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Aim: To examine the association between changes in lipids and markers of haemoconcentration (haematocrit and serum albumin) with empagliflozin, a sodium‐glucose co‐transporter‐2 inhibitor, in patients with type 2 diabetes (T2D) using pooled data from four phase 3 randomized trials. Materials and Methods: Patients with T2D received placebo (n = 825), empagliflozin 10 mg (n = 830) or 25 mg (n = 822) for 24 weeks. In post hoc mediation analyses, we assessed total changes in LDL‐cholesterol, HDL‐cholesterol, triglycerides, apolipoprotein (Apo) B, and Apo A‐I, and changes in these variables associated with, and independent of, changes in haematocrit and serum albumin at week 24 using ANCOVA models. Results: Empagliflozin versus placebo increased serum LDL‐cholesterol, HDL‐cholesterol, and Apo A‐I, decreased triglycerides (empagliflozin 10 mg only), and (non‐significantly) increased Apo B. Empagliflozin modestly increased haematocrit and serum albumin. In mediation analyses, haematocrit changes (increases) with empagliflozin were associated with significant changes (increases) in all lipid variables, including Apo B. Except for triglycerides (non‐significant), similar lipid variable associations were observed with serum albumin changes. Haematocrit‐ and serum albumin‐independent changes in lipids with empagliflozin were significant for HDL‐cholesterol (increases), mostly significant for triglycerides (decreases), and less so for other lipid fractions. Conclusion: Haematocrit and serum albumin increases were associated with increases in lipid fractions with empagliflozin. Empagliflozin‐associated changes in serum lipids, particularly LDL‐cholesterol increases, may be partly attributable to haemoconcentration resulting from increased urinary volume and subsequent volume contraction. [ABSTRACT FROM AUTHOR]

The burden of liver diseases is increasing worldwide, accounting for two million deaths annually. In the past decade, tremendous progress has been made in the basic and translational research of liver tissue engineering. Liver microtissues are small, 3D hepatocyte cultures that recapitulate liver physiology and have been used in biomedical research and regenerative medicine. This review summarizes the recent advances, challenges, and future directions in liver microtissue research. Cellular engineering approaches are used to sustain primary hepatocytes or produce hepatocytes derived from pluripotent stem cells and other adult tissues. 3D microtissues are generated using scaffold‐free assembly or scaffold‐assisted methods such as macroencapsulation, droplet microfluidics, and bioprinting. Optimization of the hepatic microenvironment entails incorporating the appropriate cell composition for enhanced cell–cell interactions and niche‐specific signals, and creating scaffolds with desired chemical, mechanical, and physical properties. Perfusion‐based culture systems such as bioreactors and microfluidic systems are used to achieve efficient exchange of nutrients and soluble factors. Taken together, systematic optimization of liver microtissues is a multidisciplinary effort focused on creating liver cultures and on‐chip models with greater structural complexity and physiological relevance for use in liver disease research, therapeutic development, and regenerative medicine. [ABSTRACT FROM AUTHOR]

Aims: This analysis assessed the efficacy and safety of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in patients with or without metabolic syndrome (MetS) using pooled data from 10 phase 3 ODYSSEY trials. Materials and Methods: Data from 4983 randomized patients (1940 with MetS; 1642 with diabetes excluded) were assessed in subgroups by MetS status. Efficacy data were analysed in 4 pools per study design: 2 placebo‐controlled pools (1 using alirocumab 150 mg every 2 weeks [Q2W], 1 using 75/150 mg Q2W) with background statin, and 2 ezetimibe‐controlled pools (both alirocumab 75/150 mg Q2W), 1 with and 1 without background statin. Alirocumab 75/150 mg indicates possible dose increase from 75 to 150 mg at Week 12 based on Week 8 LDL‐C. Results: LDL‐C percentage reduction from baseline at Week 24 with alirocumab was 63.9% (MetS) and 56.8% (non‐MetS) in the pool of alirocumab 150 mg Q2W, and 42.2% to 52.2% (MetS) and 45.0% to 52.6% (non‐MetS) in 3 pools using 75/150 mg Q2W. Levels of other lipid and lipoprotein parameters were also improved with alirocumab treatment, including apolipoprotein B, non‐high‐density lipoprotein cholesterol (non‐HDL‐C), lipoprotein(a) and HDL‐C. Overall, the percentage change at Week 24 in LDL‐C and other lipids and lipoproteins did not vary by MetS status. Adverse event rates were generally similar between treatment groups, regardless of MetS status; injection‐site reactions occurred more frequently in alirocumab vs control groups. Conclusions: Across study pools, alirocumab‐associated reductions in LDL‐C, apolipoprotein B, and non‐HDL‐C were significant vs control, and did not vary by MetS status. [ABSTRACT FROM AUTHOR]

Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin‐treated patients with T2D, we examined lipid changes in response to fenofibrate therapy using a genomewide association study (GWAS). Associations were followed‐up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects (P < 5 × 10‐6). Rare variant and gene expression changes were assessed using a false discovery rate approach. AKR7A3 and HSD17B13 were associated with lipid changes in white subjects (q < 0.2). Mice fed fenofibrate displayed reductions in Hsd17b13 gene expression (q < 0.1). Associations of variants in SMAD3, IPO11, and HSD17B13, with gene expression changes in mice indicate that transforming growth factor‐beta (TGF‐β) and NRF2 signaling pathways may influence fenofibrate effects on dyslipidemia in patients with T2D. [ABSTRACT FROM AUTHOR]

Background Hormonal status influences haemostatic factors including fibrinogen, factor VII and plasminogen activator inhibitor ( PAI-1), and concentrations differ among men, premenopausal and postmenopausal women. This study examines how phases of the menstrual cycle influence variability of fibrinogen, factor VII and PAI-1. Design We studied 103 subjects (39 premenopausal women, 18 postmenopausal women and 46 men) during three, randomized, 8-week energy- and nutrient-controlled experimental diets in the Dietary Effects on Lipids and Thrombogenic Activity ( DELTA) Study. Fasting blood samples were collected weekly during the last 4 weeks of each diet period, and haemostatic factors were quantified. Two linear mixed-effects models were used for fibrinogen, factor VII and PAI-1: one to estimate and compare group-specific components of variance, and the other to estimate additional fixed effects representing cyclical functions of day of menstrual cycle in premenopausal women. Results Systematic cyclical variation with day of menstrual cycle was observed for fibrinogen ( P < 0·0001), factor VII ( P = 0·0012) and PAI-1 ( P = 0·0024) in premenopausal women. However, the amplitude of cycling was small relative to the total magnitude of intra-individual variability. In addition, the intra-individual variance and corresponding coefficient of variation observed in premenopausal women did not differ from postmenopausal women and men. Conclusions The variability in haemostatic factors in premenopausal women is no greater than for postmenopausal women or men. Consequently, premenopausal women can be included in studies investigating haemostatic factor responses without controlling for stage of menstrual cycle. [ABSTRACT FROM AUTHOR]

RATIONALE Apolipoprotein(a) [apo(a)] is the defining protein component of lipoprotein(a) [Lp(a)], an independent risk factor for cardiovascular disease. The regulation of Lp(a) levels in blood is poorly understood in part due to technical challenges in measuring Lp(a) kinetics. Improvements in the ability to readily and reliably measure the kinetics of apo(a) using a stable isotope labeled tracer is expected to facilitate studies of the role of Lp(a) in cardiovascular disease. Since investigators typically determine the isotopic labeling of protein-bound amino acids following acid-catalyzed hydrolysis of a protein of interest [e.g., apo(a)], studies of protein synthesis require extensive protein purification which limits throughput and often requires large sample volumes. We aimed to develop a rapid and efficient method for studying apo(a) kinetics that is suitable for use in studies involving human subjects. METHODS Microfluidic device and tandem mass spectrometry were used to quantify the incorporation of [2H3]-leucine tracer into protein-derived peptides. RESULTS We demonstrated that it is feasible to quantify the incorporation of [2H3]-leucine tracer into a proteolytic peptide from the non-kringle repeat region of apo(a) in human subjects. Specific attention was directed toward optimizing the multiple reaction monitoring (MRM) transitions, mass spectrometer settings, and chromatography (i.e., critical parameters that affect the sensitivity and reproducibility of isotopic enrichment measurements). The results demonstrated significant advantages with the use of a microfluidic device technology for studying apo(a) kinetics, including enhanced sensitivity relative to conventional micro-flow chromatography, a virtually drift-free elution profile, and a stable and robust electrospray. CONCLUSIONS The technological advances described herein enabled the implementation of a novel method for studying the kinetics of apo(a) in human subjects infused with [2H3]-leucine. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Aims Left ventricular assist devices (LVADs) are increasingly used as therapeutic options for patients with advanced congestive heart failure (CHF), many of whom suffer from diabetes mellitus (DM). The aim of this study was to evaluate the effect of restoration of normal cardiac output using LVAD support on diabetes control in patients with advanced CHF. Methods and results A retrospective chart review of all clinic patients supported with long-term LVADs between July 2008 and July 2009 at Columbia University Medical Center was performed. Patients with DM diagnosed prior to device implantation were included in this analysis. Clinical and laboratory data within 1 month preceding and 6 months following LVAD implantation were collected. Of 43 LVAD patients followed in our clinic during the study period, 15 had a diagnosis of DM. Thirteen of the 15 patients were male, mean age was 63 ± 11 years, and the pre-LVAD left ventricular ejection fraction (LVEF) was 16.5 ± 5.7%. Fasting glucose levels, HbA1c, and daily insulin requirement within 1 month before and an average of 4.0 ± 2.3 months after LVAD placement were 157.7 ± 50.6 vs. 104.1 ± 21.4 mg/dL, 7.7 ± 0.9 vs. 6.0 ± 0.8.%, and 53.3 ± 51.7 vs. 24.2 ± 27.2 IU, respectively (P < 0.05 for all comparisons). Six of the 15 patients were completely free of antidiabetic medications and had blood glucose <126 mg/dL as well as HbA1c <6% after LVAD. Body mass index (BMI) was slightly increased after LVAD (28.7 ± 5.3 vs. 30.2 ± 4.1 kg/m2, P NS). Conclusion Restoration of normal cardiac output after LVAD implantation improves diabetic control in patients with advanced CHF. Additional studies are warranted to determine the mechanisms that worsen or possibly induce DM in patients with advanced CHF. [ABSTRACT FROM AUTHOR]

The article considers the potential use of the endocannabinoid system (ECS) for reducing cardiometabolic risk. The ECS influences multiple metabolic pathways in the brain and other parts of the body. One of the three general kinds of cannabimimetic compounds is herbal cannabimimetic compounds. Furthermore, the ECS impacts food intake, energy balance and both lipid and glucose homeostasis.

Strategies for the effective management of cardiovascular risk factors in patients with the metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM) are essential to help reduce cardiovascular morbidity and mortality. Treatment strategies should be multifactorial and include the promotion of therapeutic lifestyle changes, as well as pharmacologic therapies to treat individual risk factors according to current guidelines. In an accompanying article, the importance of atherogenic dyslipidemia as a risk factor for the development of cardiovascular disease in patients with MS or T2DM was highlighted. Current treatment options for managing this characteristic form of atherogenic dyslipidemia are limited and tend to be only moderately effective. The focus of this review is the current pharmacotherapies available for the management of atherogenic dyslipidemia in patients with the MS or T2DM, highlighting the rationale for combining available treatments. Novel strategies currently in clinical development are also discussed. [ABSTRACT FROM AUTHOR]

Both the metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) confer an increased risk of coronary heart disease and cardiovascular disease (CVD). As MS and T2DM become more prevalent, there will be an associated rise in the number of individuals with or at risk for CVD and its related disorders. One major underlying cause of CVD in patients with MS or T2DM is a characteristic form of atherogenic dyslipidemia. This article reviews the evidence that demonstrates that individuals with MS or T2DM are at increased risk for CVD and highlights atherogenic dyslipidemia as an important risk factor for the development of CVD in these individuals. In an accompanying article, current pharmacotherapies available for the management of atherogenic dyslipidemia in individuals with MS or T2DM are discussed. [ABSTRACT FROM AUTHOR]