Anastazia Kei

A review of the role of apolipoprotein C-II in lipoprotein metabolism and cardiovascular disease.

The focus of this review is on the role of apolipoprotein C-II (apoC-II) in lipoprotein metabolism and the potential effects on the risk of cardiovascular disease (CVD). We searched PubMed/Scopus for articles regarding apoC-II and its role in lipoprotein metabolism and the risk of CVD. Apolipoprotein C-II is a constituent of chylomicrons, very low-density lipoprotein, low-density lipoprotein, and high-density lipoprotein (HDL). Apolipoprotein C-II contains 3 amphipathic α-helices. The lipid-binding domain of apoC-II is located in the N-terminal, whereas the C-terminal helix of apoC-II is responsible for the interaction with lipoprotein lipase (LPL). At intermediate concentrations (approximately 4 mg/dL) and in normolipidemic subjects, apoC-II activates LPL. In contrast, both an excess and a deficiency of apoC-II are associated with reduced LPL activity and hypertriglyceridemia. Furthermore, excess apoC-II has been associated with increased triglyceride-rich particles and alterations in HDL particle distribution, factors that may increase the risk of CVD. However, there is not enough current evidence to clarify whether increased apoC-II causes hypertriglyceridemia or is an epiphenomenon reflecting hypertriglyceridemia. A number of pharmaceutical interventions, including statins, fibrates, ezetimibe, nicotinic acid, and orlistat, have been shown to reduce the increased apoC-II concentrations. An excess of apoC-II is associated with increased triglyceride-rich particles and alterations in HDL particle distribution. However, prospective trials are needed to assess if apoC-II is a CVD marker or a risk factor in high-risk patients.

Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance.

Background:  Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially affect insulin sensitivity.

Management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid

Cardiovascular disease (CVD) represents the leading cause of mortality worldwide. Lifestyle modifications, along with low-density lipoprotein cholesterol (LDL-C) reduction, remain the highest priorities in CVD risk management. Among lipid-lowering agents, statins are most effective in LDL-C reduction and have demonstrated incremental benefits in CVD risk reduction. However, in light of the residual CVD risk, even after LDL-C targets are achieved, there is an unmet clinical need for additional measures. Fibrates are well known for their beneficial effects in triglycerides, high-density lipoprotein cholesterol (HDL-C), and LDL-C subspecies modulation. Fenofibrate is the most commonly used fibric acid derivative, exerts beneficial effects in several lipid and nonlipid parameters, and is considered the most suitable fibrate to combine with a statin. However, in clinical practice this combination raises concerns about safety. ABT-335 (fenofibric acid, Trilipix®) is the newest formulation designed to overcome the drawbacks of older fibrates, particularly in terms of pharmacokinetic properties. It has been extensively evaluated both as monotherapy and in combination with atorvastatin, rosuvastatin, and simvastatin in a large number of patients with mixed dyslipidemia for up to 2 years and appears to be a safe and effective option in the management of dyslipidemia.

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver- and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARα subunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibrate-related PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.

Pleiotropic Effects of Nicotinic Acid: Beyond High Density Lipoprotein Cholesterol Elevation

AIMS Treatment with statins has significantly reduced cardiovascular morbidity and mortality, an effect attributed to both the low-density lipoprotein cholesterol (LDL-C) lowering capacity and the pleiotropic actions of these drugs. However, residual risk remains even after intense LDL-C lowering. Therefore, additional treatment with lipid-lowering drugs which improve other lipid parameters and have favourable non-lipid effects may be of clinical value. The aim of the present article is to review the actions of nicotinic acid and comment on the limitations and possible benefits of this drug in clinical practice. METHODS Relevant articles were identified through a Pubmed search up to July 2010. RESULTS Nicotinic acid (niacin) improves the lipid profile and has been associated with reduction in morbidity and mortality from cardiovascular disease. This favourable outcome may be due to several beneficial actions of this drug, such as antithrombotic, anti-inflammatory and antioxidant. However, its use has been limited due to side effects, especially flushing. A novel formulation with a prostaglandin D2 receptor antagonist (laropiprant) appears to substantially decrease the frequency and intensity of flushing, without affecting the other properties of niacin. Some concerns regarding treatment with nicotinic acid include impaired glucose metabolism and elevations in uric acid and homocysteine levels. CONCLUSION Nicotinic acid is a safe supplementary (to statins) lipid lowering agent which may also improve cardiovascular outcomes. Whether its combination with laropiprant will be proved equally effective and more favourable in terms of adverse effects remains to be established by large clinical trials.

Autoimmune manifestations in patients with visceral leishmaniasis

Visceral leishmaniasis (VL) is a vector-borne protozoal infection caused by replication of Leishmania species in macrophages. VL is characterized by fever, hepatosplenomegaly and cytopenia. Apart from those classic clinical characteristics, VL has been associated with autoimmune clinical and laboratory features. Reported herein are 16 consecutive patients with VL who were checked for laboratory autoimmune manifestations. A variety of autoimmune antibodies including elevated titers of antinuclear antibodies and rheumatoid factor were detected in all patients. Of note, no laboratory autoimmune manifestations were detected in the seven patients who were re-evaluated 3 months after therapy. It is concluded that autoimmune laboratory manifestations during VL infection are common. These may mistakenly lead to diagnosis of an autoimmune disorder.

The current role of thiazolidinediones in diabetes management.

Among the epidemics of modern time, type 2 diabetes mellitus (T2DM) is one of the main contributors to overall morbidity as well as mortality. A number of different treatment options are available for the management of diabetes. Among them thiazolidinediones (TZDs) is an interesting drug class since it does not target the result of T2DM, i.e., hyperglycemia but rather some of the core mechanisms of the disease. Indeed, glitazones increase insulin sensitivity by activating the peroxisome proliferator-activated receptor γ, which plays an important role in regulating various metabolic parameters. Although TZDs have an established efficacy in T2DM treatment, their usage during the past years was questioned following the emergence of some alarming data regarding their safety and especially the cardiovascular safety of rosiglitazone. As a result, there is often some skepticism about the current role of TZDs in T2DM management. This mainly affects rosiglitazone even leading to its withdrawal from several markets in contrast to pioglitazone, which has shown a beneficial cardiovascular profile. A comprehensive assessment of the benefit-to-risk ratio of TZDs is required in order to better understand the place of these drugs in T2DM management.

Review: Antiplatelet drugs: what comes next?

Antiplatelet drugs are important components in the management of atherothrombotic vascular disease. However, several limitations restrict the safety and efficacy of current antiplatelet therapy in clinical practice. Interpatient variability and resistance to aspirin and/or clopidogrel has spurred efforts for the development of novel agents. Indeed, several antiplatelet drugs are at various stages of evaluation; those at advanced stage of development are the focus of this review.

Colesevelam Plus Rosuvastatin 5 mg/Day Versus Rosuvastatin 10 mg/Day Alone on Markers of Insulin Resistance in Patients with Hypercholesterolemia and Impaired Fasting Glucose

BACKGROUND Statin use has been associated with adverse effects on insulin sensitivity and the development of new-onset diabetes. Colesevelam exhibits favorable effects on glucose metabolism. It is not known whether the combination of colesevelam plus low-dose statin has different effects on insulin resistance versus higher-dose statin in patients with impaired fasting glucose (IFG) and hypercholesterolemia. METHODS This was a prospective randomized open-label blinded end point (PROBE) study. Forty patients with hypercholesterolemia and IFG were randomized to receive rosuvastatin 5 mg/day plus colesevelam 3.75 g/day (RC, n=20) or rosuvastatin 10 mg (R, n=20) for 3 months. The primary end point was the difference in the change of homeostasis model assessment of insulin resistance (HOMA-IR) index between the groups. RESULTS HOMA-IR index significantly decreased in the RC group (-32%, P=0.04 vs. baseline) but nonsignificantly increased (+15%, P=NS) in the R group. Insulin levels decreased in the RC group (-26%, P=NS) but increased in the R group (+15%, P=NS). Both changes in HOMA-IR and insulin differed significantly between groups (both p<0.05). Glucose levels decreased in the RC group (-5%, P=NS), whereas they remained unaltered in the R group. Similar reductions in low-density lipoprotein cholesterol were observed in both groups (-45%; P<0.001 vs. baseline). Triglycerides remained unchanged in the RC group but decreased in the R group (-24%, P<0.001 vs. baseline and P=0.02 vs. RC group). CONCLUSIONS The combination of colesevelam with rosuvastatin 5 mg/day may be associated with favorable effects on markers of insulin resistance compared with rosuvastatin 10 mg/day in patients with hypercholesterolemia and IFG. Whether this is associated with less new-onset diabetes remains unknown.

Effect of hypolipidemic treatment on glycemic profile in patients with mixed dyslipidemia

AIM To assess the effect of different hypolipidemic treatment strategies on glycemic profile in mixed dyslipidemia patients. METHODS This is a prespecified analysis of a prospective, randomized, open-label, blinded end point (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (n = 100) with mixed dyslipidemia on a standard statin dose who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/d) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) or to add-on-statin micronised fenofibrate for a total of 3 mo. Fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), homeostasis model assessment of insulin resistance (HOMA-IR) index and lipid profile were evaluated at baseline and 3 mo after treatment intervention. RESULTS FPG increased in add-on ER-NA/LRPT and rosuvastatin monotherapy groups by 9.7% and 4.4%, respectively (P < 0.01 between the 2 groups and compared with baseline), while it did not significantly change in the add-on fenofibrate group. Similarly, HbA1c increased by 0.3% in add-on ER-NA/LRPT group and by 0.2% in the rosuvastatin monotherapy group (P < 0.01 for all comparisons vs baseline and for the comparison between the 2 groups), while no significant change was reported in the add-on fenofibrate group. HOMA-IR increased by 65% in add-on ER-NA/LRPT and by 14% in rosuvastatin monotherapy group, while it decreased by 6% in the add-on fenofibrate group (P < 0.01 vs baseline and for all comparisons among the groups). Non-HDL-C decreased in all groups (by 23.7%, 24.7% and 7% in the rosuvastatin, ER-NA/LRPT and fenofibrate group, respectively, P < 0.01 for all vs baseline and P < 0.01 for all vs with fenofibrate group). CONCLUSION Both addition of ER-NA/LRPT and switch to the highest dose of rosuvastatin deteriorated glycemic profile in patients with mixed dyslipidemia, while add-on fenofibrate seems to increase insulin sensitivity.