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The functional status of High-Density Lipoprotein (HDLs) is not dependent on the cholesterol content but is closely related to structural and compositional characteristics. We reported the analysis of HDL lipidome in the healthy population and the influence of serum lipids, age, gender and menopausal status on its composition. Our sample comprised 90 healthy subjects aged between 30 and 77 years. HDL lipidome was investigated by Nuclear Magnetic Resonance (NMR) spectroscopy. Among serum lipids, triglycerides, apoAI, apoB and the ratio HDL-C/apoAI had a significant influence on HDL lipid composition. Aging was associated with significant aberrations, including an increase in triglyceride content, lysophosphatidylcholine, free cholesterol, and a decrease in esterified cholesterol, phospholipids, and sphingomyelin that may contribute to increased cardiovascular risk. Aging was also associated with an atherogenic fatty acid pattern. Changes occurring in the HDL lipidome between the two genders were more pronounced in the decade from 30 to 39 years of age and over 60 years. The postmenopausal group displayed significant pro-atherogenic changes in HDLs compared to the premenopausal group. The influence of serum lipids and intrinsic factors on HDL lipidome could improve our understanding of the remodeling capacity of HDLs directly related to its functionality and antiatherogenic properties, and also in appropriate clinical research study protocol design. These data demonstrate that NMR analysis can easily follow the subtle alterations of lipoprotein composition due to serum lipid parameters.

Type 2 diabetes mellitus (T2DM) accounts for approximately 95% of all diabetes cases and is associated with a substantially elevated risk for cardiovascular disease (CVD) that is 2- to 4-times higher in patients with T2DM compared to those without. The aim of present study was to evaluate the cost effectiveness of empagliflozin compared to dapagliflozin for the treatment of patients with T2DM and established CVD in Greece. A published health economic model was used to project clinical and economic outcomes of T2DM patients receiving empagliflozin compared to those receiving dapagliflozin. Individual patient-level discrete-event simulation was conducted to predict time-to-event for CV, renal, and adverse events over patients’ lifetimes. Hazard ratios for dapagliflozin versus empagliflozin on each clinical event was estimated from DECLARE-TIMI 58 and EMPA-REG OUTCOME trials’ data using an indirect treatment comparison. Following a public payer perspective, only direct medical costs related to drug acquisition, fatal/non-fatal diabetes-related complications and adverse events were considered (€2020). Model extrapolated outcomes included life years (LY), quality-adjusted life years (QALYs), costs as well as incremental cost-effectiveness ratio (ICER). Sensitivity analyses explored the impact of changes in input data. Over a patient’s lifetime, empagliflozin was associated with longer mean survival (17.23 LY with empagliflozin vs 16.07 LY with dapagliflozin) and reduced rate of CV mortality resulting in 0.48 more QALYs (9.27 vs 8.79), at additional costs of €462. The generated ICER of empagliflozin was €965 per QALY gained. Deterministic sensitivity analysis confirmed empagliflozin’s cost-effective profile. Probabilistic sensitivity analysis revealed that the probability of empagliflozin being cost effective over dapagliflozin was 100%, at the defined threshold of €36,000 per QALY gained. Empagliflozin was estimated to be a highly cost-effective treatment option compared to dapagliflozin for the treatment of T2DM patients with established CVD in Greece.

OBJECTIVE To examine whether the circulating substrate mix may be related to the incidence of heart failure (HF) and cardiovascular (CV) mortality and how it is altered by canagliflozin treatment. RESEARCH DESIGN AND METHODS We measured fasting glucose, free fatty acids (FFA), glycerol, β-hydroxybutyrate, acetoacetate, lactate, and pyruvate concentrations in 3,581 samples from the CANagliflozin cardioVascular Assessment Study (CANVAS) trial at baseline and at 1 and 2 years after randomization. Results were analyzed by univariate and multivariate Cox proportional hazards models. RESULTS Patients in the lowest baseline FFA tertile were more often men with a longer duration of type 2 diabetes (T2D), higher urinary albumin excretion, lower HDL-cholesterol levels, higher history of CV disease (CVD), and higher use of statins and insulin. When all seven metabolites were used as predictors, FFA were inversely associated with incident hospitalized HF (hazard ratio [HR] 0.33 [95% CI 0.21–0.55]), while glycerol was a positive predictor (2.21 [1.45–3.35]). In a model further adjusted for 16 potential confounders, including prior HF and CVD and pharmacologic therapies, FFA remained a significant negative predictor. FFA and glycerol also predicted CV mortality (HR 0.53 [95% CI 0.35–0.81] and 1.81 [1.26–2.58], respectively) and all-cause death (0.50 [0.36–0.70] and 1.64 [1.22–2.18]). When added to these models, background insulin therapy was an independent positive predictor of risk of death. Canagliflozin treatment significantly increased plasma FFA and β-hydroxybutyrate regardless of background antihyperglycemic therapy. CONCLUSIONS A constitutive metabolic setup consisting of higher lipolysis may be beneficial in delaying or preventing hospitalized HF; a further stimulation of lipolysis by canagliflozin may reinforce this influence.

Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder in Western countries, comprises steatosis to nonalcoholic steatohepatitis (NASH), with the latter having the potential to progress to cirrhosis. The transition from isolated steatosis to NASH is still poorly understood, but lipidomics approach revealed that the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis and these alterations correlate with disease progression. Recent data suggest that both quantity and quality of the accumulated lipids are involved in pathogenesis of NAFLD. Changes in glycerophospholipid, sphingolipid, and fatty acid composition have been described in both liver biopsies and plasma of patients with NAFLD, implicating that specific lipid species are involved in oxidative stress, inflammation, and cell death. In this article, we summarize the findings of main human lipidomics studies in NAFLD and delineate the currently available information on the pathogenetic role of each lipid class in lipotoxicity and disease progression.

Uric acid (UA) is a risk factor associated with cardiometabolic diseases. However, the appropriate threshold of UA remains a matter of controversy.To assess whether slightly increased UA levels have any significance in middle-aged, treatment-naïve persons with new-onset hypertension.In this cross-sectional study we recruited middle-aged participants with new-onset hypertension who were treatment-naïve. Subjects below (Group 1) and above the median UA levels (Group 2) were compared regarding clinical and laboratory characteristics that are implicated in cardiovascular and renal risk. The study population consisted of 369 persons (mean age 48.4±10 years) with median UA of 4.8 mg/dl. Group 2 individuals were predominantly male and had higher levels of blood pressure, increased body mass index, waist circumference, and a greater degree of insulin resistance. Additionally, greater lipid profile abnormalities were detected. This group also exhibited a significantly decreased fractional excretion of UA. Multivariate analysis demonstrated that serum UA levels were correlated with male sex, waist circumference, estimated glomerular filtration rate (eGFR), serum calcium and insulin levels, as well as with fractional excretion of UA. A positive association between serum UA levels and the number diagnostic criteria of the metabolic syndrome (MtS) was also noticed. After reclassification of subjects according to UA quartiles, individuals with UA levels ≥ 3.8 mg/dl had significantly higher odds (2.5-fold to 9.8-fold) of having MtS after adjustment of age, sex, and eGFR.Uric acid levels in middle-aged, treatment-naïve hypertensive patients are correlated with risk factors for cardiovascular and renal disease.

The aim of this study was to assess the effect of the COVID-19 lockdown periods on the metabolic control of patients with type 2 diabetes (T2D) in three academic diabetes centers in Greece. There was a slight improvement in BMI, blood pressure and lipid values while the remaining parameters remained stable.

The introduction of continuous glucose monitoring inaugurated a new era in clinical practice by shifting the characterization of glycemic control from HbA1c to novel metrics. The one that gained widespread attention over the past decades was glycemic variability (GV), which typically refers to peaks and nadirs of blood glucose measured over a given time interval. GV can be dichotomized into two main categories: short-term and long-term. Short-term GV reflects within-day and between-day glycemic oscillations, and its contribution to diabetic complications remains an enigma. In this review, we summarize the available data about short-term GV and its possible association with both microvascular and macrovascular complications, evaluating different pathogenic mechanisms and demonstrating nonpharmaceutical, as well as pharmaceutical, therapeutic interventions.

IntroductionThe main pathophysiologic mechanism of type 2 diabetes (T2D) is insulin resistance, which exists several years before T2D diagnosis. The term ‘prediabetes’ applies to patients with insulin resistance but without overt T2D. The improvement of glucose homeostasis in these patients may prevent or delay the development of T2D and its complications. Data suggest that fenugreek, olive leaf polyphenols and bergamot extract may improve carbohydrate metabolism. We examined the effect of an agent containing fenugreek, olive leaf polyphenols and bergamot extract (active agent) on glucose homeostasis in patients with prediabetes.Material and methodsThis was a single-center, randomized, double-blind, placebo-controlled trial; patients with prediabetes (N = 100) were randomized to treatment with the active agent or placebo. The primary efficacy endpoint was the change in glycated hemoglobin (HbA1c) at 6 months after treatment initiation. Secondary endpoints included changes in other parameters of glucose metabolism and lipid profile.ResultsOverall 87 patients completed the study. No significant change in HbA1c was observed in either treatment group. Similarly, fasting plasma glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) index and lipid profile remained unaltered in both groups.ConclusionsThe administration of an agent containing fenugreek, olive leaf polyphenols and bergamot extract for 6 months did not improve glycemia or lipid parameters in patients with prediabetes.

Administration of insulin degludec and liraglutide (IDegLira) correlates to fasting lipid profile changes of diabetic patients, while data concerning apoB-containing lipoprotein subclasses and HDL lipidome are scarce. We evaluated its effect on fasting lipid parameters, apolipoproteins, apoB-containing lipoprotein subclasses and HDL lipidome in patients with type 2 diabetes.Sixty three patients with HbA1c 7 % on oral glucose-lowering drugs received either IDegLira or insulin degludec for 3 months. Lipoprotein subfraction profile was determined through Lipoprint method, whereas HDL lipid composition viaCompared to insulin degludec, IDegLira administration resulted in significantly greater reduction of total and LDL-cholesterol. On the other hand, the effect of the two drugs on apolipoprotein-B-containing lipoprotein subfractions concentration was minimal and did not differ between the 2 interventions. IDegLira, but not insulin degludec, induced an atheroprotective shift in HDL's fatty acid composition and particle core depletion in triglycerides.IDegLira administration is accompanied by total and LDL-cholesterol reduction, while sdLDL concentration only reduced in patients experiencing triglyceride reduction. IDegLira induced compositional changes of HDL particles. These changes may contribute to the cardioprotective properties of liraglutide.

Aim: To compare the effect of fixed-dose combination of Insulin Degludec and Liraglutide (IDegLira) on anthropometric, carbohydrate metabolism and lipid parameters, as well as on apoB-containing lipoprotein subclasses and HDL lipidome, in patients with type 2 diabetes (T2DM) regarding changes in triglyceride (TG) levels. Methods: Seventy-two uncontrolled patients with T2DM on oral antidiabetics were randomized to receive IDegLira or Insulin Degludec (IDeg) for a 12-week treatment. In the present study, 42 patients receiving IDegLira were included. Twenty-one presented a decrease, while the remaining an increase in TG levels. ApoB-containing lipoprotein subclasses levels were measured by LDL-Lipoprint method, whereas HDL lipidomic analysis via 1H-NMR spectroscopy. Results: In patients experiencing a decrease in TG levels after IDegLira administration, a significant decrease in body weight and BMI, by 4.4kg and 1.59kg/m2 respectively, was observed. Fasting glucose, HbA1c and HbA1c Glycation Index noted a decrease by 35 mg/dl, 1.4% and 1.1 respectively (p=0.018, p=0.004, p=0.004). IDegLira administration in this subgroup resulted in a significant reduction of total (TC) and LDL cholesterol (LDLC) by 22.5mg/dl and 13.2mg/dl, respectively. Small-dense LDLC (sdLDLC) levels significantly correlated with changes in TG levels (r=0.496, p=0.02). Furthermore, IDegLira administration resulted in significant enrichment of HDL particle core in esterified cholesterol, depletion of TG content and an atheroprotective shift in fatty acid pattern of HDLs. The aforementioned changes were significantly greater than those observed in patients receiving IDegLira and did not experience a TG reduction. Conclusions: TG reduction as a result of IDegLira administration is accompanied by greater changes in anthropometric and carbohydrate metabolism parameters, TC, LDLC, sdLDLC and HDL lipidome. Disclosure E. Pappa: None. C. Kostara: None. A. Dimou: None. E. T. Bairaktari: None. V. Tsimihodimos: None.

Aims Disturbances in red blood cells' (RBCs) membrane structure, that result in altered rheological properties, have been implicated in the pathogenesis of microvascular complications of diabetes mellitus(T2DM). However, the compositional alterations in RBCs membranes of T2DM patients have not been characterized in detail. Methods NMR-based lipidomic approach used for the global investigation of the lipidome of RBCs membrane in 20 newly diagnosed T2DM patients. Twenty healthy individuals served as controls. Results In the lipidomic analysis, the discrimination power among the two groups was of high significance. T2DM patients characterized by an increased content of cholesterol, total sphingolipids, sphingomyelin and glycolipids, and decreased total phospholipids, mainly due to phosphatidylethanolamine, total ether glycerolipids and plasmalogen-phospholipids, and higher cholesterol-to-phospholipids molecular ratio compared to controls. In T2DM, lipids were esterified with saturated rather than unsaturated fatty acids, an atherogenic pattern that may be involved in the impairment of membrane fluidity and rigidity. Conclusions NMR-based lipidomic analysis of RBCs can provide insights into molecular lipid features of membrane microenvironment that influence their vital function and rheological behavior in microvascular network in T2DM.Early identification of these disturbances, even before the onset of diabetes, could critically help to the development of novel preventative and curative therapies for reducing the risk of microvascular dysfunction.

Context Inhibitors of sodium-glucose cotransporters-2 have cardio- and renoprotective properties. However, the underlying mechanisms remain indeterminate. Objective To evaluate the effect of dapagliflozin on renal metabolism assessed by urine metabolome analysis in patients with type 2 diabetes. Design Prospective cohort study. Setting Outpatient diabetes clinic of a tertiary academic center. Patients Eighty patients with hemoglobin A1c > 7% on metformin monotherapy were prospectively enrolled. Intervention Fifty patients were treated with dapagliflozin for 3 months. To exclude that the changes observed in urine metabolome were merely the result of the improvement in glycemia, 30 patients treated with insulin degludec were used for comparison. Main Outcome Measure Changes in urine metabolic profile before and after the administration of dapagliflozin and insulin degludec were assessed by proton-nuclear magnetic resonance spectroscopy. Results In multivariate analysis urine metabolome was significantly altered by dapagliflozin (R2X = 0.819, R2Y = 0.627, Q2Y = 0.362, and coefficient of variation analysis of variance, P Conclusions Dapagliflozin significantly affects urine metabolome in patients with type 2 diabetes in a glucose lowering-independent way. Most of the observed changes can be considered beneficial and may contribute to the renoprotective properties of dapagliflozin.

Aim: Administration of fixed-dose combination of Insulin Degludec and Liraglutide (IDegLira) has been associated with changes in the lipid-profile of diabetic patients. We assessed the effect of IDegLira on serum apolipoproteins, apoB-containing lipoprotein subclasses and HDL lipidome in patients with type 2 diabetes mellitus (T2DM). Methods: Sixty uncontrolled patients with T2DM on oral antidiabetic drugs were included. Of them, thirty received IDegLira and the remaining Insulin Degludec(IDeg). Lipid and carbohydrate metabolism parameters were assessed before and following 3-month-treatment. ApoB-containing lipoprotein subclasses levels were measured by LDL-Lipoprint method, whereas HDL lipidomic analysis via 1H-NMR spectroscopy. Results: Administration of IDegLira resulted in a significant reduction of total (TC) and LDL cholesterol (LDLC) by 14.68mg/dl and 10.45mg/dl, respectively. ApoA1 and apoB decreased in patients treated with IDegLira. A non-significant change in small-dense LDLC (sdLDL-C) levels was observed that was significantly correlated with changes in TG levels (r=0.468, p=0.007). Furthermore, IDegLira administration resulted in significant enrichment of HDL particles’ core in esterified cholesterol and depletion of TGs content. IDegLira induced an atheroprotective shift in fatty acid pattern of HDLs characterized by a statistically significant lower content in saturated and higher in unsaturated fatty acids (linoleic acid, eicosapentaenoic and arachidonic acids and docosahexaenoic acid). No significant changes were observed in the IDeg group. Conclusions: Administration of IDegLira is accompanied by changes in HDL lipdome, a decrease in TC, LDLC, apoA1 and B, while the levels of sdLDL were only reduced in patients experiencing a decrease in TGs. The contribution of these changes to cardiovascular risk reduction after treatment with liraglutide in clinical trials cannot be excluded. Disclosure E. Pappa: None. C. Kostara: None. C. Tellis: None. A.D. Tselepis: None. E. Bairaktari: None. V. Tsimihodimos: None.

Background Metformin, in the absence of contraindications or intolerance, is recommended as first-line treatment for patients with type 2 diabetes mellitus (T2DM). This observational, retrospective study assessed the real-world adequacy of glycaemic control in Greek patients with T2DM initiating metformin monotherapy at maximum tolerated dose. Methods Included patients received metformin monotherapy for ≥24 months; relevant patient data were collected immediately prior to metformin initiation (baseline) and at other prespecified time points. The primary objective was to report, after 9 months of metformin treatment, the percentage of patients with baseline glycated haemoglobin (HbA1c) levels ≥6.5% (≥48 mmol/mol) achieving HbA1c Results Of the enrolled patients (N=316), 247 had baseline HbA1c ≥6.5%; following 9 months on metformin, 90 (36.4%) patients achieved HbA1c

Branched chain amino acids (BCAAs), leucine, isoleucine and valine, are essential amino acids widely studied for their crucial role in the regulation of protein synthesis mainly through the activation of the mTOR signaling pathway and their emerging recognition as players in the regulation of various physiological and metabolic processes, such as glucose homeostasis. BCAA supplementation is primarily used as a beneficial nutritional intervention in chronic liver and kidney disease as well as in muscle wasting disorders. However, downregulated/upregulated plasma BCAAs and their defective catabolism in various tissues, mainly due to altered enzymatic activity of the first two enzymes in their catabolic pathway, BCAA aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), have been investigated in many nutritional and disease states. The current review focused on the underlying mechanisms of altered BCAA catabolism and its contribution to the pathogenesis of a numerous pathological conditions such as diabetes, heart failure and cancer. In addition, we summarize findings that indicate that the recovery of the dysregulated BCAA catabolism may be associated with an improved outcome and the prevention of serious disease complications.

Objective Nephropathy is among the most common and most devastating complications of diabetes mellitus. Recent data suggest that there is a multifaceted interaction between the kidney and antidiabetic drugs. Thus, the deterioration of renal function may result in important changes in the pharmacokinetic and pharmacodynamic properties of glucose-lowering compounds. Additionally, drugs that exert their antidiabetic properties through the inhibition of proximal glucose reabsorption are now available whereas accumulating evidence suggests that some of these drugs may exert renoprotective properties that are independent of their effect on carbohydrate metabolism. Methods All articles published until the end of 2016 in PubMed that dealt with the relationship of antidiabetic drugs and the kidney were reviewed and the relevant information is presented here. Results In this review, we summarize the available evidence on the drugs that act through the inhibition of renal glucose reabsorption, discuss the adjustments in the dose of antidiabetic drugs in patients with various stages of kidney disease and explore the renoprotective potency of the various glucose-lowering compounds. Conclusion Sodium glucose cotransporter 2 inhibitors represent a very promising option for the treatment of type 2 diabetes, especially in patients with established cardiovascular disease. These drugs, along with pioglitazone and incretin mimetics may also reduce the incidence and the rate of progression of diabetic nephropathy.

Glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-IV inhibitors (collectively termed incretin-based therapies) represent two of the most widely used classes of antidiabetic drugs. These compounds exert their beneficial effects on carbohydrate metabolism through the activation of specific glucagon like peptide-1 receptors in various organs. Accumulating evidence suggests that glucagon like peptide-1 receptor agonists and dipeptidyl peptidase-IV inhibitors also affect renal function in both glucagon like peptide-1 receptor-dependent and independent manner. However, the clinical significance of these observations remains indeterminate. In this review, we summarize the available preclinical and clinical data on the effects of incretin-based therapies on renal function indices and discuss their relevance in everyday clinical practise.

Sitosterolemia is a metabolic disorder characterized by increased intestinal absorption and tissue accumulation of phytosterols. Although sitosterolemia is considered a rare disease, its prevalence may be significantly higher than initially thought. Indeed, accumulating evidence suggests that patients with unexplained hematologic abnormalities or premature cardiovascular disease in the absence of classic risk factors may exhibit disordered phytosterol metabolism. In this review, we present a patient with sitosterolemia, describe the pathophysiology and the clinical picture of this disorder, and discuss the clinical value of phytosterol supplementation in patients with primary dyslipidemias.

Background Type 2 diabetes mellitus (T2DM) is associated with an increased risk of stroke and an unfavourable outcome following stroke. Apart from pioglitazone, glucose-lowering modalities have not been shown to protect against stroke. Nevertheless, there is evidence from experimental studies of potential neuroprotective effects with dipeptidyl peptidase (DPP)-4 inhibitors, especially if treatment starts before stroke. Objective To perform a meta-analysis of available evidence regarding the risk of stroke in individuals taking DPP-4 inhibitors. Methods All available data from prospective randomized placebo-controlled trials involving DPP-4 inhibitors in T2DM patients published up to December 2015 were considered. The included trials reported data on the incidence of stroke with a recruitment rate of at least 100 diabetes patients and a follow-up of at least 12 weeks. Results A total of 19 small randomized clinical trials (RCTs) evaluating the efficacy and safety of gliptins ( n =9278), along with three multicentre prospective double-blind placebo-controlled RCTs assessing cardiovascular outcomes as the primary endpoint and involving 36,395 T2DM patients, were included in the analysis. Pooled analysis of the small RCTs showed a non-significant trend towards benefit with DPP-4 inhibitors against stroke [odds ratio (OR): 0.639, 95% confidence interval (CI): 0.336–1.212; P =0.170]. In contrast, in the analysis of RCTs reporting on cardiovascular safety, there was no difference in the risk of stroke with gliptin treatment compared with a placebo (OR: 0.996, 95% CI: 0.850–1.166; P =0.958). Conclusion The promising data from experimental studies regarding cardioprotective gliptin-associated effects against stroke were not supported by available data from trials specifically looking at cardiovascular safety.

Sodium Glucose Cotransporters 1 (SGLT1) play important roles in the intestinal absorption of glucose and the renal reabsorption of glucose, especially in patients with uncontrolled diabetes and those receiving SGLT2 inhibitors. As a consequence, the inhibition of SGLT1 transporters may represent an interesting therapeutic option in patients with diabetes. However, genetic models of SGLT1 inactivation indicate that the malfunction of these transporters may have adverse effects on various tissues. In this review, we discuss the available evidence on the beneficial and detrimental effects that the inhibition of SGLT1 transporters might have. The inhibition of SGLT1 lowers serum glucose levels through the inhibition of intestinal absorption and renal reabsorption of glucose. In addition, drugs that interfere with SGLT1-mediated transport of glucose may protect cardiac tissue by reducing glycogen accumulation and decreasing the production of reactive oxygen species. On the other hand, this strategy may result in diarrhea, volume depletion, may interfere with the correction of hypoglycemia through the oral administration of carbohydrates and could predispose to the development of euglycemic diabetic ketoacidosis. Therefore, at the moment, SGLT1 inhibition seems to represent a two-edged sword.

Background:As Mendelian Randomization (MR) studies showed no effect of variants altering HDL-cholesterol (HDL-C) levels concerning Cardiovascular Disease (CVD) and novel therapeutic interventions aiming to raise HDL-C resulted to futility, the usefulness of HDL-C is unclear.Objective:As the role of HDL-C is currently doubtful, it is suggested that the atheroprotective functions of HDLs can be attributed to the number of HDL particles, and their characteristics including their lipid and protein components. Scientific interest has focused on HDL function and on the causes of rendering HDL particles dysfunctional, whereas the relevance of HDL subclasses with CVD remains controversial.Methods:The present review discusses changes in quality as much as in quantity of HDL in pathological conditions and the connection between HDL particle concentration and cardiovascular disease and mortality. Emphasis is given to the recently available data concerning the cholesterol efflux capacity and the parameters that determine HDL functionality, as well as to recent investigations concerning the associations of HDL subclasses with cardiovascular mortality.Results:MR studies or pharmacological interventions targeting HDL-C are not in favor of the hypothesis of HDL-C levels and the relationship with CVD. The search of biomarkers that relate with HDL functionality is needed. Similarly, HDL particle size and number exhibit controversial data in the context of CVD and further studies are needed.Conclusion:There is no room for the old concept of HDL as a silver bullet,as HDL-C cannot be considered a robust marker and does not reflect the importance of HDL particle size and number. Elucidation of the complex HDL system, as well as the finding of biomarkers, will allow the development of any HDL-targeted therapy.

Type 2 diabetes mellitus and hypertension overlap in the population. In many subjects, development of diabetes mellitus is characterized by a relatively rapid increase in plasma glucose values. Whether a similar phenomenon occurs during the development of hypertension is not known. We analyzed the pattern of blood pressure (BP) changes during the development of hypertension in patients with or without diabetes mellitus using data from the MCDS (Mexico City Diabetes Study; a population-based study of diabetes mellitus in Hispanic whites) and in the FOS (Framingham Offspring Study, a community-based study in non-Hispanic whites) during a 7-year follow-up. Diabetes mellitus at baseline was a significant predictor of incident hypertension (in FOS, odds ratio, 3.14; 95% confidence interval, 2.17–4.54) independently of sex, age, body mass index, and familial diabetes mellitus. Conversely, hypertension at baseline was an independent predictor of incident diabetes mellitus (in FOS, odds ratio, 3.33; 95% CI, 2.50–4.44). In >60% of the converters, progression from normotension to hypertension was characterized by a steep increase in BP values, averaging 20 mm Hg for systolic BP within 3.5 years (in MCDS). In comparison with the nonconverters group, hypertension and diabetes mellitus converters shared a metabolic syndrome phenotype (hyperinsulinemia, higher body mass index, waist girth, BP, heart rate and pulse pressure, and dyslipidemia). Overall, results were similar in the 2 ethnic groups. We conclude that (1) development of hypertension and diabetes mellitus track each other over time, (2) transition from normotension to hypertension is characterized by a sharp increase in BP values, and (3) insulin resistance is one common feature of both prediabetes and prehypertension and an antecedent of progression to 2 respective disease states.

Recent studies suggest that the cholesterol content of HDL (high density lipoproteins) may provide limited information on their antiatherogenic properties and that the composition and particles' structure provide more information on their functionality. We used NMR-based (nuclear magnetic resonance-based) lipidomics to study the relationships of serum HDL-C (HDL-cholesterol) levels with the lipid composition of HDL particles in three groups of subjects selected on the basis of their HDL-C levels. Subjects with low and high HDL-C levels exhibited differences in HDL lipidome compared to those with normal HDL-C levels. In pattern recognition analysis, the discrimination power among all groups was of high significance. The low HDL-C group presented enrichment of the core in triglycerides and depletion in cholesterol esters, whereas the high HDL-C group showed a decrease in triglycerides content. Additionally, as HDL-C increases, all lipid classes are esterified with higher percentage of unsaturated than saturated fatty acids. In addition to the aforementioned differences, the surface layer is enriched in sphingomyelin and free cholesterol in the high HDL-C level group. NMR-based lipidomic analysis of HDL can be particularly useful since it provides insights into molecular features and helps in the characterization of the atheroprotective function of HDL lipoproteins and in the identification of novel biomarkers of cardiovascular risk.

Objective: The use of dipeptidyl-peptidase 4 (DPP4) inhibitors and glucagon like peptide 1 (GLP1) analogues for the treatment of diabetic mellitus (DM) type 2 is growing. Currently some of these agents have been approved in combination with insulin. Methods: We considered randomised controlled trials (RCTs) evaluating GLP1 analogues or DDP4 inhibitors combined with basal insulin in diabetic patients. We were limited to trials published in English language. Results: PubMed search retrieved 207 items. After excluding irrelevant items we ended with 7 eligible studies with 1808 participants. Mean baseline HbA 1c was 8.5% and median follow up was 24 weeks. Exenatide combined with insulin was used in 2 studies; DPP4 inhibitors were used in 5 studies (2 with sitagliptin, 1 with saxagliptin, 1 with vildagliptin and 1 with alogliptin). Conclusion: Incretin-based therapies combined with basal insulin are able to reduce HbA 1c by 0.5-0.7%. DPP4 inhibitors have no significant effect on weight, whereas GLP1 analogues reduced weight by 1-2 kg. Hypoglycaemia rates were generally comparable in all treatment groups. These are promising results, but the available evidence is limited. This is a poorly investigated field with few RCTs. New studies focusing on head-to-head comparisons with short-acting insulin on top of basal insulin are needed.

Introduction: Disturbances in lipid metabolism represent an integral component of dysglycemic states and may increase the risk of diabetic complications. Although from a pathophysiological viewpoint fibrates could represent the ideal drug for patients with diabetic dyslipidemia the evidence that support their use in these patients remains elusive. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a double-blind, placebo-controlled trial that randomized 9795 diabetic subjects to fenofibrate or matching placebo for an average of 5 years. Areas covered: In this review, all the findings of the FIELD trial are summarized. Expert opinion: Chronic kidney disease (reduced GFR, albuminuria or both) and the presence of metabolic syndrome significantly increase the cardiovascular risk in patients with diabetes. Fenofibrate may represent a useful therapeutic option for the treatment of atherogenic dyslipidemia in diabetic subjects. Further attention should be paid on the unique microvascul...

Cardiovascular disease is the leading cause of morbidity and mortality in the Western world. However, it appears that currently available risk assessment tools often underestimate risk, especially for patients in the intermediate-risk category. Considering the socioeconomic cost, it is imperative to correctly identify patients in the intermediate-risk category who would benefit from more aggressive treatment. A plethora of experimental and observational studies provide support that lipoprotein associated phospholipase A2 (Lp- PLA2) and secretory phospholipases A2 (sPLA2)) as well as high sensitivity C-reactive protein (hsCRP) are useful biomarkers of cardiovascular risk. Particularly, Lp-PLA2) has also been addressed as pharmacological target and we are eagerly awaiting the results of ongoing phase III clinical trials. In this review we discuss the current literature regarding the pros and cons of these biomarkers.

Background: Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined. Objective: To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships. Methods: PubMed was searched using the terms “incretins”, “GLP-1”, “GIP” and “lipids”, “dyslipidemia”, “triglycerides”, “apolipoprotein B48”. All articles published in the English language until June 2016 were assessed and the relevant information is presented here. Results: GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate. Conclusion: GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.

Several lines of evidence suggest that the lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an impor- tant role in the pathogenesis of atherosclerotic disease. From a pathophysiological point of view the enzyme bound to apolipoprotein-B-containing lipoproteins (which corresponds to more than 90% of plasma enzymatic activity) may play a proatherogenic role since it generates lysophosphatidylcholine and oxidized fatty acids, molecules that have been shown to promote atherogenesis. On the other hand, the enzyme associated with high-density lipoprotein (HDL) may play an antiatherogenic role since it protects low-density lipoprotein (LDL) from oxidation and diminishes the biological func- tions of oxidized LDL. Several large-scale, prospective studies have shown that both plasma Lp-PLA2 mass and activity represent important predictors of future cardiovascular risk in primary and secondary prevention populations. In this re- view, we summarize the current knowledge on the effect of drugs used in the treatment of cardiovascular disease on the plasma levels of Lp-PLA2. This information may help clinicians to design safe and effective therapeutic strategies for the prevention and treatment of atherosclerotic disease. Keyword: Lipoprotein-associated phospholipase A2, cardiovascular drugs, statins, fibrates.

The incidence of diabetes is continuously increasing worldwide. Pre-diabetes (defined as impaired glucose tolerance, impaired fasting glucose or both) represents an intermediate state, which often progresses to overt diabetes within a few years. In addition, pre-diabetes may be associated with increased risk of microvascular and macrovascular complications. Thus, reverting a pre-diabetic state as well as preventing the development of diabetes represents enormous challenge for the clinician. Lifestyle modification in pre-diabetic individuals was found particularly effective in the prevention of diabetes. However, compliance to lifestyle modification measures can be a crucial problem in the everyday clinical practice, especially in developing countries. During the last decade many studies support the use of anti-diabetic treatment schemes in pre-diabetic subjects to be advantageous. The American Diabetes Prevention Program (DPP) as well as other minor studies and meta-analyses has convincingly demonstrated the efficacy of metformin in this patient group. In addition, results of the 10 year DPP follow up have recently been published, demonstrating the long term safety and sustainability of metformin treatment benefits in this population. In contrast to metformin, the evidence from the use of other anti-diabetic agents (thiazolidinediones, a-glucosidase inhibitors, incretin mimetics) in pre-diabetic individuals is rather inadequate and prospective data is further needed. Furthermore, large scale studies with hard clinical endpoints are needed to delineate the effect of pre-diabetes treatment on macro- and microvascular complications. In conclusion, several strategies of patient management, mainly lifestyle modification and pharmacological interventions can prevent diabetes development in subjects diagnosed with pre-diabetes or even revert pre-diabetic state. However, whether this biochemical improvement can be translated into actual clinical benefit remains to be established. European Journal of Pharmacology

Lipoprotein glomerulopathy is a rare disorder characterized by proteinuria, renal insufficiency and disturbances in lipoprotein metabolism closely related to those observed in type III hyperlipidemia. Rare mutations in apolipoprotein E (apoE) gene may contribute to the pathogenesis of the disease. This article reviews the clinical and laboratory features of lipoprotein glomerulopathy, discusses the mechanisms that may be implicated in its pathogenesis and summarizes the currently available therapeutic options.During the past years two new apoE gene mutations were described in Caucasian patients, apoE Modena (Arg150→Cys) and apoE Las Vegas (Ala152→Asp), a finding indicating that the disease may be more common in white populations than initially thought. Results from case studies suggest that fibrates improve renal pathology and may result in the complete clinical remission of the disease. LDL-apheresis or immunoadsorption onto staphylococcal protein A may also have a role in refractory cases.Lipid glomerulopathy is a rare, poorly understood disorder with potentially detrimental consequences. The determination of the effects of apoE mutations on the structural and functional characteristics of the mature protein may provide new insights in the pathogenesis of the disease. Meanwhile, intensive lipid-lowering may reduce proteinuria and preserve renal function in this patient group.

BACKGROUND: Acute kidney injury is a relatively common complication of aminoglycoside therapy that affects 10-20% of patients receiving antibiotics of this class. Although the vast majority of patients do recover, the presence of certain risk factors may alter the clinical presentation and result in permanent renal damage. Thus, aminoglycoside-induced nephrotoxicity is a major concern and early diagnosis is critical. The aim of the present study was to characterize the early stages of aminoglycoside-induced nephrotoxicity using proton nuclear magnetic resonance ((1)H NMR) spectroscopy of urine. METHODS: We studied 19 previously healthy patients who were hospitalized in our clinic due to bacterial infections. Combined antibiotic treatment with amikacin (1 g once daily) and a beta-lactam antibiotic was instituted in all patients. Urine and blood samples were collected before and after 5 days of aminoglycoside treatment. RESULTS: (1)H NMR spectroscopic data showed increased amounts of alanine and lactic acid (+138 and +255% compared to baseline values, respectively) and decreased hippurate (-50%) after aminoglycoside treatment. In addition, fractional excretions of sodium, magnesium and calcium were significantly increased (+271, +295 and +60%, respectively). These findings indicate that aminoglycosides can affect nephron tubules through two unrelated mechanisms that produce a partial 'Fanconi-like syndrome' and a 'Bartter-like syndrome'. However, because none of the study participants developed renal failure, these alterations are probably reversible and should not be used as sensitive or specific indicators of impending renal insufficiency. CONCLUSIONS: Our study findings confirm that aminoglycosides can induce both proximal and distal renal tubular dysfunction. However, it remains unclear whether the early functional changes detected by (1)H NMR spectroscopy in patients treated with aminoglycosides are of prognostic value. Nephrol Dial Transplant

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 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.

Objective Experimental studies have shown that the preβ-1 subclass of high-density lipoprotein particles (preβ-1 HDL) may play an important role in the reverse cholesterol transport pathway as the initial acceptors of cellular cholesterol. The aim of the present study was the direct comparison of preβ-1 HDL values in individuals with various types of primary dyslipidemias. Methods Four hundred and eighty-six unrelated individuals were included in the study. According to their lipid values study participants were subdivided into four groups: control group ( n = 206), type IIA dyslipidemia group ( n = 148), type IIB dyslipidemia group ( n = 49) and type IV dyslipidemia group ( n = 83). Results All dyslipidemic patients displayed higher concentrations of preβ-1 HDL compared to control individuals. However, patients with dyslipidemias characterized by an abnormal catabolism of triglyceride-rich lipoproteins (such as dyslipidemias of type IIB and IV) tend to have higher preβ-1 HDL values compared to patients with hypercholesterolemia, and this increase is proportional to the degree of hypertriglyceridemia. In addition, patients with metabolic syndrome exhibited significantly higher levels of preβ-1 HDL compared to individuals that do not fulfill the criteria for the diagnosis of this syndrome. Multiple regression analysis revealed that serum triglyceride concentrations and body mass index (BMI) values were the most important determinants of preβ-1 HDL levels in our population. Conclusion All dyslipidemic patients exhibit increased preβ-1 HDL concentrations as compared to normolipidemic individuals. Whether this increase represents a defensive mechanism against atherosclerosis or it is indicative of impaired maturation of HDL particles and thus of a defective reverse cholesterol transport mechanism remains to be established.

Background Orlistat significantly reduced serum triglycerides (TG) in most clinical trials. Orlistat-induced TG reduction has not been studied to determine the factors contributing to TG alterations in clinical settings. Objective We examined the factors influencing TG reduction during orlistat administration, alone or in combination with fenofibrate, and we investigated the effects of these treatments on apolipoprotein C-II (ApoC-II) and C-III (ApoC-III) levels. Methods Patients with the metabolic syndrome were randomly allocated to receive orlistat 120 mg three times daily (n = 28, O group), micronized fenofibrate 200 mg/day (n = 28, F group), or both (n = 27, OF group) for 6 months. Plasma ApoC-II and ApoC-III were determined by an immunoturbidimetric assay. Results In the O group, we observed reductions of plasma ApoC-III ( P P = NS) levels. Fenofibrate administration significantly reduced concentrations of ApoC-II and ApoC-III, whereas the combination of orlistat and fenofibrate had an additive effect on these apolipoproteins. There were significant in-group reductions in serum TG levels in all treatment groups. Multivariate analysis showed that in O group's baseline TG levels were independently positively correlated, whereas the baseline ApoC-II levels were negatively correlated with TG-lowering. In the F group, baseline TG levels and ApoC-III reduction were significantly and independently correlated with TG reduction. OF group's baseline TG levels and ApoC-III reduction were independently positively correlated and baseline ApoC-II levels were negatively correlated with TG-lowering. Conclusions Orlistat-mediated TG-lowering is independently associated with baseline TG and ApoC-II levels. When orlistat is combined with fenofibrate, ApoC-III reduction is another independent contributor to TG alterations.

Background To assess the metabolic profile and the prevalence of the metabolic triad (i.e. hyperinsulinaemia, hyperapobetalipoproteinaemia, and decreased low-density lipoprotein particle size) in women characterized by the hypertriglyceridaemic waist (HTGW) phenotype and to identify cut-off values for triglycerides and waist circumference, effectively discriminating women with the metabolic triad. Methods Two hundred and twenty-eight female subjects without any history of vascular disease or diabetes mellitus attending an Outpatient Lipid Clinic setting at the University Hospital of Ioannina, Greece were studied. Results Currently available HTGW criteria for women were unable to detect any significant differences in the metabolic profile either in the pre- or post-menopausal women, and proved similar in terms of sensitivity and specificity in identifying women with the metabolic triad. A cut-off value of 1.26 mmol/L for triglycerides and 84.5 cm for waist circumference were determined by Receiver-operating Curve evaluation. Women with both triglycerides and waist circumference above these thresholds had four-fold higher odds of presenting with the metabolic triad compared with women with non-HTGW phenotype. Conclusions A HTGW phenotype definition of 1.26 mmol/L for triglycerides and 84.5 cm for waist circumference may effectively identify Mediterranean women with the atherogenic metabolic triad. Whether these criteria are also associated with a higher incidence of vascular disease and/or new-onset diabetes in women remains to be investigated. Copyright © 2007 John Wiley & Sons, Ltd.

We describe the case of a 17-year-old girl who was admitted to our clinic for drug poisoning. Twelve hours after the ingestion of 25 tablets of aspirin (12.5 g of acetylsalicylic acid), the patient had a generalized proximal tubular dysfunction characterized by glucosuria (in the face of normal serum glucose levels), proteinuria, and uric acid wasting. Further characterization of the tubular dysfunction using high-resolution proton nuclear magnetic resonance spectroscopy of the urine showed a pattern consistent with proximal tubular injury. An important characteristic of the salicylate-induced proximal tubular dysfunction in our patient was its rapid reversibility. A trend toward normalization of fractional excretion values of electrolytes was observed 2 days after ingestion. Determination of serum and urine metabolites and spectroscopy of urine 15 days later showed no evidence of tubular dysfunction. The mechanisms potentially implicated in the pathogenesis of salicylate-induced Fanconi syndrome are discussed and a brief review of the relevant literature is provided. Am J Kidney Dis