Adverse effects with semaglutide: a protocol for a systematic review with meta-analysis and trial sequential analysis.

INTRODUCTION: Semaglutide is increasingly used for the treatment of type 2 diabetes mellitus, overweight and other conditions. It is well known that semaglutide lowers blood glucose levels and leads to significant weight loss. Still, a systematic review has yet to investigate the adverse effects with semaglutide for all patient groups. METHODS AND ANALYSIS: We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medline, Embase, Latin American and Caribbean Health Sciences Literature, Science Citation Index Expanded, Conference Proceedings Citation Index-Science) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in July 2024. Two review authors will independently extract data and perform risk-of-bias assessments. We will include randomised clinical trials comparing oral or subcutaneous semaglutide versus placebo. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be myocardial infarction, stroke, all-cause hospitalisation and non-serious adverse events. Data will be synthesised by meta-analyses and trial sequential analysis; risk of bias will be assessed with Cochrane Risk of Bias tool-version 2, an eight-step procedure will be used to assess if the thresholds for statistical and clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations. ETHICS AND DISSEMINATION: This protocol does not present any results. Findings of this systematic review will be published in international peer-reviewed scientific journals. PROSPERO REGISTRATION NUMBER: CRD42024499511.

Home-based Intervention with Semaglutide Treatment of Neuroleptic-Related Prediabetes (HISTORI): protocol describing a prospective, randomised, placebo controlled and double-blinded multicentre trial.

INTRODUCTION: Subjects with schizophrenia have a 2-3 fold higher mortality rate than the general population and a reduced life expectancy of 10-20 years. Approximately one-third of this excess mortality has been attributed to obesity-related type 2 diabetes (T2D) and to cardiovascular disease. Glucagon-like peptide-1 (GLP-1) analogues increase satiety and delay gastric emptying, thereby reducing food intake and weight. GLP-1 analogues also exert beneficial effects on cardiovascular outcomes in high-risk patients with T2D.Our aim is to investigate whether 30 weeks add-on treatment with the GLP-1 analogue semaglutide can reduce HbA1c sufficiently to reverse pre-diabetes and the metabolic syndrome in overweight schizophrenic patients. METHODS AND ANALYSIS: We will perform a 30 week, two-armed, multicentre, superiority, double-blinded, randomised trial investigating the effect of weekly injections of semaglutide versus placebo in mental health facilities in Region of Southern Denmark and Region of Zealand, Denmark. In total, 154 adults with schizophrenia spectrum disease, aged 18-60 years treated with second generation antipsychotic treatment, HbA1c 39-47 mmol/mol and body mass index >27 kg/m2 will be randomised to injections of 1.0 mg semaglutide or placebo. The primary outcome is changes in HbA1c. Secondary outcomes encompass metabolic measures, psychotic symptoms and quality of life. Exploratory outcomes encompass insulin sensitivity, cardiovascular risk profile, medication adherence, general well-being and physical activity. ETHICS AND DISSEMINATION: This study will be carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. This research has obtained approval from both the Danish Medicines Agency and The Regional Committees on Health Research Ethics for Southern Denmark. TRIAL REGISTRATION NUMBER: NCT05193578 European Clinical Trials Database Number (EudraCT) 2020-004374-22, Regional Ethical Committee number S-20200182.

A multidisciplinary, shared care clinic using personalized medicine and coordinated care in patients with concomitant type 2 diabetes and cardiovascular disease. Protocol and baseline characteristics.

Background: Concomitant type 2 diabetes (T2DM) and cardiovascular disease (CVD) is frequent with a poor prognosis with high risk of comorbidities. Strict risk factor control reduces the risk for complications - yet many people do not achieve treatment targets. The complexity and fragmentation of the healthcare system may, together with the vulnerability of these patients, be a reason. Objective: The purpose of this paper is to describe the protocol of a non-randomized interventional pilot study testing the feasibility and effect of a multidisciplinary, shared care clinic using personalized medicine and coordinated care in people living with concomitant T2D and CVD. Methods: Participants were included from the Holbaek area in Denmark. People suffered from T2DM and CVD and were dysregulated regarding to HbA1c, cholesterol, micro/macroalbuminuaria or blood pressure. Participants went through a thorough evaluation to identify their needs and resources and received consultations every three months for one year. Results: A total of 63 participants with T2DM and CVD were enrolled in the clinic. The participants had a mean age of 69 years and a BMI of 30.9 kg/m2. Almost 50 % had heart failure, 95 % dyslipidemia and 91 % hypertension. Around 54 % received GLP-1 agonists and 39 % received SGLT-2-inhibitors. Perspectives: To our knowledge, a similar study with a multidisciplinary, shared care, outpatient clinic treating people living with concomitant T2DM and CVD, has not been performed previously. This study will provide information about the feasibility and efficacy of a multidisciplinary clinic based on changes in cardiovascular risk factors and medication.

Subclinical hypothyroidism in pregnancy - assessment of offspring thyroid status and mitochondrial robustness to stress.

Subclinical hypothyroidism's clinical implications on pregnancy are controversial. Consequently, thyrotropin (TSH) cutoff-values for pregnancy are continuously a subject for debate. In subclinical hypothyroidism, altered levels of thyroid hormones may affect mitochondrial function.Objectives were i) to analyze thyroid hormone levels in offspring of women with and without subclinical hypothyroidism ii) to analyze mitochondrial "robustness" in terms of MTG/TMRM ratio in pregnant women and their offspring in relation to thyroid function and iii) to perform differentiate analyses on different TSH thresholds to determine the importance of cutoff-values to results.Pregnant women were included by blood collections prior to a planned cesarean section, and cord samples were collected after delivery. Thyroid status (analyzed by Siemens Healthcare Diagnostics by an electrochemical luminescent immunoassay based on LOCI-technology) grouped the women and their offspring in euthyroid or subclinical hypothyroid, with groups established from previous recommended third-trimester cutoff-value (TSH > 3.0 mIU/L) and the recently recommended cutoff-value in Denmark (TSH > 3.7 mIU/L). Flow cytometric measurements of mitochondrial function in mononuclear blood cells with the fluorophores TetraMethylRhodamine Methyl Ester (TMRM) and Mitotracker Green (MTG) were used to evaluate mitochondrial robustness as the MTG/TMRM ratio.No significant differences in mitochondrial robustness between euthyroid and subclinical hypothyroid cohorts were observed, irrespective of TSH-cutoff applied. Maternal and cord MTG/TMRM ratios were positively correlated. Cord-TSH was elevated in subclinical hypothyroid offspring, independent of TSH cutoff applied. Cord-TSH was associated with maternal TSH-level, maternal smoking and cord arterial-pH.

Developmental scores in offspring of women with subclinical hypothyroidism in pregnancy are affected by gender and thyrotropin cutoff.

OBJECTIVES: Subclinical hypothyroidism (SCH) is defined by elevated thyrotropin (TSH) and normal level of thyroxine (T4). The definition of SCH and the cutoff for TSH normality in pregnancy are debated. In the present study, we assess offspring perinatal outcome, anthropometrics and early development in relation to different TSH levels. METHODS: An observational study with 77 singleton-pregnant women included by thyroid screening before a planned cesarean section. Two TSH-cutoffs (3.0 and 3.7 mIU/L) defined euthyroid and SCH groups, and were applied to evaluate offspring anthropometrics, complication rates (maternal blood loss, Apgar-score, cord arterial-pH, admission to neonatal intensive care unit, perinatal hypoglycemia) and offspring development. Development was evaluated by Bayley-III test in a subsample at age 6 months (n=27) and 15 months (n=22). RESULTS: Prevalence of SCH was 31.2 % at TSH-cutoff 3.0 mIU/L, and 16.9 % at TSH-cutoff 3.7 mIU/L. No differences in complications and anthropometrics were observed. In Bayley-III tests, cognitive score was decreased at 6 months (p=0.012) and at 15 months (p=0.056) by applying TSH-cutoff 3.0 mIU/L. At cutoff 3.7 mIU/L, motor score was decreased at 15 months (p=0.020). Male offspring had significantly lower cognitive scores at age 6 and 15 months (TSH-cutoff 3.0 mIU/L), and motor scores at age 15 months (TSH-cutoff 3.7 mIU/L). CONCLUSIONS: The importance of the definition of thyroid normality in pregnancy is underlined. This study suggests that a gender-effect might be present in maternal thyroid disease, and that developmental differences exist if TSH-cutoff is low. Further research is needed.

Expressions of mitochondria-related genes in pregnant women with subclinical hypothyroidism, and expressions of miRNAs in maternal and cord blood.

BACKGROUND: Subclinical hypothyroidism in pregnancy and definition by upper thyrotropin (TSH) cutoff are controversial. As mitochondria are influenced by thyroid hormones, the purpose in this study was to measure expression of mitochondria-related genes in euthyroid and subclinical hypothyroid pregnant women to obtain more knowledge of potential metabolic consequences of maternal subclinical hypothyroidism. In addition, we wished to test if applied TSH-cutoff significantly changed our results of expressed gene-levels. Moreover, we aimed to identify potential microRNA-biomarkers for subclinical hypothyroidism - markers that could be traced to offspring as well. METHODS: From a cohort of at-term pregnant women undergoing planned cesarean section, 77 women had expression levels of the mitochondria-related genes Peroxisome Proliferator-activated Receptor-γ coactivator-1ß (PGC-1ß), mitochondrial Transcription Factor A (TFAM), Superoxide Dismutase 2 (SOD2) and Nuclear Respiratory Factor 2 (NRF-2) determined by qPCR from blood sampled in prior to delivery. Two TSH-cutoff levels defining subclinical hypothyroidism (> 3.0 and > 3.7 mIU/L) were applied for the procession of results, generating two data analyses of the same cohort. In 22 pairwise maternal-cord samples (subclinical hypothyroid/euthyroid-rate 0.5, TSH-cutoff > 3.0 mIU/L), microRNA-expressions (miRNA) were analyzed. RESULTS: All gene expressions were lower in the subclinical hypothyroid group regardless of applied TSH-cutoff, but insignificant except for PGC-1ß at TSH cutoff > 3.0 mIU/L. Two miRNAs (hsa-let-7d-3p and hsa-miR-345-5p) were upregulated in blood from women and offspring (cord blood) with subclinical hypothyroidism. CONCLUSIONS: A trend towards decreased mitochondrial gene expressions in subclinical hypothyroidism were demonstrated. The miRNAs hsa-let-7d-3p and hsa-miR-345-5p might be potential markers of maternal subclinical hypothyroidism. However, larger studies are needed to verify the findings.

Impact of serial cardiopulmonary point-of-care ultrasound exams in patients with acute dyspnoea: a randomised, controlled trial.

BACKGROUND: Serial point-of-care ultrasound (PoCUS) can potentially improve acute patient care through treatment adjusted to the dynamic ultrasound findings. The objective was to investigate if treatment guided by monitoring patients with acute dyspnoea with serial cardiopulmonary PoCUS and usual care could reduce the severity of dyspnoea compared with usual care alone. METHODS: This was a randomised, controlled, blinded-outcome trial conducted in three EDs in Denmark between 9 October 2019 and 26 May 2021. Patients aged ≥18 years admitted with a primary complaint of dyspnoea were allocated 1:1 with block randomisation to usual care, which included a single cardiopulmonary PoCUS within 1 hour of arrival (control group) or usual care (including a PoCUS within 1 hour of arrival) plus two additional PoCUS performed at 2 hours interval from the initial PoCUS (serial ultrasound group). The primary outcome was a reduction of dyspnoea measured on a verbal dyspnoea scale (VDS) from 0 to 10 recorded at inclusion and after 2, 4 and 5 hours. RESULTS: There were 206 patients recruited, 102 in the serial ultrasound group and 104 in the control group, all of whom had complete follow-up. The mean difference in VDS between patients in the serial ultrasound and the control group was -1.09 (95% CI -1.51 to -0.66) and -1.66 (95% CI -2.09 to -1.23) after 4 and 5 hours, respectively. The effect was more pronounced in patients with a presumptive diagnosis of acute heart failure (AHF). A larger proportion of patients received diuretics in the serial ultrasound group. CONCLUSION: Therapy guided by serial cardiopulmonary PoCUS may, together with usual care, facilitate greater improvement in the severity of dyspnoea, especially in patients with AHF compared with usual care with a single PoCUS in the ED. Serial PoCUS should therefore be considered for routine use to aid the physician in stabilising the patient faster. TRIAL REGISTRATION NUMBER: NCT04091334.

Effects of adding exercise to usual care in patients with either hypertension, type 2 diabetes or cardiovascular disease: a systematic review with meta-analysis and trial sequential analysis.

OBJECTIVE: To assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. DESIGN: Systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. DATA SOURCES: The CENTRAL, MEDLINE, EMBASE, Science Citation Index Expanded on Web of Science and BIOSIS searched from inception to July 2020. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included all randomised clinical trials adding any form of trialist defined exercise to usual care versus usual care in participants with either hypertension, type 2 diabetes or cardiovascular disease irrespective of setting, publication status, year and language. OUTCOME AND MEASURES: The primary outcomes were all-cause mortality, serious adverse events and quality of life. DATA EXTRACTION AND SYNTHESIS: Five independent reviewers extracted data and assessed risk of bias in pairs. Our methodology was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses, Grading of Recommendations Assessment, Development and Evaluation and Cochrane Risk of Bias-version 1. RESULTS: We included 950 trials, of which 248 trials randomising 21 633 participants reported on our predefined outcomes. All included trials were at high risk of bias. The major types of exercise reported were dynamic aerobic exercise (126/248 trials), dynamic resistance exercise (25/248 trials), and combined aerobic and resistance exercise (58/248 trials). The study participants were included due to cardiovascular diseases (189/248 trials), type 2 diabetes (41/248 trials) or hypertension (16/248 trials). The median intervention period was 3 months (IQR: 2-4 months) and the median follow-up period was 6 months (IQR: 3-8 months) after randomisation. Meta-analyses and trial sequential analyses showed evidence of a beneficial effect of adding exercise to usual care when assessing all-cause mortality (risk ratio (RR) 0.82; 95% CI 0.73 to 0.93; I2=0%, moderate certainty of evidence) and serious adverse events (RR 0.79; 95% CI 0.71 to 0.88; I2=0%, moderate certainty of evidence). We did not find evidence of a difference between trials from different economic regions, type of participants, type of exercise or duration of follow-up. Quality of life was assessed using several different tools, but the results generally showed that exercise improved quality of life, but the effect sizes were below our predefined minimal important difference. CONCLUSIONS: A short duration of any type of exercise seems to reduce the risk of all-cause mortality and serious adverse events in patients with either hypertension, type 2 diabetes or cardiovascular diseases. Exercise seems to have statistically significant effects on quality of life, but the effect sizes seem minimal. PROSPERO REGISTRATION NUMBER: CRD42019142313.

User accounts on received diabetes and mental health care in a Danish setting - An interview study.

People with coexisting type 1 and 2 diabetes and mental illness have a higher mortality rate compared to the general population, among other reasons due to unregulated diabetes. One explanation might be the complexity of managing both conditions. In this interview study, we explored the accounts of delivered diabetes and mental health care of 16 individuals living with coexisting diabetes and mental illness in Denmark. A thematic analysis by Braun and Clarke was applied in the analysis. Some of the participants described the care for diabetes and mental illness to be inextricably linked to each other. Therefore, health care providers ought to focus and knowledge of both conditions as essential components in the care provided. The participants accounted for support needs in other settings beyond diabetes and mental health outpatient clinics, such as the family doctor, residential institutions, and community care. However, the inefficient collaboration between these health care settings is one of the barriers to supporting the participants' self-management.

Impact of socioeconomic position on initiation of SGLT-2 inhibitors or GLP-1 receptor agonists in patients with type 2 diabetes - a Danish nationwide observational study.

BACKGROUND: Low socioeconomic position may affect initiation of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucacon-like-peptide-1 receptor agonists (GLP-1RA) among patients with type 2 diabetes (T2D). We examined the association between socioeconomic position and initiation of SGLT-2i or GLP-1RA in patients with T2D at time of first intensification of antidiabetic treatment. METHODS: Through nationwide registers, we identified all Danish patients on metformin who initiated second-line add-on therapy between December 10, 2012, and December 31, 2020. For each time period (2012-2014, 2015-2017, and 2018-2020), we used multivariable multinomial logistic regression to associate disposable income, as proxy for socioeconomic position, with the probability of initiating a specific second-line treatment at time of first intensification. We reported probabilities standardised to the distribution of demographics and comorbidities of patients included in the last period (2018-2020). FINDINGS: We included 48915 patients (median age 62 years; 61·7% men). In each time period, high-income patients were more often men and had less comorbidities as compared with low income-patients. In each time period, the standardised probability of initiating a SGLT-2i or a GLP-1RA was significantly higher in the highest income group compared with the lowest: 11·4% vs. 9·5% (probability ratio [PR] 1·21, 95 % confidence interval [CI] 1·01-1·44) in 2012-2014; 22·6% vs. 19.6% (PR 1·15, CI 1·05-1·27) in 2015-2017; and 65·8% vs. 54·8% (PR 1·20, CI 1·16-1·24) in 2018-2020. The differences by income were consistent across multiple subgroups. INTERPRETATION: Despite a universal healthcare system, low socioeconomic position was consistently associated with a lower probability of initiating a SGLT-2i or a GLP-1RA. These disparities may widen the future socioeconomic gap in cardiovascular outcomes. FUNDING: The work was funded by unrestricted grants from 'Region Sjaelland Den Sundhedsvidenskabelige Forskningsfond' and 'Murermester Lauritz Peter Christensen og hustru Kirsten Sigrid Christensens Fond'.

Randomized Controlled Trial of the Hemodynamic Effects of Empagliflozin in Patients With Type 2 Diabetes at High Cardiovascular Risk: The SIMPLE Trial.

Treatment with the sodium-glucose cotransporter 2 inhibitor (SGLT-2i) empagliflozin significantly reduces cardiovascular events in patients with type 2 diabetes (T2D); however, the mechanisms behind the reduction in cardiovascular (CV) events are unknown. We investigated whether SGLT-2i treatment affected central hemodynamics during rest and exercise in 34 patients with diabetes in this investigator-initiated, randomized, placebo-controlled, double-blinded trial. The primary end point was change in pulmonary capillary wedge pressure (PCWP) at a submaximal ergometer workload (25 W) after 13 weeks of SGLT-2i treatment (25 mg once daily) compared with placebo. Secondary end points included changes in resting hemodynamics. Baseline and follow-up hemodynamic assessments were performed at rest, submaximal exercise (25 W), and peak exercise using right heart catheterization. Treatment with empagliflozin for 13 weeks in patients with T2D at high CV risk did not reduce left heart filling pressure more than placebo at submaximal exercise. At rest, we observed that empagliflozin reduced PCWP at a magnitude of clinical significance.

Monitoring patients with acute dyspnea with serial point-of-care ultrasound of the inferior vena cava (IVC) and the lungs (LUS): a systematic review.

PURPOSE: The primary aim was to investigate if treatment guided by serial ultrasound of the inferior vena cava-collapsibility index (IVC-CI) and B-lines on lung ultrasound (LUS) could reduce mortality, readmissions, and length of stay (LOS) in acutely dyspneic patients admitted to a hospital, compared to standard monitoring. The secondary aim was to determine how the changes of B-lines and IVC-CI are correlated to vitals and symptoms. METHODS: A systematic search was conducted on PubMed, Embase, Cochrane, Google Scholar, Web of Science, Scopus, OpenGrey, ProQuest, and databases for ongoing trials. The risk of bias was assessed according to study design. RESULTS: Of the 8258 studies identified, 50 were selected for full-text screening, and 24 studies were chosen for data extraction (19 pre-post-, two non-randomized controlled-, two randomized controlled-, and one retrospective cohort study), covering 2040 patients. Most studies were single-center and had small study populations with only heart failure patients. The risk of bias was high. No studies evaluated how the difference between two ultrasound measurements correlated with the primary outcomes. Seven studies reported that a decline in either B-lines or IVC size, or an increased IVC-CI reduced mortality, readmissions, and LOS when correlated to a single ultrasound measurement. All studies showed changes in the IVC-CI and B-lines, but these were not related to vitals or symptoms. CONCLUSION: B-lines and IVC-CI are dynamic variables that change over time and with treatment. A single ultrasound measurement can influence prognostic outcomes, but it remains uncertain if repeated scans can have the same impact.

Socioeconomic position and first-time major cardiovascular event in patients with type 2 diabetes: a Danish nationwide cohort study.

AIMS: The association between socioeconomic position and cardiovascular disease has not been well studied in patients with type 2 diabetes. We aimed to examine the association between socioeconomic position and first-time major adverse cardiovascular events (MACE) in patients with type 2 diabetes. METHODS AND RESULTS: Through the Danish nationwide registers, we identified all residents with newly diagnosed type 2 diabetes between 2012 and 2017. Based on sex-stratified multivariable cause-specific Cox regression models, we calculated the standardized absolute 5-year risk of the composite outcome of first-time myocardial infarction, stroke, or cardiovascular mortality (MACE) according to income quartiles. A total of 57 106 patients with type 2 diabetes were included. During 155 989 person years, first-time MACE occurred in 2139 patients. Among both men and women, income was inversely associated with the standardized absolute 5-year risk of MACE. In men, the 5-year risk of MACE increased from 5.7% [95% confidence interval (CI) 4.9-6.5] in the highest income quartile to 9.3% (CI 8.3-10.2) in the lowest income group, with a risk difference of 3.5% (CI 2.4-4.7). In women, the risk of MACE increased from 4.2% (CI 3.4-5.0) to 6.1% (CI 5.2-7.0) according to income level, with a risk difference of 1.9% (CI 0.8-2.9). CONCLUSION: Despite free access to medical care in Denmark, low-socioeconomic position was associated with a higher 5-year risk of first-time MACE in patients with incident type 2 diabetes. Our results suggest prevention strategies could be developed specifically for patients with low-socioeconomic position.

Mitochondrial energetics and contents evaluated by flow cytometry in human maternal and umbilical cord blood.

Background: Mitochondrial dysfunction may relate to metabolic disorders. The relation between maternal and fetal mitochondrial function needs attention due to heritage.Objectives: To evaluate the use of the staining methods TetraMethylRhodamine Methyl Ester (TMRM) and Mitotracker Green (MTG) for flow cytometric measurements of umbilical cord blood mitochondrial function. Methods: 53 euthyroid at-term pregnant women and their offspring were included by blood collections. The offspring had blood drawn from the clamped umbilical cord. Flow cytometry with MTG, TMRM and Propidium Iodide were performed the following day. A cell count (antibody coating and flow cytometry) was performed for 9 maternal and cord samples. As a quality control, blood of 32 healthy donors was evaluated by flow cytometric analyzes same day as sampling and the following day to test stability of the measurements.Results: Cord mitochondrial measurements were lower than maternal. Maternal and cord mitochondrial function were positively correlated, especially reflected by MTG fluorescence-intensity (FI). Samples stored presented with very changed fluorescence patterns. However, the fluorescence intensity ratios MTG/TMRM of stained white blood cells were related within same day measurements, depicting an extensive and common bioenergetic cellular change.Conclusion: Cord blood flow cytometry by MTG- and TMRM- staining is possible with fluorescence intensity positively correlated to maternal fluorescence intensity. Storage of blood triggers mitochondrial dynamics. The methods are applicable with certain reservations, and they benefit from their non-invasive character compared to mitochondrial evaluation by muscle-biopsies.

Adding exercise to usual care in patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease: a protocol for a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Hypertension, type 2 diabetes mellitus and cardiovascular disease are among the leading causes of mortality globally. Exercise is one of the commonly recommended interventions/preventions for hypertension, type 2 diabetes mellitus and cardiovascular disease. However, the previous reviews have shown conflicting evidence on the effects of exercise. Our objective is to assess the beneficial and harmful effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. METHODS: This protocol for a systematic review was undertaken using the recommendations of The Cochrane Collaboration, the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) and the eight-step assessment procedure suggested by Jakobsen et al. We plan to include all relevant randomised clinical trials and cluster-randomised trials assessing the effects of adding exercise to usual care for people with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP) and BIOSIS. We will systematically assess the risks of random errors using Trial Sequential Analysis as well as risks of bias of all included trials. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). DISCUSSION: The present systematic review will have the potential to aid patients, clinicians and decision-makers recommending exercise and thereby, benefit patients with hypertension, type 2 diabetes mellitus and/or cardiovascular disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019142313.

Design of a randomised controlled trial of the effects of empagliflozin on myocardial perfusion, function and metabolism in type 2 diabetes patients at high cardiovascular risk (the SIMPLE trial).

INTRODUCTION: A diagnosis of type 2 diabetes (T2D) more than doubles the risk of cardiovascular disease (CVD), with heart failure (HF) being one of the most common complications with a severe prognosis. The landmark Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Paitients (EMPA-REG OUTCOME) study demonstrated that treatment with the sodium glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin rapidly and significantly reduces CVD mortality and admission rates for HF. However, the mechanisms behind this reduction in clinical events are unknown.This study was designed to investigate the effects of the SGLT-2 inhibitor empagliflozin on myocardial perfusion and function in patients with T2D and high CVD risk. METHODS AND ANALYSIS: In this investigator-initiated, randomised, double-blind controlled clinical trial, 92 patients with T2D and established CVD or high CVD risk will be randomised to treatment with empagliflozin 25 mg or a matching placebo for 13 weeks. The primary outcome measure is change in myocardial flow reserve measured quantitatively by Rubidium-82 position emission tomography. In a substudy, invasive haemodynamics at rest and during exercise will be measured at baseline and following the intervention, using right heart catheterisation. ETHICS AND DISSEMINATION: The study protocol (v7, 02/08/2018) has been approved by the Ethics Committee of the Capital Region, Danish Data Protection Board and the Danish Medicines Agency, and it will be monitored according to the Good Clinical Practice regulations from the International Conference on Harmonization. The results be submitted to international peer-reviewed journals and be presented at conferences. The data will be made available to the public via EudraCT and www.clinicaltrials.gov. TRIAL REGISTRATION NUMBER: NCT03151343.

Effectiveness of serial focused ultrasound of the lungs and inferior vena cava for monitoring patients with acute dyspnea: a systematic review protocol.

OBJECTIVE: The objective of this review is to evaluate the effectiveness of serial focused ultrasound of the lungs (FLUS) and/or inferior vena cava (IVC) compared to standard care for monitoring patients with acute dyspnea. INTRODUCTION: Acute dyspnea is one of the most common complaints reported by patients in hospital emergency departments, and has high in-hospital mortality rates. The current methods of monitoring patients with acute dyspnea lack both sensitivity and specificity. Point-of-care FLUS and IVC is a promising monitoring tool, but an overview of the existing evidence is absent. INCLUSION CRITERIA: This review will include studies of adult patients admitted to hospital with acute dyspnea that is examined via FLUS, IVC or both a minimum of twice during hospitalization compared to standard care. METHODS: The following electronic databases will be searched: PubMed, Cochrane, Embase, Scopus, Web of Science and Google Scholar. Gray literature will be sought in OpenGrey and ProQuest. The search is limited to articles written in English, Danish, Swedish, Norwegian and German. Articles published before 2003 will be excluded from the search and duplicates will be removed. Two independent reviewers will screen and critically appraise the included studies and perform the data extraction. If possible, data will be synthesized with statistical meta-analysis; otherwise, data will be presented in narrative form. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO CRD42018116608.

[Hypertension in patients with diabetes]. / Hypertension og diabetes mellitus.

The documentation for the beneficial effects of antihypertensive treatment in patients with diabetes is overwhelming. Most patients will require three or four antihypertensive drugs to achieve blood pressure (BP) goals. The regime should include an agent that blocks the renin angiotensin aldosterone system. Reduction in albuminuria during antihypertensive treatment is indicative of renal and cardiovascular protection. Thus, if the level of albuminuria remains high, the treatment should be intensified, even in the light of achieved BP goals. Options for intensification are dual blockade, supramaximal doses of ACE-I or ARB, or addition of aldosterone or renin-blocking agents. Long-term data are awaited regarding the optimal strategy for combination therapy. Patients on intensive antihypertensive treatment should be monitored regularly.