VLDL Clearance Research Articles

Liver-targeted Angptl4 silencing by antisense oligonucleotide treatment attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice.

Angiopoietin-like 3 (ANGPTL3) and 4 (ANGPTL4) inhibit lipoprotein lipase to regulate tissue fatty acid uptake from triglyceride-rich lipoproteins such as VLDL. While pharmacological inhibition of ANGPTL3 is being evaluated as lipid-lowering strategy, systemic ANGPTL4 inhibition is not pursued due to adverse effects. This study aimed to compare the therapeutic potential of liver-specific Angptl3 and Angptl4 silencing to attenuate hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, a well-established humanized model for lipoprotein metabolism. Mice were subcutaneously injected twice-weekly with saline or liver-targeted antisense oligonucleotides against Angptl3, Angptl4, both, or a scrambled oligonucleotide. Plasma lipid levels, VLDL clearance and hepatic VLDL production were determined, and atherosclerosis development was assessed. For toxicological evaluation, cynomolgus monkeys were treated with three dosages of liver-targeted ANGPTL4-silencing oligonucleotides.Liver-targeted Angptl4 silencing reduced plasma triglycerides (-48%) and total cholesterol (-56%), explained by higher VLDL-derived fatty acid uptake by brown adipose tissue and lower VLDL production by the liver. Accordingly, Angptl4 silencing reduced atherosclerotic lesion size (-86%) and improved lesion stability. Hepatic Angptl3 silencing similarly attenuated hyperlipidemia and atherosclerosis development. While Angptl3 and Angptl4 silencing lowered plasma triglycerides in the refed and fasted state, respectively, combined Angptl3/4 silencing lowered plasma triglycerides independent of nutritional state. In cynomolgus monkeys, anti-ANGPTL4 ASO treatment was well tolerated without adverse effects. Liver-targeted Angptl4 silencing potently attenuates hyperlipidemia and atherosclerosis development in APOE*3-Leiden.CETP mice, and liver-targeted ANGPTL4 silencing is well-tolerated in non-human primates. These data warrant further clinical development of liver-targeted ANGPTL4 silencing.

Obicetrapib alone and in combination with ezetimibe reduces non-HDL-cholesterol by enhanced LDL-receptor-mediated VLDL clearance and increased net fecal sterol excretion in apoe*3-leiden.cetp mice

Obicetrapib alone and in combination with ezetimibe reduces non-HDL-cholesterol by enhanced LDL-receptor-mediated VLDL clearance and increased net fecal sterol excretion in apoe*3-leiden.cetp mice

Obicetrapib Alone and with Ezetimibe Reduces Non-HDL-C by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion

Obicetrapib Alone and with Ezetimibe Reduces Non-HDL-C by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion

A Systematic Review on the Impact of Cholesterol Levels on Diabetes Mellitus

Diabetes mellitus (DM) is a common metabolic disorder characterized by defects in insulin secretion and action, or both, resulting in chronic hyperglycemia and altered metabolism of carbohydrates, fats, and proteins. In the absence of the major risk factors, diabetes is associated with increased morbidity and mortality from cardiovascular disease. The prevalence of diabetes is 10.1 crores, as per the Indian Council of Medical Research – India Diabetes (ICMR INDIAB) study published in 2023. Serum lipid abnormalities (dyslipidemia) are commonly seen in diabetic populations, irrespective of insulin deficiency or insulin resistance. When insulin activity is very low, it severely inhibits lipoprotein lipase production, which significantly impairs the digestion of triglyceride-rich lipoproteins. As a result, there is an increase in triglyceride-rich lipoproteins and a delay in the clearance of chylomicrons and VLDL. Additionally, insulinopenia leads to a substantial increase in lipolysis in adipose tissue, causing the release of free fatty acids into the bloodstream. This higher supply of fatty acids to the liver improves triglyceride synthesis in the liver, ultimately resulting in increased production and secretion of VLDL. By lowering serum cholesterol with statins, which inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, decreases the risk of CHD.

Correlation between Very Low-Density Lipoprotein and Trygliseride with Glycated Hemoglobin Levels in Type 2 Diabetes Mellitus Patients

Patients with Type 2 Diabetes Mellitus (T2DM) have an increased prevalence of dyslipidemia, which contributes to ahigher risk of dyslipidemia- related complications in T2DM such as cardiovascular disease and stroke. This study aimed todetermine the correlation between TG and VLDL-C towards HbA1c levels in a person with T2DM. A retrospective study of 74outpatients with T2DM at Sanglah General Hospital, Denpasar, who examined serum HbA1c and lipid profiles were tracedfor serum TG. From the obtained TG profile, a secondary calculation of VLDL was carried out using the Friedewald equation(TG/5). A correlation test was used to determine the relationship between TG and VLDL-C towards HbA1c levels. Serum TG(212.95±147.46 mg/dL) and VLDL (36.69±23.54 mg/dL) were found to be higher in the group with poor glycemic control(HbA1c > 7 mg/dL) compared to serum TG (111.00±39.56 mg/dL) and VLDL (21.05±6.13 mg/dL) in the group with goodglycemic control (HbA1c ≤ 7 mg/dL) (p < 0.05). A positive correlation between serum TG (r=0.512; p < 0.001) and VLDL(r=0.18; p <0.001) towards HbA1c levels in T2DM patient was found. Insulin resistance increases the production of VLDL andApoC-III in the liver and increased chylomicron absorption in the gastrointestinal tract, causing prolonged postprandiallipemia and disruption of VLDL and TG clearance, thereby resulting in increased TG and VLDL in circulation. There is asignificant positive correlation between serum TG and VLDL towards HbA1c levels in a patient with T2DM.

TMT-Based Plasma Proteomics Reveals Dyslipidemia Among Lowlanders During Prolonged Stay at High Altitudes.

Acute exposure to high altitude perturbs physiological parameters and induces an array of molecular changes in healthy lowlanders. However, activation of compensatory mechanisms and biological processes facilitates high altitude acclimatization. A large number of lowlanders stay at high altitude regions from weeks to months for work and professional commitments, and thus are vulnerable to altitude-associated disorders. Despite this, there is a scarcity of information for molecular changes associated with long-term stay at high altitudes. In the present study, we evaluated oxygen saturation (SpO2), heart rate (HR), and systolic and diastolic blood pressure (SBP and DBP) of lowlanders after short- (7 days, HA-D7) and long-term (3 months, HA-D150) stay at high altitudes, and used TMT-based proteomics studies to decipher plasma proteome alterations. We observed improvements in SpO2 levels after prolonged stay, while HR, SBP, and DBP remained elevated as compared with short-term stay. Plasma proteomics studies revealed higher levels of apolipoproteins APOB, APOCI, APOCIII, APOE, and APOL, and carbonic anhydrases (CA1 and CA2) during hypoxia exposure. Biological network analysis also identified profound alterations in lipoprotein-associated pathways like plasma lipoprotein assembly, VLDL clearance, chylomicron assembly, chylomicron remodeling, plasma lipoprotein clearance, and chylomicron clearance. In corroboration, lipid profiling revealed higher levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL) for HA-D150 whereas high density lipoproteins (HDL) levels were lower as compared with HA-D7 and sea-level indicating dyslipidemia. We also observed higher levels of proinflammatory cytokines IL-6, TNFα, and CRP for HA-D150 along with oxidized LDL (oxLDL), suggesting vascular inflammation and proartherogenic propensity. These results demonstrate that long-term stay at high altitudes exacerbates dyslipidemia and associated disorders.

Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3’s novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

Effect of Vitamin D3 on the Postprandial Lipid Profile in Obese Patients: A Non-Targeted Lipidomics Study.

Postprandial lipemia can lead to an accumulation of atherogenic lipoproteins in the circulation associated with systemic low-grade inflammation and an increased risk of cardiovascular disease. Lifestyle and pharmacological treatments are usually prescribed for prevention. Vitamin D3 (cholecalciferol), as an anti-atherogenic agent, is being taken into consideration due to its potential beneficial effects in lipid metabolism and its anti-inflammatory potency. To assess the effects of vitamin D3 in the postprandial lipid profile in obese, vitamin D-deficient women, a non-targeted lipidomics approach using liquid chromatography coupled to a quadrupole time-of flight mass spectrometer was used to identify and quantitate a wide-range of circulating lipid species, including diglycerides, lysophosphatidylcholines, phosphatidylcholines, phosphatidylethanolamines, sphingomyelins and triglycerides. The most important changes were found in plasmatic sphingomyelin levels, which experience a decrease after vitamin D3 intake. Our results suggest a turnover of sphingomyelins, probably due to an increased activity of neutral sphingomyelinases, and, therefore, with implications in the clearance of chylomicrons, LDL and VLDL, decreasing postprandial inflammation and macrophage adherence to endothelia, potentially improving cardiovascular disease risk.

Chronic fructose intake does not induce liver steatosis and inflammation in female Sprague-Dawley rats, but causes hypertriglyceridemia related to decreased VLDL receptor expression.

Sugar-sweetened beverage intake is a risk factor for insulin resistance, dyslipidemia, fatty liver, and steatohepatitis (NASH). Sub-chronic supplementation of liquid fructose, but not glucose, in female rats increases liver and plasma triglycerides without inflammation. We hypothesized that chronic supplementation of fructose would cause NASH and liver insulin resistance. We supplemented female Sprague-Dawley rats with water or either fructose or glucose 10% w/v solutions under isocaloric conditions for 7months. At the end, plasma analytes, insulin, and adiponectin were determined, as well as liver triglyceride content and the expression of key genes controlling inflammation, fatty acid synthesis and oxidation, endoplasmic reticulum stress, and plasma VLDL clearance, by biochemical and histological methods. Although sugar-supplemented rats increased their energy intake by 50-60%, we found no manifestation of liver steatosis, fibrosis or necrosis, unchanged plasma or tissue markers of inflammation or fibrosis, and reduced liver expression of gluconeogenic enzymes, despite both sugars increased fatty acid synthesis, mTORC1, and IRE1 activity, while decreasing fatty acid oxidation and PPARα activity. Only fructose-supplemented rats were hypertriglyceridemic, showing a reduced expression of VLDL receptor and lipoprotein lipase in skeletal muscle and vWAT. Glucose-supplemented rats showed increased adiponectinemia, which would explain the different metabolic outcomes of the two sugars. Chronic liquid simple sugar supplementation, as the sole risk factor, is not enough for female rats to develop NASH and increased liver gluconeogenesis. Nevertheless, under isocaloric conditions, only fructose induced hypertriglyceridemia, thus confirming that also the type of nutrient matters in the development of metabolic diseases.

Abstract 579: In vitro Models Concur With Clinical Results to Confirm Pleiotropic Mechanisms of Action for Gemcabene

Introduction: Gemcabene, a fraudulent fatty acid, induces biological properties in nonclinical models, of which many translate to clinical findings in dyslipidemia patients. Its known mechanism of action includes reduction of the overall hepatic de novo triglyceride and cholesterol synthesis, and increase in VLDL clearance. Clinical benefits in various human populations infer that other mechanisms are involved that warrant evaluation. Methods and Results: We assessed the gemcabene effects in other molecular mechanistic models, particularly to study inhibition of human ATP Citrate Lyase (hACL), apolipoprotein gene expression in Sandwich-Cultured Transporter Certified TM Human Hepatocytes (SCHH), and expression of genes related to inflammation and cell signaling. Gemcabene, MEDICA-16, palmitic acid and their CoA thioesters were studied in a recombinant hACL in vitro assay system. Gemcabene-CoA thioester, but not the parent compound, inhibited recombinant hACL activity in vitro in a dose-dependent manner, in agreement with results obtained with palmitoyl-CoA and palmitic acid. Unlike palmitic acid, MEDICA-16, and bempedoic acid, gemcabene does not form a CoA ester in human hepatocytes: radioisotope studies show 98.8% parent gemcabene. Further, gemcabene potential on the gene expression of lipogenesis and inflammation markers was assessed in SCHH. Gemcabene showed significant regulation of HMG-CoA synthase 2 (HMGCS2) and CRP mRNAs. A marked induction response of the HMGCS2 mRNA content was observed, ranging from 2.26- to 2.73-fold (p ≤ 0.05) over control in SCHH treated with all concentrations of gemcabene (500, 1000, and 1500 μM). Also, a clear and statistically significant (p-value ≤ 0.05) concentration-related suppression response of CRP mRNA content was observed, ranging from (-2.58)- to (-2.65)-fold below control in SCHH treated with 1000 and 1500 μM gemcabene. Finally, RT-PCR analysis of liver samples from STAM TM mice treated with gemcabene revealed its downregulating effect on inflammatory, lipogenic, lipoprotein metabolism, and cell signaling genes: TNF-α, MCP-1, NF-κB, ApoC-III, and ACC1. Conclusion: Gemcabene manifests its pharmacological profile in lipid management and inflammation by multiple mechanisms of action.

Role of Estrogens in the Regulation of Liver Lipid Metabolism.

Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride, and cholesterol metabolism to influence cardiovascular risk.The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increases VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides.Many aspects of sex differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in the muscle, adipose, and liver. In humans, 17β-estradiol (E2) is the predominant circulating estrogen and signals through estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and G-protein-coupled estrogen receptor (GPER). Over 1000 human liver genes display a sex bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues or specific aspects of the signaling pathways in order to recapitulate the protective physiology of premenopause therapeutically after menopause.

Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor.

Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4rmut mice) and the LDL receptor (Ldlr-/- mice). Mc4rmut mice develop obesity due to hyperphagia. Double-mutant mice (Mc4rmut;Ldlr-/-) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4rmut mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4rmut;Ldlr-/-. Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis.

Effect of losartan and spironolactone on triglyceride-rich lipoproteins in diabetic nephropathy

Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can improve dyslipidemia in patients with diabetes and albuminuria. Whether combined ACEi+ARB or ACEi+mineralocorticoid receptor blockade improves dyslipidemia is not known....

Abstract 17: APOC3 A43T Variant Promotes ApoC-III Catabolism and Accelerates TG-rich Lipoprotein Clearance in Mice and Humans

Humans with loss-of-function (LoF) variants in APOC3 , the gene encoding apolipoprotein C-III (apoC-III), have significantly reduced plasma triglycerides (TG) and protection from coronary disease. These findings suggest that apoC-III may be a viable therapeutic target for decreasing vascular risk through TG reduction, and that elucidation of the protective mechanism of APOC3 LoF variants would inform such strategies. We report here the protective mechanism of the APOC3 A43T missense variant, one of four recently identified CAD-protective variants. By genotyping >8,000 human participants with low TG, we identified 17 APOC3 A43T carriers and phenotyped 6 carriers and 54 matched controls. A43T heterozygotes demonstrate a significant reduction in apoC-III levels relative to non-carriers (50% reduction, P<0.05), resulting in decreased plasma TG (50% reduction, P<0.05). We generated viral vectors expressing WT or A43T apoC-III and expressed these in humanized mouse models to further explore the mechanism of reduced apoC-III levels due to the A43T variant. Mice expressing human CETP and the apoC-III A43T variant exhibit reduced plasma apoC-III (50% reduction, P<0.0001) despite equal hepatic expression and secretion relative to controls expressing WT human apoC-III. These mice also exhibit reduced plasma TG and VLDL-C, and increased HDL-C relative to WT-expressing mice, fully recapitulating the protective lipoprotein profile of the human A43T carriers. Radioisotope-labeled apoC-III turnover studies showed that the A43T mutation causes a >3-fold higher apoC-III clearance rate in vivo (P<0.0001) due to defective integration into lipoprotein particles and accelerated renal catabolism (40% increase, P<0.01). This results in increased lipoprotein lipase (LPL) activity (27% increase, P<0.01) and faster chylomicron-TG clearance (97% increase, P<0.01) in vivo . We are currently performing analogous studies of WT vs. A43T apoC-III turnover and VLDL clearance in human APOC3 A43T carriers. Collectively, our results support the rationale for therapeutic efforts to target circulating apoC-III through disruption of its binding to lipoproteins, mirroring the genetics-driven approaches for targeting PCSK9 that have recently yielded novel therapies.

Visceral leishmaniasis, hypertriglyceridemia and secondary hemophagocytic lymphohistiocytosis

cytokines, an upregulation of adhesion molecules and MHC I and II molecules on mono/macrophages, and an expansion of inflammatory monocytes. This exaggerated inflammatory response is responsible for necrosis and organ failure and results in uncontrolled proliferation and phagocytic activity of histiocytes [2]. Hypertriglyceridemia (fasting, greater than or equal to 265 mg/100 ml) is one of the current diagnostic criteria for HLH [2]. Several studies link hypertriglyceridemia to inhibition of lipoprotein lipase (LPL) by tumor necrosis factor-α (TNF-α), and TNF-α is a powerful autocrine and paracrine regulator of adipose tissue [3]. Indeed, many different sources of intense and prolonged T-lymphocyte/macrophage activation may be associated with dyslipidemia (particularly with hypertriglyceridemia) through inappropriate release of TNF-a, IFN-g, GM-CSF and respectively, of IL-1/IL-6, leading to adipose tissue lipolysis with increased VLDL secretion, decreased VLDL clearance, increased hepatic fatty acid synthesis, and suppression of fatty acid oxidation with HIV infection being the wellknown paradigm of this mechanism (possibly enhanced by some antiretroviral drugs). In PubMed there are at least 70 papers in which the association leishmaniasis/(hemophagocytic or haemophagocytic) is present. Leishmania parasites have been found to be the most common protozoan trigger of acquired HLH. In a multicenter prospective study conducted to determine the frequency of HLH syndrome in children with VL, ten children out of 24 (41 %) with VL developed HLH syndrome [4]. HLH incidence in European adult population is about 1/800,000/year, with a reported prevalence of parasitic infections of 2.4 % (53 out of 2197 subjects), and of Leishmania spp. of 0.77 % (17 out of 2197) as a trigger. The clinical picture of VL with HLH initially can be indistinguishable from HLH of other etiology, potentially Dear Sir,

Abstract 17824: Gemcabene and Atorvastatin Alone and Combined Markedly Reduce LDL-C in LDL Receptor-deficient Mice, a Model of Homozygous Familial Hypercholesterolemia

Background: Gemcabene (Gem) is a late-stage Phase 2 clinical candidate being evaluated for the reduction of low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemia (HoFH) patients. Combination therapy includes statins as standard of care to treat this genetic disorder. LDL-deficient (LDLr) mice have been widely used with lipid-lowering agents to demonstrate LDL-C lowering with good translation to clinical efficacy. We have previously shown that atorvastatin (Atorva) reduces LDL-C and apoB in the LDLr deficient mice and in casein-fed (endogenous hypercholesterolemic) rabbits. Experiment and Results: In the current study, we assessed Gem and Atorva effects alone and in combination on reduction of LDL-C in chow-fed LDLr deficient mice, an animal model of HoFH. Baseline LDL-C and total cholesterol were 246±20 mg/dL and 329±23 mg/dL in these mice Female LDLr deficient mice (n=10) were treated with Atorva alone (60mg/kg/day), Gem alone (60/mg/kg/day) or the agents combined (Atorva + Gem)(each at 60 mg/kg/day) for 14 days. Following treatments with Atorva, Gem, and Atorva+Gem, fasting LDL-C reduced by 22%, 55% and 72%, respectively, and total cholesterol by 21%, 47%, and 58%, respectively; showing additional reduction of 50% LDL-C by Gem on top of Atorva alone. Since LDLr are absent in these mice, similar to HoFH patients, the LDL-C lowering by Gem could be due to reduced VLDL production rates. Indeed, our studies in rat hepatocytes and in apoB100-only mice (apobec-1 knockout) showed reduced radioactivity in cholesterol and triglyceride fractions in the hepatocytes and in the plasma and liver of mice administered 14C acetate, suggesting cholesterol and fatty acid synthesis inhibition as a mechanism of LDL-C lowering. Gem also enhances the clearance of VLDL in normal rats. We propose both mechanisms may contribute to LDL-C reduction in LDLr deficient mice. A more detailed kinetic study of Gem in LDLr deficient models is underway to verify these proposed mechanisms. Conclusions: Gemcabene alone and combined with atorvastatin significantly (55-72%) reduced LDL-C in this predictive in-vivo HoFH disease model. These findings suggest that treatment with Gem on top of standard of care therapy by statins may benefit HoFH patients.

Abstract 13654: Gemcabene Monotherapy and in Combination With Atorvastatin Lowers High Sensitivity C-Reactive Protein (hsCRP) in a Phase 2 Clinical Trial

Background: It is well established that inflammation plays a key role the progression of atherosclerosis and that serum high sensitivity c-reactive protein (hsCRP), may be a good marker of the degree of underlying vascular inflammation. Thus hsCRP has been recognized as a predictor of cardiovascular risk and lipid lowering drugs, such as statins, which also result in a reduction of hsCRP may be more likely to reduce cardiovascular events. Gemcabene is an inhibitor of hepatic cholesterol, triglyceride, and apoC-III synthesis resulting in decreased assembly of VLDL and enhances the systemic clearance of VLDL and its subsequently production of remodeled lipoproteins including LDL. Study Design and Results: In an 8-week double blind randomized, placebo-controlled, dose-ranging, efficacy and safety Phase 2 study, gemcabene 300, 600 and 900 mg/day administered as monotherapy or in combination with atorvastatin 10, 20 and 80 mg/day resulted in a significant and dose dependent reduction of LDL-C (Study 4141001). A secondary objective of this study was to evaluate the modulation of hsCRP by gemcabene. Of 277 patients randomized, 250 (90%) completed the study. Baseline mean LDL-C was 174.7mg/dL, and median hsCRP = 2.5 mg/L. The median % reduction in hsCRP with Gemcabene 300, 600 and 900 mg monotherapy was 25.8%, 41.5% and 35.3% respectively compared with 9.4% for placebo. The rank-transformed data showed significant difference favoring gemcabene over placebo in the 600 and 900 mg groups (p=0.0070 and p =0.0018, respectively). Co-administration of 300, 600, and 900 mg gemcabene with atorvastatin aggregated over the dose range showed decreases in hsCRP beyond atorvastatin monotherapy (which ranged from 27-41%) by an additional 16% (p=0.0237), 23% (p=0.0017) and 28% (p=0.0001), respectively. Conclusions: Gemcabene significantly lowered hsCRP alone and on top of statins in hypercholesterolemic patients.

Abstract P210: Lipoprotein Profiles in Patients With and Without Psoriasis

Introduction: Psoriasis is associated with chronically heightened systemic inflammatory tone and increased risk for cardiovascular disease. It remains to be established if the psoriatic state itself associates with dyslipidemia. Hypothesis: The lipid profile of patients with psoriasis is more atherogenic compared to disease-free control patients. Methods: The concentration and size of lipoprotein particles were measured using nuclear magnetic resonance spectroscopy in 221 patients with a diagnosis of psoriasis (53.6% men; mean age=56.6 years; mild cases=31%; moderate/severe only skin=27%; arthritis=27%)) and 689 disease-free persons matched by sex and age. We compared means of lipoprotein particle concentration and size using a univariate general linear model and adjusting for body-mass index, waist circumference, diabetes, use of lipid lowering-drugs, as well as duration/severity of psoriasis. Results: Patients with psoriasis were more overweight, had larger waist circumference, and a higher frequency of diabetes and use of lipid-lowering drugs. Total LDL particle means (nmol/L) for the psoriasis and control groups were 1436 (1378-1494) vs. 1420 (1388-1452) (P=0.4), respectively. The mean concentration of IDL was higher in patients with psoriasis compared to controls: 143.6 (130.7-156.5) vs. 106.1 (99.1-113.2), P<0.01. Large and small LDL particle concentrations were similar between groups. Large VLDL/chylomicron particle concentrations (nmol/L) were higher in psoriasis patients compared to controls 6.1 (5.2-7.0) vs. 4.0 (3.6-4.5) (P<0.01). Total HDL particle and subfractions were not statistically different between groups. The mean size (nm) of VLDL was higher in psoriasis patients: 50.2 (49.2-51.2) vs. 46.2 (45.6-46.7) (P<0.001) for psoriasis and controls, respectively. In contrast, mean sizes of LDL and HDL particles were similar (P=0.3). Adjustment for covariates above mentioned did not change these findings. The absence/presence of arthritis did not change the results. Conclusion: Patients with psoriasis have a more atherogenic lipid profile compared to controls with higher levels of IDL and VLDL of large and small size. In addition, the greater mean size of VLDL particles in psoriasis compared to controls suggests enhanced secretion of triglyceride loaded VLDL, impaired lipolysis and impaired clearance of remnant IDL.

Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-Cholesterol

ObjectiveNiacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for familial dysbetalipoproteinemia (FD).Approach and ResultsMice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by -39% and triglycerides by −50%, (both P<0.001). Simvastatin and the combination reduced total cholesterol (−30%; −55%, P<0.001) where the combination revealed a greater reduction compared to simvastatin (−36%, P<0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P<0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to the endothelium (−46%; −47%, P<0.01; −53%, P<0.001), atherosclerotic lesion area (−78%; −49%, P<0.01; −87%, P<0.001) and severity. Compared to simvastatin, the combination increased plaque stability index [(SMC+collagen)/macrophages] (3-fold, P<0.01). Niacin and the combination reduced T cells in the aortic root (−71%, P<0.01; −81%, P<0.001). Lesion area was strongly predicted by nonHDL-cholesterol (R2 = 0.69, P<0.001) and to a much lesser extent by HDL-cholesterol (R2 = 0.20, P<0.001).ConclusionNiacin decreases atherosclerosis development mainly by reducing nonHDL-cholesterol with modest HDL-cholesterol-raising and additional anti-inflammatory effects. The additive effect of niacin on top of simvastatin is mostly dependent on its nonHDL-cholesterol-lowering capacities. These data suggest that clinical beneficial effects of niacin are largely dependent on its ability to lower LDL-cholesterol on top of concomitant lipid-lowering therapy.

Abstract 361: Characterization of Lipoproteins in the Hypertriglyceridemic Fredrickson-Levy Dyslipidemic Phenotypes with Chylomicrons: The Very Large Database of Lipids (VLDL-7)

Background The major dyslipidemia (DL) classes (I-V) are relatively rare with limited phenotypic characterization across large populations. Methods We studied 1,340,614 U.S. adults from the Very Large Database of Lipids and identified those with chylomicron (CM) excess (types I and V). Lipid testing was by ultracentrifugation (VAP, Atherotech, Birmingham, AL). The distributions of total cholesterol (TC), HDL-C, LDL-C and triglycerides (TG) in the database were superimposable with those in the NHANES 2007-2008 survey. We used the following criteria to classify the excess lipoprotein components of DL in subjects with TG &gt;130 mg/dL: CM defined by TG/Total cholesterol (TC) ratio &gt; 9 only (Type I) and CM with &gt;90th percentile VLDL-C (Type V). Subjects with types II, III, or IV DL were excluded. Results Type I DL was characterized by very high TG and very low HDL-C, LDLr-C, non-HDL-C and normal VLDL-C and RLP-C. Type V was characterized by TG approximately twice that of type I, low HDL-C and LDLr-C, and elevated VLDL-C, RLP-C and non-HDL-C. The VLDL3-C/IDL-C ratio was approximately 2, twice that of the non-CM groups (Table). Summary To our knowledge, this is the largest single report of subjects with these rare hyper-CM phenotypes. The findings support the mechanism of reduced CM clearance and impaired conversion of VLDL to IDL and LDL. The marked reduction in HDL-C is consistent with cholesterol ester transport protein mediated TG-Cholesterol ester exchange between CM and apoB100 lipoproteins.