Diagnostic lipid changes in patients with visceral leishmaniasis.

BACKGROUND: Visceral leishmaniasis (VL) has been associated with the increase in triglyceride (TG) levels and the decrease in high-density lipoprotein cholesterol (HDL-C) concentration. The aim of the study was to evaluate whether there is a diagnostic cut-off point in these lipid profile changes. MATERIALS AND METHODS: We included 100 patients with febrile infections. Analytically, 22 patients with VL, 18 patients with leptospirosis, 20 patients with Brucella melitensis, and 40 age- and sex-matched patients with fever and proven bacteremia (endocarditis and pyelonephritis). The lipid parameters were assessed for their diagnostic accuracy using logistic regression and receiver operating characteristic statistics. RESULTS: It was observed that coexistence of HDL-C < 15 mg/dL and ΤG > 180 mg/dL had 100% sensitivity and 67.5% specificity for the confirmation of VL. The corresponding positive and negative predictive values were 59.4% and 100%, respectively. CONCLUSION: Coexistence of high TGs and low HDL-C values may suggest VL infection in a febrile patient.

Effects of PCSK9 Inhibitors on Other than Low-Density Lipoprotein Cholesterol Lipid Variables.

Low-density lipoprotein cholesterol (LDL-C) is a major cardiovascular risk factor, but other lipid variables such as triglycerides (TRGs), high-density lipoprotein cholesterol (HDL-C) and lipoprotein a [Lp(a)] also affect cardiovascular risk. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors significantly lower LDL-C concentration but also modestly improve the concentrations of TRGs and HDL-C and more robustly decrease Lp(a) levels. The review presents the associated mechanisms of the beneficial effects of PCSK9 inhibitors on the other than LDL-C lipid variables, including the effects on lipid/apolipoprotein secretion and clearance and the heteroexchange between lipoproteins, as well as the possible effects on other variables involved in lipid metabolism such as sortilin. Proprotein convertase subtilisin/kexin type 9 inhibitors improve the overall lipid profile, and these beneficial effects may play a role in the reduction of cardiovascular risk.

Uric acid and cardiovascular risk: What genes can say.

BACKGROUND: Although the relationship of elevated serum uric acid levels and cardiovascular disease has been established in a great number of studies, the causal relevance of this finding remains ambiguous. An approach to evaluate the causal relevance of biomarkers is to exploit the natural randomised allocation of allelic variation in genes affecting their level, also known as Mendelian randomisation. AIM: The aim of this paper is to review the current literature regarding serum uric acid levels and cardiovascular and renal disease risk in Mendelian randomisation studies. METHODS: PubMed and Scopus databases were searched to retrieve Mendelian studies regarding uric acid, hyperuricaemia and cardiovascular risk. CONCLUSIONS: Genetic evidence based on conventional and novel Mendelian randomisation approaches suggest a modest, if any, causal effect of serum uric acid concentration on the development of cardiovascular disease, suggesting that further study of uric acid genes is needed in order to elucidate the relationship of serum uric acid levels and cardiovascular disease.

Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias?

Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-ß HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established.

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.

The safety of ezetimibe and simvastatin combination for the treatment of hypercholesterolemia.

INTRODUCTION: In the light of the most recent and stricter dyslipidemia treatment guidelines, the need for combination hypolipidemic therapy is increasing. Ezetimibe plus simvastatin is available as a fixed dose therapy offering an efficient hypolipidemic treatment choice. Based on the positive results of the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) trial, the use of this drug combination is expected to increase in the next years. AREAS COVERED: This review discusses the current evidence regarding the safety of ezetimibe/simvastatin combination. Current evidence regarding possible associated side effects (musculoskeletal, gastrointestinal, endocrine, hematological, renal, ophthalmologic, allergic, malignancy) and drug interactions of this combination is thoroughly discussed. EXPERT OPINION: Ezetimibe and simvastatin treatment, either as a single pill or the combined use of the individual compounds, offers limited additional risk compared with simvastatin monotherapy and comprises a safe and efficient choice for dyslipidemia treatment in high-risk and diabetic patients.

Statin use in prediabetic patients: rationale and results to date.

Prediabetes increases the risk for new-onset diabetes mellitus in patients receiving statins and this risk is dose- and time- dependent. Explanations for the conversion of a predisposed individual to diabetes are ambiguous including reductions in ubiquinone and adiponectin levels. However, the risk of new-onset diabetes mellitus is far outweighed by the statin-induced considerable decrease in cardiovascular events. Thus, prediabetic patients at high cardiovascular risk should not be denied high-dose statin therapy due to the small increase in the risk of developing diabetes since statins, especially at higher doses, cause greater reductions in cardiovascular events compared with standard statin doses. Moreover, lifestyle modification or even antidiabetic drugs are highly recommended in these individuals.

Dysbetalipoproteinemia: Two cases report and a diagnostic algorithm.

Dysbetalipoproteinemia is a rare familial dyslipidemia characterized by approximately equally elevated serum cholesterol and triglyceride levels due to accumulated remnant lipoproteins in apolipoprotein E2/E2 homozygotes. It is associated with an increased risk for premature cardiovascular disease. Thus, making a diagnosis of dysbetalipoproteinemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up can be challenging. Diagnosis of dysbetalipoproteinemia should be considered in patients mixed dyslipidemia when the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated low density lipoprotein (LDL) and directly measured LDL cholesterol concentrations. Other indices are also informative in the diagnostic process. We present herein two phenotypically different cases (a 44-year-old man with severe hypertriglyceridemia and a 49-year-old woman with mixed dyslipidemia) of genotypically proven familial dysbetalipoproteinemia and a diagnostic algorithm of the disease.

Emerging drugs for hyperlipidaemia: an update.

INTRODUCTION: Hypercholesterolaemia is a significant risk factor for cardiovascular disease (CVD), a major cause of morbidity and mortality. Up to now, the appropriate management has been aggressive hypolipidaemic therapy, particularly with statins, aiming at certain low-density lipoprotein cholesterol (LDL-C) levels for each patient population. This strategy has reduced CVD-related morbidity and mortality. However, many cardiovascular events still occur, probably as a consequence of lipid disorders other than high LDL-C concentration or other risk factors. Because statins do not eliminate the residual CVD risk, there seems to be place for novel lipid modifying drugs with different mechanisms of action. AREAS COVERED: This review is an update since 2010 regarding lipid-modifying drugs in development and their potent role in clinical practice. It focuses on cholesterol ester transfer protein inhibitors, mainly anacetrapib and evacetrapib, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides, pre-protein convertase subtilisin kexin-9 inhibitors and high-density lipoprotein mimetics. EXPERT OPINION: Several novel lipid-modifying drugs may be beneficial for certain patient populations. However, ongoing and future studies with clinical outcomes will clarify their actual role in clinical practice.

Nicotinic acid/laropiprant reduces platelet count but increases mean platelet volume in patients with primary dyslipidemia.

INTRODUCTION: Nicotinic acid (NA) has been associated with reduced cardiovascular morbidity and mortality. Of note, beyond its lipid-modifying actions, NA possesses a number of not yet thoroughly defined pleiotropic actions including anti-inflammatory and antithrombotic effects. As a growing body of evidence points towards mean platelet volume (MPV) and platelet distribution width (PDW) as independent risk factors for cardiovascular disease, it would be interesting to evaluate the effect of NA on these platelet indices. MATERIAL AND METHODS: We recruited 50 consecutive patients with dyslipidemia who were treated with a conventional statin dose (10-40 mg simvastatin or 10-20 mg atorvastatin or 5-20 mg rosuvastatin) and had not achieved the low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) goal. Add-on-statin treatment with extended release (ER) NA/laropiprant (1,000/20 mg/day for the first 4 weeks followed by 2,000/40 mg/day for the next 8 weeks) was given to all patients for 3 months. RESULTS: The ER-NA/laropiprant resulted in a 20% reduction in platelet count (from 277,150/µl (min: 163,000/µl - max: 223,400/µl) to 220,480/µl (min: 141,000/µl - max: 319,000/µl), p < 0.001), while it increased MPV by 3.5% (from 11.4 fl (min: 9.2 fl - max: 13.6 fl) to 11.8 fl (min: 9.5 fl - max: 14.1 fl), p = 0.01), without affecting PDW significantly (from 14.6 fl (min: 10.5 fl - max: 19.3 fl) to 14.5 fl (min: 11 fl - max: 21.1 fl), p = NS). CONCLUSIONS: The NA is associated with reduced platelet count but with increased MPV, thereby raising questions regarding NA's antithrombotic and vasculoprotective properties.

Effect of switch to the highest dose of rosuvastatin versus add-on-statin fenofibrate versus add-on-statin nicotinic acid/laropiprant on oxidative stress markers in patients with mixed dyslipidemia.

INTRODUCTION: Oxidative stress plays an important role in atherosclerosis. Both F2-isoprostane (8-iso-PGF2a) and oxidized low-density lipoprotein (ox-LDL) have emerged as biomarkers of oxidative stress and have been proposed as useful biomarkers that could potentially be used as indicators of cardiovascular disease. METHODS: This is a prespecified analysis of a prospective, randomized, open-label, blinded endpoint (PROBE) study (ClinicalTrials.gov identifier: NCT01010516). Patients (N = 100) with mixed dyslipidemia on a standard statin dose (10-40 mg simvastatin or 10-20 mg atorvastatin or 5-10 mg rosuvastatin) who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) (1000/20 mg/day for the first 4 weeks followed by 2000/40 mg/day for the next 8 weeks) or to add-on-statin micronized fenofibrate (200 mg/day) for a total of 3 months. Levels of plasma and urine F2-isoprostane and plasma ox-LDL were assessed at baseline and 3 months later. RESULTS: Plasma F2-isoprostane levels decreased similarly in all groups. On the other hand, both ox-LDL and urine F2-isoprostane levels decreased similarly in the add-on ER-NA/LRPT and rosuvastatin monotherapy group, while a less pronounced decrease was observed in the add-on fenofibrate group. CONCLUSIONS: All treatment interventions reduced the concentration of the assessed oxidative stress markers, but the reduction was more pronounced in the add-on ER-NA/LRPT and rosuvastatin monotherapy groups, compared with add-on fenofibrate. Specifically designed studies should address the abovementioned risk factors modulation in terms of cardiovascular risk.

No association between high-density lipoprotein levels and ventricular repolarization indexes in subjects with primary hypercholesterolemia.

OBJECTIVE: Data regarding the effect of lipid parameters on repolarization are sparse. Recent data indicate that reconstituted HDL administration shortens repolarization in cardiomyocytes as well as the corrected QT (QTc) interval in human subjects. We investigated the potential association of high-density lipoprotein cholesterol (HDL-C) levels with conventional and novel electrocardiographic markers of ventricular repolarization in patients with hypercholesterolemia. METHODS: Consecutive subjects with primary hypercholesterolemia were recruited. We recorded clinical and laboratory parameters as well as electrocardiographic indexes. With regard to ventricular repolarization, we calculated the QTc interval, the T peak-to-end (Tpe) interval, and the Tpe/QT ratio. RESULTS: The study population consisted of 440 patients (199 men) with a median age of 56 [48-65] years. The correlation analysis (Spearman's) failed to show any association between HDL-C and any of the studied electrocardiographic parameter. Moreover, no correlation between other lipid parameters and the electrocardiograhic indexes was evident. Also, a comparison of the ventricular repolarization parameters between different HDL-C quartile groups (HDL-Q1: ≤ 1.11 mmol/L; HDL-Q2: 1.12-1.29 mmol/L; HDL-Q3: 1.30-1.53 mmol/L; HDL-Q4: ≥ 1.54 mmol/L) was performed. Specifically, the differences in QTc (p: 0.372), Tpe in leads II (p: 0.356), V2 (p: 0.372), V5 (p: 0.112), and Tpe/QT in leads II (p: 0.348), V2 (p: 0.162), V5 (p: 0.122) were not significant. CONCLUSION: HDL-C levels are not associated with the QTc interval or indexes of repolarization dispersion in patients with primary hypercholesterolemia. The potential antiarrhythmic efficacy of HDL should be further evaluated in the setting of myocardial ischemia where dynamic changes in the heterogeneity of ventricular repolarization ensue.

Antiplatelet treatment in the secondary prevention of coronary and cerebrovascular disease: is there any place for novel agents?

Ischemic heart disease and cerebrovascular disease remain major health problems with associated mortality and quality-of-life consequences. Antiplatelet agents, including thienopyridines and the new P2Y12 inhibitors, have been shown to improve survival in the secondary prevention setting. We review the available evidence on the effectiveness and safety of previous established as well as novel antithrombotic agents in the secondary prevention of cardiovascular disease with a special focus on cerebrovascular disease.

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 ß-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.

Lipid-modulating treatments for mixed dyslipidemia increase HDL-associated phospholipase A2 activity with differential effects on HDL subfractions.

The effect of lipid-modulating treatments on modification of high density lipoprotein (HDL) subfractions remains unknown. In this study, mixed dyslipidemia patients (n = 100) inadequately controlled with a standard statin dose were randomized to switch to 40 mg of rosuvastatin or add-on extended release nicotinic acid/laropiprant (ER-NA/LRPT) or add-on fenofibrate. The cholesterol concentrations of HDL (HDL-C) subfractions and HDL-associated lipoprotein-associated phospholipase A2 (HDL-Lp-PLA2) activity were assessed at baseline and 3 months later. We observed that large HDL-C increased by 50 and 6 % in the add-on-ER-NA/LRPT and rosuvastatin groups, respectively, while it decreased by 20 % in the add-on-fenofibrate group (p < 0.01 vs baseline for all groups and p < 0.01 for all comparisons among groups). On the other hand, small HDL-C decreased by 17 % in the add-on-ER-NA/LRPT group (p < 0.01 vs baseline), while it increased by 25 % in the add-on-fenofibrate group (p < 0.01 vs baseline) without any change in the rosuvastatin group (p < 0.01 for all comparisons among groups). HDL-Lp-PLA2 activity increased by 55, 33 and 18 % in add-on-ER-NA/LRPT, add-on-fenofibrate and rosuvastatin groups, respectively (p < 0.01 for all comparisons vs baseline and for all comparisons among groups). In conclusion, add-on-ER-NA/LRPT was associated with an increase in large HDL-C and a decrease in small HDL-C, while opposite effects were noticed in the add-on-fenofibrate group. Add-on-ER-NA/LRPT was associated with the most pronounced increase in HDL-Lp-PLA2 activity.

Effect of hypolipidemic treatment on emerging risk factors in mixed dyslipidemia: a randomized pilot trial.

BACKGROUND: The effects of different hypolipidemic treatment strategies on emerging atherosclerosis risk factors remain unknown. MATERIALS AND 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 dyslipidaemia on a standard statin dose who had not achieved lipid targets were randomized to switch to the highest dose of rosuvastatin (40 mg/day) or to add-on-statin extended release nicotinic acid (ER-NA)/laropiprant (LRPT) or to add-on-statin micronized fenofibrate for a total of 3 months. RESULTS: Following 3 months of treatment, low-density lipoprotein (LDL) particle size increased equally in all groups. Similarly, all treatments were associated with comparable small dense LDL cholesterol reduction. Apolipoprotein B levels decreased by 15%, 7% and 4% in the rosuvastatin, add-on ER-NA/LRPT and add-on fenofibrate group, respectively (P < 0.01 for all compared with baseline, P < 0.01 for all comparisons between groups). Only add-on ER-NA/LRPT was associated with lipoprotein (a) reduction (26%, P < 0.01 compared with baseline). Rosuvastatin monotherapy and add-on ER-NA/LRPT groups were associated with 56% and 24% reduction in high-sensitivity C-reactive protein levels (hsCRP), respectively (P < 0.01 compared with baseline), while add-on fenofibrate was not associated with changes in hsCRP concentration. Lipoprotein-associated phospholipase A2 (Lp-PLA2) activity decreased similarly in both rosuvastatin and add-on fenofibrate groups, while add-on ER-NA/LRPT was associated with a more pronounced Lp-PLA2 activity reduction. ER-NA/LRPT was associated with more side effects compared with rosuvastatin and add-on fenofibrate. CONCLUSIONS: Add-on ER-NA/LRPT followed by switch to the highest dose rosuvastatin were associated with more pronounced beneficial modifications in emerging cardiovascular risk factors compared with add-on fenofibrate in patients with mixed dyslipidaemia.

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.

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.

Electrolyte and acid-base disorders in inflammatory bowel disease.

INFLAMMATORY BOWEL DISEASE (IBD) IS A CHRONIC INFLAMMATORY INTESTINAL DISORDER ENCOMPASSING TWO MAJOR ENTITIES: Crohn's disease and ulcerative colitis. Intestinal inflammatory processes reduce the absorption of sodium, chloride and calcium, while they increase potassium secretion. In addition, mild to severe metabolic alkalosis may occur in IBD patients, mainly depending on the severity of the disease and the part of the gastrointestinal tract being affected. The aim of this review is the presentation of the electrolyte and acid-base disturbances in IBD and how the activity state of the disease and/or treatment may affect them.