非贝齐联合治疗组(45例),疗程24周;观察两种治疗方案在有效性、安全性、达标率及不良反应发生率等方面差异.结果 2例患者因出现不良反应终止治疗,其余98例患者的各项血脂指标均得到了不同程度地调控,总达标率为71.43%.两组患者在一般临床资料及基础血脂水平方面差异无统计学意义;但疗程结束后,联合治疗组患者的血清甘油三酯水平(1.52±0.46) mmol/L低于单药治疗组(1.91±0.82) mmol/L,血清高密度脂蛋白胆固醇(1.17±0.17) mmol/L高于单药治疗组(0.95±0.20) mmol/L,且有统计学意义.结论辛伐他汀和吉非贝齐小剂量联合治疗能够安全有效地、更为全面地调节老年人原发性混合性高脂血症的血脂紊乱.     

The investigation and treatment of hyperlipidaemia in general practice.

An investigation was made into the incidence of type IIa hyperlipidaemia in two generations of a family in which there was a tendency to develop premature ischaemic heart disease. Forty-three per cent of those tested showed a lipoprotein abnormality characteristic type IIa hyperlipidaemia. Treatment of this condition, by dietary and drug therapy, was uniformaly successful. The importance of early detection of this condition by the general practitioner is emphasized, in view of the high incidence of premature ischaemic heart disease in such patients.     

A review of combined hyperlipidaemia and its treatment with fenofibrate

Approximately 15% of myocardial infarction survivors less than 60 years of age have a plasma lipid abnormality defined as combined hyperlipidaemia. Patients with this condition are at substantial risk for future cardiovascular events. Combined hyperlipidaemia involves elevations in both plasma triglycerides and low-density lipoprotein (LDL) cholesterol and may share similarities with hyperapolipoproteinaemia, LDL-pattern B and the small LDL-pattern. Treatment is directed at reduction of LDL-cholesterol and plasma triglyceride values. Nicotinic acid and the fibric acid derivatives are useful therapeutic agents. Fenofibrate is a fibric acid derivative that lowers both triglycerides and LDL-cholesterol in combined hyperlipidaemia. In combined hyperlipidaemia, fenofibrate has been shown to reduce significantly plasma triglycerides by approximately 40%, LDL-cholesterol by 6%, and to increase high-density lipoprotein cholesterol by 15%. Apoproteins are favourably altered with increases in apoprotein-A, decreases in apoprotein-E and inconsistent decreases in apoprotein-B. Fenofibrate is well tolerated with primarily dermatological side-effects.     

Central and peripheral haemodynamic effects of hyperglycaemia,hyperinsulinaemia, hyperlipidaemia or a mixed meal

The aim of the present study was to evaluate the haemodynamic changes during hyperinsulinaemia, hyperglycaemia or hypertriglyceridaemia in relation to those following a mixed meal. Ten subjects were subjected to hypertriglyceridaemia (3.9 mmol/l) for 2 h by an infusion of Intralipid and heparin. Nine subjects received a hyperglycaemic clamp (12.5 mmol/l) with octreotide and low-dose insulin infusion to maintain normoinsulinaemia (10 m-units/l). Ten subjects received saline for 2 h as a control and, thereafter, 2 h of normoglycaemic hyperinsulinaemic clamp (80 m-units/l). Finally, ten subjects were evaluated for 2 h following an ordinary mixed meal. Calf blood flow was measured by venous occlusion plethysmography and cardiac index by thoracic bioimpedance. Both the mixed meal and normoglycaemic hyperinsulinaemia lowered total peripheral resistance, and increased calf blood flow and cardiac index, whereas blood pressure decreased (P <0.05-0.001). Both hyperglycaemia and hypertriglyceridaemia increased calf blood flow, but blood pressure was unchanged. Total peripheral resistance was unchanged in hypertriglyceridaemia, whereas hyperglycaemia induced a significant increase. Normoglycaemic hyperinsulinaemia induced a haemodynamic pattern similar, but to a lesser extent, to the pattern seen following a mixed meal. Hyperinsulinaemia seems to be a major mediator of the haemodynamic response, but other factors are obviously also of great importance. Hypertriglyceridaemia and hyperglycaemia induced haemodynamic responses that are not similar to those seen following a mixed meal.     

急性冠脉综合征早期应用辛伐他汀疗效观察

目的　观察急性冠脉综合征 (ACS)早期应用辛伐他汀对血脂、缺血事件发生的影响。方法　将 4 0例ACS患者随机分为治疗组 (n =2 0 )和对照组 (n =2 0 ) ,治疗 2 4周 ,观察用药前后血脂、缺血事件发生情况。结果　治疗组用药后血脂明显下降 (P <0 . 0 5 ) ,对照组用药前后血脂无显著变化 (P >0 .0 5 )。缺血事件的总发生例数治疗组明显低于对照组 (χ2 =4 . 80 ,P =0 . 0 2 85 )。两组治疗前后肝、肾功能、肌酸磷酸激酶均无明显变化。结论　ACS早期应用辛伐他汀可明显降低缺血事件。     

Dual bezafibrate-simvastatin therapy for combined hyperlipidaemia

Statins and fibrates are both effective in the treatment of hyperlipidaemias but are not recommended in combination because episodes of rhabdomyolysis have followed combined Iovastatin-gemfibrozil therapy. We assessed treatment with dual bezafibrate-simvastatin therapy in routine clinical practice. In 22 patients, total cholesterol, LDL-cholesterol and triglycerides fell by 20.1% ( P >0.0001), 35-1% ( P >0.001) and 31% ( P >0.05) respectively, and HDL-cholesterol rose by 18.4% ( P >0.05) on combination therapy. The reduction in cholesterol. followed the introduction of simvastatin, while the decrease in triglycerides followed treatment with bezafibrate. No patient developed myopathy. We conclude that dual simvastatin-bezafibrate therapy is well tolerated and may reduce triglyceride concentrations, but offers no advantage in cholesterol reduction over treatment with simvastatin alone.     

Scalp pain and hyperlipidaemia

Acute pancreatitis and eruptive xanthomata are the only recognised direct complications of severe hypertriglyceridaemia, although peripheral neuropathy has been described in patients with hyperlipidaemia. We describe a patient with mixed hyperlipidaemia presenting with severe scalp pain and eruptive xanthomata. Both resolved with treatment. We suspect that high triglyceride concentration can affect the function of sensory nerve fibres.     

Incorporation of simvastatin in PLLA membranes for guided bone regeneration: effect of thermal treatment on simvastatin release

Electrospun membranes based on biodegradable polymers are promising materials to be used for guided bone regeneration (GBR) therapy. The incorporation of osteostimulatory compounds can improve the biofunctionality of those membranes, making them active players in bone regeneration. Simvastatin has been shown to promote osteogenic differentiation both in vitro and in vivo. However, in most of these systems, the drug was quickly released, not matching the pace of bone regeneration. The aim of this study was to develop poly(l-lactic acid) (PLLA) membranes containing simvastatin (SV) that have a prolonged drug release rate, compatible with GBR applications. To this end, SV was mixed with PLLA and electrospun. The membranes were subjected to a thermal treatment in order to increase the crystallinity of PLLA. Morphological, structural and chemical properties of the electrospun membranes were characterized. The effect of the thermal treatment on the release profile of SV was evaluated by near physiological release experiments at 37 °C. The osteostimulatory potential was determined by in vitro culture of the membranes with rat bone marrow stromal cells (rBMSCs). The results confirmed that the thermal treatment led to an increase in polymer crystallinity and a more sustained release of SV. In vitro assays demonstrate cellular proliferation over time for all the membranes and a significant increase in osteogenic differentiation for the membranes containing SV subjected to thermal treatment.

Thermal treatment resulted in a sustained release of simvastatin and a positive response from rBMSCs.     

A randomised comparison of simvastatin versus simvastatin and low cholesterol diet in the treatment of hypercholesterolaemia

There is little evidence to show that strict dietary modification alone confers any significant impact on cardiac events in primary and secondary prevention of coronary heart disease. Given the efficacy of the statins, the need for strict dietary modification in patients on statin therapy has been questioned. This study was performed to assess 1) the added benefit on serum lipid levels of a strict low-fat dietary regimen in patients with hypercholesterolaemia already treated with simvastatin; 2) the efficacy of simvastatin on the lipid profile of our sample Asian population; and 3) the tolerability and side-effect profile of simvastatin. This study was a prospective evaluation of 60 patients with hypercholesterolaemia treated with simvastatin who were subjected to either a normal diet or a dietitian guided low-fat diet. Assessment of the effects on serum lipid levels, side-effects, biochemical and haematological markers were performed. After 24 weeks of treatment, a strict dietitian guided low-fat diet conferred no additional benefit over and above what was achieved by simvastatin alone. Furthermore, a higher dose of simvastatin was needed in the dietitian guided diet group to achieve the target LDL-cholesterol level. Simvastatin resulted in a significant positive alteration of lipid profiles in all patients. The drug was well tolerated, with no significant change in either haematological or biochemical indices. Simvastatin is a highly effective cholesterol-lowering drug with a beneficial effect on the entire lipid spectrum in a cross-section of Asian patients, and is well tolerated. A dietitian guided dietary approach confers no additional advantage once statin therapy has been initiated.     

Effects of fluvastatin treatment on insulin sensitivity in patients with hyperlipidaemia

This study aimed to determine the effects of fluvastatin treatment on insulin sensitivity in patients with hyperlipidaemia. Non-obese, normoglycaemic, normotensive patients with hyperlipidaemia (n = 20) and a reference group of healthy subjects of similar age, sex, and body mass index (n = 20) were evaluated. Patients with other causes of peripheral insulin resistance were excluded. All participants underwent a diagnostic protocol, which included measurements of insulin sensitivity index and other metabolic parameters. Insulin sensitivity was assessed by Homeostasis Model Assessment (HOMA). Serum insulin levels were tested by radioimmunoassay. Patients were treated with fluvastatin 40 mg once daily for 3 months. Before fluvastatin treatment, fasting serum insulin levels were significantly raised in patients with hyperlipidaemia compared with subjects from the reference group (19.1 +/- 13.4 versus 8.1 +/- 3.4 microIU/ml). The fasting serum insulin levels and HOMA-estimated insulin sensitivity were correlated in the whole group. Correlation analysis showed a significant relationship between HOMA-estimated insulin resistance and plasma cholesterol and triglyceride concentrations. Patients with hyperlipidaemia had reduced insulin sensitivity that was reflected by high serum fasting insulin levels. Anti-hyperlipidaemic treatment with fluvastatin increases insulin sensitivity.     

Post-prandial metabolism of triglyceride-rich lipoproteins in non-insulin-dependent diabetic patients before and after bezafibrate treatment

Retarded post-prandial (pp) lipid clearance is potentially a major component of the increased cardiovascular risk incurred by hypertriglyceridaemic non-insulin-dependent diabetic mellitus (NIDDM) patients. The effect of bezafibrate (Bz, 400 mg per day for 5 weeks on chylomicron (CM) and remnant clearance after loads of 100 g of fat and vitamin A was therefore explored in 10 male patients (glycaemia 11.9 ±3.3 TG 4.5 ±2.4 mmol L^–1). In all subjects CM-TG and retinyl palmitate (RP) were reduced by 50%, but 8-h non-CM (remnant) RP decreased only in initially mildly hypertriglyceridaemic subjects (?35%, P <0.05), while in three patients with very elevated initialTG (ε_3/3, ε_3/2 and ε_2/2 genotypes) 8-h remnant RP increased by 100%. The decrease in pp CM-TG correlated with that of fasting Sf 20–400 (r = 0.686, P = 0.026), suggesting that improved lipolysis was a major determinant of hypolipidaemic effect. Apo CIII synthesis is known to be depressed by Bz: concentrations were lower under Bz (P <0.05). A positive correlation (r =0.880, P <0.001) with fasting TG before treatment and its disappearance after treatment suggested an involvement of high concentrations with hypertriglyceridaemia. Post-prandial non-esterified fatty acids were decreased by 35 in correlation with a significant (?19%, P <0.05) improvement in fasting glycaemia (r =-.801, P <0.005). These results suggest that Bz acts both on lipolysis and on removal of CM remnants, but that removal can become saturated when lipolysis is massively improved.     

Post-prandial metabolism of triglyceride-rich lipoproteins in non-insulin-dependent diabetic patients before and after bezafibrate treatment

Retarded post-prandial (pp) lipid clearance is potentially a major component of the increased cardiovascular risk incurred by hypertriglyceridaemic non-insulin-dependent diabetic mellitus (NIDDM) patients. The effect of bezafibrate (Bz, 400 mg per day for 5 weeks on chylomicron (CM) and remnant clearance after loads of 100 g of fat and vitamin A was therefore explored in 10 male patients (glycaemia 11.9 ±3.3 TG 4.5 ±2.4 mmol L^–1). In all subjects CM-TG and retinyl palmitate (RP) were reduced by 50%, but 8-h non-CM (remnant) RP decreased only in initially mildly hypertriglyceridaemic subjects (−35%, P  <0.05), while in three patients with very elevated initialTG (ε3/3, ε_3/2 and ε_2/2 genotypes) 8-h remnant RP increased by 100%. The decrease in pp CM-TG correlated with that of fasting Sf 20–400 ( r  = 0.686, P  = 0.026), suggesting that improved lipolysis was a major determinant of hypolipidaemic effect. Apo CIII synthesis is known to be depressed by Bz: concentrations were lower under Bz ( P  <0.05). A positive correlation ( r  =0.880, P  <0.001) with fasting TG before treatment and its disappearance after treatment suggested an involvement of high concentrations with hypertriglyceridaemia. Post-prandial non-esterified fatty acids were decreased by 35 in correlation with a significant (−19%, P  <0.05) improvement in fasting glycaemia ( r  =-.801, P  <0.005). These results suggest that Bz acts both on lipolysis and on removal of CM remnants, but that removal can become saturated when lipolysis is massively improved.