Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia.

BACKGROUND: A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9, as an add-on treatment to optimized lipid-lowering therapy in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia. METHODS AND RESULTS: A total of 806 patients who were receiving stable and optimized lipid-lowering therapy but did not achieve their low-density lipoprotein cholesterol (LDL-C) targets were enrolled and randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or matching placebo every 2 weeks, or ongericimab 300 mg or matching placebo every 4 weeks for 52 weeks. Efficacy and safety were evaluated in 802 patients who received at least 1 dose of ongericimab or placebo. The primary end point was the percentage change in LDL-C from baseline to week 24. Our findings demonstrated that the least-squares mean difference of percentage change in LDL-C from baseline to week 24 was -67.7% (95% CI, -72.5% to -63.0%; P<0.0001) in the ongericimab 150 mg every 2 weeks group compared with the placebo every 2 weeks group, and -61.2% (95% CI, -67.1% to -55.2%; P<0.0001) in the ongericimab 300 mg every 4 weeks group compared with the placebo every 4 weeks group. These reductions were sustained up to week 52. Furthermore, treatment with ongericimab favorably altered other lipid parameters. A similar incidence of adverse events was observed in the ongericimab and placebo groups. CONCLUSIONS: Ongericimab, as an add-on treatment to optimized lipid-lowering therapy, significantly reduced LDL-C and was well-tolerated in Chinese patients with primary hyperlipidemia and mixed dyslipidemia who did not achieve their LDL-C targets. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04781114.

Prevalence of Dysbetalipoproteinemia in the UK Biobank According to Different Diagnostic Criteria.

CONTEXT: Dysbetalipoproteinemia (DBL) is a multifactorial disorder that disrupts the normal metabolism of remnant lipoproteins, causing increased risk of cardiovascular disease. However, establishing a proper diagnosis is difficult and the true prevalence of the disease in the general population remains unknown. OBJECTIVE: The objectives were to study the prevalence of the disease and to validate the performance of different clinical diagnostic criteria in a large population-based cohort. METHODS: This study included 453 437 participants from the UK Biobank. DBL was established in participants having an ε2ε2 genotype with mixed dyslipidemia or lipid-lowering therapy use (n=964). The different diagnostic criteria for DBL were applied in individuals without lipid-lowering medication (n=370 039, n=534 DBL), to compare their performance. RESULTS: Overall, 0.6% of participants had an ε2ε2 genotype, of which 36% were classified as DBL, for a disease prevalence of 0.2% (1:469). The prevalence of DBL was similar between the different genetic ancestries (≤0.2%). Several diagnostic criteria showed good sensitivity for the diagnosis of DBL (>90%), but they suffered from a very low positive predictive value (0.6%-15.4%). CONCLUSION: This study reported for the first time the prevalence of DBL in the UK Biobank according to genetic ancestry. Furthermore, we provided the first external validation of different diagnostic criteria for DBL in a large population-based cohort and highlighted the fact that these criteria should not be used to diagnose DBL alone but should rather be used as a first screening step to determine which individuals may benefit from genetic testing to confirm the diagnosis.

Correlation between different levels and patterns of dyslipidemia and glomerular filtration rate in patients with type 2 diabetes: A cross-sectional survey of a regional cohort.

BACKGROUND: Due to the high cardiovascular risk in patients with diabetic nephropathy, more attention should be paid to lipid levels and dyslipidemia in these patients. The current study investigated the association between single and mixed dyslipidemia patterns, estimated glomerular filtration rate (eGFR), and different chronic kidney disease (CKD) stages. METHODS: This cross-sectional study evaluated 4059 patients with type 2 diabetes (T2D). TG, TC, LDL-C, and HDL-C were measured. Non-HDL-C and AIP were calculated. We estimated eGFR using the CKD-EPI equation. RESULTS: With the progression of the kidney failure stage, mean levels of TG, LDL-C, non-HDL-C, and AIP decreased. HDL-C levels decreased with the advance of the CKD stage in men but did not change significantly in women. The prevalence of single dyslipidemia, including high LDL-C and high non-HDL-C, decreased with the advancing CKD stage. The prevalence of mixed dyslipidemia patterns, including high AIP and high LDL-C, high AIP and high non-HDL-C, showed a significant downward tendency. TG and AIP levels were negatively, and HDL-C levels were positively correlated with eGFR after adjusting for the risk factors. Also, CKD stage 3 was positively related to the risk of high TG and low HDL-C. CONCLUSION: This study shows that blood lipids decreased with the progression of renal failure in patients with T2D. However, after adjustment, TG and AIP levels had negative, and HDL-C levels had a positive correlation with eGFR, which could be consistent with the hypothesis that eGFR decreases with increasing TG or AIP levels or decreasing HDL-C levels.

Combined Dyslipidemia in Children and Adolescents: a Proposed New Management Approach.

PURPOSE OF REVIEW: Combined dyslipidemia (CD), the predominant abnormal lipid pattern in children and adolescents, is characterized by moderate/severe triglyceride elevation with reduced high-density lipoprotein cholesterol. CD is prevalent, present in 30-50% of obese adolescents. Epidemiologic and lipid sub-population findings demonstrate CD to be highly atherogenic. In the short term, CD responds well to lifestyle change; long-term results are lacking. RECENT FINDINGS: Major longitudinal studies now confirm that CD in childhood predicts early cardiovascular disease events in adults. Targeted nutritional interventions can be safely and effectively introduced in young children. These findings support introduction of a new approach to CD management. New evidence supporting the atherosclerotic risk associated with CD and the effectiveness of lifelong diet interventions is reviewed and a new family-based primordial approach to CD beginning in infancy is proposed. Aligned with existing pediatric care recommendations, this has the potential to significantly decrease the development of CD.

Efficacy and Safety of Evolocumab in Chinese Patients with Primary Hypercholesterolemia and Mixed Dyslipidemia: 12-Week Primary Results of the HUA TUO Randomized Clinical Trial.

INTRODUCTION: Evolocumab, a fully human proprotein convertase/subtilisin kexin type 9 inhibitor antibody, significantly lowers low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes mellitus and hyperlipidemia and mixed dyslipidemia. This 12-week study evaluated the efficacy and safety of evolocumab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia at different levels of cardiovascular disease risk. METHODS: HUA TUO was a 12-week randomized, double-blind, placebo-controlled study. Chinese patients aged 18 years or older on stable optimized statin therapy were randomized 2:2:1:1 to receive evolocumab 140 mg every 2 weeks (Q2W), evolocumab 420 mg monthly (QM), or a matching placebo. The coprimary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12 and at week 12. RESULTS: Overall, 241 randomized patients (mean [standard deviation] age, 60.2 [10.3] years) received evolocumab 140 mg Q2W (n = 79), evolocumab 420 mg QM (n = 80), placebo Q2W (n = 41), or placebo QM (n = 41). At weeks 10 and 12, the placebo-adjusted least-squares mean percent change from baseline in LDL-C for the evolocumab 140 mg Q2W group was - 70.7% (95% CI - 78.0% to - 63.5%); - 69.7% (95% CI - 76.5% to - 63.0%) for the evolocumab 420 mg QM group. Significant improvements in all other lipid parameters were observed with evolocumab. The patient incidence of treatment-emergent adverse events was similar between the treatment groups and across dosing regimens. CONCLUSION: In Chinese patients with primary hypercholesterolemia and mixed dyslipidemia, 12-week treatment with evolocumab significantly lowered LDL-C and other lipids, and was safe and well tolerated (NCT03433755).

Dyslipidemia and PCSK9 inhibitors - practical focused update of indication and reimbursement criteria.

PCSK9 inhibitors are modern and effective hypolipidemic drugs for lowering LDL-cholesterol, which belong to the „biological therapy“. Their prescription is limited to specialized centers and to the fulfillment of other conditions set by SÚKL. This article lists the current valid criteria under which they can be indicated for reimbursement from public health insurance, and comments conditions and limitations in terms of the possibility of their fulfillment in clinical practice.

Effect of 1PC111, a Fixed-dose Combination of Pitavastatin and Ezetimibe, Versus Pitavastatin or Ezetimibe Monotherapy on Lipid Profiles in Patients With Hypercholesterolemia or Mixed Dyslipidemia: A Randomized, Double-blind, Multicenter, Phase III Study.

PURPOSE: This study aimed to show that the efficacy of 1PC111 is superior to that of either ezetimibe or pitavastatin alone (monotherapy) for the treatment of hypercholesterolemia. METHODS: This was a multicenter, randomized, double-blind, Phase III study. Patients with hypercholesterolemia or mixed dyslipidemia were randomized to receive 1PC111 (which was a fixed-dose combination of pitavastatin 2 mg and ezetimibe 10 mg), pitavastatin 2 mg, or ezetimibe 10 mg daily for 12 weeks. The primary end point was the difference in the percent change in LDL-C from baseline to week 12 between the 1PC111 and each monotherapy group. The secondary end points were the percent change in other lipid profiles from baseline to each visit. All patients were assessed for adverse events until end of study. FINDINGS: A total of 388 patients were randomly assigned to the 1PC111 (n = 128), pitavastatin (n = 132), or ezetimibe (n = 128) group. Generally, baseline characteristics were similar among the 3 groups. A statistically significant decrease in the LDL-C level at week 12 was observed in the 1PC111 group (-50.50% [14.9%]) compared with either the pitavastatin (-36.11% [11.4%]; P < 0.001) or ezetimibe (-19.85% [12.4%]; P < 0.001) group. Also, there was a statistically significant difference between 1PC111 and each monotherapy group in the reduction in total cholesterol, non-HDL-C, and apolipoprotein B levels. Moreover, there was a trend toward more efficient lowering of LDL-C levels in elderly patients (age ≥65 years) than in younger patients (age <65 years) by 1PC111 treatment. In patients given a class I recommendation for atherosclerotic cardiovascular disease prevention, the percentage of patients achieving the LDL-C target of <100 mg/dL at week 12 was significantly higher in the 1PC111 group than in both monotherapy groups (P < 0.001). Overall, the incidence of adverse events was similar among 3 groups. IMPLICATIONS: 1PC111 was more effective in improving lipid profiles and achieving the LDL-C goal than pitavastatin or ezetimibe alone for hypercholesterolemia treatment. Furthermore, 1PC111 may provide more benefit in treating elderly patients. CLINICALTRIALS: gov identifier: NCT04643093.

Biologic therapy for dyslipidemia.

Dyslipidemia treatment represents a very dynamically growing segment of pharmacotherapy, including a production of biological agents. Nowadays, they are targeting at various proteins that are involved in the synthesis, transport, or metabolism of lipoproteins. This review provides a statement of current options for the biological treatment of dyslipidemias and for other products that have the potential to broaden its spectrum in the near future.

Don't we forget about biological therapy of hypercholesterolemia with PCSK9-inhibitors?

In many patients it is difficult to achieve the current very low target LDL-cholesterol levels, recommended for the prevention of atherosclerotic cardiovascular events. If statin therapy or statins in combination with ezetimibe are not sufficient, addition of PCSK9 inhibitors should be considered. PCSK9 inhibitors reduce LDL-CH by an average of 50-60 % and reduce the risk of atherosclerotic cardiovascular events. They are currently reserved for patients with atherosclerotic cardiovascular disease and for patients with familial hypercholesterolaemia, in whom despite intensive hypolipidemic therapy statins with ezetimibe the target LDL-cholesterol value is not reached. In these patients, PCSK9 inhibitors may also be indicated in case of statin intolerance.

Cardiometabolic Risk Factors in Rosuvastatin-Treated Men with Mixed Dyslipidemia and Early-Onset Androgenic Alopecia.

Men with early-onset androgenetic alopecia are characterized by hormonal profiles similar to those observed in women with polycystic ovary syndrome. The purpose of this research was to investigate levels of cardiometabolic risk factors in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-treated men with early-onset androgenic alopecia. We studied two matched rosuvastatin-treated groups of men with mixed dyslipidemia: subjects with early-onset androgenic alopecia (group A) and subjects with normal hair growth (group B). Plasma lipids, glucose homeostasis markers, and levels of sex hormones, uric acid, hsCRP, homocysteine, fibrinogen, and 25-hydroxyvitamin D were measured before entering the study and six months later. Both groups differed in insulin sensitivity and levels of calculated bioavailable testosterone, dehydroepiandrosterone-sulfate, uric acid, hsCRP, fibrinogen, and 25-hydroxyvitamin D. Though observed in both study groups, treatment-induced reductions in total cholesterol, LDL cholesterol, hsCRP, and fibrinogen were more pronounced in group B than group A. Moreover, only in group A did rosuvastatin deteriorate insulin sensitivity, and only in group B did the drug affect uric acid, homocysteine, and 25-hydroxyvitamin D. The impact of rosuvastatin on cardiometabolic risk factors correlated with insulin sensitivity, calculated bioavailable testosterone, and dehydroepiandrosterone-sulfate. The obtained results suggest that men with early-onset androgenic alopecia may benefit to a lesser degree from rosuvastatin treatment than their peers.

Effect of Berberine Plus Bezafibrate Administration on the Lipid Profile of Patients with Mixed Dyslipidemia: A Pilot Clinical Trial.

To evaluate the effect of berberine (BBR) plus bezafibrate administration on the lipid profile of patients with mixed dyslipidemia. A double-blind randomized pilot clinical trial with parallel groups was carried out in 36 patients, aged 30-60 years with mixed dyslipidemia [triglycerides (TG) ≥1.7 mM and total cholesterol (TC) ≥5.2 mM]. Patients were assigned to 3 groups of 12 patients each, receiving oral administration during 90 days of BBR 500 mg t.i.d., bezafibrate 400 mg b.i.d., or BBR 500 mg t.i.d. plus bezafibrate 400 mg b.i.d, respectively. Clinical evaluation, lipid profile, glucose, creatinine, and uric acid levels were measured before and after the pharmacological intervention. Kruskal-Wallis, Wilcoxon, Mann-Whitney U, and χ2 tests were used for statistical analyses; a P ≤ .05 was considered statistically significant. BBR reduced TC levels. Bezafibrate decreased TG, TC, low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein (VLDL) concentrations. BBR plus bezafibrate decreased TG (2.6 ± 0.8 vs. 1.3 ± 0.7 mM, P = .007), TC (6.3 ± 0.7 vs. 4.6 ± 1.2 mM, P = .005), LDL-C (3.4 ± 0.6 vs. 2.2 ± 1.3 mM, P = .037), and VLDL (0.5 ± 0.2 vs. 0.2 ± 0.1 mM, P = .007) levels. Bezafibrate and BBR plus bezafibrate significantly decreased TG, TC, LDL-C, and VLDL concentrations, and thus, remitting the diagnosis of mixed dyslipidemia in 90% of the patients.

A simplified diagnosis algorithm for dysbetalipoproteinemia.

BACKGROUND: Dysbetalipoproteinemia (DBL) is a disease of remnant lipoprotein accumulation caused by a defective apolipoprotein (apo) E and is associated with a considerable atherogenic burden. However, there exists confusion concerning the diagnosis of this disorder, and as a consequence, misdiagnosis is frequent. OBJECTIVE: The objective of the present study is to propose an algorithm for the diagnosis of DBL using simple clinical variables. METHODS: In a large cohort of 12,434 dyslipidemic patients, 4891 patients presented with mixed dyslipidemia (total cholesterol ≥ 5.2 mmol/L [200 mg/dL] and triglycerides ≥ 2.0 mmol/L [175 mg/dL]), and 188 DBL patients were identified based on the presence of an elevated very-low-density lipoprotein cholesterol/triglyceride ratio and were carriers of apoE2/E2. The APOE genotype or phenotype as well as the lipoprotein ultracentrifugation results were available for all patients. RESULTS: Among the laboratory variables associated with the lipid profile, the non-high-density lipoprotein cholesterol (HDL-C)/apoB ratio was the best predictor of DBL diagnosis based on the C-statistic. Previous proposed criteria had either low sensitivity or low specificity for the diagnosis of DBL. Using a non-HDL-C/apoB cut point of 3.69 mmol/g (1.43 in conventional units) followed by the presence of apoE2/E2 resulted in a good sensitivity (94.8%), negative predictive value (99.8%), specificity (99.6%), positive predictive value (88.5%), accuracy (99.4%), and area under the curve (0.97 [0.95-0.99]) for the prediction of DBL. CONCLUSION: We therefore propose a 3-step algorithm for the diagnosis of DBL using total cholesterol and triglycerides as a first step, the non-HDL-C/apoB ratio as a second screening criterion and finally the APOE genotype, lipoprotein ultracentrifugation, or electrophoresis as a confirmatory test.

Apabetalone - BET protein inhibition in cardiovascular disease and Type 2 diabetes.

Apabetalone is the first selective BET protein inhibitor in the field of cardiovascular diseases (CVD). BET proteins are epigenetic regulators that link upstream epigenetic modifications to downstream gene expression. Inhibition of BET proteins by apabetalone has been shown to modulate reverse cholesterol transport, coagulation, inflammation and vascular calcification. Furthermore, apabetalone reduces circulating markers of CVD risk and plaque vulnerability. Post-hoc pooled analyses suggest a potential reduction in risk of major adverse cardiac events (MACE) in patients with Type 2 diabetes (T2D) and stable CVD. However, the current cardiovascular outcomes trial BET-on-MACE failed to detect the assumed 30% reduction of MACE by apabetalone in patients with T2D after an acute coronary syndrome.

Atherogenic dyslipidemia increases the risk of incident diabetes in statin-treated patients with impaired fasting glucose or obesity.

AIM: To investigate which metabolic factors increase the risk of incident diabetes (T2D) in statin-treated patients. METHODS: A retrospective study conducted in Greece including 1241 consecutive individuals with dyslipidemia attending a lipid clinic for ≥3 years. After defining associations with incident T2D, we assessed the risk of new-onset T2D based on the presence of impaired fasting glucose (IFG), atherogenic dyslipidemia, and overweight/obesity. RESULTS: After excluding 166 patients with baseline T2D and 193 subjects taking lipid-lowering therapy at the baseline visit, 882 participants were included in the study. Eleven percent (n=94) developed T2D during their follow-up (median 6 years; IQR: 4-10). Baseline patients' age (OR: 1.05; 95% CI: 1.02-1.08, p<0.01), family history of diabetes (OR: 3.58; 95% CI: 1.86-6.91, p<0.01), IFG (OR: 6.56; 95% CI: 3.53-12.12, p<0.01), overweight/obesity (OR: 2.65; 95% CI: 1.39-5.05, p<0.01), atherogenic dyslipidemia (OR: 3.27; 95% CI: 1.50-7.15, p<0.01), and treatment with high-intensity statins (OR: 3.51; 95% CI: 1.89-6.51, p<0.01) were independently associated with increased risk of T2D in statin-treated patients. Among the IFG subjects, atherogenic dyslipidemia (OR: 3.44; 95% CI: 1.31-9.04, p=0.01) and overweight/obesity (OR: 2.54; 95% CI: 1.14-5.66, p<0.05) independently increased the risk of T2D. Among the overweight/obese ones, atherogenic dyslipidemia independently increased the risk of T2D (adjusted OR: 5.60; 95% CI: 2.19-14.30, p<0.01). CONCLUSION: Atherogenic dyslipidemia appears to be an independent risk factor for new-onset T2D in statin-treated patients, while IFG, overweight/obesity and family history of diabetes remain risk factors for new-onset T2D in this group.

Effects of Evolocumab on the ApoA1 Remnant Ratio: A Pooled Analysis of Phase 3 Studies.

INTRODUCTION: The apolipoprotein A1 (apoA1) remnant ratio has been identified as an independent cardiovascular (CV) risk factor. Higher apoA1 remnant ratios may predict lower CV risk in some patients. This analysis aimed to evaluate the effects of evolocumab on the change from baseline in the apoA1 remnant ratio compared with placebo. METHODS: This pooled post hoc analysis included 2464 patients with mixed dyslipidemia treated with evolocumab 140 mg every 2 weeks (Q2W) or 420 mg once monthly (QM) in three phase 3 evolocumab trials. The apoA1 remnant ratio was calculated by dividing apoA1 by the difference between non-high-density lipoprotein cholesterol (non-HDL-C) and low-density lipoprotein cholesterol (LDL-C). ApoA1 remnant ratio strata were generated using previously published tertile (< 4.7, 4.7-6.8, and > 6.8) and partitioning categories (< 3.6, 3.6-6.0, and > 6.0). RESULTS: The baseline apoA1 remnant ratio in evolocumab and placebo treatment arms was 7.1 and 7.3, respectively. At week 12, evolocumab 140 mg Q2W and 420 mg QM increased the apoA1 remnant ratio by 25.0% and 33.6%, respectively, versus placebo (p < 0.0001 for both groups). When patients were categorized by week 12 apoA1 remnant ratio thresholds (< 3.6 vs. > 3.6, and < 4.7 vs. > 4.7), those with higher week 12 apoA1 remnant ratios were significantly more likely to have also achieved a target non-HDL-C level of < 100 mg/dl. In the subset of women > 50 years of age, the proportion of patients at apoA1 remnant ratio thresholds < 3.6, 3.6-6.0, and > 6.0 at baseline shifted toward or remained at higher thresholds at week 12. CONCLUSIONS: This post hoc analysis suggests that evolocumab increases the apoA1 remnant ratio. FUNDING: Amgen Inc. Plain language summary available for this article.

Efficacy and Safety of Policosanol Plus Fenofibrate Combination Therapy in Elderly Patients with Mixed Dyslipidemia: A Randomized, Controlled Clinical Study.

BACKGROUND: Policosanol is a mixture of long-chain alcohols isolated from sugar cane. This controlled, randomized clinical trial was designed to compare the efficacy and safety of fenofibrate, policosanol and a combination of these 2 in lowering low-density-lipoprotein cholesterol (LDL-C) in elderly patients with mixed dyslipidemia. METHODS: A total of 102 patients aged ≥60years were randomly assigned into 3 groups: patients receiving a 24-week therapy of fenofibrate (200 mg/day), policosanol (20 mg/day) or fenofibrate + policosanol combination. Lipids were evaluated at baseline, after 16 and after 24 weeks of therapy. Brachial-ankle pulse wave velocity (ba-PWV) was performed, and SF-36 questionnaires were used to evaluate the patients' quality of life. The primary endpoint was the percentage reduction in LDL-C. The secondary end points included percentage change in nonhigh density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), triglyceride, high-density-lipoprotein cholesterol (HDL-C), ba-PWV and SF-36 scores. Safety was assessed by adverse events and laboratory parameters. RESULTS: LDL-C, non-HDL-C and TC were decreased, respectively after treatment with policosanol for 24 weeks (P < 0.01). Treatment with policosanol + fenofibrate resulted in significantly greater reductions in TC, non-HDL-C and LDL-C compared to fenofibrate alone (P < 0.01, respectively). There were significant increases in SF-36 scores in the policosanol and policosanol + fenofibrate groups (P < 0.05), and significant improvements of ba-PWV in the 2 groups (P < 0.01). There were no serious adverse events or significant changes in laboratory variables after any of the treatment regimens. CONCLUSIONS: Policosanol + fenofibrate combination therapy significantly improved lipid parameters, arterial stiffness, and quality of life, with good tolerability.

Comparison of Efficacy and Safety of Fixed Dose Combination of Rosuvastatin and Choline Fenofibrate to Fixed Dose Combination of Rosuvastatin and Fenofibrate in Patients of Mixed Dyslipidemia: A Randomized, Open-label, Multicentre Clinical Trial in Indian Population.

INTRODUCTION: This study was conducted to evaluate the safety and efficacy of fixed-dose combination (FDC) of rosuvastatin and choline fenofibrate in comparison to rosuvastatin and fenofibrate FDC among Indian patients of mixed dyslipidemia. This would be a first study evaluating FDC of rosuvastatin and choline fenofibrate in Indian population. METHODS: A multicenter, open-label, randomized, active controlled, comparative, parallel-design study was conducted at 12 centers spread all across India. Mixed dyslipidemic patients aged 18-70 years were randomized to FDC of rosuvastatin 10 mg and choline fenofibrate 135 mg (RCF group) and FDC of rosuvastatin 10 mg and fenofibrate 160 mg (RF group) once daily for approximately 180 days. The primary endpoint of study was percentage change in serum triglyceride level at the end of study from baseline. RESULTS: Of 290 patients screened, 240 patients were enrolled in this study (120 patients in each group). At the end of 180 days, there was a significant reduction in triglyceride level in both the groups (-37.7% in RCF group and -37.8% reduction in RF group; P < 0.0001 for both); however, the difference between both the groups was not statistically significant (P = 0.94). Similarly, there was significant increase (P < 0.0001 for both) in high-density lipoprotein cholesterol (HDL-C) in both groups (+17.8% in RCF group and +14.9% in rosuvastatin fenofibrate RF group). Low-density lipoprotein cholesterol (LDL-C), very low-LDL (VLDL-C), and total cholesterol were also reduced significantly in both groups (P < 0.0001). However, the difference between two groups for increase in HDL-C and decrease in LDL-C, VLDL-C, and total cholesterol was not significant. Both the treatments were safe and well tolerated. CONCLUSION: Overall, FDC of rosuvastatin and choline fenofibrate is as safe and effective as rosuvastatin and fenofibrate combination in Indian patients with mixed dyslipidemia with added advantage improved patient compliance as it can be taken irrespective of intake of food.

Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis.

BACKGROUND: Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. OBJECTIVE: To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. METHODS: Obese, nondiabetic, hypertriglyceridemic males (n = 19) with low high-density lipoprotein-cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. RESULTS: Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein-cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein-cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein CIII to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. CONCLUSION: A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation.

Duality of statin action on lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome: Quantity vs quality over time and implication of CETP.

BACKGROUND: Statins impact the metabolism, concentrations, composition, and function of circulating lipoproteins. OBJECTIVE: We evaluated time course relationships between statin-mediated reduction in atherogenic apolipoprotein B (ApoB)-containing particles and dynamic intravascular remodeling of ApoAI-containing lipoprotein subpopulations in the mixed dyslipidemia of metabolic syndrome. METHODS: Insulin-resistant, hypertriglyceridemic, hypercholesterolemic, obese males (n = 12) were treated with pitavastatin (4 mg/d) and response evaluated at 6, 42, and 180 days. RESULTS: Reduction in low-density lipoprotein (LDL) cholesterol, ApoB, and triglycerides (TGs) was essentially complete at 42 days (-38%, -32%, and -35%, respectively); rapid reduction equally occurred in remnant cholesterol, ApoCII, CIII, and E levels (day 6; -35%, -50%, -23%, and -26%, respectively). Small dense LDLs (LDL4 and LDL5 subpopulations) predominated at baseline and were markedly reduced on treatment (-29% vs total LDL mass). Cholesteryl ester (CE) transfer protein activity and mass decreased progressively (-18% and -16%, respectively); concomitantly, TG depletion (up to -49%) and CE enrichment occurred in all high-density lipoprotein (HDL) particle subpopulations with normalization of CE/TG mass ratio at 180 days. ApoAI was redistributed from LpAI to LpAI:AII particles in HDL2a and HDL3a subpopulations; ApoCIII was preferentially depleted from LpAI:AII-rich particles on treatment. CONCLUSION: Overall, statin action exhibits duality in mixed dyslipidemia, as CE transfer protein-mediated normalization of the HDL CE/TG core lags markedly behind subacute reduction in elevated levels of atherogenic ApoB-containing lipoproteins. Normalization of the HDL neutral lipid core is consistent with enhanced atheroprotective function. The HDL CE/TG ratio constitutes a metabolomic marker of perturbed HDL metabolism in insulin-resistant states, equally allowing monitoring of statin impact on HDL metabolism, structure, and function.