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Background The cumulative effect of postpartum weight retention from each pregnancy in a woman’s life may contribute to her risk of ultimately developing type 2 diabetes and cardiovascular disease. However, there is limited direct evidence supporting this hypothesis. Thus, we sought to characterize the impact of postpartum weight retention on the trajectories of cardiovascular risk factors over the first 5-years after pregnancy. Methods In this prospective observational cohort study, 330 women (mean age 35.7±4.3 years, mean prepregnancy body mass index 25.2±4.8 kg/m2 , 50.9% primiparous) underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, oral glucose tolerance test, insulin sensitivity/resistance (Matsuda index, HOMA-IR), C-reactive protein (CRP), adiponectin) at 1-year, 3-years, and 5-years postpartum. Based on the magnitude of weight change between pre-pregnancy and 5-years postpartum, they were stratified into the following 3 groups: weight loss (n=100), weight gain 0–6% (n=110), and weight gain≥6% (n=120). Results At 1-year postpartum, cardiovascular risk factors did not differ between the groups. However, an adverse risk factor profile progressively emerged in the weight retention groups at 3- and 5-years. Indeed, after covariate adjustment, there was stepwise worsening (from the weight loss group to weight gain 0–6% to weight gain≥6% group) of the following cardiovascular risk factors at 5-years: triglycerides (p=0.001), HDL (p=0.02), LDL (p=0.01), apolipoprotein-B (p=0.003), Matsuda index (p<0.0001), HOMA-IR (p<0.0001), fasting glucose (p=0.07), and CRP (p=0.01). Moreover, on logistic regression analyses, weight gain≥6% emerged as an independent predictor of prediabetes/diabetes at 5-years (adjusted OR=3.40, 95%CI: 1.63–7.09). Conclusion Postpartum weight retention predicts trajectories of worsening cardiovascular risk factors and glucose intolerance over the first 5-years after delivery, consistent with its postulated contribution to future vascular disease in women. [ABSTRACT FROM AUTHOR]

Background: Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity. Methods: ASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration. Results: ASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function. Conclusion: ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein (LDL)-cholesterol is positively associated with cardiovascular disease (CVD) and inversely associated with type 2 diabetes, which could detract from lipid modification. Here, we examined whether lipid traits potentially relevant to CVD aetiology, i.e. apolipoprotein B (apoB), triglycerides (TG) and lipoprotein(a) [Lp(a)] exhibited the same associations. We investigated sex-specifically, including the role of sex hormones, because sex disparities exist in lipid profile and type 2 diabetes. We also replicated where possible. Methods: We used Mendelian randomization (MR) to examine sex-specific associations of apoB, TG and Lp(a) with type 2 diabetes, HbA1c, fasting insulin, fasting glucose, testosterone and estradiol in the largest relevant sex-specific genome-wide association studies (GWAS) in people of European ancestry and replicated where possible. We also assessed sex-specific associations of liability to type 2 diabetes with apoB, TG and Lp(a). Results: Genetically predicted apoB and Lp(a) had little association with type 2 diabetes or glycemic traits in women or men. Genetically predicted higher TG was associated with higher type 2 diabetes risk [odds ratio (OR) 1.44 per standard deviation (SD), 95% confidence interval (CI) 1.26 to 1.65], HbA1c and fasting insulin specifically in women. Higher TG was associated with lower testosterone in women and higher testosterone in men, but with lower estradiol in men and women. Genetic liability to type 2 diabetes was associated with higher TG in women, and possibly with lower apoB in men. Conclusions: Lipid traits potentially relevant to CVD aetiology do not exhibit contrasting associations with CVD and type 2 diabetes. However, higher TG is associated with higher type 2 diabetes risk and glycemic traits, which in turn further increases TG specifically in women, possibly driven by sex hormones. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein (LDL)-cholesterol is positively associated with cardiovascular disease (CVD) and inversely associated with type 2 diabetes, which could detract from lipid modification. Here, we examined whether lipid traits potentially relevant to CVD aetiology, i.e. apolipoprotein B (apoB), triglycerides (TG) and lipoprotein(a) [Lp(a)] exhibited the same associations. We investigated sex-specifically, including the role of sex hormones, because sex disparities exist in lipid profile and type 2 diabetes. We also replicated where possible. Methods: We used Mendelian randomization (MR) to examine sex-specific associations of apoB, TG and Lp(a) with type 2 diabetes, HbA1c, fasting insulin, fasting glucose, testosterone and estradiol in the largest relevant sex-specific genome-wide association studies (GWAS) in people of European ancestry and replicated where possible. We also assessed sex-specific associations of liability to type 2 diabetes with apoB, TG and Lp(a). Results: Genetically predicted apoB and Lp(a) had little association with type 2 diabetes or glycemic traits in women or men. Genetically predicted higher TG was associated with higher type 2 diabetes risk [odds ratio (OR) 1.44 per standard deviation (SD), 95% confidence interval (CI) 1.26 to 1.65], HbA1c and fasting insulin specifically in women. Higher TG was associated with lower testosterone in women and higher testosterone in men, but with lower estradiol in men and women. Genetic liability to type 2 diabetes was associated with higher TG in women, and possibly with lower apoB in men. Conclusions: Lipid traits potentially relevant to CVD aetiology do not exhibit contrasting associations with CVD and type 2 diabetes. However, higher TG is associated with higher type 2 diabetes risk and glycemic traits, which in turn further increases TG specifically in women, possibly driven by sex hormones. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease remains the leading cause of mortality in individuals with diabetes and improved understanding of its pathophysiology is needed. We investigated the association of a large panel of metabolites and molecular lipid species with future cardiovascular events in type 1 diabetes. Methods: The study included 669 individuals with type 1 diabetes. Non-targeted serum metabolomics and lipidomics analyses were performed using mass spectrometry. Data on cardiovascular events (cardiovascular mortality, coronary artery disease, stroke, and peripheral arterial interventions) were obtained from Danish Health registries and analyzed by Cox hazards models. Metabolites and molecular lipid species were analyzed in univariate models adjusted for false discovery rate (FDR). Metabolites and molecular lipid species fulfilling a pFDR < 0.05 were subsequently analyzed in adjusted models including age, sex, hemoglobin A1c, mean arterial pressure, smoking, body mass index, low-density lipoprotein cholesterol, estimated glomerular filtration rate, urinary albumin excretion rate and previous cardiovascular disease. Analyses of molecular lipid species were further adjusted for triglycerides and statin use. Results: Of the included participants, 55% were male and mean age was 55 ± 13 years. Higher 4-hydroxyphenylacetic acid (HR 1.35, CI [1.01–1.80], p = 0.04) and lower threonine (HR 0.81, CI [0.67–0.98] p = 0.03) were associated with development of cardiovascular events (n = 95). In lipidomics analysis, higher levels of three different species, diacyl-phosphatidylcholines (PC)(36:2) (HR 0.82, CI [0.70–0.98], p = 0.02), alkyl-acyl-phosphatidylcholines (PC-O)(34:2) (HR 0.76, CI [0.59–0.98], p = 0.03) and (PC-O)(34:3) (HR 0.75, CI [0.58–0.97], p = 0.03), correlated with lower risk of cardiovascular events, whereas higher sphingomyelin (SM)(34:1) (HR 1.32, CI [1.04–1.68], p = 0.02), was associated with an increased risk. Conclusions: Circulating metabolites and molecular lipid species were associated with future cardiovascular events in type 1 diabetes. While the causal effect of these biomolecules on the cardiovascular system remains unknown, our findings support that omics-based technologies, although still in an early phase, may have the potential to unravel new pathways and biomarkers in the field of cardiovascular disease in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Assessing the spectrum of disease risk associated with hypertriglyceridemia is needed to inform potential benefits from emerging triglyceride lowering treatments. We sought to examine the associations between a full range of plasma triglyceride concentration with five clinical outcomes. Methods: We used linked data from primary and secondary care for 15 M people, to explore the association between triglyceride concentration and risk of acute pancreatitis, chronic pancreatitis, new onset diabetes, myocardial infarction and all-cause mortality, over a median of 6–7 years follow up. Results: Triglyceride concentration was available for 1,530,411 individuals (mean age 56·6 ± 15·6 years, 51·4% female), with a median of 1·3 mmol/L (IQR: 0.9.to 1.9). Severe hypertriglyceridemia, defined as > 10 mmol/L, was identified in 3289 (0·21%) individuals including 620 with > 20 mmol/L. In multivariable analyses, a triglyceride concentration > 20 mmol/L was associated with very high risk for acute pancreatitis (Hazard ratio (HR) 13·55 (95% CI 9·15–20·06)); chronic pancreatitis (HR 25·19 (14·91–42·55)); and high risk for diabetes (HR 5·28 (4·51–6·18)) and all-cause mortality (HR 3·62 (2·82–4·65)) when compared to the reference category of ≤ 1·7 mmol/L. An association with myocardial infarction, however, was only observed for more moderate hypertriglyceridaemia between 1.7 and 10 mmol/L. We found a risk interaction with age, with higher risks for all outcomes including mortality among those ≤ 40 years compared to > 40 years. Conclusions: We highlight an exponential association between severe hypertriglyceridaemia and risk of incident acute and chronic pancreatitis, new diabetes, and mortality, especially at younger ages, but not for myocardial infarction for which only moderate hypertriglyceridemia conferred risk. [ABSTRACT FROM AUTHOR]

Background: Insulin resistance is a risk factor for cardiovascular disease. Recently, we have developed a novel index, FLAIS (Fasting Laboratory Assessment of Insulin Sensitivity), which accurately reflects insulin sensitivity, measured with hyperinsulinemic-euglycemic clamp, in different groups of subjects. The aim of the present study was to assess the relationship of FLAIS with cardiovascular risk factors in a population-based study. Methods: The study group comprised 339 individuals from the ongoing Białystok Plus study, without previously known diabetes. Clinical examination, oral glucose tolerance test and the measurement of blood laboratory parameters were performed. Results: Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) was diagnosed in 165 individuals whereas type 2 diabetes was diagnosed in 19 subjects. FLAIS was lower in individuals with prediabetes and diabetes in comparison with individuals with normal glucose tolerance. FLAIS was significantly related to waist circumference, systolic and diastolic blood pressure, triglycerides, HDL-cholesterol and LDL-cholesterol in the entire study group and in the subgroups with normal glucose tolerance and with prediabetes/diabetes. HOMA-IR, QUICKI and Matsuda index were not related to blood pressure and LDL-cholesterol in individuals with normal glucose tolerance. Majority of the adjusted models with FLAIS were characterized by better fit with the data in comparison with other indices for all cardiovascular risk factors except waist circumference. Conclusions: FLAIS represents useful index to assess the cluster of insulin resistance-associated cardiovascular risk factors in general population. [ABSTRACT FROM AUTHOR]

Background: Distinguishable sex differences exist in fat mass and muscle mass. High fat mass and low muscle mass are independently associated with cardiovascular disease (CVD) risk factors in people living with type 2 diabetes; however, it is unknown if the association between fat mass and CVD risk is modified by muscle mass, or vice versa. This study examined the sex-specific interplay between fat mass and muscle mass on CVD risk factors in adults with type 2 diabetes living with overweight and obesity. Methods: Dual-energy X-ray absorptiometry (DXA) measures were used to compute fat mass index (FMI) and appendicular muscle mass index (ASMI), and participants were separated into high-fat mass vs. low-fat mass and high-muscle mass vs. low-muscle mass. A two-way analysis of covariance (ANCOVA: high-FMI vs. low-FMI by high-ASMI vs. low-ASMI) was performed on CVD risk factors (i.e., hemoglobin A1C [A1C]; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; triglycerides; systolic and diastolic blood pressure; cardiorespiratory fitness, depression and health related-quality of life [HR-QoL]) at baseline and following a 1-year intensive lifestyle intervention (ILI) for females and males separately, with a primary focus on the fat mass by muscle mass interaction effects. Results: Data from 1,369 participants (62.7% females) who completed baseline DXA were analyzed. In females, there was a fat mass by muscle mass interaction effect on A1C (p = 0.016) at baseline. Post-hoc analysis showed that, in the low-FMI group, A1C was significantly higher in low-ASMI when compared to high-ASMI (60.3 ± 14.1 vs. 55.5 ± 13.5 mmol/mol, p = 0.023). In the high-FMI group, there was no difference between high-ASMI and low-ASMI (56.4 ± 12.5 vs. 56.5 ± 12.8 mmol/mol, p = 0.610). In males, only high-FMI was associated with higher A1C when compared to low-FMI (57.1 ± 14.4 vs. 54.2 ± 12.0 mmol/mol, p = 0.008) at baseline. Following ILI, there were significant fat mass by muscle mass interaction effects on changes in the mental component of HR-QoL in males. Conclusion: Considering that A1C predicts future CVD, strategies to lower A1C may be especially important in females with low fat and low muscle mass living with type 2 diabetes. Our results highlight the complicated and sex-specific contribution of fat mass and muscle mass to CVD risk factors. [ABSTRACT FROM AUTHOR]

Background: Both lipid and glucose abnormalities are associated with hypertension (HTN). However, it is unclear whether the triglyceride-glucose (TyG) index is associated with HTN. Therefore the aim of this study is to investigate the association of the TyG index and HTN and to compare the discriminative power of the TyG index, lipid, glycemic parameters for the risk of HTN in elderly individuals. Methods: The present study was nested in a longitudinal (REACTION) study from May 2011 to December 2011, which was designed to demonstrate the association of abnormal glucose metabolism with the risk of cancer in the Chinese population. In total, 47,808 participants were recruited in this cross-sectional study. The TyG index was divided into five groups: the < 20% group, the 20–39% group, the 40–59% group, the 60–79% group and the ≥ 80% group, according to quintile division of the subjects. Three multivariate logistic regression models were used to evaluate the association between the TyG vs. lipid parameters, glycemic parameters and HTN. Results: Multivariate logistic regression analysis shows that compared with lipid and glycemic parameters, the TyG index remains significantly associated with HTN in either total subjects or subjects separated into men and women (odds ratio (OR) 1.33, 95% confidence interval (CI) 1.18–1.51, p < 0.0001 in total subjects; OR 1.39, 95% CI 1.11–1.74, p = 0.0042 in men; OR 1.28, 95% CI 1.11–1.49, p = 0.0010 in women). In a stratified analysis, an elevated TyG index is significantly associated with HTN in the subgroup of the oldest age (≥ 65) (OR 1.67, 95% CI 1.30–2.14, p < 0.0001), as well as with obesity (Body mass index (BMI) ≥ 28 kg/m2) (OR 1.85, 95% CI 1.29–2.66, p = 0.0009) or lower estimated glomerular filtration rate (eGFR) (< 90 mL/(min·1.73 m2)) (OR 1.72, 95% CI 1.33–2.21, p < 0.0001). Conclusion: The TyG index is significantly associated with HTN and shows the superior discriminative ability for HTN compared with lipid and glycemic parameters in the Chinese elderly population. [ABSTRACT FROM AUTHOR]

Objective: Long-term treatment with up to 1.8 mg liraglutide improves cardiovascular and all-cause mortality in patients with type 2 diabetes at high risk for cardiovascular disease (CVD) and is currently under investigation in subjects without diabetes. Aim of our study was to investigate whether high dose (3 mg) short-term (5 weeks) treatment with liraglutide in obese patients with no overt type 2 diabetes affects metabolites, lipid and lipoprotein profile and components of activin–follistatin axis in cardiovascular beneficial or detrimental way. Research design and methods: Twenty obese patients participated in a randomized, placebo-controlled, cross-over, double-blind study and were administrated liraglutide 3 mg or placebo for 5 weeks. Metabolites, fatty acids, lipid–lipoprotein profile and concentrations of activins and follistatins (250 parameters) were assessed in serum at start and completion of each treatment. Results: Concentrations of important cardiovascular markers such as total, free and remnant cholesterol were reduced with liraglutide before and after adjusting for weight loss. Similarly, reductions in number of small and medium size LDL particles and in their total lipid concentration were observed with liraglutide and partially weight-loss related. Tyrosine levels were reduced and behenic acid levels were increased whereas only minor changes were observed in HDL, VLDL and IDL. Concentrations of activin AB and follistatin were significantly reduced in liraglutide-treated group. Conclusions: Treatment of obese patients without overt type 2 diabetes with high dose of liraglutide for a short period of time induces changes in lipid–lipoprotein and hormonal profile that are suggestive of lower risk of atherosclerosis and CVD. Trial registration ClinicalTrials.gov Identifier: NCT02944500. Study ID Number 2015P000327. Registered November 2016 [ABSTRACT FROM AUTHOR]

Background: We investigated whether or to what extent the interaction of lipoprotein (a) [Lp(a)] with cholesterol-containing lipids was associated with angiographic coronary collateralization in type 2 diabetic patients with chronic total occlusion. Methods: Serum levels of Lp(a), total cholesterol, low-density lipoprotein–cholesterol (LDL-C), high-density lipoprotein–cholesterol (HDL-C), and triglyceride were determined and non-HDL-C was calculated in 706 type 2 diabetic and 578 non-diabetic patients with stable coronary artery disease and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3). Results: For diabetic and non-diabetic patients, Lp(a), total cholesterol, LDL-C, and non-HDL-C levels were higher in patients with poor coronary collateralization than in those with good collateralization, whereas HDL-C and triglyceride levels were similar. After adjustment for potential confounding factors, tertiles of Lp(a), total cholesterol, LDL-C and non-HDL-C remained independent determinants for poor collateralization. A significant interaction between Lp(a) and total cholesterol, LDL-C or non-HDL-C was observed in diabetic patients (all P interaction < 0.001) but not in non-diabetics. At high tertile of total cholesterol (≥ 5.35 mmol/L), LDL-C (≥ 3.36 mmol/L) and non-HDL-C (≥ 4.38 mmol/L), diabetic patients with high tertile of Lp(a) (≥ 30.23 mg/dL) had an increased risk of poor collateralization compared with those with low tertile of Lp(a) (< 12.66 mg/dL) (adjusted OR = 4.300, 3.970 and 4.386, respectively, all P < 0.001). Conclusions: Increased Lp(a) confers greater risk for poor coronary collateralization when total cholesterol, LDL-C or non-HDL-C are elevated especially for patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: The relationship between dyslipidemia, inflammation and CV organ damage in type 2 diabetes mellitus (T2DM) is complex. Insulin resistance and inflammatory cytokines interleukins (ILs) increase plasma triglycerides (TG). ILs also up-regulate expression of matrix-metalloproteinases (MMPs) that, together with TG, decrease high density lipoprotein cholesterol (HDL) levels. High TG, low HDL, increased ILs and MMPs trigger structural and functional changes in different parts of cardiovascular (CV) system. To understand better the role of lipids and inflammation in CV organ damage, the present study investigated the inter-relationships between lipids, ILs and MMPs, as well as the associations of lipids, ILs and MMPs with various CV measures, both in diabetic and non-diabetic population (nonT2DM). Methods: In T2DM patients (N = 191) and nonT2DM subjects (N = 94) were assessed carotid intima-media thickness (cIMT) and inter-adventitial diameter (IADiam), carotid wave speed (ccaWS), carotid-femoral pulse wave velocity (cfPWV), left ventricular (LV) mass, LV systolic (s′) and early diastolic (e′) longitudinal velocities of mitral annulus, together with glycemic control, lipid profile, IL-6, IL-18 and MMP-12. Results: T2DM patients, as compared to nonT2DM subjects, had significantly higher plasma levels of IL-6, IL-18, MMP-12 and lower HDL (P < 0.05–0.0001). They had also higher cIMT, IADiam, ccaWS, cfPWV and LV mass, and lower e′ velocity (P < 0.005–0.0001). Both in T2DM patients and nonT2DM subjects, MMP-12 increased with IL-6 (r = 0.43 and 0.39; P < 0.0001) and IL-18 (r = 0.32 and 0.42; P < 0.0001), and HDL decreased with MMP-12 (r = − 0.29 and − 0.42; P < 0.0001). In both populations, MMP-12 was directly associated with IADiam, ccaWS, cfPWV and LV mass (r = 0.42, 0.32, 0.26 and 0.29; P < 0.0001 in T2DM patients, and r = 0.39, 0.28, 0.32 and 0.27; P < 0.01–0.0001 in nonT2DM subjects). In multivariate analysis, MMP-12 remained independently related to IADiam, ccaWS, cfPWV and LV mass in T2DM patients, and to IADiam only in nonT2DM subjects. Conclusions: This cross-sectional study demonstrated a direct association between ILs and MMP-12, as well as an inverse association between MMP-12 and HDL, both in T2DM patients and in nonT2DM subjects. In T2DM patients, who had higher levels of ILs and MMP-12, the latter was independently related to several structural and functional markers of preclinical CV organ damage. [ABSTRACT FROM AUTHOR]

Background: Carotid artery intima-media thickness (cIMT) progression is a surrogate marker of atherosclerosis with a high predictive value for future CVD risk. This study evaluates the comparative efficacies of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on cIMT progression. Methods: We conducted a network meta-analysis (NMA) to evaluate the relative efficacies of several drug classes in modifying cIMT progression. After a literature search in several electronic databases, studies were selected by following predetermined eligibility criteria. An inverse variance-heterogeneity model was used for NMA. Sensitivity analyses were performed to check the reliability of the overall NMA, and transitivity analyses were performed to examine the effects of modifiers on the NMA outcomes. Results: Data were taken from 47 studies (15,721 patients; age: 60.2 years [95% confidence interval (CI) 58.8, 61.6]; BMI: 27.2 kg/m2 [95% CI 26.4, 28.0]; and gender: 58.3% males [95% CI 48.3, 68.3]). Treatment duration was 25.8 months [95% CI 22.9, 28.7]. Of the 13 drug classes in the network, treatment with phosphodiesterase III inhibitors was the most effective in retarding annual mean cIMT against network placebo (weighted mean difference (WMD) − 0.059 mm [95% CI − 0.099, − 0.020) followed by the calcium channel blockers (WMD − 0.055 mm [95% CI − 0.099, 0.001]) and platelet adenosine diphosphate inhibitors (WMD − 0.033 mm [95% CI − 0.058, 0.008]). These 3 drug classes also attained the same positions when the NMA was conducted by using first-year changes in mean cIMT. In transitivity analyses, longer treatment duration, higher body mass index (BMI), and a higher baseline cIMT were found to be independently associated with a lesser reduction in annual mean cIMT. However, in a multivariate analysis with these 3 modifiers, none of these factors was significantly associated with annual change in mean cIMT. In the placebo group, age was inversely associated with annual change in mean cIMT independently. Conclusion: Phosphodiesterase III inhibitors and calcium channel blockers are found more effective than other drug classes in retarding cIMT progression. Age, BMI, and baseline cIMT may have some impact on these outcomes. [ABSTRACT FROM AUTHOR]

Background: Coronary atherosclerosis progresses faster in patients with diabetes mellitus (DM) and causes higher morbidity and mortality in such patients compared to non-diabetics ones (non-DM). We quantify changes in plaque volume and plaque phenotype during lipid-lowering therapy in DM versus non-DM patients using advanced intracoronary imaging. Methods: We analyzed data from 61 patients with stable angina pectoris included to the PREDICT trial searching for prediction of plaque changes during intensive lipid-lowering therapy (40 mg rosuvastatin daily). Geometrically correct, fully 3-D representation of the vascular wall surfaces and intravascular ultrasound virtual histology (IVUS-VH) defined tissue characterization was obtained via fusion of two-plane angiography and IVUS-VH. Frame-based indices of plaque morphology and virtual histology analyses were computed and averaged in 5 mm long baseline/follow-up registered vessel segments covering the entire length of the two sequential pullbacks (baseline, 1-year). We analyzed 698 5-mm-long segments and calculated the Liverpool active plaque score (LAPS). Results: Despite reaching similar levels of LDL cholesterol (DM 2.12 ± 0.91 mmol/l, non-DM 1.8 ± 0.66 mmol/l, p = 0.21), DM patients experienced, compared to non-DM ones, higher progression of mean plaque area (0.47 ± 1.15 mm2 vs. 0.21 ± 0.97, p = 0.001), percent atheroma volume (0.7 ± 2.8% vs. - 1.4 ± 2.5%, p = 0.007), increase of LAPS (0.23 ± 1.66 vs. 0.13 ± 1.79, p = 0.018), and exhibited more locations with TCFA (Thin-Cap Fibro- Atheroma) plaque phenotype in 5 mm vessel segments (20.3% vs. 12.5%, p = 0.01). However, only non-DM patients reached significant decrease of LDL cholesterol. Plaque changes were more pronounced in PIT (pathologic intimal thickening) compared to TCFA with increased plaque area in both phenotypes in DM patients. Conclusion: Based on detailed 3D analysis, we found advanced plaque phenotype and further atherosclerosis progression in DM patients despite the same reached levels of LDLc as in non-DM patients. [ABSTRACT FROM AUTHOR]

Cardiovascular disease, predominantly ischemic heart disease (IHD), is the leading cause of death in diabetes mellitus (DM). In addition to eliciting cardiomyopathy, DM induces a 'wicked triumvirate': (i) increasing the risk and incidence of IHD and myocardial ischemia; (ii) decreasing myocardial tolerance to ischemia-reperfusion (I-R) injury; and (iii) inhibiting or eliminating responses to cardioprotective stimuli. Changes in ischemic tolerance and cardioprotective signaling may contribute to substantially higher mortality and morbidity following ischemic insult in DM patients. Among the diverse mechanisms implicated in diabetic impairment of ischemic tolerance and cardioprotection, changes in sarcolemmal makeup may play an overarching role and are considered in detail in the current review. Observations predominantly in animal models reveal DM-dependent changes in membrane lipid composition (cholesterol and triglyceride accumulation, fatty acid saturation vs. reduced desaturation, phospholipid remodeling) that contribute to modulation of caveolar domains, gap junctions and T-tubules. These modifications influence sarcolemmal biophysical properties, receptor and phospholipid signaling, ion channel and transporter functions, contributing to contractile and electrophysiological dysfunction, cardiomyopathy, ischemic intolerance and suppression of protective signaling. A better understanding of these sarcolemmal abnormalities in types I and II DM (T1DM, T2DM) can inform approaches to limiting cardiomyopathy, associated IHD and their consequences. Key knowledge gaps include details of sarcolemmal changes in models of T2DM, temporal patterns of lipid, microdomain and T-tubule changes during disease development, and the precise impacts of these diverse sarcolemmal modifications. Importantly, exercise, dietary, pharmacological and gene approaches have potential for improving sarcolemmal makeup, and thus myocyte function and stress-resistance in this ubiquitous metabolic disorder. [ABSTRACT FROM AUTHOR]

Background: Recently, genetic studies have suggested a causal relationship between cholesterol remnants and ischemic heart disease. We aimed to determine whether cholesterol remnants and its marker, triglyceride levels, are associated with cardiac function as determined by sensitive echocardiographic measures in a population of patients with type 2 diabetes. Methods: Comprehensive echocardiography including 2D-speckle tracking echocardiography was performed on a representative sample of 924 patients with type 2 diabetes-730 of whom were treated with statins. These were recruited from two large secondary care centers. Results: In multivariable analyses, triglycerides and cholesterol remnants were not associated with left ventricular ejection fraction, but with subtle measures of systolic function, including global longitudinal strain by speckle tracking and longitudinal displacement by tissue Doppler echocardiography: global longitudinal strain [0.33 % (0.14), p = 0.02 per doubling in cholesterol remnants and 0.28 % (0.13), p = 0.03 per doubling in triglyceride levels] and with longitudinal displacement [-0.25 mm (0.10), p = 0.01 per doubling in cholesterol remnants and -0.25 mm (0.09), p = 0.005 per doubling in triglyceride levels]. Subgroup analyses of patients receiving statin therapy and patients without known heart disease revealed similar results, but the association was not present in patients with known heart disease. Conclusion: In patients with type 2 diabetes, subtle decrease in left ventricular function is present with increasing levels of cholesterol remnants and triglyceride levels indicating an effect of these on cardiac function that is not detectable by conventional echocardiography. [ABSTRACT FROM AUTHOR]

Background: PCSK9 inhibition is a new powerful cholesterol-lowering strategy. Recently, it was reported that CETP inhibitors influence PCSK9 levels as an off-target effect. We explored the relationship between circulating PCSK9 levels and CETP activity in patients with metabolic disease who were not on lipid-lowering therapy. Methods: Plasma CETP activity and PCSK9 levels were measured in 450 participants (median age, 58 years; 49% women) who attended the metabolism unit because of metabolic syndrome (MetS) (78%), atherogenic dyslipidemia (32%), obesity (50%), type 2 diabetes mellitus (72%), and other risk factors (13%). A 6 week lipid-lowering drug wash-out period was established in treated patients. Results: Both PCSK9 levels and CETP activity were higher in patients with an increasing number of MetS components. PCSK9 levels were positively correlated with CETP activity in the entire cohort (r = 0.256, P < 0.0001) independent of age, gender, body mass index (BMI), systolic blood pressure (SBP), LDL cholesterol (LDL-C), triglycerides and glucose. Individuals with the loss-of-function PCSK9 genetic variant rs11591147 (R46L) had lower levels of PCSK9 (36.5%, P < 0.0001) and LDL-C (17.8%, P = 0.010) as well as lower CETP activity (10.31%, P = 0.009). This association remained significant in the multiple regression analysis even after adjusting for gender, age, BMI, LDL-C, triglycerides, glucose, lecithin-cholesterol acyltransferase, SBP and MetS (P = 0.003). Conclusions: Our data suggest a metabolic association between PCSK9 and CETP independent of lipid-lowering treatment. The clinical implications of this metabolic relationship could be relevant for explaining the effect of PCSK9 and CETP inhibition on overall lipid profiles. [ABSTRACT FROM AUTHOR]

Background: The genetic contribution to complex diseases or traits, including cardio-metabolic traits, has been elucidated recently by large-scale genome-wide association studies. These genome-wide association studies have indicated that most pleiotropic loci contain genes associated with lipids. Clinically, lipid related abnormalities are strongly associated with other diseases such as type 2 diabetes, coronary artery disease and hypertension. The aim of this study was to evaluate the shared genetic background of lipids and other cardio-metabolic traits. Methods: We conducted meta-analyses of the association between 157 published lipid-associated loci and 10 cardio- metabolic traits in 14,028 Korean individuals genotyped using the Exome chip (Illumina HumanExome BeadChip). We also examined whether the pleiotropic effects of such loci constituted independent (i.e., biological) pleiotropy or mediated pleiotropy in these metabolic pathways. Results: Eighteen lipid-associated loci were significantly associated with one of six cardio-metabolic traits after correction for multiple testing (P < 3.70 ? 10-4). Region 12q24.12 had pleiotropic effects on fasting plasma glucose, blood pressure and obesity-related traits (body mass index and waist-hip ratio) independent of its effects on the lipid profile. Lipid risk scores, calculated according to whether or not subjects carried the risk allele for lipid traits, were significantly associated with fasting plasma glucose, blood pressure and obesity-related traits. Conclusions: The 12q24.12 region showed ethnic-specific genetic pleiotropy among cardio-metabolic traits in this study. Our findings may help to account for molecular mechanisms based on shared genetic background underlying not only dyslipidemia, but also cardiovascular disease and type 2 diabetes. [ABSTRACT FROM AUTHOR]

Background: Recent data support the renewed interest in hypertriglyceridemia as a possible important therapeutic target for cardiovascular risk reduction. This study was designed to address the question of all-cause mortality during extended follow-up of the BIP trial in patients stratified by baseline triglyceride levels. Methods: In the BIP trial 3090 patients with proven coronary artery disease were randomized to bezafibrate 400 mg/ day or placebo. All-cause mortality data after 20 years of follow-up, were obtained from the National Israeli Population Registry. Patients with hypertriglyceridemia (triglycerides ≥200 mg/dL, n = 458) were equally distributed among the study groups (15% in both placebo and bezafibrate groups). Results: During follow-up 1869 patients died (952 in placebo vs. 917 in bezafibrate group). Following multivariate adjustment allocation to bezafibrate was associated with small but significant 10% mortality risk reduction (HR 0.90; 95% CI 0.82-0.98, p = 0.026). Variables associated with significantly increased mortality risk were history of a past MI, NYHA class, diabetes, age, higher BMI and glucose level. In patients with hypertriglyceridemia multivariate analysis demonstrated a 25% all-cause mortality risk reduction associated with allocation to bezafibrate (HR 0.75, CI 95% 0.60-0.94; p = 0.012). In patients without hypertriglyceridemia bezafibrate had no significant effect on long-term mortality. Conclusions: During long-term follow-up bezafibrate-allocated patients experienced a modest but significant 10% reduction in the adjusted risk of mortality. This effect of bezafibrate was more prominent among patients with baseline hypertriglyceridemia (25% mortality risk reduction). [ABSTRACT FROM AUTHOR]

Background: Diabetes is a major cardiovascular risk factor. However, its influence on the rate of occurrence of cardiovascular (CV) events during a clinical trial that included a diabetes subgroup has not yet been quantified. Aims: To establish equations relating baseline diabetes prevalence and incident CV events, based on comparator arms data of major lipid-modifying trials. Methods: Meta-analysis of primary outcomes (PO) rates of key prospective trials, for which the baseline proportion of diabetics was reported, including studies having specifically reported CV outcomes within their diabetic subgroups. Results: 47 studies, representing 330,376 patients (among whom 124,115 diabetics), were analyzed as regards the relationship between CV outcomes rates (including CHD) and the number of diabetics enrolled. Altogether, a total of 18,445 and 16,156 events occurred in the comparator and treatment arms, respectively. There were significant linear relationships between diabetes prevalence and both PO and CHD rates (%/year): y = 0.0299*x + 3.12 [PO] (p = 0.0128); and y = 0.0531*x+ 1.54 [CHD] (p = 0.0094), baseline diabetes predicting PO rates between 3.12 %/year (no diabetic included) and 6.11 %/year (all patients diabetic); and CHD rates between 1.54 %/year (no diabetic) and 6.85 %/year (all patients diabetic). The slopes of the equations did not differ according to whether they were derived from primary or secondary prevention trials. Conclusions: Absolute and relative CV risk associated with diabetes at inclusion can be readily predicted using linear equations relating diabetes prevalence to primary outcomes or CHD rates. [ABSTRACT FROM AUTHOR]

Background Evidence from the literature suggests diminished acetylsalicylic acid (ASA) treatment efficacy in type 2 diabetes (DM2). High onaspirin platelet reactivity (HAPR) in DM2 has been linked to poor glycemic and lipid control. However, there are no consistent data on the association between HAPR and insulin resistance or adipose tissue metabolic activity. The aim of this study was to assess the relationship between laboratory response to ASA and metabolic control, insulin resistance and adipokines in DM2. Methods A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median Methods A total of 186 DM2 patients treated with oral antidiabetic drugs and receiving 75 mg ASA daily were included in the analysis. Response to ASA was assessed by measuring serum thromboxane B2 (TXB2) concentration and expressed as quartiles of TXB2 level. The achievement of treatment targets in terms of glycemic and lipid control, insulin resistance parameters (including Homeostatic Model Assessment-Insulin Resistance, HOMA-IR, index), and serum concentrations of high-molecular weight (HMW) adiponectin, leptin and resistin, were evaluated in all patients. Univariate and multivariate logistic regression analyses were performed to determine the predictive factors of serum TXB2 concentration above the upper quartile and above the median Conclusions These results suggest that in DM2, the most important predictor of HAPR is younger age. Younger DM2 patients may therefore require total daily ASA doses higher than 75 mg, preferably as a twice-daily regimen, to achieve full therapeutic effect. Higher BMI and lower HMW adiponectin concentration were also associated with less potent ASA effect. This is the first study to demonstrate an association of lower adiponectin concentration with higher serum TXB2 level in patients treated with ASA. [ABSTRACT FROM AUTHOR]

Sepsis is a common disease that continues to increase in incidence in the world. Diseases, such as diabetes, may make the situation worse. Diabetic patients are at increased risk for common infections. This study was designed to investigate the role of glibenclamide on myocardial injury by lipopolysaccharides (LPS) in streptozotocin induced diabetic mice (STZ-mice). Methods LPS was used to induce endotoxemia in STZ-mice. Heart rate and mean arterial pressure were measured by MPA-HBBS. Serum epinephrine level was measured by enzyme-linked immunosorbent assays (ELISA). Myocardial injury was examined by light and transmission electron microscope and TUNEL staining. Macrophage infiltration was measured by immunohistochemistry. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) levels in myocardial tissue and serum in STZ-mice, and in conditional medium of primary cultured peritoneal macrophages were determined by ELISA. Nalp3 and Caspase-1 protein levels were measured by Western blotting analysis. Results STZ administration decreased body weight and increased blood glucose in C57BL/6 mice. LPS injection caused decreases of heart rate and mean arterial pressure, and elevated serum epinephrine level in C57BL/6 mice. Compared with control mice without STZ treatment, LPS induced more severe myocardial injury and macrophage infiltration in STZ-mice, which was attenuated by pretreatment of glibenclamide. LPS stimulation enhanced the levels of IL- 1β and TNF-α in both cardiac tissue and serum. Glibenclamide pretreatment significantly inhibited the serum levels of pro-inflammatory cytokines. Either high glucose or LPS increased the levels of IL-1β and TNF-α in the conditional medium of peritoneal macrophages. Glibenclamide treatment suppressed the increase of IL-1β level induced by high glucose and LPS. Furthermore, Nalp3 and Caspase-1 levels were markedly increased by high glucose plus LPS, and both proteins were significantly inhibited by glibenclamide treatment. Conclusions We conclude that glibenclamide could attenuate myocardial injury induced by LPS challenge in STZ-mice, which was possibly related to inhibiting inflammation through Nalp3 inflammasomes. [ABSTRACT FROM AUTHOR]

Background: Non-fasting triglyceride-rich lipoproteins cholesterol (TRL-C) contributes to cardiovascular risk, in that it includes remnant cholesterol (RC). TRL-C is computed as total C - [LDL-C + HDL-C]. Such calculation applies only if LDL-C is directly measured, or obtained from a non-Friedewald's formula, a method as yet never benchmarked against independent markers of TRL burden. Methods: The Discriminant Ratio (DR) methodology was used in 120 type 2 diabetic patients in order: (i) to compute TRL-C from non-fasting lipids, (ii) to establish the performance of TRL-C and TRL-C/apoA-I (vs. TG-based markers) to grade TRLs and atherogenic dyslipidemia (AD), and (iii) to relate TRL-C with non-fasting TG. Results: Depending on apoB100 availability, TRL-C (mg/dL) can be derived from non-fasting lipids in two ways: (a) total cholesterol (TC) - [(0.0106 * TC - 0.0036 * TG + 0.017 * apoB100 - 0.27) * 38.6] - HDL-C, and (b) TC - [(0.0106 * TC - 0.0036 * TG + 0.017 * [0.65 * (TC - HDL-C) + 6.3] - 0.27) * 38.6] - HDL-C. Discrimination between log[TG] and TRL-C was similar (DR 0.94 and 0.84, respectively), whereas that of log[TG]/HDL-C was better than TRL-C/apoA-I (DR 1.01 vs. 0.65; p 0.0482). All Pearson's correlations between pairs reached unity, allowing formulation of two unbiased equivalence equations: (a) TRL-C = 97.8 * log[TG] - 181.9, and (b) TRL-C/apoA-I = 8.15 * (log[TG]/HDL-C) - 0.18. Conclusions: TRL-C and log[TG] are as effective and interchangeable for assessing remnant atherogenic particles. For grading TRL-AD, it is best to use log[TG]/HDL-C, inherently superior to TRL-C/apoA-I, while measuring the same underlying variable. [ABSTRACT FROM AUTHOR]

Background: Although hypercaloric interventions are associated with nutritional, endocrine, metabolic, and cardiovascular disorders in obesity experiments, a rational distinction between the effects of excess adiposity and the individual roles of dietary macronutrients in relation to these disturbances has not previously been studied. This investigation analyzed the correlation between ingested macronutrients (including sucrose and saturated and unsaturated fatty acids) plus body adiposity and metabolic, hormonal, and cardiovascular effects in rats with diet-induced obesity. Methods: Normotensive Wistar-Kyoto rats were submitted to Control (CD; 3.2 Kcal/g) and Hypercaloric (HD; 4.6 Kcal/g) diets for 20 weeks followed by nutritional evaluation involving body weight and adiposity measurement. Metabolic and hormonal parameters included glycemia, insulin, insulin resistance, and leptin. Cardiovascular analysis included systolic blood pressure profile, echocardiography, morphometric study of myocardial morphology, and myosin heavy chain (MHC) protein expression. Canonical correlation analysis was used to evaluate the relationships between dietary macronutrients plus adiposity and metabolic, hormonal, and cardiovascular parameters. Results: Although final group body weights did not differ, HD presented higher adiposity than CD. Diet induced hyperglycemia while insulin and leptin levels remained unchanged. In a cardiovascular context, systolic blood pressure increased with time only in HD. Additionally, in vivo echocardiography revealed cardiac hypertrophy and improved systolic performance in HD compared to CD; and while cardiomyocyte size was unchanged by diet, nuclear volume and collagen interstitial fraction both increased in HD. Also HD exhibited higher relative β-MHC content and β/α-MHC ratio than their Control counterparts. Importantly, body adiposity was weakly associated with cardiovascular effects, as saturated fatty acid intake was directly associated with most cardiac remodeling measurements while unsaturated lipid consumption was inversely correlated with these effects. Conclusion: Hypercaloric diet was associated with glycemic metabolism and systolic blood pressure disorders and cardiac remodeling. These effects directly and inversely correlated with saturated and unsaturated lipid consumption, respectively. [ABSTRACT FROM AUTHOR]

Background: Diabetes is characterized by profound lipid abnormalities. The objective of this study was to examine changes in concentrations of lipids and apolipoprotein B among participants stratified by glycemic status (diabetes, undiagnosed diabetes, prediabetes, and normoglycemia) in the United States from 1988-1991 to 2005-2008. Methods: We used data from 3202 participants aged ⩾20 years from the National Health and Nutrition Examination Survey (NHANES) III (1988-1991) and 3949 participants aged ⩾20 years from NHANES 2005-2008. Results: Among participants of all four groups, unadjusted and adjusted mean concentrations of total cholesterol, low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B, but not triglycerides, decreased significantly. Among participants with prediabetes and normoglycemia, unadjusted and adjusted mean concentrations of high-density lipoprotein cholesterol increased significantly. Adjusted mean log-transformed concentrations of triglycerides decreased in adults with undiagnosed diabetes and prediabetes. During 2005-2008, unadjusted concentrations of apolipoprotein B ⩾80 mg/dl were observed in 72.8% of participants with diagnosed diabetes, 87.9% of participants with undiagnosed diabetes, 86.6% of participants with prediabetes, and 77.2% of participants with normoglycemia. The unadjusted use of cholesterol-lowering medications rose rapidly, especially among participants with diabetes (from ~1% to ~49%, P <0.001). The use of fenofibrate, gemfibrozil, and niacin rose significantly only among adults with diagnosed diabetes (from ~4;2% to ~8%, P = 0.011). Conclusion: Lipid profiles of adults with diabetes improved during the approximately 16-year study period. Nevertheless, large percentages of adults continue to have elevated concentrations of apolipoprotein B. [ABSTRACT FROM AUTHOR]

Background: Few large-scale, real-world studies have assessed the relative associations of lipid fractions with diabetic microvascular events. The main objective of this study was to evaluate the association of the lipid profile components, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (TG), and non-high density lipoprotein cholesterol (non-HDL-C) with microvascular complications (MVCs) in type 2 diabetes mellitus (T2DM) patients.Methods: This observational cohort study queried the HealthCore Integrated Research Database (HIRDSM) for newly-diagnosed (Index Date) 18-64-year-old patients with diabetes mellitus between 01/01/2005-06/30/2010. Inclusion required ≥12 months pre-index continuous health plan eligibility and ≥1 pre-index lipid profile result. Patients with polycystic ovary syndrome and prior MVCs were excluded. Incident complications were defined as the earliest occurrence of diabetic retinopathy, peripheral neuropathy, and/or nephropathy post-index. Cox proportional models and Kaplan-Meier (KM) curves were used to evaluate associations among variables. Results: Of the patients (N = 72,267), 50.05 % achieved HDL-C, 64.28 % LDL-C, 59.82 % TG, and 56.79 % non-HDL-C American Diabetes Association goals at baseline. During follow-up (mean, 21.74 months), there were 5.21 microvascular events per 1,000 patient-months. A 1-mg/dL increase in HDL-C was associated with 1 % decrease in any MVC risk (P < .0001), but for LDL-C, TG, and non-HDL-C, 1-mg/dL increase resulted in increases of 0.2 % (P < .0001), 0.1 % (P < 0.001) and 0.3 % (P < 0.001) in MVC risk. Patients achieving HDL-C goals had a 11 % lower risk of MVC versus non-achievers (RR 0.895, [95 % CI, 0.852-0.941], P < .0001). Similarly, TG goal attainment was associated with a lowered risk for any MVC (RR 0.849, [95 % CI, 0.808-0.892], P < .0001). Evaluation of KM survivalcurves demonstrated no significant difference in the risk of MVCs between patients achieving vs. not achieving LDL-C goals, but did demonstrate a difference in MVC risk between patients achieving vs. not achieving non-HDL-C goals. Conclusion: This study demonstrates significant independent associations among lipid fractions and risk for microangiopathy. These findings suggest that attaining established ADA goals for HDL-C, TG, and non-HDL-C may reduce risk for microvascular events among patients with diabetes. [ABSTRACT FROM AUTHOR]

The article offers information on the research conducted by the authors related to cardiac lipid content, which is unresponsive to a physical activity training intervention in type 2 diabetic patients, despite improved ejection fraction. It states that increased cardiac lipid content has been associated with diabetic cardiomyopathy.

Background: Dyslipidaemia is an important but modifiable risk factor of cardiovascular disease (CVD) in type 2 diabetes. Yet, the effectiveness of lipid regulating drugs in Asians is lacking. We examined the effects of lipid control and treatment with lipid regulating drugs on new onset of CVD in Chinese type 2 diabetic patients. Methods: In this prospective cohort consisting of 4521 type 2 diabetic patients without history of CVD and naïve for lipid regulating treatment recruited consecutively from 1996 to 2005, 371 developed CVD after a median follow-up of 4.9 years. We used Cox proportional hazard regression to obtain the hazard ratios (HR) of lipids and use of lipid regulating drugs for risk of CVD. Results: The multivariate-adjusted HR (95% confidence interval) of CVD in patients with high LDL-cholesterol (≥ 3.0 mmol/L) was 1.36 (1.08 - 1.71), compared with lower values. Using the whole range value of HDL-cholesterol, the risk of CVD was reduced by 41% with every 1 mmol/L increase in HDL-cholesterol. Plasma triglyceride did not predict CVD. Statins use was associated with lower CVD risk [HR = 0.66 (0.50 - 0.88)]. In sub-cohort analysis, statins use was associated with a HR of 0.60 (0.44 - 0.82) in patients with high LDL-cholesterol (≥ 3.0 mmol/L) and 0.49 (0.28 - 0.88) in patients with low HDL-cholesterol. In patients with LDL-cholesterol < 3.0 mmol/L, use of fibrate was associated with HR of 0.34 (0.12 - 1.00). Only statins were effective in reducing incident CVD in patients with metabolic syndrome [(HR = 0.58(0.42-0.80)]. Conclusions: In Chinese type 2 diabetic patients, high LDL-cholesterol and low HDL-cholesterol predicted incident CVD. Overall, patients treated with statins had 40-50% risk reduction in CVD compared to non-users. [ABSTRACT FROM AUTHOR]

Background: Four single nucleotide polymorphisms (SNPs) (rs2237892, rs2237895, rs2237897, and rs2283228) in KCNQ1 are reported to be associated with type 2 diabetes mellitus (T2DM), possibly caused by a reduction in insulin secretion and higher fasting glucose, but the results are inconsistent. We investigated whether these 4 genetic markers are associated with serum lipid metabolism in a middle-aged Chinese Han population. Methods: We enrolled 398 consecutive patients, including 180 with premature coronary artery disease (CAD) (male < 55 years, female < 65 years) and 218 controls without documented CAD. All subjects were genotyped for 4 SNPs by using the ligase detection reaction method. Fasting blood sugar (FBS) and plasma concentrations of total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), apolipoprotein A1(apo A1), and apolipoprotein B (apo B) were determined by standard biochemical methods. Main anthropometric and metabolic characteristics are analyzed among 3 genotypes at rs2283228, rs2237895, rs2237897, or rs2237892 in KCNQ1. Results: The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, and TT were present in rs2237897 and rs2237892. The minor genotypes CC at rs2283228 and TT at rs2237892 were associated with higher levels of TG (P = 0.007 and 0.026, respectively). Furthermore, subjects with the CC genotype at rs2283228 had lower levels of HDL-C and apo A1 than in the other 2 genotype groups (P = 0.052 and 0.055, respectively). No other associations were detected between these 4 SNPs and FBS or other lipid parameters. Conclusions: Our data suggest that rs2283228 and rs2237892 in KCNQ1 are associated with lipid metabolism in a middle-aged Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Adiponectin acts as an antidiabetic, antiinflammatory and antiatherogenic adipokine. These effects are assumed to be mediated by the recently discovered adiponectin receptors AdipoR1 and AdipoR2. Aim: The purpose of this study was to determine whether variations in the AdipoR1 and AdipoR2 genes may contribute to insulin resistance, dyslipidemia and inflammation. Methods: We sequenced all seven coding exons of both genes in 20 unrelated German subjects with metabolic syndrome and tested genetic variants for association with glucose, lipid and inflammatory parameters. Results: We identified three AdipoR2 variants (+795G/A, +870C/A and +963C/T) in perfect linkage disequilibrium (r² = 1) with a minor allele frequency of 0.125. This haplotype was associated with higher plasma adiponectin levels and decreased fasting triglyceride, VLDL-triglyceride and VLDL-cholesterol levels. No association, however, was observed between the AdipoR2 SNP cluster and glucose metabolism. Conclusion: To our knowledge, this is the first study to identify an association between genetic variants of the adiponectin receptor genes and plasma adiponectin levels. Furthermore, our data suggest that AdipoR2 may play an important role in triglyceride/VLDL metabolism. [ABSTRACT FROM AUTHOR]

Objective: The Use of Rosuvastatin versus Atorvastatin iN type 2 diabetes mellitUS (URANUS) study compared rosuvastatin with atorvastatin for the reduction of low-density lipoprotein cholesterol (LDL-C) in patients with type 2 diabetes. Methods: After a 6-week dietary run-in, patients aged = 18 years with type 2 diabetes and LDLC = 3.3 mmol/L were randomised to double-blind treatment with rosuvastatin 10 mg (n = 232) or atorvastatin 10 mg (n = 233) for 4 weeks. Doses were then titrated up to a maximum of rosuvastatin 40 mg or atorvastatin 80 mg over 12 weeks to achieve the 1998 European LDL-C goal (<3.0 mmol/L). Results: Rosuvastatin reduced LDL-C levels significantly more than atorvastatin during the fixeddose and titration periods (p < 0.0001). Significantly more patients reached the 1998 LDL-C goal with rosuvastatin 10 mg compared with atorvastatin 10 mg at 4 weeks (81% vs 65%, p < 0.001). At 16 weeks, significantly more patients achieved their LDL-C goal with rosuvastatin compared with atorvastatin (94% vs 88%, p < 0.05) and more patients receiving rosuvastatin remained at their starting dose with reduced requirement for dose titration. At 4 weeks, 65% of rosuvastatin patients had reached their 2003 European LDL-C goal (< 2.5 mmol/L), compared with 33% of atorvastatin patients (p < 0.0001). Both treatments were similarly well tolerated with no unexpected safety concerns. Conclusion: At the start dose and following dose titration, rosuvastatin was significantly more effective than atorvastatin at reducing LDL-C and achieving European LDL-C goals in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Although less clinical intervention studies have been performed with fibrates than with statins, there are evidences indicating that fibrates may reduce risk of cardiovascular events. The potential clinical benefit of the fenofibrate will be specified by the ongoing Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, which rationale, methods and aims have been just published. Controlled clinical trials show similar or even greater cardiovascular benefits from statins-based therapy in patient subgroups with diabetes compared with overall study populations. Therefore, statins are the drug of first choice for aggressive lipid lowering actions and reducing risk of coronary artery disease in these patients. However, current therapeutic use of statins as monotherapy is still leaving many patients with mixed atherogenic dyslipidemia at high risk for coronary events. A combination statin/fibrate therapy may be often necessary to control all lipid abnormalities in patients with metabolic syndrome and diabetes adequately, since fibrates provide additional important benefits, particularly on triglyceride and HDL-cholesterol levels. Thus, this combined therapy concentrates on all the components of the mixed dyslipidemia that often occurs in persons with diabetes or metabolic syndrome, and may be expected to reduce cardiovascular morbidity and mortality. Safety concerns about some fibrates such as gemfibrozil may lead to exaggerate precautions regarding fibrate administration and therefore diminish the use of the seagents. However, other fibrates, such as bezafibrate and fenofibrate appear to be safer and better tolerated. We believe that a proper co-administration of statins and fibrates, selected on basis of their safety, could be more effective in achieving a comprehensive lipid control as compared with monotherapy. [ABSTRACT FROM AUTHOR]

Background: Hypertriglyceridemia in combination with low HDL cholesterol levels is a risk factor for cardiovascular disease. Our objective was to evaluate the efficacy of ciprofibrate for the treatment of this form of dyslipidemia and to identify factors associated with better treatment response. Methods: Multicenter, international, open-label study. Four hundred and thirty seven patients were included. The plasma lipid levels at inclusion were fasting triglyceride concentrations between 1.6-3.9 mM/l and HDL cholesterol ⩽ 1.05 mM/l for women and ⩽ 0.9 mM/l for men. The LDL cholesterol was below 4.2 mM/l. All patients received ciprofibrate 100 mg/d. Efficacy and safety parameters were assessed at baseline and at the end of the treatment. The primary efficacy parameter of the study was percentage change in triglycerides from baseline. Results: After 4 months, plasma triglyceride concentrations were decreased by 44% (p < 0.001). HDL cholesterol concentrations were increased by 10% (p < 0.001). Non-HDL cholesterol was decreased by 19%. A greater HDL cholesterol response was observed in lean patients (body mass index < 25 kg/m²) compared to the rest of the population (8.2 vs 19.7%, p < 0.001). In contrast, cases with excess body weight had a larger decrease in non-HDL cholesterol levels (-20.8 vs - 10.8%, p < 0.001). There were no significant complications resulting from treatment with ciprofibrate. Conclusions: Ciprofibrate is efficacious for the correction of hypertriglyceridemia / low HDL cholesterol. A greater decrease in non-HDL cholesterol was found among cases with excess body weight. The mechanism of action of ciprofibrate may be influenced by the pathophysiology of the disorder being treated. [ABSTRACT FROM AUTHOR]

Background: Dyslipidaemia has always been regarded as the cornerstone of arteriosclerosis and is related to the pathogenesis of renal insufficiency. However, it is unclear which routinely available lipid parameter is related to urinary albumin to creatinine ratio (UACR). The purpose of this study was to examine the lipid abnormalities associated with UACR in the general population in China. Methods: The present study was nested in an ongoing Risk Evaluation of cAncers in Chinese diabetic Individuals: A lONgitudinal (REACTION) study, which was designed to demonstrate the association of abnormal glucose metabolism with the risk of cancer in the Chinese population. This cross-sectional study included 34, 569 subjects (11, 390 males and 23, 179 females) from 8 different regional community cohorts, with an average age of 57.9 years. The UACR data were divided into the < 25% group, the 25–49% group, the 50–74% group, and the ≥ 75% group according to the quartile division of the centre where the subjects visited. The lipid classes were defined according to the guidelines for the prevention and treatment of dyslipidaemia in Chinese adults. Multiple logistic regression analysis was used to evaluate the association of the lipid parameters and UACR. Results: Multivariable regression analysis revealed that compared with the other lipid parameters, triglycerides (TG) showed an adjusted odds ratio that was significant in model 1–4. This relationship was attenuated after adjusting for Haemoglobin A1c (HbA1c) and blood pressure (BP), but TG ≥ 2.3 mmol/L was still significantly associated with UACR in total subjects and in both men and women (OR: 1.131, 95% CI 1.065–1.203, P < 0.001 in total subjects; OR: 1.134, 95% CI 1.022–1.258, P = 0.017 in men; OR: 1.129, 95% CI 1.046–1.219, P = 0.002 in women). In the stratified analysis, elevated TG was significantly associated with increased urinary albumin in subjects with eGFR ≥ 90 mL/min per 1.73 m2, 5.6 ≤ FBG < 7.0 or 7.8 ≤ PBG < 11.1 mmol/L, 24 ≤ BMI < 28 kg/m2, 120 ≤ SBP < 140 and/or 80 ≤ DBP < 90 mmHg. Conclusions: We conclude that high TG levels rather than total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or non-high-density lipoprotein cholesterol levels are associated with UACR in the general population in China. [ABSTRACT FROM AUTHOR]

Background: Early glucose lowering intervention in subjects with type 2 diabetes mellitus was demonstrated to be beneficial in terms of micro- and macrovascular risk reduction. However, most of currently ongoing cardiovascular outcome trials are performed in subjects with manifest atherosclerosis and long-standing diabetes. Therefore, the aim of this study is to investigate the effects of the dipeptidylpeptidase-4 inhibitor linagliptin in subjects with coronary artery disease (CAD) but early type 2 diabetes mellitus (T2DM) on a set of cardiovascular surrogate measurements. Methods: In this randomized, placebo-controlled, double-blind, single-center study, we included subjects with early diabetes (postchallenge diabetes (2 h glucose > 200 mg/dl) or T2DM treated with diet only or on a stable dose of metformin monotherapy and an HbA1c < 75 mmol/mol) and established CAD. Participants were randomized to receive either linagliptin (5 mg) once daily orally or placebo for 12 weeks. The primary outcome was the change in flow mediated dilatation (FMD). The secondary objective was to investigate the effect of linagliptin treatment on arginine bioavailability ratios [Global arginine bioavailability ratio (GABR) and arginine to ornithine ratio (AOR)]. Arginine, ornithine and citrulline were measured in serum samples with a conventional usual amino acid analysis technique, involving separation of amino acids by ion exchange chromatography followed by postcolumn continuous reaction with ninhydrin. GABR was calculated by l-arginine divided by the sum of (l-ornithine plus l-citrulline). The AOR was calculated by dividing l-arginine by l-ornithine levels. Group comparisons were calculated by using a two-sample t-test with Satterthwaite adjustment for unequal variances. Results: We investigated 43 patients (21% female) with a mean age of 63.3 ± 8.2 years. FMD at baseline was 3.5 ± 3.1% in the linagliptin group vs. 4.0 ± 2.9% in the placebo group. The change in mean FMD in the linagliptin group was not significantly different compared to the change in the placebo group (0.43 ± 4.84% vs. − 0.45 ± 3.01%; p = 0.486). No significant improvements were seen in the arginine bioavailability ratios (GABR; p = 0.608 and AOR; p = 0.549). Conclusion: Linagliptin treatment in subjects with CAD and early T2DM did not improve endothelial function or the arginine bioavailability ratios. Trial registration ClinicalTrials.gov, NCT02350478 (https://clinicaltrials.gov/ct2/show/NCT02350478) [ABSTRACT FROM AUTHOR]