LDL‐C/HDL‐C ratio in subjects with cardiovascular disease and a low HDL‐C: results of the RADAR (Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport) study

ABSTRACT

Background: The ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (LDL‐C/HDL‐C) is a reliable predictor of cardiovascular risk. Low HDL‐C levels in patients with coronary artery disease are associated with a high risk for cardiovascular events.

Objectives: This study compared the effects of rosuvastatin and atorvastatin on the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C.

Methods: Patients aged 40–80 years with established cardiovascular disease and HDL‐C < 1.0?mmol/L (< 40?mg/dL) entered a 6‐week dietary run-in period, before randomisation to open-label treatment with rosuvastatin 10?mg (n = 230) or atorvastatin 20?mg (n = 231) for 6 weeks. Doses were increased after 6 weeks to rosuvastatin 20?mg or atorvastatin 40?mg, and after 12 weeks to rosuvastatin 40?mg or atorvastatin 80?mg. Serum lipid parameters were measured at baseline and 6, 12 and 18 weeks.

Results: After 6 weeks of treatment, mean percentage change from baseline in LDL‐C/HDL‐C ratio was –47.0% in the rosuvastatin group and –41.9% in the atorvastatin group (?p < 0.05 for between-group comparison). After 12 and 18 weeks of treatment, change from baseline was –53.0% and –57.3%, respectively, for rosuvastatin, compared with –47.9% and –49.6%, respectively, for atorvastatin (?p < 0.01 and p < 0.001, respectively, for between-group comparison). Rosuvastatin also reduced LDL‐C, total cholesterol and non-HDL‐C significantly more than atorvastatin at all three time points, and significantly improved total cholesterol/HDL‐C and apolipoprotein B/A‐I ratios.

Conclusions: Rosuvastatin 10, 20 and 40?mg is significantly more effective than atorvastatin 20, 40 and 80?mg, respectively, in improving the LDL‐C/HDL‐C ratio in patients with cardiovascular disease and low HDL‐C. Further studies are required to clarify the benefits of rosuvastatin for reduction of cardiovascular risk.     

Atorvastatin increases expression of low‐density lipoprotein receptor mRNA in human circulating mononuclear cells

1. 3‐Hydroxy‐3‐methylglutaryl coenzyme A reductase (HMGCR) inhibitors, or statins, are commonly used to lower plasma cholesterol levels. HMGCR and the low‐density lipoprotein (LDL) receptor (LDLR) are of central importance to cholesterol homeostasis and yet there is a paucity of data on the effect of statins on the regulation of the LDLR and HMGCR in humans. 2. In the present study, we examined the effect of atorvastatin on the expression of HMGCR, LDLR and LDLR‐related protein (LRP) mRNA in circulating mononuclear cells. Twelve human volunteers were treated with atorvastatin, 20 mg/day for 4 weeks. 3. Atorvastatin decreased plasma total and LDL–cholesterol by 29% (P < 0.0001) and 41% (P < 0.001), respectively, and increased LDLR mRNA abundance, in absolute terms, by 35% (P < 0.001) and 31% (P < 0.0001) and 37% (P = 0.01) relative to reference GAPDH and β‐actin mRNA, respectively. In contrast, atorvastatin had no significant effect on LRP or HMGCR mRNA levels. 4. The increase in LDLR mRNA in circulating mononuclear cells agrees with the few human studies conducted, as well as with in vitro and animal studies, whereas the unchanged HMGCR mRNA is consistent with the hepatic specificity of atorvastatin. The present study firmly documents an increase in LDLR mRNA levels in response to statin administration in normal humans.     

Influence of atorvastatin on fractional and subfractional composition of serum lipoproteins and MMP activity in mice with Triton WR 1339-induced lipaemia

Objectives The effects of atorvastatin on the atherogenic and anti‐atherogenic lipoprotein‐cholesterol (C‐LP) and lipoprotein‐triglyceride (TG‐LP) fractions and subfractions at the early stage of murine acute hyperlipidaemia, and its pleiotropic anti‐inflammatory effects via the activity of matrix metalloproteinases (MMPs) were studied. Methods Atorvastatin (75 mg/kg) was administered to ICR mice with acute lipaemia induced by a single injection of Triton WR 1339 (500 mg/kg). A novel small‐angle X‐ray scattering (SAXS) method was used for the determination of the fractional and subfractional composition of C‐LP and TG‐LP. Key finding In Triton WR 1339‐treated mice, there was a drastic increase in the atherogenic low‐density C‐LP (C‐LDL) fraction, intermediate density lipoprotein‐cholesterol (C‐IDL) subfraction, and very low‐density C‐LP (C‐VLDL) fractions (C‐VLDL_3–5 subfraction). Additionally, there was an increase in the C‐HDL₃ subfraction. Treatment of lipaemia with atorvastatin resulted in the normalization of the atherogenic C‐LDL fraction and the C‐IDL subfraction. A decrease in C‐VLDL (C‐VLDL_3–5 subfraction), total cholesterol and, especially, triglyceride (TG) concentrations was also demonstrated. Similar results were obtained with the TG‐LP fractions and subfractions. Additionally, atorvastatin treatment resulted in an increase in the serum and liver MMP activity. Conclusion High‐dose atorvastatin therapy exerts its rapid lipid‐lowering and pleiotropic effect(s) in the early stages of acute lipaemia induced with Triton WR‐1339.     

Effect of ezetimibe monotherapy on the concentration of lipoprotein subfractions in patients with primary dyslipidaemia

ABSTRACT

Background: Recent studies suggest that the distribution of lipoprotein subfractions is an independent predictor of vascular events. Therefore, we evaluated the effect of ezetimibe (a selective cholesterol transport inhibitor) on the concentrations of lipoprotein subfractions in patients with primary dyslipidaemia.

Materials and methods: Patients (n = 50) with primary dyslipidaemias were recruited. The concentrations of the individual lipoprotein subfractions were measured using the Lipoprint system at baseline and after 16 weeks of treatment.

Results: Ezetimibe reduced total, low-density lipoprotein cholesterol (LDL?C) and non-high-density lipoprotein cholesterol (HDL?C) values as well as apolipoprotein B concentrations. Subfractionation of apolipoprotein B-containing lipoproteins showed that the reduction in LDL?C values was due to a fall in the concentrations of all LDL subfractions. However, a more pronounced trend towards a decrease in the concen­trations of dense LDL subfractions was observed. Patients with triglyceride values >1.7?mmol/L had significantly greater reductions in the concentrations of small, dense LDL particles compared with those with normal triglyceride levels (49 vs. 19%, respectively; p < 0.05). Ezetimibe decreased the concentrations of HDL?C mainly due to a fall in the concentration of dense HDL subfractions.

Conclusion: Ezetimibe can favourably affect the distribution of LDL subfractions, especially in patients with elevated triglyceride values. Further studies are needed to clarify the significance of the ezetimibe-induced reduction in the concentrations of dense HDL particles.     

The DISCOVERY PENTA study: a DIrect Statin COmparison of LDL‐C Value – an Evaluation of Rosuvastatin therapY compared with atorvastatin

ABSTRACT

Background: International guidelines emphasize the need to achieve recommended low-density lipoprotein cholesterol (LDL‐C) levels in order to reduce morbidity and mortality associated with coronary heart disease (CHD). However, many patients with hypercholesterolemia fail to achieve LDL‐C goals on treatment.

Objective: The primary objective was to compare the efficacy of rosuvastatin and atorvastatin for enabling patients to achieve National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL‐C goals. Secondary objectives were European LDL‐C goal achievement, changes in the lipid profile, and safety.

Research design and methods: This 12‐week, multicenter, multinational, randomized, open-label trial compared the efficacy and safety of rosuvastatin 10?mg with atorvastatin 10?mg in statin-naïve and switched patients with primary hypercholesterolemia from Brazil, Colombia, Mexico, Portugal, and Venezuela.

Results: A total of 1124 patients with similar baseline characteristics were randomized to the two treatment groups. After 12 weeks of treatment, a significantly greater percentage of patients receiving rosuvastatin 10?mg compared with atorvastatin 10?mg achieved NCEP ATP III LDL‐C goals (71.2% vs 61.4%, p < 0.001), 1998 European LDL‐C goals (73.5% vs 59.2%, p < 0.001) and 2003 European LDL‐C goals (58.9% vs 44.6%, p < 0.001). Rosuvastatin treatment was associated with significant reductions in LDL‐C and total cholesterol (TC) and, in statin-naïve patients, a significant increase in high-density lipoprotein cholesterol (HDL‐C) compared with atorvastatin treatment. Both treatments were well tolerated with a similar incidence of adverse events. Clinically significant elevations in creatinine, creatine kinase or hepatic transaminases were low and similar between treatment groups.

Conclusions: Rosuvastatin 10?mg is significantly more effective at achieving NCEP ATP III and European LDL‐C goals, lowering LDL‐C and TC in both naïve and switched patients and increasing HDL‐C in naïve patients than atorvastatin 10?mg, with a similar safety and tolerability profile. This study also provides evidence regarding the comparative effects of rosuvastatin versus atorvastatin in Latin American and Portuguese populations.     

Gender‐Specific Association Between ABCC2 ‐24C>T SNP and Reduction in Triglycerides in Chilean Patients Treated With Atorvastatin

Statins are the first‐line therapy prescribed to lower plasma cholesterol levels. Although being safe and showing several beneficial cholesterol‐independent pleiotropic effects, a significant variability regarding statin's therapeutic goals has been abundantly documented, but less understood. We aimed to investigate the influence of the ABCC2 ‐24C>T single nucleotide polymorphism on Chilean hypercholesterolaemic individuals treated for 4 weeks with 10 mg/day atorvastatin. A total of 127 individuals medicated with atorvastatin 10 mg/day/4 weeks were included. Lipid profiles were determined before and after drug administration by conventional assays. Genotyping of the ABCC2 rs717620 SNP (‐24C>T) was performed with TaqMan^® Drug Metabolism Genotyping Assays. As expected, atorvastatin reduced TC, LDL‐C and TG concentrations (p < 0.05). Also, HDL‐C levels were increased (p < 0.05). Minor allele frequency for the rs717620 was 0.232. Overall, atorvastatin response was not associated with the ABCC2 rs717620 SNP (p > 0.05). Nonetheless, in male individuals carrying the ‐24T allele, we observed an attenuated reduction in both TG values and the TG/HDL‐C ratio after 10 mg/day atorvastatin. This study indicates that TG levels and the TG/HDL‐C ratio are affected by the rs717620 SNP in Chilean males but not female individuals after atorvastatin treatment.     

Positive correlation between probucol in low density lipoprotein and LDL-lowering

Summary The relationship between the content of probucol in plasma and lipid lowering was studied after administration of probucol. The study group consisted of 44 patients with Type II hyperlipidaemia (mean age 56 y).Total cholesterol level was decreased from 293 to 232 mg · dl^–1 by the administration of probucol. The plasma probucol concentration was 2.03 mg · dl^–1 after 4 weeks of administration of 500 mg b. d. Although there was no relationship between the change in total cholesterol and the plasma probucol, a linerar relation was observed between the decrease in LDL-cholesterol concentration and the probucol concentration in LDL. Neither the VLDL nor the HDL-probucol content were related to the magnitude of the decrease in lipoprotein cholesterol.The present study has demonstrated that an increase in the probucol content in LDL was associated with a decrease in plasma LDL-cholesterol.     

High‐density lipoproteins,platelets and the pathogenesis of atherosclerosis

1. Prospective and interventional studies demonstrate an inverse relationship between plasma high‐density lipoprotein (HDL)–cholesterol and the incidence of coronary artery disease. Although the atheroprotective effects of HDL are usually attributed to the reverse cholesterol transport, in which HDL shuttles cholesterol from cells in the arterial wall to the liver, other mechanisms are also under investigation. 2. Platelets are involved in both the initiation and progression of atherosclerotic lesions. In addition, the formation of thrombi over ruptured atherosclerotic plaques results in the narrowing or complete occlusion of coronary arteries. Current experimental evidence suggests that HDL may exert antiplatelet effects and thereby counteract the development of atherothrombotic vascular disease. 3. In vitro studies show that HDL inhibits agonist‐stimulated platelet aggregation, fibrinogen binding, granule secretion and liberation of thromboxane A₂. Inhibitory effects of HDL are mediated, in part, by scavenger receptor type B1 and/or the apolipoprotein E receptor apoER2/LRP8 and are linked to the induction of intracellular signalling cascades encompassing stimulation of protein kinase C, cytoplasmatic alkalization and generation of nitric oxide. 4. Populational studies demonstrate that there is an inverse association between plasma HDL levels and recurrent venous thromboembolism. In addition, HDL–cholesterol has been identified as an independent predictor of acute platelet thrombus formation. The administration of reconstituted HDL particles in humans attenuates ex vivo platelet activation. 5. The present review summarizes recent advances in understanding HDL–platelet interactions and discusses the potential use of HDL‐like particles in the therapy of thrombosis.     

High‐density lipoprotein: A potent inhibitor of inflammation

1. Inflammation is an important process, driving the progression of atherosclerosis. Stemming inflammation may be a mechanism to inhibit the progression of this disease. 2. High‐density lipoprotein (HDL), a particle inversely related to cardiovascular disease, has been described as having a number of anti‐inflammatory functions. It has been shown that HDL inhibits endothelial inflammation in both in vitro and in vivo models, reducing the expression of key cell adhesion molecules. In addition, HDL has been shown to have an effect on the coagulation pathway by inhibiting platelet activation and reducing thrombus formation. Furthermore, by reducing the activation of leucocytes, HDL can inhibit leucocyte recruitment to the endothelium. 3. High‐density lipoprotein infusion studies conducted in patients with inflammatory diseases have shown that acute treatment with HDL can effectively inhibit inflammation in vivo. Thus, HDL has been proven to be a potent inhibitor of inflammation, acting on a number of pathways, and this may suggest that HDL could be applied as an anti‐inflammatory molecule for a number of diseases. 4. The present review highlights these important studies and reviews data on the anti‐inflammatory effects of HDL from in vitro and in vivo studies, in both humans and animal models of atherosclerosis and inflammatory‐related diseases.     

Ezetimibe and low density lipoprotein subfractions: an ongoing debate

Abstract

There is evidence that small dense low density lipoprotein (sdLDL) subfractions are more atherogenic than buoyant LDL. Therefore, it is relevant to assess the effect of lipid lowering drugs on LDL subfractions. In this editorial we discuss the effect of ezetimibe (EZE; a cholesterol transport inhibitor) alone or in combination with a statin, on sdLDL levels. We conclude that, based on currently available evidence, more studies are needed before a definitive answer can be provided regarding the effect of EZE on sdLDL levels.     

(TTA)n Polymorphism in 3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A and Response to Atorvastatin in Coronary Artery Disease Patients

Abstract: 3‐Hydroxy‐3‐methylglutaryl‐coenzyme A reductase inhibitors have been used clinically for lowering total and low‐density lipoprotein cholesterol. Interindividual pharmacological differences observed with this treatment have been attributed to genetic differences. The aim of this study was to assess the association in the low‐density lipoprotein cholesterol reduction by atorvastatin and (TTA)n polymorphism in the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase gene in patients with coronary artery disease. Changes in total cholesterol levels, triglycerides, high‐sensitivity C‐reactive protein and free F₂‐isoprostanes were also evaluated. In an open study, patients received 40 mg atorvastatin daily for 8 weeks. Genotyping was done through polymerase chain reaction. The genotype distribution of the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (TTA)n polymorphism was: >10/>10 in 22 out of 64 patients (34%), >10/10 in 14 out of 64 patients (22%) and 10/10 in 28 out of 64 patients (44%). The reduction of low‐density lipoprotein cholesterol levels by atorvastatin was not different between allelic variants (TTA)n repeat polymorphism. Reductions in high‐sensitivity C‐reactive protein were observed in atorvastatin‐treated patients with alleles >10/>10 and 10/10. Free F₂‐isoprostanes and total cholesterol were also significantly lower after treatment for all alleles, irrespective of type of polymorphism. In conclusion, the changes induced by atorvastatin treatment on low‐density lipoprotein cholesterol, total cholesterol, triglycerides, high‐sensitivity C‐reactive protein and free F₂‐isoprostane concentrations were not related to the presence of 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase polymorphism (TTA)n.     

Effect of ezetimibe in patients who cannot tolerate statins or cannot get to the low density lipoprotein cholesterol target despite taking a statin

ABSTRACT

Background: Recent guidelines underline the need for high-risk patients to reach strict low density lipoprotein cholesterol (LDL?C) targets (1.8–2.6?mmol/L; 70–100?mg/dL), and specifically mention the possible use of combination therapy (e.g. statin + ezetimibe) to achieve these goals.

Methods: A retrospective case-note audit was carried out to assess the response to administering ezetimibe in patients unable to tolerate statins (Group 1), or high dose of statins (Group 2) and patients who cannot achieve the LDL?C target (2.6?mmol/L; 100?mg/dL) despite taking a statin (Group 3).

Results: Ezetimibe lowered LDL?C levels by 20–29% across the 3 patient groups after 2–3 months of treatment. High density lipoprotein cholesterol (HDL?C) levels tended to remain unchanged, although there was a consistent trend for a fall if baseline values were ‘high’. However, the LDL-C/HDL-C ratio changed significantly and favourably in all groups. The fall in fasting triglyceride levels in all groups was greater (reaching 19–25%) when baseline levels were ≥ 1.5 or 1.7?mmol/L (136–150?mg/dL). There were no marked abnormalities in liver function tests or creatine kinase activity. In Group 3 there was a significant trend for a fall in serum creatinine levels across the tertiles of baseline creatinine values.

Limitations of the present study include the small sample size (especially in Groups 1 and 2), its short-term duration and the absence of event-based end-points. Therefore, the results are hypothesis-generating rather than conclusive.

Conclusions: When used alone or added to a statin, ezetimibe favourably altered the LDL?C/HDL?C ratio and lowered triglyceride levels. Ezetimibe was well tolerated in patients with statin intolerance and was associated with a 26% fall in LDL?C. An additional action may be some degree of improved renal function. Further studies are needed to confirm these findings.     

Anti‐oxidant properties of high‐density lipoprotein and atherosclerosis

1. High‐density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically. 2. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport. The functions of HDL that have recently attracted attention include anti‐inflammatory and anti‐oxidant activities. High anti‐oxidant and anti‐inflammatory activities of HDL are associated with protection from cardiovascular disease. 3. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Conversely, these activities are compromised in many pathological states associated with inflammation. 4. The focus of the present review is on the anti‐oxidant and anti‐inflammatory functions of HDL and its individual components in relation to protection from atherosclerosis.     

The effects of ezetimibe and orlistat,alone or in combination,on high-density lipoprotein (HDL) subclasses and HDL-associated enzyme activities in overweight and obese patients with hyperlipidaemia

Background: High-density lipoprotein (HDL) includes discrete subfractions. HDL exhibits anti-atherogenic properties, which have been partly linked to the activity of HDL-associated enzymes, such as the lipoprotein associated phospholipase A₂ (HDL-LpPLA₂) and paraoxonase-1 (PON1). Objective: We assessed in an open-label randomised study the effect of orlistat and ezetimibe, alone or in combination, on plasma HDL subclasses and HDL-associated enzyme activities in overweight and obese subjects (body mass index > 28 kg/m²) with hypercholesterolemia [total cholesterol > 200 mg/100 ml (5.2 mmol/l)]. Methods: Eighty-six people were prescribed a low-fat low-calorie diet and were randomly allocated to receive orlistat 120 mg, three times daily (O group), ezetimibe 10 mg/day (E group) or both (OE group) for 6 months. HDL subfractions were determined using a polyacrylamide gel-tube electrophoresis method. Results: Levels of HDL cholesterol (HDL-C) and apolipoprotein AI did not change significantly in any group. In group O the cholesterol concentration of HDL-2 subclass increased significantly, while the cholesterol of HDL-3 subclass decreased significantly. In groups E and OE HDL-2 subclass did not significantly change, while the cholesterol concentration of HDL-3 subclass decreased significantly. We observed a non-significant decrease in the HDL-LpPLA₂ and PON1 activity in all groups. However, the ratios of both enzyme activities to low-density lipoprotein cholesterol (LDL-C) levels (an index of atherogenicity) significantly increased in all groups. Conclusion: Although HDL-C levels did not change after treatment with orlistat and ezetimibe, alone or in combination, there were alterations of the HDL-2 and HDL-3 subclasses. The activity of HDL-LpPLA₂ and PON1 per mg LDL-C increased significantly in all groups.     

HMGCR rs17671591 SNP Determines Lower Plasma LDL‐C after Atorvastatin Therapy in Chilean Individuals

Lipid‐lowering response to statin therapy shows large interindividual variability. At a genome‐wide significance level, single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR have been implicated in this differential response. However, the influence of these variants is uncertain in the Chilean population. Hence, we aimed to evaluate the contribution of PCSK9 rs7552841 and HMGCR rs17671591 SNPs as genetic determinants of atorvastatin response in Chilean hypercholesterolaemic individuals. One hundred and one hypercholesterolaemic patients received atorvastatin 10 mg/day for 4 weeks. Plasma lipid profile (TC, HDL‐C, LDL‐C and TG) was determined before and after statin treatment, and SNPs were identified by allelic discrimination using TaqMan^® SNP Genotyping Assays. Adjusted univariate and multivariate analyses' models were used for statistical analyses, and a p‐value <0.05 was considered significant. From baseline (week 0) to the study end‐point (week 4), significant reductions were observed in plasma TC, LDL‐C and TG (p < 0.001), while HDL‐C levels were increased (p < 0.001). Multivariate analysis showed no association between lipid levels and atorvastatin therapy for the PCSK9 variant. However, the HMGCR rs17671591 T allele contributed to basal HDL‐C concentration variability along with a higher increase in this lipid fraction after statin medication. In addition, this allele determined greater plasma LDL‐C reductions after therapy with atorvastatin. Our data suggest that the HMGCR rs17671591 polymorphism can constitute a genetic marker of lower plasma LDL‐C and enhanced HDL‐C concentration after atorvastatin therapy in the Chilean population.     

Treating to target patients with primary hyperlipidaemia:comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study)

ABSTRACT

Objectives: In a 24-week, open-label, randomized, parallel-group study, we compared the efficacy and metabolic effects, beyond low density lipoprotein cholesterol (LDL-C)-lowering, of atorvastatin (ATV) and rosuvastatin (RSV) in cardiovascular diseasefree subjects with primary hyperlipidaemia, treated to an LDL-C target (130 mg/dL).

Methods: After a 6‐week dietary lead-in period, patients were randomized to RSV 10?mg/day (?n = 60) or ATV 20?mg/day (?n = 60). After 6 weeks on treatment the dose of the statin was increased (to RSV 20?mg/day or ATV 40?mg/day) if the treatment goal was not achieved. A control group of healthy volunteers (?n = 60) was also included for the validation of baseline serum and urinary laboratory parameters. The primary outcome was the percentage of patients reaching the LDL‐C goal; secondary outcomes were changes in lipid and non-lipid metabolic parameters.

Results: A total of 45 patients (75.0%) in the RSV-treated group and 43 (71.7%) in the ATV-treated group achieved the treatment target at the initial dose. Both regimens were generally well tolerated and there were no withdrawals due to treatment-related serious adverse events. Similar significant reductions in total cholesterol, LDL‐C, apolipoprotein (apo) B, triglycerides, apoB/apoA1 ratio, fibrinogen and high-sensitivity C‐reactive protein levels were seen. RSV had a significant high density lipoprotein cholesterol (HDL‐C)-raising effect and showed a trend towards increasing apoA1 levels. Glycaemic control and renal function parameters were not influenced by statin therapy. ATV, but not RSV, showed a significant hypouricaemic effect.

Conclusions: RSV and ATV were equally efficacious in achieving LDL‐C treatment goals in patients with primary hyperlipidaemia at the initial dose and following dose titration. RSV seems to have a significantly higher HDL‐C-raising effect, while ATV lowers serum uric acid levels.     

Lipid and lipoprotein responses to oral combined hormone replacement therapy in normolipemic obese women with controlled type 2 diabetes mellitus

This study investigated the effects of oral combined hormone replacement therapy (OCHRT) on lipid concentrations and subpopulation distribution of lipoproteins in nine postmenopausal women with type 2 diabetes mellitus and moderate glycemic control. After 16 weeks of continuous daily therapy of conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg, the mean concentration of high-density lipoprotein (HDL) cholesterol showed a statistically significant increase of 16.7%, predominantly in the HDL2 subfraction. No statistically significant changes in mean concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very low-density lipoprotein (VLDL) triglycerides, apolipoprotein A1, or apolipoprotein B were evident. Likewise, no changes were found in the average diameter of VLDL, LDL, or HDL particles; triglyceride concentrations of VLDL subfractions; cholesterol concentrations of LDL subfractions; or chemical composition of plasma LDL. These findings lend further support to the use of OCHRT in postmenopausal women with diabetes to decrease their risk for coronary artery disease.     

Interaction between a commercially available St. John’s wort product (Movina) and atorvastatin in patients with hypercholesterolemia

Objective The aim of this study was to assess the effect of treatment with a St. John’s wort product (Movina) on cholesterol [total cholesterol, low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol] and triglyceride levels in patients with hypercholesterolemia on treatment with a stable dose of atorvastatin in a controlled, randomised, open, crossover interaction study. Methods Sixteen patients with hypercholesterolemia treated with a stable dose of atorvastatin (10–40 mg/daily) for at least 3 months were treated with Movina one tablet (containing 300 mg of hypericum perforatum) twice daily and control (a commercially available multivitamin tablet Vitamineral). After a run-in period of 4 weeks, patients were randomised to treatment with either Movina or control for 4 weeks in a crossover design. The atorvastatin dose was kept unchanged during the study period (12 weeks), and assessments of total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides were performed in the morning with the patients in the fasting condition. The difference between control and active treatment in LDL cholesterol after 4 weeks of treatment was the primary endpoint. Results All patients completed the study. The St. John’s wort product significantly increased the serum level of LDL cholesterol compared with control (2.66 mmol/l compared with 2.34 mmol/l, p = 0.004). A significant increase in total cholesterol was also observed (5,10 mmol/l compared with 4.78 mmol/l, p = 0.02). No statistically significant change was observed in HDL cholesterol (1.59 mmol/l and 1.56 mmol/l, p = 0.49) or in triglycerides (1.87 mmol/l and 1.94 mmol/l, p = 0.60). No product-related side effects were reported Conclusion An interaction was observed between the studied St.-John’s-wort-containing product and atorvastatin. Physicians and patients should be aware of this interaction and if treatment with a St. John’s wort product is considered necessary, then there may be a need for increasing the dose of atorvastatin.     

Anacetrapib for the treatment of dyslipidaemia: the last bastion of the cholesteryl ester transfer protein inhibitors?

Introduction: Inhibition of cholesteryl ester transfer protein (CETP) has emerged as a potential way to decrease cardiovascular risk by raising high density lipoprotein (HDL) cholesterol and lowering low density lipoprotein (LDL) cholesterol concentrations. However, high profile withdrawals of several CETP inhibitors have cast doubt over this hypothesis. Despite this concern, anacetrapib appears to be safe, well-tolerated and delivers a substantial increases in HDL cholesterol and reductions in LDL cholesterol as monotherapy and when combined with a statin.

Areas covered: We discuss the role of CETP and HDL cholesterol as therapeutic targets, describe the pharmacokinetics and pharmacodynamics of anacetrapib, as well as report on the recent clinical trials.

Expert opinion: The focus of CETP inhibition has shifted from HDL cholesterol-raising to LDL cholesterol-lowering. Although anacetrapib appears to be safe and is effective in altering lipid-related biochemical parameters of interest, its effect on cardiovascular outcomes remains unknown. Extrapolation of LDL cholesterol lowering to improved cardiovascular outcomes is not possible, because LDL and HDL functionality in the setting of anacetrapib treatment is unclear. The results of the phase III REVEAL randomised controlled trial will be critical for anacetrapib to establish a place in clinical care.