Evolocumab effectiveness in the real-world setting: Austrian data from the pan-European observational HEYMANS study.

BACKGROUND: This real-world study examined clinical characteristics and dyslipidemia management among patients initiating evolocumab across 12 European countries. Austrian data are reported. METHODS: Data of consenting adults were collected for ≤ 6 months prior to evolocumab initiation (baseline) and ≤ 30 months post-initiation. Patient characteristics, lipid lowering therapy (LLT, i.e. statin and/or ezetimibe) and lipid values were collected from medical records. RESULTS: In Austria, 363 patients were enrolled. At baseline, 52% of patients initiated evolocumab without background LLT; the median (Q1, Q3) initial low-density lipoprotein cholesterol (LDL-C) level was 142 (111, 187) mg/dL. Within 3 months of evolocumab treatment, median LDL­C decreased by 59% to 58 (37, 91) mg/dL. This reduction was maintained over time, despite consistently infrequent use of background LLT. LDL-C < 55 mg/dL was attained by 65% of patients (76% with, 55% without background LLT). Evolocumab persistence was ≥ 90% at month 12 and month 30. CONCLUSION: In Austria, patients were initiated on evolocumab at LDL­C levels almost 3­times higher than the guideline-recommended clinical goal (< 55 mg/dL). Persistence with evolocumab was very high. Evolocumab led to a rapid and sustained LDL­C reduction with 65% attaining the LDL­C goal. Patients using evolocumab in combination with statins and/or ezetimibe were more likely to attain their LDL­C goal and thus decrease cardiovascular risk.

Longer-Term Efficacy and Safety of Evinacumab in Patients With Refractory Hypercholesterolemia.

Importance: Patients with refractory hypercholesterolemia who do not achieve their guideline-defined low-density lipoprotein cholesterol (LDL-C) thresholds despite treatment with maximally tolerated combinations of lipid-lowering therapies (LLTs) have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Objective: To evaluate longer-term efficacy and safety of evinacumab in patients with refractory hypercholesterolemia. Design, Setting, and Participants: This randomized clinical trial included a 2-week screening period followed by a 16-week double-blind treatment period (DBTP) for subcutaneous regimens (evinacumab, 450 mg, once weekly [QW]; evinacumab, 300 mg, QW; evinacumab, 300 mg, every 2 weeks; or placebo QW) or a 24-week DBTP for intravenous regimens (evinacumab, 15 mg/kg, every 4 weeks [Q4W]; evinacumab, 5 mg/kg, Q4W; or placebo Q4W); a 48-week open-label treatment period (OLTP) for intravenous treatment only; and a 24-week follow-up period. Patients from 85 sites across 20 countries were recruited for the study; patients with primary hypercholesterolemia (defined as heterozygous familial hypercholesterolemia or established clinical ASCVD without familial hypercholesterolemia) who entered the 48-week OLTP were included. In addition, the patients' hypercholesterolemia was refractory to maximally tolerated LLTs. Interventions: All patients entering the OLTP received evinacumab, 15 mg/kg, intravenously Q4W. Main Outcomes and Measures: Efficacy outcomes included change in LDL-C level and other lipid/lipoprotein parameters from baseline to week 72 (end of the OLTP). Safety outcomes included assessment of treatment-emergent adverse events (TEAEs). Results: A total of 96 patients (mean [SD] age, 54.4 [11.3] years; 52 female [54.2%]) entered the OLTP, of whom 88 (91.7%) completed the OLTP. Mean (SD) baseline LDL-C level was 145.9 (55.2) mg/dL. At week 72, evinacumab, 15 mg/kg, reduced mean (SD) LDL-C level from baseline by 45.5% (28.7%) in the overall cohort. Evinacumab, 15 mg/kg, reduced mean (SD) apolipoprotein B (38.0% [22.1%]), non-high density lipoprotein cholesterol (48.4% [23.2%]), total cholesterol (42.6% [17.5%]), and median (IQR) fasting triglyceride (57.2% [65.4%-44.4%]) levels at week 72 from baseline in the overall cohort. TEAEs occurred in 78 of 96 patients (81.3%). Serious TEAEs occurred in 9 of 96 patients (9.4%); all were considered unrelated to study treatment. Conclusions and Relevance: In patients with refractory hypercholesterolemia, evinacumab provided sustained reductions in LDL-C level and was generally well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT03175367.

Filling the gap: Genetic risk assessment in hypercholesterolemia using LDL-C and LPA genetic scores.

Routine genetic testing in hypercholesterolemia patients reveals a causative monogenic variant in less than 50% of affected individuals. Incomplete genetic characterization is partly due to polygenic factors influencing low-density-lipoprotein-cholesterol (LDL-C). Additionally, functional variants in the LPA gene affect lipoprotein(a)-associated cholesterol concentrations but are difficult to determine due to the complex structure of the LPA gene. In this study we examined whether complementing standard sequencing with the analysis of genetic scores associated with LDL-C and Lp(a) concentrations improves the diagnostic output in hypercholesterolemia patients. 1.020 individuals including 252 clinically diagnosed hypercholesterolemia patients from the FH Register Austria were analyzed by massive-parallel-sequencing of candidate genes combined with array genotyping, identifying nine novel variants in LDLR. For each individual, validated genetic scores associated with elevated LDL-C and Lp(a) were calculated based on imputed genotypes. Integrating these scores especially the score for Lp(a) increased the proportion of individuals with a clearly defined disease etiology to 68.8% compared to 46.6% in standard genetic testing. The study highlights the major role of Lp(a) in disease etiology in clinically diagnosed hypercholesterolemia patients, of which parts are misclassified. Screening for monogenic causes of hypercholesterolemia and genetic scores for LDL-C and Lp(a) permits more precise diagnosis, allowing individualized treatment.

Simulation of bempedoic acid and ezetimibe in the lipid-lowering treatment pathway in Austria using the contemporary SANTORINI cohort of high and very high risk patients.

OBJECTIVE: The low-density lipoprotein cholesterol goals in the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guidelines necessitate greater use of combination therapies. We describe a real-world cohort of patients in Austria and simulate the addition of oral bempedoic acid and ezetimibe to estimate the proportion of patients reaching goals. METHODS: Patients at high or very high cardiovascular risk on lipid-lowering treatments (excluding proprotein convertase subtilisin/kexin type 9 inhibitors) from the Austrian cohort of the observational SANTORINI study were included using specific criteria. For patients not at their risk-based goals at baseline, addition of ezetimibe (if not already received) and subsequently bempedoic acid was simulated using a Monte Carlo simulation. RESULTS: A cohort of patients (N = 144) with a mean low-density lipoprotein cholesterol of 76.4 mg/dL, with 94% (n = 135) on statins and 24% (n = 35) on ezetimibe monotherapy or in combination, were used in the simulation. Only 36% of patients were at goal (n = 52). Sequential simulation of ezetimibe (where applicable) and bempedoic acid increased the proportion of patients at goal to 69% (n = 100), with a decrease in the mean low-density lipoprotein cholesterol from 76.4 mg/dL at baseline to 57.7 mg/dL overall. CONCLUSIONS: The SANTORINI real-world data in Austria suggest that a proportion of high and very high-risk patients remain below the guideline-recommended low-density lipoprotein cholesterol goals. Optimising use of oral ezetimibe and bempedoic acid after statins in the lipid-lowering pathway could result in substantially more patients attaining low-density lipoprotein cholesterol goals, likely with additional health benefits.

[Mental disorders and diabetes mellitus (Update 2023)]. / Psychische und neurokognitive Erkrankungen und Diabetes mellitus (Update 2023).

Psychiatric disorders and psychological problems are common in patients with diabetes mellitus. There is a twofold increase in depression which is associated with suboptimal glycemic control and increased morbidity and mortality. Other psychiatric disorders with a higher incidence of diabetes are cognitive impairment, dementia, disturbed eating behavior, anxiety disorders, schizophrenia, bipolar disorders and borderline personality disorder. The coincidence of mental disorders and diabetes has unfavorable influences on metabolic control and micro- and macroangiopathic complications. Improvement of therapeutic outcome is a challenge in the modern health care system. The intentions behind this position paper are to rise awareness of this special set of problems, to intensify cooperation between involved health care providers and to reduce incidence of diabetes mellitus as well as morbidity and mortality from diabetes in this patient group.

Long-term persistence with evolocumab treatment and sustained reductions in LDL-cholesterol levels over 30 months: Final results from the European observational HEYMANS study.

BACKGROUND AND AIMS: Variability in low-density lipoprotein-cholesterol (LDL-C) level control at a population level is associated with poor cardiovascular outcomes. Limited data exist on LDL-C level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. Using data from the HEYMANS registry, this analysis aimed to assess evolocumab persistence and discontinuation over 30 months of evolocumab treatment and to evaluate at a population level the variability in LDL-C level reductions during the study period. METHODS: HEYMANS was a prospective registry of adults initiating evolocumab in routine clinical practice in 12 European countries. Data were collected for up to and including 6 months before evolocumab initiation and up to 30 months after. Evolocumab discontinuation was analysed for two time periods: 0-12 months and 12-30 months. RESULTS: In total, 1951 patients were included in the study. The median reduction in LDL-C levels was 58% within 3 months after evolocumab initiation; this reduction was maintained over 30 months. More than 90% of patients continued receiving evolocumab at 12 months and 30 months of follow-up. Of patients with an LDL-C level measurement during follow-up, approximately 85% achieved a ≥30% reduction from baseline at each follow-up visit and approximately 60% achieved a ≥50% reduction. CONCLUSIONS: Evolocumab therapy was associated with sustained LDL-C level reductions up to 30 months, and persistence with evolocumab remained high, both at 12 and 30 months. Expanding the use of monoclonal antibodies such as evolocumab could provide improvements in LDL-C level control at a population level in European clinical practice.

Bariatric surgery prevents carotid wall thickness progression.

BACKGROUND: Bariatric surgery is a treatment option for patients with severe obesity and improves parameters of cardiovascular and/or metabolic disease. Carotid intima media thickness (C-IMT) is a surrogate measure of subclinical atherosclerosis. Previous studies showed short to mid-term arrest and even regression of C­IMT progression following bariatric surgery. We aimed to investigate the long-term effect of weight loss on C­IMT progression 10 years after bariatric surgery in comparison to a population-based control cohort. METHODS: In total, 21 eligible patients were examined preoperatively, at 5 and 10 years after bariatric surgery. Anthropometric parameters, plasma triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), insulin, and glucose were assessed at all three study visits. C­IMT was measured via B­mode scans of the common carotid artery. C­IMT progression was measured in an age-matched and BMI-matched cohort selected from the population-based Bruneck study to compare with changes in C­IMT progression after bariatric surgery. RESULTS: C­IMT remained stable over the 10-year observation period after bariatric surgery. The control cohort showed a significant C­IMT progression over 10 years. The difference in C­IMT progression over 10 years was significant (p < 0.01) between both cohorts. CONCLUSION: Weight loss induced by bariatric surgery halts the natural progression of C­IMT over a 10-year observation period.

Familial hypercholesterolemia: A systematic review of modeling studies on screening interventions.

BACKGROUND AND AIMS: FH is still underdiagnosed. Cost-effectiveness results of preventive screening strategies vary. We aimed at systematically assessing the benefits, harms and cost effectiveness of screening for familial hypercholesterolemia (FH) and at providing an overview of the main characteristics and methodological approaches of applied decision-analytic models. METHODS: A systematic literature search was conducted in MEDLINE, EconLit, CRD-databases and the CEA-registry for FH screening starting 2012. Earlier studies were included from a published systematic review. Results were reported in standardized semi-quantitative evidence tables. Costs were converted to current euros. Incremental cost-effectiveness ratios (ICERs) were recalculated according to economic guidelines. RESULTS: Out of our 211 retrieved studies, eight were included in the review in addition to six studies from an earlier review. Studies were conducted in Europe (UK, The Netherlands, Spain, Poland), USA and Australia evaluating cascade (CS), opportunistic (OS), universal screening (UniS), or combinations using genetic testing, clinical criteria or combinations. Studies evaluating only CS identified strategies with an ICER of up to 37,100 EUR/quality-adjusted life-year (QALY) but some strategies were dominated depending on test combinations. UniS of newborns in combination with CS had an ICER≤15,000 EUR/QALY for sequential cholesterol-genetic screening. In other studies, UniS was dominated by OS/CS. CONCLUSIONS: Our systematic review demonstrates the values of FH screening and provides an overview of potentially relevant screening strategies to be tested using a decision-analytic model for the respective country or region. Future research is needed on the transferability of results to other countries and modeling spillover effects to newborns.

Low-density lipoprotein cholesterol levels exceed the recommended European threshold for PCSK9i initiation: lessons from the HEYMANS study.

AIMS: To describe the characteristics of patients receiving evolocumab in clinical practice across 12 European countries and simulate the association between low-density lipoprotein cholesterol (LDL-C) reduction and cardiovascular (CV) risk reduction. METHODS AND RESULTS: The characteristics of hyperlipidaemic patients at initiation of evolocumab and treatment patterns study-HEYMANS (n = 1952) is a prospective registry of patients ≥18 years old who initiated evolocumab from 1 August 2015 onwards. Mean (standard deviation) age was 60 (10.8), 85% had a prior CV event, 45% were diagnosed with familial hypercholesterolaemia (FH), and 60% had statin intolerance. At evolocumab initiation, 43% were receiving any statin, 16% were receiving ezetimibe without statin, and 41% received no background lipid-lowering therapy (LLT), with LDL-C levels reflecting local proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) reimbursement criteria. Median LDL-C decreased from 3.98 to 1.63 mmol/L within 3 months of evolocumab initiation and was maintained over 24 months. Overall, 58% achieved risk-based 2019 European Society of Cardiology/European Atherosclerosis Society LDL-C goals but that proportion was higher (68%) in patients receiving background LLT compared with those not receiving background LLT (44%). In patients with atherosclerotic cardiovascular disease without FH, the simulated relative CV risk reduction associated with evolocumab treatment was 34% (25-44%). CONCLUSION: Across Europe, LDL-C levels at evolocumab initiation were three times higher than recommended thresholds for PCSK9i initiation, reflecting disparities between implementation and guidelines. More patients attained risk-based LDL-C goals when receiving evolocumab in combination with LLT vs. those not receiving combination therapy. Population health could be improved and LDL-C goals better attained if LDL-C thresholds for PCSK9i reimbursement were lowered, enabling more patients to receive combination therapy when needed.

Changes in Anthropometric and Fitness Characteristics Over a Decade of Young Elite Alpine Ski Racers.

PURPOSE: The aim of this study was to evaluate whether anthropometric and fitness characteristics have changed between former and current elite male and female Austrian young ski racers (U11-U15). METHODS: A battery of anthropometric, general, and skiing-specific fitness tests was conducted annually. In total, 1517 participants (846 males, 671 females) who were tested in 2005-2009 ("former athletes" n = 805) and 2015-2019 ("current athletes" n = 712) were included. Independent t tests and Cohen d were calculated to compare the two 5-y periods, separated by sex and age group. The level of significance was set at P < .05. RESULTS: No significant change in anthropometric characteristics was found over the decade. Current young ski racers performed significantly better in the maximal core flexion strength test in all age categories (ES = 0.88-1.50; P < .02). Core extension strength values were higher in current male U12 and female U12 and U13 athletes (ES = 0.54-0.71; P < .01) and better postural stability values in the lateral direction were found in the age categories U12 and U14 (ES = 0.36-0.68; P < .05), as well as in the forward/backward direction in the age categories U12-U14 (ES = 0.38-1.12; P < .03). Lower-leg extension strength values were apparent in the current U13-U15 age categories (ES = 0.36-1.03; P ≤ .001) and lower drop-jump reactive strength indices in the U13-U15 male athletes (ES = 0.49-0.80; P < .01). CONCLUSIONS: Current and former young ski racers differ significantly in some fitness parameters, which might lead to the assumption that some aspects (such as core strength) have gained more focus in athletic training during the last years compared with 15 y ago.

Evinacumab in Patients with Refractory Hypercholesterolemia.

BACKGROUND: Patients with refractory hypercholesterolemia, who have high low-density lipoprotein (LDL) cholesterol levels despite treatment with lipid-lowering therapies at maximum tolerated doses, have an increased risk of atherosclerosis. In such patients, the efficacy and safety of subcutaneous and intravenous evinacumab, a fully human monoclonal antibody against angiopoietin-like 3, are not known. METHODS: In this double-blind, placebo-controlled, phase 2 trial, we enrolled patients with or without heterozygous familial hypercholesterolemia who had refractory hypercholesterolemia, with a screening LDL cholesterol level of 70 mg per deciliter or higher with atherosclerosis or of 100 mg per deciliter or higher without atherosclerosis. Patients were randomly assigned to receive subcutaneous or intravenous evinacumab or placebo. The primary end point was the percent change from baseline in the LDL cholesterol level at week 16 with evinacumab as compared with placebo. RESULTS: In total, 272 patients were randomly assigned to the following groups: subcutaneous evinacumab at a dose of 450 mg weekly (40 patients), 300 mg weekly (43 patients), or 300 mg every 2 weeks (39 patients) or placebo (41 patients); or intravenous evinacumab at a dose of 15 mg per kilogram of body weight every 4 weeks (39 patients) or 5 mg per kilogram every 4 weeks (36 patients) or placebo (34 patients). At week 16, the differences in the least-squares mean change from baseline in the LDL cholesterol level between the groups assigned to receive subcutaneous evinacumab at a dose of 450 mg weekly, 300 mg weekly, and 300 mg every 2 weeks and the placebo group were -56.0, -52.9, and -38.5 percentage points, respectively (P<0.001 for all comparisons). The differences between the groups assigned to receive intravenous evinacumab at a dose of 15 mg per kilogram and 5 mg per kilogram and the placebo group were -50.5 percentage points (P<0.001) and -24.2 percentage points, respectively. The incidence of serious adverse events during the treatment period ranged from 3 to 16% across trial groups. CONCLUSIONS: In patients with refractory hypercholesterolemia, the use of evinacumab significantly reduced the LDL cholesterol level, by more than 50% at the maximum dose. (Funded by Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT03175367.).

Metabolic recovery after weight loss surgery is reflected in serum microRNAs.

INTRODUCTION: Bariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue. RESEARCH DESIGN AND METHODS: We measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up. RESULTS: Higher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction. CONCLUSIONS: Since liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.

Long-term trends in the prescription of antidiabetic drugs: real-world evidence from the Diabetes Registry Tyrol 2012-2018.

INTRODUCTION: Prescription patterns of antidiabetic drugs in the period from 2012 to 2018 were investigated based on the Diabetes Registry Tyrol. To validate the findings, we compared the numbers with trends of different national registries conducted in a comparable period of time. RESEARCH DESIGN AND METHODS: Medication data, prescription patterns, age groups, antidiabetic therapies and quality parameters (hemoglobin A1c, body mass index, complications) of 10 875 patients with type 2 diabetes from 2012 to 2018 were retrospectively assessed and descriptively analyzed. The changes were assessed using a time series analysis with linear regression and prescription trends were plotted over time. RESULTS: Sodium/glucose cotransporter 2 inhibitors (SGLT-2i) showed a significant increase in prescription from 2012 to 2018 (p<0.001), as well as metformin (p=0.002), gliptins (p=0.013) and glucagon-like peptide-1 agonists (GLP-1a) (p=0.017). Significant reduction in sulfonylurea prescriptions (p<0.001) was observed. Metformin was the most frequently prescribed antidiabetic drug (51.3%), followed by insulin/analogs (34.6%), gliptins (28.2%), SGLT-2i (11.7%), sulfonylurea (9.1%), glitazones (3.7%), GLP-1a (2.8%) and glucosidase inhibitors (0.4%). CONCLUSIONS: In this long-term, real-world study on prescription changes in the Diabetes Registry Tyrol, we observed significant increase in SGLT-2i, metformin, gliptins and GLP-1a prescriptions. In contrast prescriptions for sulfonylureas declined significantly. Changes were consistent over the years 2012-2018. Changes in prescription patterns occurred even before the publication of international and national guidelines. Thus, physicians change their prescription practice not only based on published guidelines, but even earlier on publication of cardiovascular outcome trials.

Tubuloglomerular Feedback in Renal Glucosuria: Mimicking Long-term SGLT-2 Inhibitor Therapy.

A patient with renal glucosuria due to a congenital knock-out of the sodium-glucose cotransporter 2 (SGLT-2) protein because of a compound heterozygous mutation in the SLC5A2 gene may provide a natural model mimicking the effects of long-term SGLT-2 inhibitor therapy, which has been shown to exert kidney-protective effects beyond its antidiabetic properties. One possible mechanism for the protective effects of SGLT-2 inhibitor therapy might be the activation of tubuloglomerular feedback by increased outflow of sodium, chloride, and glucose to distal parts of the nephron, including the macula densa. Subsequently, afferent arteriolar vasoconstriction is induced and blood flow, intraglomerular filtration pressure, and glomerular filtration rate (GFR) all decline. However, prolonged tubuloglomerular feedback activation could change the sensitivity of tubuloglomerular feedback and hence decrease the beneficial effects of SGLT-2 inhibition on kidney function. Tubuloglomerular feedback is mediated by the Na+/K+/2Cl- cotransporter. Hence furosemide, which blocks this cotransporter, is a medical option to test tubuloglomerular feedback because GFR should increase after administration of this loop diuretic. In our patient with long-term activated tubuloglomerular feedback due to SGLT-2 mutations, we show that the sensitivity of tubuloglomerular feedback is maintained, demonstrated by an increase in GFR measured using iohexol clearance following furosemide administration. This observation supports the idea that long-term SGLT-2 inhibitor therapy is kidney protective through a functional tubuloglomerular feedback.

[Mental disorders and diabetes mellitus (Update 2019)]. / Psychische Erkrankungen und Diabetes mellitus (Update 2019).

Psychiatric disorders and psychological problems are common in patients with diabetes mellitus. There is a twofold increase in depression which is associated with suboptimal glycemic control and increased morbidity and mortality. Other psychiatric disorders with a higher incidence of diabetes mellitus are cognitive impairment, dementia, disturbed eating behavior, anxiety disorders, schizophrenia, bipolar disorders and borderline personality disorder. The coincidence of mental disorders and diabetes mellitus has unfavorable influences on metabolic control and micro- and macroangiopathic complications. Improvement of therapeutic outcome is a challenge in the modern health care system. The intentions behind this position paper are to rise awareness of this special set of problems, to intensify cooperation between involved health care providers and to reduce incidence of diabetes mellitus as well as morbidity and mortality from diabetes in this patient group.

Supervised Short-term High-intensity Training on Plasma Irisin Concentrations in Type 2 Diabetic Patients.

Irisin is a myokine involved in adipocyte transformation. Its main beneficial effects arise from increased energy expenditure. Irisin production is particularly stimulated by physical exercise. The present study investigates the changes of plasma irisin in type 2 diabetic patients performing 2 different training modalities. Fourteen type 2 diabetic patients underwent 4 week of supervised high-intensity interval training (HIT; n=8) or continuous moderate-intensity training (CMT; n=6), with equivalent total amounts of work required. Plasma samples were collected in the resting state atbaseline and one day after the exercise intervention to analyse resting plasma irisin, blood lipids, blood glucose, hsCRP, Adiponectin, Leptin and TNF-α concentrations. In addition, body composition and VO2peak were determined Resting plasma irisin increased after HIT (p=0.049) and correlated significantly with plasma fasting glucose at follow-up (r=0.763; p=0.006). CMT did not significantly change the amount of plasma irisin, although follow-up values of plasma irisin correlated negatively with fat-free mass (r=-0.827, p=0.002) and with fasting plasma glucose (r = - 0.934, p=0.006). Plasma irisin was found to increase with higher training intensity, confirming the assumption that exercise intensity, in addition to the type of exercise, may play an important role in the stimulation of the irisin response.

Adiponectin, Leptin and Visfatin in Hypoxia and its Effect for Weight Loss in Obesity.

Rationale: Hypoxia induces leptin gene expression in human adipocytes via hypoxia-inducible factors (HIF-α/ß). Under ambient moderate hypoxia, leptin in adipocytes is elevated for at least 14 days. Leptin is supposedly involved in the reduced food intake, increased utilization of fatty acids for energy production and possible weight loss observed at high altitudes. Literature on adiponectin and visfatin in high altitude is inconsistent with reports of elevated levels and non-elevated levels. Exercise in hypoxia studies in obese subjects have shown a significant weight loss after up to 3 weeks, but it is unclear if this effect holds up for longer time periods. Therefore, we aimed to investigate 32 obese subjects completing 52 exercise and rest sessions within 8 months at either moderate or sham hypoxia and to analyze leptin, adiponectin, and visfatin mRNA-expression at different time points of exposure. Methods: Abdominal subcutaneous fat biopsies were taken from 32 obese subjects before, after 3 months and after 8 months of intervention. Subjects were randomly divided into two groups and exercised at moderate intensity at two different study sites twice a week. The IG was exposed to normobaric hypoxia (FiO2: 14.0 ± 0.2%,) at exercise and at rest (FiO2: 12.0 ± 0.2%) and the CG to sham hypoxia. Quantitative real-time polymerase chain reaction (qPCR) was used in order to determine mRNA-levels of leptin, adiponectin, and visfatin. Results: No differences in leptin levels after 3 and 8 months compared to baseline and between groups were found. There was no significant difference regarding adiponectin or visfatin at any time point compared to baseline in the hypoxia group, but an increase after 3 months was seen in the control group at normoxia compared to the hypoxia group (adiponectin: p = 0.029 and visfatin: p = 0.014). Conclusion: In this first several months' duration randomized sham controlled hypoxia exercise and rest study with obese subjects, we found no time extended leptin mRNA-expression in subjects under hypoxia after 3 and 8 months compared to baseline levels. Moderate exercise in normoxia not in hypoxia leads to elevated adiponectin and visfatin levels after 3 months.

Short-term effects of dapagliflozin on insulin sensitivity, postprandial glucose excursion and ketogenesis in type 1 diabetes mellitus: A randomized, placebo-controlled, double blind, cross-over pilot study.

We investigated the short-term effects of dapagliflozin as adjunct to insulin on insulin sensitivity, postprandial glucose excursions and ketone body production in type 1 diabetes mellitus (T1DM). A total of seven male patients completed the randomized, double-blind, placebo-controlled cross-over trial, receiving 10 mg of dapagliflozin daily for 3 days, followed by placebo, or the reverse. At Day 3, hyperinsulinaemic, euglycaemic clamps and oral glucose tolerance test clamps with repeated blood sampling were performed. Required glucose infusion and blood glucose excursions did not differ significantly between dapagliflozin treatment and placebo (P = 0.491; P = 0.342). Prior to oral glucose, total ketone bodies showed a higher trend following dapagliflozin treatment (P = 0.051). Following oral glucose, total ketone bodies decreased while concentrations of total GLP-1 were higher following dapagliflozin (P = 0.009). Non-esterified free fatty acids did not differ between dapagliflozin treatment and placebo and ketonuria was absent under both conditions. In T1DM, short-term addition of dapagliflozin to insulin influenced neither postprandial glucose excursions nor insulin sensitivity. Following oral glucose, total ketone bodies decreased in parallel with an increase in GLP-1 concentrations, which were higher under dapagliflozin treatment as compared with placebo.

The Role of Omega-3 Fatty Acids in Reverse Cholesterol Transport: A Review.

The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) on cardiovascular disease have been studied extensively. However, it remains unclear to what extent n-3 PUFAs may impact Reverse Cholesterol Transport (RCT). RCT describes a mechanism by which excess cholesterol from peripheral tissues is transported to the liver for hepatobiliary excretion, thereby inhibiting foam cell formation and the development of atherosclerosis. The aim of this review is to summarize the literature and to provide an updated overview of the effects of n-3 PUFAs on key players in RCT, including apoliprotein AI (apoA-I), ATP-binding cassette transporter A1 (ABCA1), ABCG1, apoE, scavenger receptor class B type I (SR-BI), cholesteryl ester transfer protein (CETP), low-density lipoprotein receptor (LDLr), cholesterol 7 alpha-hydroxylase (CYP7A1) and ABCG5/G8. Based on current knowledge, we conclude that n-3 PUFAs may beneficially affect RCT, mainly by influencing high-density lipoprotein (HDL) remodeling and by promoting hepatobiliary sterol excretion.

Dynamics of Bile Acid Profiles, GLP-1, and FGF19 After Laparoscopic Gastric Banding.

Context: An increase of bile acids (BAs), fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. However, data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB). Objective: To assess the fasting BA, FGF19, and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immunometabolic parameters. Furthermore, hepatic farnesoid X receptor (FXR) expression and regulation of FXR-dependent genes were analyzed. Design and Setting: Observational study at the University Hospital Innsbruck. Patients: Twenty obese patients. Interventions: Fasting plasma samples were taken before, 3, 6, and 12 months after LAGB. Liver biopsies were obtained at surgery and after 6 months postoperatively. Main Outcome Measures: BA profiles, GLP-1 and FGF19 levels, hepatic FXR expression and regulation of FXR target genes were determined. Results: Total, conjugated, and secondary BAs transiently increased 3 months after LAGB (P < 0.01). Only one BA, glycolithocholic acid sulfate, remained significantly elevated throughout the whole follow-up period (P < 0.05). GLP-1 had increased transiently 3 months after surgery (P < 0.01), whereas FGF19 levels increased continuously (P < 0.05). Insulin, homeostasis model assessment index, C-reactive protein, FGF19, and GLP-1 correlated positively with different BAs. No differences were seen in hepatic FXR expression and FXR-regulated genes. Conclusions: Our study results, not only identified LAGB-induced changes in BAs and BA-induced hormones, but also revealed associations between changes in BA profile with GLP-1 and FGF19.