The 2-hydroxy-nevirapine metabolite as a candidate for boosting apolipoprotein A1 and for modulating anti-HDL antibodies.

The antiretroviral nevirapine (NVP) is associated to a reduction of atherosclerotic lesions and increases in high-density lipoprotein (HDL)-cholesterol. Despite being a hepatotoxic drug, which forbids its re-purposing to other therapeutic areas, not all NVP metabolites have the same potential to induce toxicity. Our aim was to investigate the effects of NVP and its metabolites in an exploratory study, towards the identification of a candidate to boost HDL. A pilot prospective (n = 11) and a cross-sectional (n = 332) clinical study were performed with the following endpoints: HDL-cholesterol and apolipoprotein A1 (ApoA1) levels, anti-HDL and anti-ApoA1 antibodies titers, paraoxonase, arylesterase and lactonase activities of paraoxonase-1, and NVP's metabolite profile. NVP treatment increased HDL-cholesterol, ApoA1 and paraoxonase-1 activities, and lowered anti-HDL and anti-ApoA1 titers. In the prospective study, the temporal modulation induced by NVP was different for each HDL-related endpoint. The first observation was a decrease in the anti-HDL antibodies titers. In the cross-sectional study, the lower titers of anti-HDL antibodies were associated to the proportion of 2-hydroxy-NVP (p = 0.03). In vitro models of hepatocytes were employed to clarify the individual contribution of NVP's metabolites for ApoA1 modulation. Long-term incubations of NVP and 2-hydroxy-NVP in the metabolically competent 3D model caused an increase in ApoA1 reaching 43 % (p < 0.05) and 86 % (p < 0.001), respectively. These results support the contribution of drug biotransformation for NVP-induced HDL modulation, highlighting the role of 2-hydroxy-NVP as ApoA1 booster and its association to lower anti-HDL titers. This biotransformation-guided approach allowed us to identify a non-toxic NVP metabolite as a candidate for targeting HDL.

Genetic contribution to lipid target achievement with statin therapy: a prospective study.

Statin therapy response is highly variable. Variants of lipid metabolism genes and statin pharmacokinetic modulators could play a role, however, the impact of most of these variants remains unconfirmed. A prospective and multicenter study included 252 patients was carried out in order to assess, according to achievement of LDL-C or non-HDL-C therapeutic targets and quantitative changes in lipid profiles, the impact of CETP, ABCA1, CYP2D6, and CYP2C9 gene candidate variants on the simvastatin, atorvastatin, and rosuvastatin response. Patients carrier ABCA1 rs2230806 and CYP2D6*3 variants are less likely to achieve therapeutic lipid targets (p = 0.020, OR = 0.59 [0.37, 0.93]; p = 0.040, OR = 0.23 [0.05, 0.93], respectively). Among CETP variants, rs708272 was linked to a 10.56% smaller reduction in LDL-C with rosuvastatin (95% CI = [1.27, 19.86] %; p = 0.028). In contrast, carriers of rs5882 had a 13.33% greater reduction in LDL-C (95% CI = [25.38, 1.28]; p = 0.032). If these findings are confirmed, ABCA1, CYP2D6, and CETP genotyping could be used to help predict which statin and dosage is appropriate in order to improve personalized medicine.

Trials and Tribulations of CETP Inhibitors.

The development of CETP (cholesteryl ester transfer protein) inhibitors has had a long and difficult course with 3 compounds failing in phase III clinical trials. Finally, the REVEAL (Randomized Evaluation of the Effects of Anacetrapib through Lipid modification) trial has shown that the CETP inhibitor anacetrapib decreased coronary heart disease when added to statin therapy. Although the result is different to earlier studies, this is likely related to the size and duration of the trial. The benefit of anacetrapib seems to be largely explained by lowering of non-HDL-C (high-density lipoprotein cholesterol), rather than increases in HDL-C. Although the magnitude of benefit for coronary heart disease appeared to be moderate, in part this may have reflected aspects of the trial design. Anacetrapib treatment was associated with a small increase in blood pressure, but was devoid of major side effects and was also associated with a small reduction in diabetes mellitus. Treatment with CETP inhibitors, either alone or in combination with statins, could provide another option for patients with coronary disease who require further reduction in LDL (low-density lipoprotein) and non-HDL-C.

Evidence for changing lipid management strategy to focus on non-high density lipoprotein cholesterol.

Low-density lipoprotein cholesterol (LDL-C) has been recommended as the primary treatment target on lipid management in coronary heart disease (CHD) patients for past several decades. However, even by aggressive LDL-C lowering treatment, patients still present a significant residual risk of major adverse cardiovascular events (MACE). Non-high-density lipoprotein cholesterol (non-HDL-C) contained all the atherogenic lipoproteins, such as chylomicron, very-low density lipoprotein (VLDL), LDL, intermediate density lipoprotein (IDL). Many prospective observation studies have found that non-HDL-C was better than LDL-C in predicting risks of MACE. Since non-HDL-C appears to be superior for risk prediction beyond LDL-C, current guidelines have emphasize the importance of non-HDL-C for guiding cardiovascular prevention strategies and have flagged non-HDL-C as a co-primary therapeutic target. The goals of non-HDL-C were recommended as 30 mg/dl higher than the corresponding LDL-C goals, but the value seemed inappropriate. This review provide evidence for changing lipid management strategy to focus on non-HDL-C and appropriate values for adding to LDL-C goals would be proposed.

Cholesterol Efflux Capacity, High-Density Lipoprotein Particle Number, and Incident Cardiovascular Events: An Analysis From the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).

BACKGROUND: Recent failures of drugs that raised high-density lipoprotein (HDL) cholesterol levels to reduce cardiovascular events in clinical trials have led to increased interest in alternative indices of HDL quality, such as cholesterol efflux capacity, and HDL quantity, such as HDL particle number. However, no studies have directly compared these metrics in a contemporary population that includes potent statin therapy and low low-density lipoprotein cholesterol. METHODS: HDL cholesterol levels, apolipoprotein A-I, cholesterol efflux capacity, and HDL particle number were assessed at baseline and 12 months in a nested case-control study of the JUPITER trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin), a randomized primary prevention trial that compared rosuvastatin treatment to placebo in individuals with normal low-density lipoprotein cholesterol but increased C-reactive protein levels. In total, 314 cases of incident cardiovascular disease (CVD) (myocardial infarction, unstable angina, arterial revascularization, stroke, or cardiovascular death) were compared to age- and gender-matched controls. Conditional logistic regression models adjusting for risk factors evaluated associations between HDL-related biomarkers and incident CVD. RESULTS: Cholesterol efflux capacity was moderately correlated with HDL cholesterol, apolipoprotein A-I, and HDL particle number (Spearman r= 0.39, 0.48, and 0.39 respectively; P<0.001). Baseline HDL particle number was inversely associated with incident CVD (adjusted odds ratio per SD increment [OR/SD], 0.69; 95% confidence interval [CI], 0.56-0.86; P<0.001), whereas no significant association was found for baseline cholesterol efflux capacity (OR/SD, 0.89; 95% CI, 0.72-1.10; P=0.28), HDL cholesterol (OR/SD, 0.82; 95% CI, 0.66-1.02; P=0.08), or apolipoprotein A-I (OR/SD, 0.83; 95% CI, 0.67-1.03; P=0.08). Twelve months of rosuvastatin (20 mg/day) did not change cholesterol efflux capacity (average percentage change -1.5%, 95% CI, -13.3 to +10.2; P=0.80), but increased HDL cholesterol (+7.7%), apolipoprotein A-I (+4.3%), and HDL particle number (+5.2%). On-statin cholesterol efflux capacity was inversely associated with incident CVD (OR/SD, 0.62; 95% CI, 0.42-0.92; P=0.02), although HDL particle number again emerged as the strongest predictor (OR/SD, 0.51; 95% CI, 0.33-0.77; P<0.001). CONCLUSIONS: In JUPITER, cholesterol efflux capacity was associated with incident CVD in individuals on potent statin therapy but not at baseline. For both baseline and on-statin analyses, HDL particle number was the strongest of 4 HDL-related biomarkers as an inverse predictor of incident events and biomarker of residual risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.

Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial.

BACKGROUND: Sodium-glucose co-transporter-2 inhibitors (SGLT2i) reduce glucose levels, body weight, and blood pressure, possibly resulting in cardiovascular protection. In phase III trials, SGLT2i were shown to increase HDL cholesterol. We aimed to evaluate whether the SGLT2i dapagliflozin affects HDL function in a randomized placebo-controlled trial. METHODS: Thirty-three type 2 diabetic patients were randomized to receive dapagliflozin 10 mg or placebo for 12 weeks on top of their glucose lowering medications. The primary end-point was the change in cholesterol efflux capacity (CEC) from macrophages at study end versus baseline. Secondary endpoints were changes in: distribution of HDL subfractions, lipid profile, activity of enzymes that mediate HDL antioxidant properties (PON1 and ARE) and cholesterol metabolism (CETP), HbA1c, body weight and composition. RESULTS: Thirty-one patients completed the study, n = 16 in the placebo group and n = 15 in the dapagliflozin group. Patients randomized to dapagliflozin were older and had lower adiposity indexes, although these differences disappeared after correction for multiple testing. Therapy with dapagliflozin reduced HbA1c by 0.9% and body weight by 3.1 kg, mainly attributable to reduction of body water and lean mass. As compared to placebo, dapagliflozin reduced CEC (-6.7 ± 2.4 versus 0.3 ± 1.8%; p = 0.043), but this effect was no longer significant after adjusting for age and BMI. No change was detected in HDL cholesterol, HDL subfractions, activity of PON1, ARE, and CETP. CONCLUSIONS: Despite improvements in glucose control and reduction in body weight, therapy with dapagliflozin exerted no significant effect on HDL cholesterol levels and HDL functionality. Trial registration EudraCT 2014-004270-42; NCT02327039.

Does Evolocumab, as a PCSK9 Inhibitor, Ameliorate the Lipid Profile in Familial Hypercholesterolemia Patients? A Meta-Analysis of Randomized Controlled Trials.

Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a member of regulatory serine proteases which is mostly expressed in liver. In the physiological condition, LDL-C binds to LDL receptors (LDLRs) and via endocytosis, LDLRs are degraded. PCSK9 binds to the epidermal growth factor-like repeat A (EGFA) domain of extracellular LDLRs, and then physiological recycling of LDLRs from surface of liver is cancelled, resulting in elevation of circulating LDL-C in plasma. To evaluate whether evolucomab, as PCSK9 inhibitor monoclonal antibody, ameliorates lipid profile in familial hypercholesterolemia (FH) patients, this meta-analysis has been conducted. PubMed, Web of Science (ISI) and Scopus databases were searched for studies which had investigated the efficacy of evolucomab. Types of outcome investigated were percentage changes from baseline of the lipid profile. Our meta-analysis shows that evolucomab at the dosage of 420 mg monthly could decrease LDL-C  by 54.71%, TC by 35.08%, VLDL-C by 28.37 %, ratio of TC to HDL-C by 39.14 %, triglycerides by 12.11 %, and increased HDL-C by 6.06% from baseline compared to placebo at the end of study in FH patients. Our findings indicate that evolocumab could be a hopeful agent for challenging patients, such as statin intolerance or patients who fail to attain the target goal of LDL-C despite consumption of maximum doses of statins. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Curcumin Lowers Serum Lipids and Uric Acid in Subjects With Nonalcoholic Fatty Liver Disease: A Randomized Controlled Trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common hepatic diseases in the general adult population. Dyslipidemia, hyperuricemia, and insulin resistance are common risk factors and accompanying features of NAFLD. Curcumin is a dietary natural product with beneficial metabolic effects relevant to the treatment of NAFLD. AIM: To assess the effects of curcumin on metabolic profile in subjects with NAFLD. METHODS: Patients diagnosed with NAFLD (grades 1-3; according to liver sonography) were randomly assigned to curcumin (1000 mg/d in 2 divided doses) (n = 50) or control (n = 52) group for a period of 8 weeks. All patients received dietary and lifestyle advises before the start of trial. Anthropometric measurements, lipid profile, glucose, insulin, glycated hemoglobin, and uric acid concentrations were measured at baseline and after 8 weeks of follow-up. RESULTS: Eighty-seven subjects (n = 44 and 43 in the curcumin and control group, respectively) completed the trial. Supplementation with curcumin was associated with a reduction in serum levels of total cholesterol (P < 0.001), low-density lipoprotein cholesterol (P < 0.001), triglycerides (P < 0.001), non-high-density lipoprotein cholesterol (P < 0.001), and uric acid (P < 0.001), whereas serum levels of high-density lipoprotein cholesterol and glucose control parameters remained unaltered. Curcumin was safe and well tolerated during this study. CONCLUSION: Results of the present trial suggest that curcumin supplementation reduces serum lipids and uric acid concentrations in patients with NAFLD.

Sugar-Sweetened Beverage Intake Is Positively Associated with Baseline Triglyceride Concentrations, and Changes in Intake Are Inversely Associated with Changes in HDL Cholesterol over 12 Months in a Multi-Ethnic Sample of Children.

BACKGROUND: Intake of sugar-sweetened beverages (SSBs) is linked to greater cardiometabolic risk in adults. Although longitudinal evidence is sparse among children, SSB intake reduction is targeted to reduce cardiometabolic risk factors in this group. OBJECTIVE: We investigated characteristics associated with consumption of SSBs in a multi-ethnic sample of children/adolescents and measured cross-sectional and longitudinal associations between SSB intake and plasma HDL cholesterol and triglycerides (TGs) over 12 mo. METHODS: In a diverse cohort of children aged 8-15 y, cross-sectional associations (n = 613) between baseline SSB intake and blood lipid concentrations and longitudinal associations (n = 380) between mean SSB intake, changes in SSB intake, and lipid changes over 12 mo were assessed with multivariable linear regression. RESULTS: Greater SSB intake was associated with lower socioeconomic status, higher total energy intake, lower fruit/vegetable intake, and more sedentary time. In cross-sectional analysis, greater SSB intake was associated with higher plasma TG concentrations among consumers (62.4, 65.3, and 71.6 mg/dL in children who consumed >0 but <2, ≥2 but <7, and ≥7 servings/wk, respectively; P-trend: 0.03); plasma HDL cholesterol showed no cross-sectional association. In the longitudinal analysis, mean SSB intake over 12 mo was not associated with lipid changes; however, the 12-mo increase in plasma HDL-cholesterol concentration was greater among children who decreased their intake by ≥1 serving/wk (4.6 ± 0.8 mg/dL) compared with children whose intake stayed the same (2.0 ± 0.8 mg/dL) or increased (1.5 ± 0.8 mg/dL; P = 0.02). CONCLUSIONS: In a multi-ethnic sample of children, intake of SSBs was positively associated with TG concentrations among consumers, and changes in SSB intake were inversely associated with HDL cholesterol concentration changes over 12 mo. Further research in large diverse samples of children is needed to study the public health implications of reducing SSB intake among children of different racial/ethnic groups. The Daily D Health Study was registered at clinicaltrials.gov as NCT01537809.

ApoA-I-Directed Therapies for the Management of Atherosclerosis.

Several recent reports have raised doubts about the atheroprotective role of high-density lipoprotein cholesterol (HDL-C). Nevertheless, a substantial body of work supports the validity of pharmacological interventions able to enhance HDL function, as opposed to raising HDL-C levels per se. In this article, we briefly review the development of pharmacological interventions that target apoA-I and HDL function as a means of reducing atherosclerotic risk: small molecule pharmaceuticals, small HDL mimetic peptides, and infusion of apoA-I-containing particles.

Lipids, blood pressure and kidney update 2015.

The most important studies and guidelines in the topics of lipid, blood pressure and kidney published in 2015 were reviewed. In lipid research, the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial revalidated the concept "lower is better" for low density lipoprotein (LDL)-cholesterol as a target for therapy, increasing the necessity of treatment the high-risk patients to achieve LDL-C goals. After these results, ezetimibe might become the preferred additional drug in the combination therapy of lipid disorders because of oral dosage form and lower acquisition cost. However, for the statin-intolerant patients and those patients requiring essential reductions in LDL-C to achieve their goals, new therapies, including PCSK9 inhibitors remain promising drugs. In blood pressure research, American Heart Association (AHA)/American College of Cardiology (ACC) 2015 guidelines recommended a target for blood pressure below 140/90 mmHg in stable or unstable coronary artery disease patients and below 150/90 mmHg in patients older than 80 years of age, however the recent results of the Systolic Blood Pressure Intervention Trial (SPRINT) trial have suggested that there might be significant benefits, taking into account cardiovascular risk, for hypertensive patients over 50 without diabetes and blood pressure levels <120/80. In kidney research, reducing the progression of chronic kidney disease and related complications such as anemia, metabolic acidosis, bone and mineral diseases, acute kidney injury and cardiovascular disease is still a goal for clinicians.

The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination.

UNLABELLED: Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function. CONCLUSION: Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI.

Effects of cholesteryl ester transfer protein inhibitors on human lipoprotein metabolism: why have they failed in lowering coronary heart disease risk?

PURPOSE OF REVIEW: To examine the recent advances in our knowledge of cholesteryl ester transfer protein (CETP) inhibitors, heart disease risk reduction, and human lipoprotein metabolism. RECENT FINDINGS: CETP inhibitors block the transfer of cholesteryl ester from HDLs to triglyceride-rich lipoproteins (TRLs), thereby raising HDL cholesterol and lowering TRL cholesterol, and in some cases LDL cholesterol. Two CETP inhibitors, dalcetrapib and torcetrapib, have been tested in large clinical trials in statin-treated coronary heart disease patients and have shown no clinical benefit compared to placebo. Anacetrapib and evacetrapib, two potent CETP inhibitors, are now being tested in large clinical trials. Torcetrapib has been shown to decrease the fractional catabolic rate (FCR) of HDL apolipoproteins (apo) A-I and A-II, enhance the FCR of TRL apoB-100 and apoE, and decrease TRL apoB-48 production, but has no significant effects on fecal cholesterol excretion in humans. Anacetrapib also delays the FCR of HDL apoA-I. SUMMARY: CETP inhibitors form a complex between themselves, CETP, and HDL particles, which may interfere with the many physiologic functions of HDL, including reverse cholesterol transport. Available data would suggest that CETP inhibitors will fail as lipid-altering medications to reduce coronary heart disease risk because of interference with normal human HDL metabolism.

ß3-Adrenoceptor activation attenuates atherosclerotic plaque formation in ApoE(-/-) mice through lowering blood lipids and glucose.

AIM: To examine the effects of ß3-adrenoceptor (ß3-AR) activation on atherosclerotic plaque development in ApoE(-/-) mice. METHODS: Thirty six week-old male ApoE(-/-) mice on a high-fat diet were treated with atorvastatin (10 mg·kg(-1)·d(-1), po), BRL37344 (ß3-AR agonist, 1.65 or 3.30 µg/kg, ip, twice a week) or SR52390A (ß3-AR antagonist, 50 µg/kg, ip, twice a week) for 12 weeks. Wild-type C57BL/6J mice receiving a normal diet were taken as healthy controls. At the end of the treatments, serum levels of triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), non-high density lipoprotein cholesterol (nHDL-C), glucose and insulin were measured. The thoracic aortas were dissected out, the area of atherosclerotic plaques and extent of fibrosis in the plaques were examined using HE and Masson's trichome staining, respectively. RESULTS: Compared to wild-type mice, ApoE(-/-) mice fed on a high-fat diet exhibited prominent hyperlipidemia and insulin resistance, associated with large area of atherosclerotic plaques and great extent of fibrosis in aortas. Atorvastatin significantly decreased the serum levels of TC and nHDL-C, and reduced the plaque area and collagen content in aortas. BRL37344 significantly decreased the serum levels of TG, TC, nHDL-C, glucose and insulin, and increased HDL-C and the insulin sensitivity, and dose-dependently reduced the plaque area and collagen content in aortas. SR52390A treatment did not affect any parameters studied. CONCLUSION: The ß3-AR agonist impedes the progression of atherosclerosis in ApoE(-/-) mice, through improvement of the lipid and glucose profiles.

Lipoproteins and cancer: The role of HDL-C, LDL-C, and cholesterol-lowering drugs.

Cholesterol is an amphipathic sterol molecule that is vital for maintaining normal physiological homeostasis. It is a relatively complicated molecule with 27 carbons whose synthesis starts with 2-carbon units. This in itself signifies the importance of this molecule. Cholesterol serves as a precursor for vitamin D, bile acids, and hormones, including estrogens, androgens, progestogens, and corticosteroids. Although essential, high cholesterol levels are associated with cardiovascular and kidney diseases and cancer initiation, progression, and metastasis. Although there are some contrary reports, current literature suggests a positive association between serum cholesterol levels and the risk and extent of cancer development. In this review, we first present a brief overview of cholesterol biosynthesis and its transport, then elucidate the role of cholesterol in the progression of some cancers. Suggested mechanisms for cholesterol-mediated cancer progression are plentiful and include the activation of oncogenic signaling pathways and the induction of oxidative stress, among others. The specific roles of the lipoprotein molecules, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), in this pathogenesis, are also reviewed. Finally, we hone on the potential role of some cholesterol-lowering medications in cancer.

'Trig-onometry': non-high-density lipoprotein cholesterol as a therapeutic target in dyslipidaemia.

Targeting elevations in low-density lipoprotein cholesterol (LDL-C) remains the cornerstone of cardiovascular prevention. However, this fraction does not adequately capture elevated triglyceride-rich lipoproteins (TRLs; e.g. intermediate-density lipoprotein, very low density lipoprotein) in certain patients with metabolic syndrome or diabetic dyslipidaemia. Many such individuals have residual cardiovascular risk that might be lipid/lipoprotein related despite therapy with first-line agents (statins). Epidemiological evidence encompassing > 100,000 persons supports the contention that non-high-density lipoprotein cholesterol (non-HDL-C) is a superior risk factor vs. LDL-C for incident coronary heart disease (CHD) in certain patient populations. In studies with clinical end-points evaluated in the current article, a 1:1 to 1:3 relationship was observed between reductions in non-HDL-C and in the relative risk of CHD after long-term treatment with statins, niacin (nicotinic acid) and fibric-acid derivatives (fibrates); this relationship increased to 1:5 to 1:10 in smaller subgroups of patients with elevated triglycerides and low HDL-C levels. Treatment with statin-, niacin-, fibrate-, ezetimibe-, and omega 3 fatty acid-containing regimens reduced non-HDL-C by approximately 9-65%. In a range of clinical trials, long-term treatment with these agents also significantly decreased the incidence of clinical/angiographic/imaging efficacy outcome variables. For patients with dyslipidaemia, consensus guidelines have established non-HDL-C treatment targets 30 mg/dl higher than LDL-C goals. Ongoing prospective randomised controlled trials should help to resolve controversies concerning (i) the clinical utility of targeting non-HDL-C in patients with dyslipidaemia; (ii) the most efficacious and well-tolerated therapies to reduce non-HDL-C (e.g. combination regimens); and (iii) associations between such reductions and clinical, angiographic, and/or imaging end-points.

Effect of ABCG1 gene DNA methylations on the lipid-lowering efficacy of simvastatin.

Aim: We investigated the effect of ABCG1 gene DNA methylation in the lipid-lowering efficacy of simvastatin. Materials & methods: An extreme sampling approach was used to select 211 individuals from the top and bottom 15% of adjusted lipid-lowering response residuals to simvastatin after eight consecutive weeks. DNA methylation was measured before treatment by the MethylTarget bisulfite sequencing method. Results:ABCG1_A DNA methylations were negatively associated with baseline high-density lipoprotein cholesterol (HDL-C) and the change in HDL-C after treatment. ABCG1_C methylations were also related to the change in triglyceride and HDL-C. Moreover, mean ABCG1_A and ABCG1_C methylations explain 7.2% of the ΔTC (total cholesterol) and 17.5% of the ΔHDL-C level variability, respectively. Conclusion: DNA methylations at the ABCG1 gene play significant inhibitory effects in the lipid-lowering therapy of simvastatin.

The Rise and Fall "ing" of the HDL Hypothesis.

Earlier epidemiological studies have shown an inverse correlation between high-density lipoprotein cholesterol (HDLc) and coronary heart disease (CHD). This observation along with the finding that reverse cholesterol transport is mediated by HDL, supported the hypothesis that the HDL molecule has a cardioprotective role. More recently, epidemiological data suggest a U-shaped curve correlating HDLc and CHD. In addition, randomized clinical trials of drugs that significantly increase plasma HDLc levels, such as nicotinic acid and cholesterol ester transfer protein (CETP) inhibitors failed to show a reduction in major adverse cardiovascular events. These observations challenge the hypothesis that HDL has a cardioprotective role. It is possible that HDL quality and function is optimal only when de novo synthesis of apo A-I occurs. Inhibition of turnover of HDL with currently available agents yields HDL molecules that are ineffective in reverse cholesterol transport. To test this hypothesis, newer therapeutic drugs that increase de novo production of HDL and apo A-I should be tested in clinical trials.

Using Genetic Variants in the Targets of Lipid Lowering Therapies to Inform Drug Discovery and Development: Current and Future Treatment Options.

Mendelian randomization studies and "human knock-out" studies of rare loss-of-function coding variants suggest that plasma levels of low-density lipoprotein-cholesterol LDL-C, triglycerides (TGs), and lipoprotein(a) (Lp(a)) are causally associated with the risk of cardiovascular disease, and, therefore, therapies directed against these targets should reduce the risk of cardiovascular events. However, several therapies directed against these targets have failed to reduce the risk of cardiovascular events in large-scale randomized trials, thus suggesting that causality is not sufficient evidence to establish genetic target validation. Instead, the critical question that needs to be answered to improve drug discovery and development is how much a causal biomarker needs to be changed to produce a clinically meaningful benefit in a short-term trial. This review describes how to use naturally randomized genetic evidence to accurately anticipate the results of randomized trials evaluating current and future lipid lowering therapies, inform the design of randomized trials, and transform the drug discovery and development process.

Hypolipidemic, antioxidant and antiatherogenic property of sardine by-products proteins in high-fat diet induced obese rats.

AIMS: Fish by-products valorization on account of their richness in bioactive compounds may represent a better alternative to marine products with a view to economic profitability and sustainable development. In this study, we compared the effect of sardine by-product proteins (SBy-P), with those of the fillets (SF-P) or casein (Cas), on growth parameters, serum leptin level, lipids disorders, lipid peroxidation and reverse cholesterol transport, in diet-induced obese rats. MAIN METHODS: Obesity was induced by feeding rats a high-fat diet (20% sheep fat), during 12 weeks. At body weight (BW) of 400 ±â€¯20 g, eighteen obese rats were divided into three homogenous groups and continue to consume the high-fat diet for 4 weeks containing either, 20% SBy-P, SF-P or Cas. KEY FINDINGS: The results showed that SBy-P, compared to SF-P and Cas, efficiently reduced food intake (FI), BW gain and serum leptin level, and improved blood lipids levels and reverse cholesterol transport by reducing total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-HDL1-C) serum levels, increasing the level of high-density lipoprotein cholesterol (HDL2-C and HDL3-C), and enhancing lecithin: cholesterol acyltransferase (LCAT) activity. Furthermore, they attenuated lipid peroxidation by increasing atheroprotective activity of the paraoxonase-1 (PON-1). SIGNIFICANCE: Sardine by-product proteins due to their richness in certain essential amino acids, highlight weight-loss, lipid-lowering, antioxidant and anti-atherogenic potentials, contributing to the improvement of the complications associated with obesity.