Severe Dyslipidemia Research Articles

Abstract 298: Fibrate use in patients with type 2 diabetes

Diabetes mellitus is considered to be a coronary heart disease (CHD) equivalent, with heart disease and stroke accounting for the majority of diabetes-related deaths. As a result, patients with diabetes require aggressive treatment of CHD risk factors, including dyslipidemia. In addition to targeted reduction of LDL cholesterol, current guidelines recommend addition of a fibrate (gemfibrozil, fenofibrate, or clofibrate) in patients with established CHD and atherogenic dyslipidemia: triglycerides (TG) 200-499 mg/dL and HDL cholesterol (HDL-C) ≤40 mg/dL. Fibrates have also been recommended for patients with TG ≥500 mg/dL to reduce risk of acute pancreatitis. Yet, data supporting the use of fibrates in these settings remains variable and inconclusive. We therefore sought to provide an in-depth analysis of patterns of fibrate use among patients with type 2 diabetes between 2001 and 2010. Using Ingenix administrative claims, we identified 71,161 patients age ≥18 years old with an established diagnosis of type 2 diabetes (ICD-9 250.XX) and ≥3 years of continuous enrollment who were newly initiated on a fibrate between 2001 and 2010. Lab results were available for a subset of 18,863 (26.5%) patients, who were included in final analysis. During each 2-year period, between 77.6% - 84.1% of patients had a lipid test performed within the preceding 12 months (p=0.59 for change in testing over time). The prevalence of atherogenic dyslipidemia increased over time, from 20.8% (2001-2002) to 41.2% (2009-2010); 4.84% rise per 2-year period (p=0.002). The prevalence of severe atherogenic dyslipidemia (HDL-C ≤40 mg/dL and TG ≥500 mg/dL), also increased over time, from 9.3% in 2001-2002 to 13.6% in 2009-2010; 1.17% rise per 2-year period (p=0.002). In contrast, percent of patients with TG ≥500 mg/dL decreased over time, from 20.5% in 2001-2002 to 16.7% in 2009-2010; 1.19% decline per 2-year period (p=0.03). Initiation of new fibrate therapy in treatment naïve patients with diabetes remained constant; 2.0% in 2001-2002 and 1.6% in 2009-2010 (p=0.93). Subgroup analysis of patients with atherogenic dyslipidemia also showed no significant change in fibrate initiation over time; 11.4% in 2001-2002 and 15.7% in 2009-2010 (p=0.3). Similarly, while there was a trend toward increased initiation of fibrates among patients with TG ≥500 mg/dL, this trend was not statistically significant (27.4% in 2001-2002 and 41.6% in 2009-2010; 3.34% change per 2-year period (p=0.09)). In conclusion, the prevalence of atherogenic dyslipidemia among patients with type 2 diabetes has increased significantly over the past decade. However, fibrate use in all patients with type 2 diabetes, including those specifically with atherogenic dyslipidemia, has remained constant throughout the observation period, despite lack of conclusive evidence supporting its use.

ASSA13-16-3 Dyslipidemia in Chinese Elderly Patients with Acute Myocardial Infarction

Objective To investigate lipid levels in Chinese elderly patients with acute myocardial infarction (AMI), subsequently to grasp the characteristics of dyslipidemia and improve lipid control. Methods A retrospective analysis of 1213 patients hospitalised with AMI in our hospital from May 2007 to July 2011. Differences in lipid profiles [Total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglyceride (TG), non-high-density lipoprotein cholesterol (N-HDL) etc.] were analysed between the non-elderly and elderly AMI patients, in which a sub aged analysis was also performed. Results Compared with the non-elderly group, the levels of TC, LDL, TG, TC/HDL, LDL/HDL, TG/HDL, N-HDL, apolipoprotein B were lower in the elder, while in which HDL, lipoprotein (a), and apolipoprotein A were higher. Female AMI patients were with higher levels of TC, LDL, HDL, N-HDL, apolipoprotein A and apolipoprotein B than the male in 60 to 69 year-old group. In the 70 to 79-year-old patients with AMI, TC, TG, HDL, N- HDL and apolipoprotein A were higher in the female than those in the male. Higher levels of TC, N-HDL, and apolipoprotein A were also observed in the female in the 80-year-old group. Comparison of lipid levels in the elderly with the same sex in different age groups showed TC, LDL, TG and N-HDL in the 60–69-year-old age group were higher than those in the 70–79 and ≥ 80 year-old age groups, without difference in HDL among the three groups. The lipid levels in the same sex are comparable between 70 to 79-year-old group and ≥ 80-year-old group. The ratio of AMI patients with normal lipid was significantly higher in the elderly than the non-elderly (34.89% vs. 20.21%). Isolated low HDL accounted for the largest proportion of combined lipid abnormalities in patients with AMI. Conclusions Dyslipidemia in Chinese elderly patients with AMI was less serious than the non-elderly patients. In all age groups of elderly AMI, women had more severe dyslipidemia than men. Dyslipidemia was more serious in the younger old than that in the older old. Isolated low HDL was the most common combined lipid abnormality for both elderly and non-elderly patients with AMI.

Treatment of Severe Genetic Dyslipidemia: Where Are We Going?

Treatment of Severe Genetic Dyslipidemia: Where Are We Going?

Paradoxical Negative HDL Cholesterol Response to Atorvastatin and Simvastatin Treatment in Chinese Type 2 Diabetic Patients

There is extensive but controversial evidence on the diverse effects of statins on the level of high-density lipoprotein cholesterol (HDL-C). Some of these effects may limit the benefits of statins in terms of cardiovascular risk reduction. To identify the conditions for beneficial effects, this study investigated the response to atorvastatin and simvastatin treatment in type 2 diabetic patients with elevated low-density lipoprotein cholesterol (LDL-C). 2,872 subjects with type 2 diabetes from a disease management program were investigated. Patients with LDL-C ≥130 mg/dl or total cholesterol ≥200 mg/dl were put onto statin therapy by the National Health Insurance system in Taiwan. 1,080 patients who completed 1 year of statin treatment were analyzed. There were significant reductions in LDL-C in both the atorvastatin (37.1%) and simvastatin (34.3%) group after one year of treatment compared with baseline levels. Unexpectedly, the majority of diabetic patients who received atorvastatin or simvastatin did not show an increase in HDL-C levels. 59.8% of patients had a significant HDL-C reduction (ΔHDL-C ≤ -3%) after atorvastatin treatment. Multivariate logistic regression analysis showed that the following patients were at higher risk of HDL-C reduction after 12 months: (i) patients in whom statin therapy was initiated aged <65 years and who had a BMI ≥24 kg/m(2), (ii) male patients with a baseline HDL-C >40 mg/dl, and (iii) female patients with a baseline HDL-C >50 mg/dl. However, diabetic patients with severe atherogenic dyslipidemia (LDL-C ≥130, TG ≥204, and HDL-C ≤34 mg/dl) obtained more benefits in terms of HDL-C change after statin therapy. Diabetic patients, except those with severe atherogenic dyslipidemia, are prone to a decrease in serum HDL-C level after statin treatment, particularly after atorvastatin treatment.

Lipoprotein apheresis: State of the art and novelties

Lipoprotein apheresis (LA) is an extracorporeal technique which permits the unselective or specific removal of lipoproteins, namely Low Density Lipoproteins (LDL), as well as other apolipoprotein B100-containing lipoproteins from plasma. LA represents a selective upgrade (with both clinical and metabolic advantages) from conventional forms of extracorporeal therapy such as plasma-exchange (PEX) which was used in the seventies to treat severe hypercholesterolemia. The primary reason for using is the treatment of homo-, double- (or compound) and heterozygous familial hypercholesterolemia (Hoz-, DHtz,- Htz,-FH). This technique has also been shown to be efficacious in the treatment of other severe forms of hyperlipoproteinemia such as: hyperLp(a)lipoproteinemia, the familial combined hyperlipoproteinemia and other varieties associated with an elevated cardiovascular risk (CVR) when used in patients who are poor- or non-responders to pharmacological treatment following specific guidelines for the reduction of cholesterol in plasma. Patients with these severe forms of dyslipidemia and, particularly, those affected by FH are subject to coronary ischemic events and thus require an intensive, efficacious, continuous, and personalized form of therapy. A therapy based solely on current available drugs does not achieve the desired results in the Hoz- and DHtz forms of FH or in approximately 10–20% of the Htz form. For the aforementioned clinical conditions, LA treatment offers a necessary therapeutic approach. LA can also be applied in the prevention of secondary recurrence of coronary ischemic events and of arterial stenosis which appears, rather frequently after vascular surgery (coronary by-pass, percutaneous transluminal angioplasty). Clinical trials have shown that statins provide a major reduction in cardiovascular morbidity and mortality, but often fail to attain desirable LDL-cholesterol target level in Hoz- and DHtz- (Compound) FH high cardiovascular risk patients. Intolerance to statins is also relatively frequent in Htz-FH and non-FH patients. LA has effectively replaced pharmacological cholesterol-lowering therapy for decades. Young high CVR risk patients survived to adulthood thanks only to LA. More recently, promising novel compounds aimed at other molecular targets are being studied for the treatment of severe dyslipidemia: Lomitapide, Mipomersen, PCSK9 inhibitors and HDL-enhancers. It is expected that these potent new agents will be combined with LA in the treatment of the most severe forms of hyperlipidemia.

South African Dyslipidaemia Guideline Consensus Statement:

South Africa (SA) is home to a heterogeneous population with a wide range of cardiovascular risk factors. Cholesterol reduction in combination with aggressive management of modifiable risk factors, including nutrition, physical activity, blood pressure and smoking, can help to reduce and prevent morbidity and mortality in individuals who are at increased risk of cardiovascular events. This updated consensus guide to management of dyslipidaemia in SA is based on the updated European Society of Cardiology and European Atherosclerosis Society dyslipidaemia guidelines published in 2016. For individuals who are not considered to be at high or very high cardiovascular risk, the decision whether to treat and which interventional strategy to use is based on a cardiovascular risk score calculated using total cholesterol, high-density lipoprotein cholesterol (HDL-C), gender, age and smoking status. The cardiovascular risk score refers to the 10-year risk of any cardiovascular event and includes 4 categories of risk (low, moderate, high and very high). People with established cardiovascular disease, diabetes mellitus, chronic kidney disease and genetic or severe dyslipidaemias are considered to already be at high or very high risk and do not require risk scoring. Therapeutic lifestyle change is the mainstay of management for all patients. The need for and intensity of drug therapy is determined according to baseline low-density lipoprotein (LDL-C) levels and the target LDL-C concentration appropriate to the individual. LDL-C treatment targets are based on pre-treatment risk and are as follows: &lt;3 mmol/L in low- and moderate risk cases; &lt;2.5 mmol/L and a reduction of at least 50% if the baseline concentration is 2.5 - 5.2 mmol/L in high-risk cases; and &lt;1.8 mmol/L and a reduction of at least 50% if the baseline concentration is 1.8 - 3.5 mmol/L in very high-risk cases. A statin is usually recommended first-line; the specific agent is based on the required degree of cholesterol reduction, comorbidities and co-prescribed medication. Special attention should be paid to children with a family history of genetic or severe dyslipidaemia, who should be screened for dyslipidaemia from 8 years of age. In SA, HIV infection is not considered to be a significant cardiovascular risk factor and treatment recommendations for HIV-positive individuals are the same as for the general population, with careful choice of pharmacotherapy to avoid potential adverse drug-drug interactions. The benefit of statins in individuals older than 70 years is uncertain and clinical judgement should be used to guide treatment decisions and to avoid side-effects and overmedication in this group.

Klinische Befunde und rationelle Differenzialdiagnostik der diabetischen Dyslipidämie

Diabetes mellitus type 2 in particular facilitates the manifestation of dyslipidemia, which in turn has a strong impact on the risk of diabetic patients to suffer from macrovascular or microvascular complications and also acute pancreatitis. This article describes the characteristics of diabetic dyslipidemia and discusses the diagnostic and prognostic value of classical and novel laboratory tests for further stratification. Moreover, the clinical and biochemical presentation as well as primary and secondary causes of severe dyslipidemia are described.

Severe Dyslipidaemia after the Addition of Raltegravir to a Lopinavir/Ritonavir-Containing Regimen

We describe a 55-year-old HIV-1-infected male who developed severe dyslipidaemia (total cholesterol 600 mg/dl, triglycerides >5,000 mg/dl, high density lipoprotein <5 mg/dl) after raltegravir was added to his lopinavir/ritonavir-containing regimen. To our knowledge, this is the first reported case of severe dyslipidaemia associated with the addition of raltegravir to a lopinavir/ritonavir-based regimen, suggestive of a possible drug interaction. The lipid profile quickly normalized following discontinuation of lopinavir/ritonavir and continuation of raltegravir, suggesting that lopinavir/ritonavir was the primary driver for the adverse event. With increasing interest in nucleoside-sparing regimens, knowledge of clinically significant adverse events such as this is important for HIV clinicians when selecting regimens for patients with highly resistant virus or drug tolerability issues.

Complementary and Alternative Medicine Treatments Among Stroke Patients in India

Background: Complementary and alternative medicine (CAM) is commonly used by persons with stroke throughout the world, particularly in Asia. Objective: The objectives of this study were to determine the frequency of CAM use and the factors that predict the use of CAM in stroke patients. Methods: This study was carried out in the stroke units of Christian Medical College, Ludhiana, and Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India, from June 2010 to December 2010. Participants were interviewed using a structured questionnaire (≥6 months post stroke). Outcomes were assessed using a modified Rankin Scale (mRS). Results: Three hundred fourteen stroke patients were interviewed; mean age was 57.4 ± 12.9 years, and 230 (73.2%) patients were men. Of 314 patients, 114 (36.3%) had used the following CAM treatments: ayurvedic massage, 67 (59.3%); intravenous fluids, 22 (19.5%); herbal medicines, 17 (15%); homeopathy, 15 (13.3%); witchcraft, 3 (2.7%); acupuncture, 3 (2.7%); opium intake, 10 (8.8%); and other nonconventional treatments, 10 (8.8%). Patients with severe stroke (P < .0001), limb weakness (P < .0001), dysphagia (P = .02), dyslipidemia (P = .007), hypertension (P = .03), or hemorrhagic stroke (P <.0001) and patients with poor outcome (mRS >2; P < .0001) often used CAM treatments. Conclusion: More than one-third of the patients in this study opted for CAM. Presence of limb weakness, dysphagia, dyslipidemia, hypertension, hemorrhagic stroke, severe stroke, and poor outcome predicted the use of CAM.

A 7-year experience with the surgery of biliopancreatic diversion in the modification of Hess-Marceau for the treatment of morbid obesity and type 2 diabetes

We examined 292 patients (mean age 37,5±9,1 years) with morbid obesity (initial BMI 47,3±7,0 kg/m2), from which 72 patients had type 2 diabetes, before and after biliopancreatic diversion in Hess-Marceau modification, conducted from 2003 to 2010. Along with a significant and steady weight loss, the most important advantage of surgery is its high efficiency in treatment of disturbances in carbohydrate and lipid metabolism in patients with morbid obesity and associated type 2 diabetes and severe atherogenic dyslipidemia.

Simvastatin but not bezafibrate decreases plasma lipoprotein-associated phospholipase A2 mass in type 2 diabetes mellitus: Relevance of high sensitive C-reactive protein, lipoprotein profile and low-density lipoprotein (LDL) electronegativity

ObjectivePlasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels predict incident cardiovascular disease, impacting Lp-PLA2 as an emerging therapeutic target. We determined Lp-PLA2 responses to statin and fibrate administration in type 2 diabetes mellitus, and assessed relationships of changes in Lp-PLA2 with subclinical inflammation and lipoprotein characteristics. MethodsA placebo-controlled cross-over study (three 8-week treatment periods with simvastatin (40mg daily), bezafibrate (400mg daily) and their combination) was carried out in 14 male type 2 diabetic patients. Plasma Lp-PLA2 mass was measured by turbidimetric immunoassay. ResultsPlasma Lp-PLA2 decreased (−21±4%) in response to simvastatin (p<0.05 from baseline and placebo), but was unaffected by bezafibrate (1±5%). The drop in Lp-PLA2 during combined treatment (−17±3%, p<0.05) was similar compared to that during simvastatin alone. The Lp-PLA2 changes during the 3 active lipid lowering treatment periods were related positively to baseline levels of high sensitive C-reactive protein, non-HDL cholesterol, triglycerides, the total cholesterol/HDL cholesterol ratio and less LDL electronegativity (p<0.02 to p<0.01), and inversely to baseline Lp-PLA2 (p<0.01). LpPLA2 responses correlated inversely with changes in non-HDL cholesterol, triglycerides and the total cholesterol/HDL cholesterol ratio during treatment (p<0.05 to p<0.02). ConclusionsIn type 2 diabetes mellitus, plasma Lp-PLA2 is likely to be lowered by statin treatment only. Enhanced subclinical inflammation and more severe dyslipidemia may predict diminished LpPLA2 responses during lipid lowering treatment, which in turn appear to be quantitatively dissociated from decreases in apolipoprotein B lipoproteins. Conventional lipid lowering treatment may be insufficient for optimal LpPLA2 lowering in diabetes mellitus.

Abstract 341: Akt1 Deletion Promotes Survival in a Model of Spontaneous Myocardial Infarction and Atherosclerosis

The role of Akt1 kinase in cardiac dysfunction and atherosclerosis is hotly contested. Many models use transient Akt1 activation or deletion to study its function in cardiac diseases. The effects of Akt1 knockout were tested in mouse models dependent on short-term Western diets to induce atherosclerotic lesions; however, in these models, the complete cascade ending in infarction does not occur. In contrast, the ApoE -/- /SR-BI -/- double knockout (DKO) mouse represents a model of spontaneous myocardial infarction resulting from severe dyslipidemia and atherosclerosis leading to death between 5-7 weeks of age. In DKO mice and humans, dyslipidemia and inflamed arterial occlusions lead to plaque rupture and myocardial infarction. Importantly, Akt1 activation is dramatically elevated in the myocardium and endothelium of DKO vs. WT mice. To assess the role of chronic Akt1 activation in atherosclerosis, we generated ApoE -/- /SR-BI -/- /Akt1 -/- triple knockout (TKO) mice. We found that TKO mice exhibited decreased cardiac dysfunction and hypertrophy resulting in longer lifespan vs. DKO. In addition, TKO mice have diminished endothelial VCAM expression, decreased atherosclerotic lesions in vivo , and reduced foam cell formation in vitro . ROS production, which is regulated by Akt1 signaling and contributes to atherosclerosis during dyslipidemia, was reduced in TKO hearts, plasma, endothelial cells, and macrophages. This led to reduced proatherogenic lipid oxidation product accumulation in TKO vs. DKO. Moreover, Akt1 deletion in TKO mice decreased levels of CD36, the main oxidized lipid receptor, in hearts, on endothelial cells, and on macrophages. Thus, during dyslipidemia, chronic Akt1 activation results in elevated oxidative stress, generation of proatherogenic lipid oxidation products, and expression of CD36 (a known atherothrombotic regulator) resulting in enhanced atherosclerosis and spontaneous myocardial infarction. Inhibition of Akt1 by genetic deletion results in partial rescue of mice leading to decreased atherosclerosis, improved cardiac function, and elongated lifespan. Continued study of chronic Akt1 activation and its effects on atherosclerosis will enable the development of additional targets for heart disease therapeutics.

Abstract 24: MicroRNA-27b Is a Regulatory Hub in Lipid Metabolism and Is Altered in Dyslipidemia

Cellular and plasma lipid levels are tightly controlled by complex gene regulatory mechanisms. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression and have emerged as important modulators of lipid homeostasis, but the extent of their role has not been systematically investigated. In this study, we performed high-throughput small RNA sequencing and detected approximately n=150 miRNAs in mouse liver. We then employed an unbiased, in silico strategy to identify miRNA regulatory hubs in lipid metabolism, and miR-27b was identified as the strongest such hub in human and mouse liver. In addition, hepatic miR-27b levels were determined to be sensitive to plasma hyperlipidemia, as evidenced by its 3-fold up-regulation in the liver of mice on a high-fat diet (42% calories from fat). Further, we showed in a human hepatocyte cell line (Huh7) that miR-27b regulates the expression (mRNA and protein) of several key lipid-metabolism genes. Finally, hepatic levels of miR-27b and its target genes, which include ANGPTL3 and GPAM , were inversely regulated in a mouse model of severe dyslipidemia and atherosclerosis. Conclusion: miR-27b is responsive to lipid levels, and acts as a “regulatory hub” in lipid metabolism, controlling multiple genes involved in dyslipidemia.

Catechin prevents severe dyslipidemia-associated changes in wall biomechanics of cerebral arteries in LDLr−/−:hApoB+/+ mice and improves cerebral blood flow

Endothelial dysfunction and oxidative stress contribute to the atherosclerotic process that includes stiffening of large peripheral arteries. In contrast, our laboratory previously reported a paradoxical increase in cerebrovascular compliance in LDLr(-/-):hApoB(+/+) atherosclerotic (ATX) mice (7). We hypothesized that prevention of cerebral artery endothelial dysfunction with a chronic dietary antioxidant intake would normalize the changes in cerebral artery wall structure and biomechanics and prevent the decline in basal cerebral blood flow associated with atherosclerosis. Three-month-old ATX mice were treated, or not, for 3 mo with the polyphenol (+)-catechin (CAT; 30 mg·kg(-1)·day(-1)) and compared with wild-type controls. In isolated, pressurized cerebral arteries from ATX mice, CAT prevented endothelial dysfunction (deterioration of endothelium-dependent, flow-mediated dilations; P < 0.05), the inward hypertrophic structural remodeling (increase in the wall-to-lumen ratio; P < 0.05), and the rise in cerebrovascular compliance (rightward shift of the stress-strain curve measured in passive conditions, reflecting mechanical properties of the arterial wall; P < 0.05). Doppler optical coherence tomography imaging in vivo confirmed these findings, showing that cerebral compliance was higher in ATX mice and normalized by CAT (P < 0.05). CAT also prevented basal cerebral hypoperfusion in ATX mice (P < 0.05). Active remodeling of the cerebrovascular wall in ATX mice was further suggested by the increase (P < 0.05) in pro-metalloproteinase-9 activity, which was normalized by CAT. We conclude that, by preserving the endothelial function, a chronic treatment with CAT prevents the deleterious effect of severe dyslipidemia on cerebral artery wall structure and biomechanical properties, contributing to preserving resting cerebral blood flow.

Disruption of Endothelial Peroxisome Proliferator-Activated Receptor γ Accelerates Diet-Induced Atherogenesis in LDL Receptor-Null Mice

Peroxisome proliferator-activated receptor γ (PPARγ) is widely expressed in vessel walls, and it's activation by agonists showed beneficial effects in cardiovascular diseases. However, the role of endothelial cell (EC) PPARγ in atherogenesis is not fully understood. To assess the contribution of endothelial-specific PPARγ in atherosclerosis, EC-specific PPARγ disruption and LDL receptor (LDLR) double-knockout (PPARγ(ΔEC)/LDLR(-/-)) mice were developed. When challenged with a high-cholesterol diet for 4 weeks, PPARγ(ΔEC)/LDLR(-/-) mice exhibited severe atherosclerotic lesions compared to either their littermate controls or macrophage-specific PPARγ disruption and LDLR double knockout (PPARγ(ΔMΦ)/LDLR(-/-)) mice. Metabolic analysis showed severe dyslipidemia and significant increase in systolic blood pressure in the PPARγ(ΔEC)/LDLR(-/-) mice. Histological analysis and real-time quantitative PCR suggested an exacerbated inflammation in PPARγ(ΔEC)/LDLR(-/-) mice, as revealed by the increases of proinflammatory gene expression and macrophage infiltration in vivo and in vitro. Furthermore, in vivo endothelial permeability was also increased by endothelial PPARγ disruption. Bone-marrow transplantation studies, which reconstituted hematopoietic PPARγ, demonstrated that the accelerated atherogenesis was due to endothelial PPARγ deficiency. Endothelial PPARγ plays an important protective role in atherogenesis.

Fenofibrate

Fenofibrate is a fibric acid derivative indicated for the treatment of severe hypertriglyceridaemia and mixed dyslipidaemia in patients who have not responded to nonpharmacological therapies. The lipid-modifying effects of fenofibrate are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. Fenofibrate improves the lipid profile (particularly triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with dyslipidaemia. Compared with statin monotherapy, fenofibrate monotherapy tends to improve TG and HDL-C levels to a significantly greater extent, whereas statins improve low-density lipoprotein-cholesterol (LDL-C) and total cholesterol levels to a significantly greater extent. Fenofibrate is also associated with promoting a shift from small, dense, atherogenic LDL particles to larger, less dense LDL particles. Combination therapy with a statin plus fenofibrate generally improves the lipid profile to a greater extent than monotherapy with either agent in patients with dyslipidaemia and/or type 2 diabetes mellitus or the metabolic syndrome. In the pivotal FIELD and ACCORD trials in patients with type 2 diabetes, fenofibrate did not significantly reduce the risk of coronary heart disease events to a greater extent than placebo, and simvastatin plus fenofibrate did not significantly reduce the risk of major cardiovascular (CV) events to a greater extent than simvastatin plus placebo. However, the risk of some nonfatal macrovascular events and the incidence of certain microvascular outcomes were reduced significantly more with fenofibrate than with placebo in the FIELD trial, and in the ACCORD trial, patients receiving simvastatin plus fenofibrate were less likely to experience progression of diabetic retinopathy than those receiving simvastatin plus placebo. Subgroup analyses in the FIELD and ACCORD Lipid trials indicate that fenofibrate is of the greatest benefit in decreasing CV events in patients with atherogenic dyslipidaemia. Fenofibrate is generally well tolerated when administered alone or in combination with a statin. Thus, in patients with dyslipidaemia, particularly atherogenic dyslipidaemia, fenofibrate is a useful treatment option either alone or in combination with a statin.

Effect of Niacin on Erectile Function in Men Suffering Erectile Dysfunction and Dyslipidemia

Dyslipidemia is closely related to erectile dysfunction (ED). Evidence has shown that the lipid-lowering agent, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statins), can improve erectile function. However, information about the potential role of another class of lipid-lowering agent, niacin, is unknown. To assess the effect of niacin alone on erectile function in patients suffering from both ED and dyslipidemia. A single center prospective randomized placebo-controlled parallel-group trial was conducted. One hundred sixty male patients with ED and dyslipidemia were randomized in a one-to-one ratio to receive up to 1,500 mg oral niacin daily or placebo for 12 weeks. The primary outcome measure was the improvement in erectile function as assessed by question 3 and question 4 of the International Index of Erectile Function (IIEF Q3 and Q4). Secondary outcome measurements included the total IIEF score, IIEF-erectile function domain, and Sexual Health Inventory for Men (SHIM) score. From the overall analysis, the niacin group showed a significant increase in both IIEF-Q3 scores (0.53 ± 1.18, P < 0.001) and IIEF-Q4 scores (0.35 ± 1.17, P = 0.013) compared with baseline values. The placebo group also showed a significant increase in IIEF-Q3 scores (0.30 ± 1.16, P = 0.040) but not IIEF-Q4 scores (0.24 ± 1.13, P = 0.084). However, when patients were stratified according to the baseline severity of ED, the patients with moderate and severe ED who received niacin showed a significant improvement in IIEF-Q3 scores (0.56 ± 0.96 [P = 0.037] and 1.03 ± 1.20 [P < 0.001], respectively) and IIEF-Q4 scores (0.56 ± 1.03 [P = 0.048] and 0.84 ± 1.05 [P < 0.001], respectively] compared with baseline values, but not for the placebo group. The improvement in IIEF-EF domain score for severe and moderate ED patients in the niacin group were 5.28 ± 5.94 (P < 0.001) and 3.31 ± 4.54 (P = 0.014) and in the placebo group were 2.65 ± 5.63 (P < 0.041) and 2.74 ± 5.59 (P = 0.027), respectively. There was no significant improvement in erectile function for patients with mild and mild-to-moderate ED for both groups. For patients not receiving statins treatment, there was a significant improvement in IIEF-Q3 scores (0.47 ± 1.16 [P = 0.004]) for the niacin group, but not for the placebo group. Niacin alone can improve the erectile function in patients suffering from moderate to severe ED and dyslipidemia.

Familial Hypercholesterolemia: Present and Future Management

Patients suffering from familial hypercholesterolemia (FH) are characterized by increased plasma levels of low-density lipoprotein cholesterol (LDL-C) levels and are at increased risk for premature cardiovascular disease (CVD). Current guidelines emphasize the need to aggressively lower LDL-C in FH patients, and statins are the cornerstone in the current regimen. However, additional therapies are eagerly awaited, especially for those patients not tolerating statin therapy or not reaching the goals for therapy. Our understanding of LDL metabolism has improved over the last years and an increasing number of potential novel targets for therapy have been recently identified. Apart from novel targets, we have also been confronted with novel modalities of treatment, such as mRNA antisense therapy. Some of these emerging therapies have proven to be effective in lowering plasma LDL-C levels and are as such expected to have beneficial effects on CVD. Hopefully, they will enrich our armamentarium against the severe dyslipidemia observed in FH patients in the not too distant future.

Apheresis-inducible cytokine pattern change in severe, genetic dyslipidemias

Objective: The effects of direct adsorption of lipids LDL-apheresis (DALILDL-a) on plasma cytokines in two Homozygous and heterozygous familial hypercholesterolemic (HozFH, HtzFH) and in four HyperLp(a)lipoproteinemic [HyperLp(a)] patients, were evaluated.Methods: Plasma, macrophage inflammatory proteins 1α (MIP-1α), macrophage inflammatory proteins 1β (MIP-1β), monocyte chemoattractant protein-1 (MCP-1), RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted), granulocyte-colony stimulating factor (GCSF), granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin-1α (IL-1α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interleukin-6 (IL-6), interferon-γ (IFN-γ), concentrations, were measured before and after LDL-a on three consecutive sessions for each patient.Results: MIP-1α was significantly reduced (P=0.05), while MIP-1β was significantly increased (P=0.05). Plasma MCP-1 was reduced, although not significantly, while RANTES was significantly increased (P=0.05). GCSF and GM-CSF were both significantly reduced (GM-CSF: P=0.05, GCSF: P=0.05, respectively). IL-1α level was significantly reduced (P=0.001). IL-1β, IL-6, and IFN-γ levels were significantly reduced in plasma after apheresis (IL-1β: P=0.001, IL-6: T1 P=0.001; T2 P=0.05, respectively, IFN-γ: P=0.001). IL-2 level in plasma was significantly reduced at T0, and T2, (P=0.001). However, IL-2 level showed a statistically significant increase at T1 (P=0.001). A significant correlation between IL-1α and IFN-γ was found: r=0.882 (P=0.001).Conclusions: In this study LDL-a induced profound changes in several circulating cytokines and promoted anti-inflammatory and anti-atherogenic cytokine profile in plasma of patients with severe dyslipidemia, with pre-existing angiographically demonstrated Coronary heart disease (CHD), and aortic valvular disease (#=1) (AVD).

Apolipoprotein E4 exaggerates diabetic dyslipidemia and atherosclerosis in mice lacking the LDL receptor.

OBJECTIVEWe investigated the differential roles of apolipoprotein E (apoE) isoforms in modulating diabetic dyslipidemia—a potential cause of the increased cardiovascular disease risk of patients with diabetes.RESEARCH DESIGN AND METHODSDiabetes was induced using streptozotocin (STZ) in human apoE3 (E3) or human apoE4 (E4) mice deficient in the LDL receptor (LDLR−/−).RESULTSDiabetic E3LDLR−/− and E4LDLR−/− mice have indistinguishable levels of plasma glucose and insulin. Despite this, diabetes increased VLDL triglycerides and LDL cholesterol in E4LDLR−/− mice twice as much as in E3LDLR−/− mice. Diabetic E4LDLR−/− mice had similar lipoprotein fractional catabolic rates compared with diabetic E3LDLR−/− mice but had larger hepatic fat stores and increased VLDL secretion. Diabetic E4LDLR−/− mice demonstrated a decreased reliance on lipid as an energy source based on indirect calorimetry. Lower phosphorylated acetyl-CoA carboxylase content and higher gene expression of fatty acid synthase in the liver indicated reduced fatty acid oxidation and increased fatty acid synthesis. E4LDLR−/− primary hepatocytes cultured in high glucose accumulated more intracellular lipid than E3LDLR−/− hepatocytes concomitant with a 60% reduction in fatty acid oxidation. Finally, the exaggerated dyslipidemia in diabetic E4LDLR−/− mice was accompanied by a dramatic increase in atherosclerosis.CONCLUSIONSApoE4 causes severe dyslipidemia and atherosclerosis independent of its interaction with LDLR in a model of STZ-induced diabetes. ApoE4-expressing livers have reduced fatty acid oxidation, which contributes to the accumulation of tissue and plasma lipids.