Biotechnology Approaches for the Treatment of Dyslipidemia.

BACKGROUND: Despite advances in the development of lipid-lowering therapies, clinical trials have shown that a significant residual risk of cardiovascular disease persists. Specifically, new drugs are needed for non-responding or statin-intolerant subjects or patients considered at very high risk for cardiovascular events even though are already on treatment with the best standard of care. RESULTS AND CONCLUSIONS: Besides, genetic and epidemiological studies and Mendelian randomization analyses have strengthened the linear correlation between the concentration of low-density lipoprotein cholesterol (LDL-C) and the incidence of cardiovascular events and highlighted various novel therapeutic targets. This review describes the novel strategies to reduce the levels of LDL-C, non-HDL-C, triglyceride, apolipoprotein B, and Lp(a), focusing on those developed using biotechnology-based strategies.

Effect of metformin and flutamide on insulin, lipogenic and androgen-estrogen signaling, and cardiometabolic risk in a PCOS-prone metabolic syndrome rodent model.

Polycystic ovary syndrome (PCOS) is highly associated with cardiometabolic risk and the metabolic syndrome (MetS), predisposing women to increased risk of developing type 2 diabetes and cardiovascular disease. Metformin is commonly used to treat insulin resistance-glucose intolerance, and flutamide, an androgen receptor (AR) antagonist, is used to target hyperandrogenemia and dyslipidemia. Currently, the physiological mechanism of action of these treatments on androgen, lipidogenic, and insulin signaling pathways remains unclear in PCOS. The aim of this study was to investigate the effects and mechanisms of action of metformin and flutamide on plasma lipid-apolipoprotein (Apo)B-lipoprotein and insulin-glucose metabolism, and endocrine-reproductive indices in a PCOS-prone MetS rodent model. PCOS-prone rodents were treated with metformin (300 mg/kg body wt), flutamide (30 mg/kg body wt), or metformin + flutamide combination treatment for 6 wk. Metformin was shown to improve fasting insulin and HOMA-IR, whereas flutamide and combination treatment were shown to reduce plasma triglycerides, ApoB48, and ApoB100, and this was associated with decreased intestinal secretion of ApoB48/triglyceride. Flutamide and metformin were shown to reduce plasma androgen indices and to improve ovarian primary and preovulatory follicle frequency. Metformin treatment increased hepatic estrogen receptor (ER)α, and metformin-flutamide decreased intestinal AR and increased ERα mRNA expression. Metformin-flutamide treatment upregulated hepatic and intestinal insulin signaling, including insulin receptor, MAPK1, and AKT2. In conclusion, cardiometabolic risk factors, in particular ApoB-hypertriglyceridemia, are independently modulated via the AR, and understanding the contribution of AR and insulin-signaling pathways further may facilitate the development of targeted interventions in high-risk women with PCOS and MetS.

The effects of different therapeutic modalities on cardiovascular risk factors in women with polycystic ovary syndrome: A randomized controlled study.

OBJECTIVE: This study was designed to evaluate the effects of 3 mg drospirenone/30 µg ethinyl estradiol (OC) alone or combined with 1700 mg metformin on metabolic risk factors. MATERIALS AND METHODS: In this randomized, prospective, controlled study, 87 non-obese (18-30 BMI) women of reproductive age (18-39) with polycystic ovary syndrome (PCOS) were assigned to control (n = 17), OC (n = 21), combination (n = 20) and metformin (n = 29) therapy groups. RESULTS: Adiponectin levels changed -28.27%, -20.37% and 35.78% after OC, combination and metformin therapies, respectively. High sensitive C-reactive protein levels (hsCRP) changed with OC, combination and metformin therapies by 102.32%, 3.2% and -7.14%, respectively. Plasminogen activator inhibitor-1 levels decreased 41.34% in the metformin group. Apolipoprotein-B levels changed in a manner similar to changes in hsCRP levels. The homeostatic model insulin resistance index changed significantly between the groups following treatment (p = 0.001). CONCLUSION: Six cycles of treatments with OC alone may cause metabolic variables to deteriorate in non-obese women with PCOS. The addition of metformin to OC may ameliorate some aspects of this effect.

Effects of obeticholic acid on lipoprotein metabolism in healthy volunteers.

The bile acid analogue obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist in development for treatment of several chronic liver diseases. FXR activation regulates lipoprotein homeostasis. The effects of OCA on cholesterol and lipoprotein metabolism in healthy individuals were assessed. Two phase I studies were conducted to evaluate the effects of repeated oral doses of 5, 10 or 25 mg OCA on lipid variables after 14 or 20 days of consecutive administration in 68 healthy adults. Changes in HDL and LDL cholesterol levels were examined, in addition to nuclear magnetic resonance analysis of particle sizes and sub-fraction concentrations. OCA elicited changes in circulating cholesterol and particle size of LDL and HDL. OCA decreased HDL cholesterol and increased LDL cholesterol, independently of dose. HDL particle concentrations declined as a result of a reduction in medium and small HDL. Total LDL particle concentrations increased because of an increase in large LDL particles. Changes in lipoprotein metabolism attributable to OCA in healthy individuals were found to be consistent with previously reported changes in patients receiving OCA with non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.

The controversy over the use of cholesteryl ester transfer protein inhibitors: is there some light at the end of the tunnel?

BACKGROUND: According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. MATERIALS AND METHODS: This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. RESULTS: Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. CONCLUSION: These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.

Comparative Characterization of Hepatic Distribution and mRNA Reduction of Antisense Oligonucleotides Conjugated with Triantennary N-Acetyl Galactosamine and Lipophilic Ligands Targeting Apolipoprotein B.

TriantennaryN-acetyl galactosamine (GalNAc, GN3) and lipophilic ligands such as cholesterol andα-tocopherol conjugations dramatically improve the distribution and efficacy of second-generation antisense oligonucleotides (ASOs) in the whole liver. To characterize ligands for delivery to liver cells based on pharmacokinetics and efficacy, we used a locked nucleic acid gapmer of ASO targeting apolipoprotein B as a model compound and evaluated the amount of ASO and apolipoprotein B mRNA in the whole liver, hepatocytes, and nonparenchymal (NP) cells as well as plasma total cholesterol after administration of ASO conjugated with these ligands to mice. Compared with unconjugated ASO, GN3 conjugation increased the amount (7-fold) and efficacy (more than 10-fold) of ASO in hepatocytes only and showed higher efficacy than the increased rate of the amount of ASO. On the other hand, lipophilic ligand conjugations led to increased delivery (3- to 5-fold) and efficacy (5-fold) of ASO to both hepatocytes and NP cells. GN3 and lipophilic ligand conjugations increased the area under the curve of ASOs and the pharmacodynamic duration but did not change the half-life in hepatocytes and NP cells compared with unconjugated ASO. In the liver, the phosphodiester bond between ASO and these ligands was promptly cleaved to liberate unconjugated ASO. These ligand conjugations reduced plasma total cholesterol compared with unconjugated ASO, although these ASOs were well tolerated with no elevation in plasma transaminases. These findings could facilitate ligand selection tailored to liver cells expressed in disease-related genes and could contribute to the discovery and development of RNA interference-based therapy.

Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy.

Sodium taurocholate cotransporting polypeptide (NTCP) is a multiple transmembrane transporter predominantly expressed in the liver, functioning as a functional receptor for HBV. Through our continuous efforts to identify NTCP as a novel HBV target, we designed and synthesized a series of new compounds based on the structure of our previous compound NT-5. Molecular docking and MD simulation validated that a new compound named NTI-007 can tightly bind to NTCP, whose efficacy was also measured in vitro virological examination and cytotoxicity studies. Furthermore, autophagy was observed in NTI-007 incubated HepG2.2.15 cells, and results of q-PCR and Western blotting revealed that NTI-007 induced autophagy through NTCP-APOA1-HBx-Beclin1-mediated pathway. Taken together, considering crucial role of NTCP in HBV infection, NTCP-mediated autophagic pathway may provide a promising strategy of HBV therapy and given efficacy of NTI-007 triggering autophagy. Our study suggests pre-clinical potential of this compound as a novel anti-HBV drug candidate.

Effects of ursodeoxycholic acid therapy on carotid intima media thickness, apolipoprotein A1, apolipoprotein B, and apolipoprotein B/A1 ratio in nonalcoholic steatohepatitis.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a prevalent liver disease that is increasingly being associated with cardiovascular disease. Ursodeoxycholic acid (UDCA) may have antioxidant and anti-inflammatory activities, and may reduce liver injury in NASH. To date, no studies have assessed the efficacy of UDCA in carotid intima media thickness (CIMT), serum lipids, apolipoprotein A1 (apo A), apolipoprotein B (apo B), and apolipoprotein B/A1 (apo B/A1) ratios in patients with NASH. PATIENTS AND METHODS: In this prospective study, 30 patients with biopsy-proven NASH and 25 healthy adults as a control group were evaluated. None of the participants had diabetes, hypertension, or hyperlipidemia. Patients with NASH received UDCA 15 mg/kg/day for 6 months. BMI, waist circumference, homeostasis model assessment, lipids, apo A1, apo B, apo B/A1 ratios, and CIMT were analyzed before and after the treatment period. RESULTS: At the end of the study, there were no statistically significant changes in BMI or waist circumference. Liver enzymes decreased gradually. The homeostasis model assessment decreased from 3.4 ± 1.89 to 2.06 ± 1.68 (P < 0.001). No significant changes in the mean triglyceride, total cholesterol, low-density lipoprotein, or apo B levels were observed. The mean high-density lipoprotein (42.9 ± 7.1 vs. 45.5 ± 9.8; P = 0.037) and apo A1 (127.6 ± 17.7 vs. 135.9 ± 22.2; P = 0.02) increased significantly. Apo B/A1 ratios tended to decrease, but this decrease was not statistically significant. The mean CIMT decreased significantly (0.56 ± 0.15 vs. 0.47 ± 0.12; P = 0.001). CONCLUSION: UDCA treatment in NASH patients resulted in statistically significant reductions in the mean CIMT over a 6-month period. We believe that this benefit of UDCA may have resulted from decreased insulin resistance and increased serum high-density lipoprotein-apo A1 levels. However, larger, longer-term studies are needed to confirm this effect of UDCA in NASH.

Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome.

BACKGROUND: Liver-selective thyromimetic agents could provide a new approach for treating dyslipidaemia. METHODS: We performed a multicentre, randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of eprotirome, a liver-selective thyroid hormone receptor agonist, in 98 patients with primary hypercholesterolaemia. After previous drug wash-out and dietary run-in, patients received 100 or 200 µg day(-1) eprotirome or placebo for 12 weeks. The primary end-point was change in serum LDL cholesterol; secondary end-points included changes in other lipid parameters and safety measures. RESULTS: Eprotirome treatment at 100 and 200 µg daily reduced serum LDL cholesterol levels by 23 ± 5% and 31 ± 4%, respectively, compared with 2 ± 6% for placebo (P < 0.0001). Similar reductions were seen in non-HDL cholesterol and apolipoprotein (apo) B, whereas serum levels of HDL cholesterol and apo A-I were unchanged. There were also considerable reductions in serum triglycerides and lipoprotein(a), in particular in patients with elevated levels at baseline. There was no evidence of adverse effects on heart or bone and no changes in serum thyrotropin or triiodothyronine, although the thyroxine level decreased. Low-grade increases in liver enzymes were evident in most patients. CONCLUSION: In hypercholesterolaemic patients, the liver-selective thyromimetic eprotirome decreased serum levels of atherogenic lipoproteins without signs of extra-hepatic side effects. Selective stimulation of hepatic thyroid hormone receptors may be an attractive way to modulate lipid metabolism in hyperlipidaemia.

[Homozygous familial hypercholesterolemia]. / Ailevi hiperkolesterolemi tedavisinde yeni ajanlar: Lomitapide--Mipomersen.

Familial hypercholesterolemia (FH) is caused by genetic deficiency of LDL receptors leading to extremely high cholesterol levels and atherosclerosis at early ages. For the prevention of early atherosclerotic cardiovascular events, effective reduction of LDL-cholesterol is necessary from the early ages. However, particularly in homozygous patients, it's almost impossible to achieve target LDL-cholesterol levels with antilipid agents including statin agents, due to the severe LDL receptor dysfunction. LDL apheresis is an effective treatment modality in severe AH patients. However, the invasive, chronic time consuming nature of this treatment decreases the compliance of these patients. Moreover, atherosclerosis progress in 25% of the patients undergoing regular and effective apheresis even though since early ages. Clinical data also indicate that there is still an unmet medical need for new effective treatments for AH patients. This review will address new therapeutic strategies targeting Apolipoprotein (Apo) B including MTTP inhibitor Lomitapideand oligonucleotide Mipomersen. As both agents are targeted against ApoB, they are expected to be effective even in receptor negative homozygous AH patients.

The efficacy and safety of ezetimibe/simvastatin combination compared with intensified lipid-lowering treatment strategies in diabetic subjects with and without metabolic syndrome.

AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.

Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study.

AIMS: Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. METHODS AND RESULTS: A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2-3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. CONCLUSIONS: Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited.

Paraoxonase enzyme activity is enhanced by zinc supplementation in hemodialysis patients.

BACKGROUND AND AIMS: Patients on maintenance hemodialysis (HD) face an increased risk of atherosclerosis, a crucial problem and the leading cause of cardiovascular morbidity and mortality. This study was designed to evaluate the effects of zinc supplementation on paraoxonase (PON) enzyme activity in patients on HD. METHODS: This double-blind randomized controlled trial was conducted from June 2005 to June 2007. Sixty HD patients were enrolled and divided into two groups: treatment (case) and control. The treatment and control groups were treated with 100 mg/day zinc or placebo, respectively, for 2 months. Serum zinc concentration was measured by atomic absorption spectrophotometry. PON activity was evaluated by spectrophotometric method. Lipid profile was determined using commercial kits, and apolipoprotein AI (Apo-AI) and B (Apo-B) levels were measured by commercial immunoturbidimetric kits. RESULTS: In the case group, there was no significant change in the serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and Apo-B levels, while the serum levels of high-density lipoprotein (HDL), Apo-AI, and PON activity were significantly increased (p = 0.02). In the control group, although significant increases were observed in the serum levels of TC, TG, and Apo-B (p = 0.009, 0.019, and 0.001, respectively), the serum PON activity was significantly decreased (p = 0.025) and the serum levels of HDL, LDL, and Apo-AI were not changed. At the end of intervention period, the serum level of Apo-AI and PON activity were significantly higher in the case group. CONCLUSIONS: Zinc supplementation increased both the activity of PON and the serum level of Apo-AI in the HD patients.

Meta-analysis of comparison of effectiveness of lowering apolipoprotein B versus low-density lipoprotein cholesterol and nonhigh-density lipoprotein cholesterol for cardiovascular risk reduction in randomized trials.

This study evaluated the relation between apolipoprotein B (apoB) decrease and coronary heart disease, stroke, and cardiovascular disease risk. Bayesian random-effects meta-analysis was used to evaluate the association of mean absolute apoB decrease (milligrams per deciliter) with relative risk of coronary heart disease (nonfatal myocardial infarction and coronary heart disease death), stroke (nonfatal stroke and fatal stroke), or cardiovascular disease (coronary heart disease, stroke, and coronary revascularization). Analysis included 25 trials (n = 131,134): 12 on statin, 4 on fibrate, 5 on niacin, 2 on simvastatin-ezetimibe, 1 on ileal bypass surgery, and 1 on aggressive versus standard low-density lipoprotein (LDL) cholesterol and blood pressure targets. Combining the 25 trials, each 10-mg/dl decrease in apoB was associated with a 9% decrease in coronary heart disease, no decrease in stroke, and a 6% decrease in major cardiovascular disease risk. Non-high-density lipoprotein (non-HDL) cholesterol decrease modestly outperformed apoB decrease for prediction of coronary heart disease (Bayes factor [BF] 1.45) and cardiovascular disease (BF 2.07) risk decrease; apoB decrease added to non-HDL cholesterol plus LDL cholesterol decrease slightly improved cardiovascular disease risk prediction (1.13) but did not improve coronary heart disease risk prediction (BF 1.03) and worsened stroke risk prediction (BF 0.83). In the 12 statin trials, apoB and non-HDL cholesterol decreases similarly predicted cardiovascular disease risk; apoB improved coronary heart disease prediction when added to non-HDL cholesterol/LDL cholesterol decrease (BF 3.33) but did not improve stroke risk prediction when added to non-HDL cholesterol/LDL cholesterol decrease (BF 1.06). In conclusion, across all drug classes, apoB decreases did not consistently improve risk prediction over LDL cholesterol and non-HDL cholesterol decreases. For statins, apoB decreases added information to LDL cholesterol and non-HDL cholesterol decreases for predicting coronary heart disease but not stroke or overall cardiovascular disease risk decrease.

Low-density lipoprotein-lowering strategies: target versus maximalist versus population percentile.

PURPOSE OF REVIEW: Maximalist low-density lipoprotein (LDL)-lowering strategies such as lowering LDL as much as possible or, alternatively, using the most potent LDL-lowering regimens have become increasingly popular. Almost all attention has focused on the potential advantages of these approaches with little focus on their potential disadvantages. Moreover, it is increasingly assumed that the lower and lower is better and better approach is supported by unassailable evidence. RECENT FINDINGS: This article will examine how strongly the findings of the statin clinical trials actually support the maximalist strategy. We will also introduce a new approach, the population percentile strategy, which is based on the fact that the amount of cholesterol in LDL can differ substantially. When cholesterol-depleted LDL particles are present, LDL cholesterol (LDL-C) underestimates apolipoprotein B (apoB) and LDL particle number. Statins lower LDL-C and nonhigh-density lipoprotein cholesterol (non-HDL-C) more than they lower apoB and LDL particle number. This means that, even if LDL-C, non-HDL-C and apoB are equal markers of on-treatment risk, apoB is a better marker of the adequacy of LDL-lowering therapy. SUMMARY: Our analysis indicates that the LDL-lowering regimen should be tailored to the individual using a population percentile strategy to ensure the greatest number of patients receive the greatest overall benefit. With this approach, apoB is the best marker of the adequacy of LDL-lowering therapy.

Consistency of extended-release niacin/laropiprant effects on Lp(a), ApoB, non-HDL-C, Apo A1, and ApoB/ApoA1 ratio across patient subgroups.

BACKGROUND: According to prior analyses, extended-release niacin/laropiprant (ERN/LRPT) consistently reduces low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) and increases high-density lipoprotein cholesterol (HDL-C) levels across a wide range of dyslipidemic patient subgroups. OBJECTIVES: This analysis examined ERN/LRPT's consistency across four phase III, randomized, double-blind trials in improving other lipid/lipoprotein parameters associated with cardiovascular risk, across several key dyslipidemic patient subgroups. METHODS: In three of the studies, the randomized population included patients with primary hypercholesterolemia or mixed hyperlipidemia; in the remaining study, the population included patients with type 2 diabetes mellitus. The lipid-altering consistency of ERN/LRPT's efficacy was evaluated versus the pre-defined comparator (placebo or active control) among key subgroups of sex, race (White, non-White), region (US, ex-US), baseline age (<65 years, ≥65 years), use of statin therapy (yes, no), coronary heart disease (yes, no), risk status (low, multiple, high), and type of hyperlipidemia (primary hypercholesterolemia, mixed dyslipidemia), as well as across baseline LDL-C, HDL-C, and TG levels. The consistency of the treatment effects on lipoprotein(a).[Lp(a)], apolipoprotein B (ApoB), non-HDL-C, ApoA1, and ApoB/ApoA1 ratio was evaluated by examining treatment difference estimates of the percentage change from baseline with 95% confidence intervals. RESULTS: Treatment with ERN/LRPT produced significantly greater improvements in Lp(a), ApoB, non-HDL-C, ApoA1, and ApoB/ApoA1 ratio compared with placebo/active comparator in each study. These effects were generally consistent across key subgroups within each study. CONCLUSION: ERN/LRPT produced lipid-altering efficacy on the parameters evaluated in four controlled studies; these effects were generally consistent across all examined subgroups. ERN/LRPT represents an effective and reliable therapeutic option for the treatment of dyslipidemia in a wide range of patient types. CLINICAL TRIAL REGISTRATION: Registered as Clinicaltrials.gov NCT00269204, NCT00269217, NCT00479388, and NCT00485758.

Effects of simvastatin on carotenoid status in plasma.

BACKGROUND AND AIMS: Carotenoids are potent antioxidants mainly transported in the low density lipoprotein (LDL) fraction. They may also influence the immune response and inverse associations with inflammatory markers have been reported. We investigated whether simvastatin, by exerting both lipid-lowering and anti-inflammatory effects, altered the carotenoid status in plasma. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. Lipids, oxidized LDL (ox-LDL), C-reactive protein (CRP), interleukin (IL)-6, oxygenated carotenoids (lutein, zeaxanthin, ß-cryptoxanthin) and hydrocarbon carotenoids (α-carotene, ß-carotene, lycopene) were measured in plasma. Simvastatin use was associated with significant reductions in total cholesterol, LDL, ox-LDL and CRP. Simvastatin therapy also resulted in reduced plasma levels of both oxygenated and hydrocarbon carotenoids. However, when adjusted for lipids, all carotenoids except ß-cryptoxanthin showed significant increases after simvastatin therapy. Both crude and lipid-adjusted carotenoids were inversely correlated with CRP and IL-6 in plasma but the change in carotenoid status during simvastatin therapy was not specifically related to any changes in inflammatory markers. CONCLUSIONS: To summarize, the change in carotenoid status during simvastatin therapy was mainly attributed to the lowering of cholesterol and not to the suppression of inflammatory activity. After adjustment for lipids, the levels of lutein, lycopene, α-carotene and ß-carotene were significantly increased by simvastatin suggesting an increased ratio of carotenoids per particle.

The role of non-HDL cholesterol in risk stratification for coronary artery disease.

Despite aggressive lipid-lowering therapy, patients continue to be at significant risk of coronary heart disease (CHD). Assessment of non-high-density lipoprotein cholesterol (non-HDL-C) provides a measure of cholesterol contained in all atherogenic particles. In the third Adult Treatment Panel (ATP III) guidelines of the US National Cholesterol Education Program, non-HDL-C was introduced as a secondary target of therapy in persons with triglycerides ≥200 mg/dL. A recent meta-analysis of the relationship between non-HDL-C reduction and CHD risk showed non-HDL-C as an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have a 1:1 relationship between percent non-HDL-C lowering and percent CHD reduction. In the EPIC-Norfolk prospective population study, 21,448 participants without diabetes or CHD between 45 and 79 years of age were followed for 11.0 years. Participants with high non-HDL-C levels were at increased CHD risk independently of their LDL-C levels. Also, compared to apolipoprotein B, non-HDL-C appears to be a better choice given the fact that no additional tests or costs are needed and established cut points are already available. Future guidelines should emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies with an increased need to have non-HDL-C reported on routine lipid panels.

Long-term curcumin administration protects against atherosclerosis via hepatic regulation of lipoprotein cholesterol metabolism.

SCOPE: Atherosclerosis is a major cause of cardiovascular disease caused by high cholesterol. Stains are widely prescribed to lower cholesterol levels, but natural dietary compounds may also be effective. Therefore, we studied the effect of the natural dietary compound curcumin on atherosclerosis and its underlying mechanisms based on plasma and hepatic lipid metabolism. METHODS AND RESULTS: LDLR(-/-) mice were fed a high-cholesterol diet and treated with curcumin, lovastatin or control (n=10 per group) for 18 wk. Aortic arch sections revealed curcumin ameliorated early atherosclerotic lesions, lipid infiltration, ICAM-1 and VCAM-1 localization, similar to lovastatin treatment. Furthermore, curcumin lowered plasma cholesterol, triglycerides, LDL cholesterol and Apo B levels as well as CETP activity, while curcumin increased plasma HDL cholesterol and liver Apo A-I expression, similar to lovastatin treatment. Curcumin caused transcriptional inhibition of HMG-CoA reductase, independent of ACAT1 and ACAT2 expression. Hepatic PPARα and LXRα expression was upregulated by curcumin treatment. Hepatic complement factor D (Cfd) and systemic CRP levels, markers of immune complement pathway activation, were significantly reduced by curcumin treatment. CONCLUSION: Long-term curcumin treatment lowers plasma and hepatic cholesterol and suppresses early atherosclerotic lesions comparable to the protective effects of lovastatin. The anti-atherogenic effect of curcumin is mediated via multiple mechanisms including altered lipid, cholesterol and immune gene expression.