Tirzepatide is a dual-acting glucagon-like peptide-1 analog and a glucose-dependent insulinotropic polypeptide analog. The disease-specific weight-reducing effects associated with tirzepatide use are well established, but its adverse effects have not been systematically assessed and may not be disease-specific. This systematic review aimed to assess the adverse effects associated with tirzepatide use compared with placebo in patients at increased risk of cardiovascular events. We searched six electronic databases and other sources from inception to June 16, 2025. Randomized clinical trials comparing tirzepatide with placebo in patients at increased risk of cardiovascular events were eligible for inclusion. The literature search identified 8866 records after removal of duplicates. Two review authors screened all studies for eligibility. Data were synthesized using meta-analysis and Trial Sequential Analysis (TSA). Risk of bias was assessed with Cochrane Risk of Bias tool – version 2; an eight-step procedure was used to assess whether thresholds for statistical significance were crossed, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations. Primary outcomes were all-cause mortality and serious adverse events (SAEs). Secondary outcomes included non-serious adverse events (nsAEs). The analysis included 21 trials, randomizing 8043 participants to tirzepatide versus placebo. Beta-binomial regression showed no evidence of a difference when assessing all-cause mortality (odds ratio 1.02, 95

Individuals with schizophrenia suffer from reduced life expectancy, primarily due to obesity-related metabolic disorders and cardiovascular disease (CVD). The presence of cardiac autonomic neuropathy (CAN) may contribute to CVD, but CAN is reversible, and it may improve following weight loss. Semaglutide, a GLP-1 receptor agonist (GLP-1RA), induces weight loss and improves cardio-metabolic risk factors. Therefore, this study evaluated the impact of semaglutide on CAN in individuals with schizophrenia. We conducted a double-blind, randomized, placebo-controlled trial with 154 adults (18–60 years, BMI ≥27 kg/m2) who were receiving treatment with second-generation antipsychotics (SGAs) for schizophrenia and prediabetes (HbA1c: 39–47 mmol/mol). Participants were randomized (1:1) to receive once-weekly semaglutide or placebo (titrated to 1.0 mg or maximally tolerated dose) for 30 weeks. A total of 141 participants completed the trial (semaglutide: 74; placebo: 67). CAN prevalence was high (84

OBJECTIVE:To examine the effects of semaglutide on insulin sensitivity, insulin resistance, and β-cell function and explore whether these changes were mediated by weight loss in overweight or obese individuals with schizophrenia and prediabetes receiving second-generation antipsychotics. RESEARCH DESIGN AND METHODS:In this 30-week, double-blind trial, 154 participants were randomized to semaglutide (n = 77) or placebo (n = 77); 141 (91.5%) completed the study. Baseline and end-of-study assessments included fasting glucose, insulin, C-peptide, HOMA2 of β-cell function, HOMA2 of insulin sensitivity, HOMA of insulin resistance, and body weight. RESULTS:Participants (56% women, mean age 38.3 years) provided complete insulin data in 131 cases. Compared with placebo, semaglutide significantly reduced fasting glucose (-0.87 mmol/L [95% CI -1.15, -0.59]; P < 0.001), improved insulin sensitivity (8.60 [5.82, 13.65]; P = 0.001), and lowered insulin resistance (-0.69 [-1.00, -0.20]; P = 0.006). Mean weight loss was 9.2 kg and mediated improvements in insulin sensitivity (estimate 7.82; P = 0.01) and insulin resistance (estimate -0.75; P = 0.01). Nonsignificant trends were observed toward reduced fasting insulin (-52.3 pmol/L; P = 0.11) and C-peptide (-182.9 pmol/L; P = 0.096), with a modest, nonsignificant increase in β-cell function (8.10; P = 0.19). CONCLUSIONS:Semaglutide significantly improved insulin sensitivity, reduced insulin resistance, lowered fasting glucose, and promoted substantial weight loss in patients with antipsychotic-induced metabolic disturbances. Weight loss partly mediated the metabolic improvements, while β-cell function remained largely unchanged. These findings support semaglutide as a potential strategy for mitigating metabolic dysfunction in this high-risk population.

Objective To examine the effects of semaglutide on insulin sensitivity, resistance, and beta-cell function, and to explore whether these changes were mediated by weight loss in overweight or obese individuals with schizophrenia and prediabetes receiving second-generation antipsychotics (SGAs). Research Design and Methods In this 30-week, double-blind trial, 154 participants were randomized to semaglutide (n=77) or placebo (n=77); 141 (91.5%) completed the study. Baseline and end-of-study assessments included fasting glucose, insulin, C-peptide, beta-cell function (HOMA-B), insulin sensitivity (HOMA-2S), insulin resistance (HOMA-IR), and body weight. Results Participants (56% women, mean age 38.3 years) provided complete insulin data in 131 cases. Compared with placebo, semaglutide significantly reduced fasting glucose (-0.87 mmol/L; 95% CI [-1.15, -0.59]; p<0.001), improved insulin sensitivity (+8.60; 95% CI [5.82, 13.65]; p=0.001), and lowered insulin resistance (-0.69; 95% CI [-1.00, -0.20]; p=0.006). Mean weight loss was 9.2 kg and mediated improvements in insulin sensitivity (estimate: 7.82; p=0.01) and resistance (estimate: -0.75; p=0.01). Non-significant trends were observed toward reduced fasting insulin (-52.3 pmol/L; p=0.11) and C-peptide (-182.9 pmol/L; p=0.096), with a modest, non-significant increase in beta-cell function (+8.10; p=0.19). Conclusions Semaglutide significantly improved insulin sensitivity, reduced insulin resistance, lowered fasting glucose, and promoted substantial weight loss in patients with antipsychotic-induced metabolic disturbances. Weight loss partly mediated the metabolic improvements, while beta-cell function remained largely unchanged. These findings support semaglutide as a potential strategy for mitigating metabolic dysfunction in this high-risk population.

Patients with schizophrenia have reduced life expectancy due to cardiovascular disease and obesity-related type 2 diabetes, exacerbated by second-generation antipsychotic (SGA) medication. Existing interventions have shown limited effect. To assess the effect of the once-weekly glucagon-like peptide-1 receptor agonist semaglutide in SGA-treated adults (aged 18-60 years) with schizophrenia, prediabetes (glycosylated hemoglobin A 1 c [HbA 1 c ], 5.7%-6.4% of total hemoglobin) (to convert HbA 1 c from percentage of total hemoglobin to mmol/mol, use the following formula: (HbA 1 c % − 2.152)/0.09148), and overweight or obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, ≥27). This placebo-controlled, double-blinded randomized clinical trial was conducted from January 2022 to May 2024, with 30 weeks of follow-up, among regional community-based mental health services in 2 regions of Denmark (Region of Southern Denmark and Region of Zealand). SGA-treated patients with schizophrenia, prediabetes, and overweight or obesity were randomized to semaglutide or placebo. Data analysis was completed from May 2024 to January 2025. Once-weekly subcutaneous semaglutide or placebo for 30 weeks; semaglutide was titrated up to 1.0 mg/week over 8 weeks. The primary outcome was change in HbA 1 c . Secondary end points included changes in body weight, schizophrenia symptoms based on Positive and Negative Syndrome Scale 6 (PANSS-6) score, and physical and mental quality of life (QoL) (assessed via the 36-item Short Form Survey, version 2 [SF-36v2]). A total of 154 patients were recruited and randomized 1:1 to semaglutide or placebo (87 female participants (56.5%); mean [SD] age, 38.3 [10.7] years). Of 154 randomized patients, 141 (91.5%) completed the trial—74 of 77 patients randomized to semaglutide (96%) and 67 of 77 randomized to placebo (87%). Semaglutide reduced HbA 1 c by 0.46% of total hemoglobin (95% CI, −0.56% to −0.36%) and body weight by 9.21 kg (95% CI, −11.68 to −6.75). An HbA 1 c less than 5.7% of total hemoglobin was achieved in 81% vs 19% of patients treated with semaglutide and placebo, respectively ( P < .001); improvements in high-density cholesterol by 10.81 mg/dL (95% CI, 2.70-18.53; P = .007) and triglycerides by −29.20 mg/dL (95% CI, −55.75 to 2.65; P = .03) (to convert to millimoles per liter, multiply by 0.0113) were also observed. Finally, semaglutide improved physical QoL by 3.75 points on the SF-36v2 (95% CI, 1.52-5.98; P = .001) but had no significant effect on mental QoL scores or PANSS-6 score. Gastrointestinal symptoms were more frequent in semaglutide-treated patients. A few semaglutide-treated patients were hospitalized more frequently than observed in the placebo-treated group, but the number of serious adverse effects did not differ between groups. In this multicenter, double-blinded randomized clinical trial, 30 weeks of administration of semaglutide, up to 1.0 mg/week, was safe, lowered blood glucose (as measured by HbA 1 c ) and weight, and improved physical QoL in SGA-treated patients with schizophrenia, prediabetes, and obesity without worsening mental health. ClinicalTrials.gov Identifier: NCT05193578

Introduction Cardiovascular diseases remain the leading cause of mortality worldwide. Tirzepatide is approved for the treatment of type 2 diabetes mellitus and overweight and is increasingly used. The adverse effects with tirzepatide may not be disease-specific and have not been assessed previously.Methods and analysis We will conduct a systematic review and search major medical databases (Cochrane Central Register of Controlled Trials, Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded (SCI-EXPANDED), Conference Proceedings Citation Index—Science (CPCI-S)) and clinical trial registries from their inception and onwards to identify relevant randomised clinical trials. We expect to conduct the literature search in January 2025. Two review authors will independently extract data and perform risk of bias assessments. We will include randomised clinical trials comparing tirzepatide versus placebo or no intervention in all patient groups with an increased risk of cardiovascular events. 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 the Cochrane Risk of Bias tool—version 2. We will systematically 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 CRD42024599035.

Physical activity (PA) has anti-inflammatory effects, but its impact on individuals with multimorbidity (two or more chronic conditions) is unclear. We examined the association between device-measured (i.e., accelerometers) PA and inflammatory biomarkers in people with multimorbidity. In a, preplanned, cross-sectional analysis from the MOBILIZE trial, 214 participants with multimorbidity provided data on PA and inflammatory biomarkers including interleukin-1 receptor antagonist (IL-1ra), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF), and interleukin-6 (IL-6). The primary outcome was minutes per day of moderate-to-vigorous physical activity (MVPA). Adjusted robust regression models were used to evaluate associations, and BMI was explored as a mediator. Higher MVPA was associated with lower IL-1ra levels, with a 2% reduction in IL-1ra for each additional minute of MVPA per day. Participants with at least 10 min/day of MVPA had 33%-45% lower IL-1ra levels compared to those with less than 1 min/day. Similar results were observed for secondary outcomes. BMI did not mediate the MVPA-IL-1ra relationship. Even small increases in MVPA appear to be associated with low-grade inflammation in individuals with multimorbidity. These findings support the promotion of PA in line with WHO guidelines for physical activity even in people with multimorbidity.

Importance:Patients with schizophrenia have reduced life expectancy due to cardiovascular disease and obesity-related type 2 diabetes, exacerbated by second-generation antipsychotic (SGA) medication. Existing interventions have shown limited effect. Objectives:To assess the effect of the once-weekly glucagon-like peptide-1 receptor agonist semaglutide in SGA-treated adults (aged 18-60 years) with schizophrenia, prediabetes (glycosylated hemoglobin A1c [HbA1c], 5.7%-6.4% of total hemoglobin) (to convert HbA1c from percentage of total hemoglobin to mmol/mol, use the following formula: (HbA1c % - 2.152)/0.09148), and overweight or obesity (body mass index [BMI], calculated as weight in kilograms divided by height in meters squared, ≥27). Design, Setting, and Participants:This placebo-controlled, double-blinded randomized clinical trial was conducted from January 2022 to May 2024, with 30 weeks of follow-up, among regional community-based mental health services in 2 regions of Denmark (Region of Southern Denmark and Region of Zealand). SGA-treated patients with schizophrenia, prediabetes, and overweight or obesity were randomized to semaglutide or placebo. Data analysis was completed from May 2024 to January 2025. Intervention:Once-weekly subcutaneous semaglutide or placebo for 30 weeks; semaglutide was titrated up to 1.0 mg/week over 8 weeks. Main Outcomes and Measures:The primary outcome was change in HbA1c. Secondary end points included changes in body weight, schizophrenia symptoms based on Positive and Negative Syndrome Scale 6 (PANSS-6) score, and physical and mental quality of life (QoL) (assessed via the 36-item Short Form Survey, version 2 [SF-36v2]). Results:A total of 154 patients were recruited and randomized 1:1 to semaglutide or placebo (87 female participants (56.5%); mean [SD] age, 38.3 [10.7] years). Of 154 randomized patients, 141 (91.5%) completed the trial-74 of 77 patients randomized to semaglutide (96%) and 67 of 77 randomized to placebo (87%). Semaglutide reduced HbA1c by 0.46% of total hemoglobin (95% CI, -0.56% to -0.36%) and body weight by 9.21 kg (95% CI, -11.68 to -6.75). An HbA1c less than 5.7% of total hemoglobin was achieved in 81% vs 19% of patients treated with semaglutide and placebo, respectively (P < .001); improvements in high-density cholesterol by 10.81 mg/dL (95% CI, 2.70-18.53; P = .007) and triglycerides by -29.20 mg/dL (95% CI, -55.75 to 2.65; P = .03) (to convert to millimoles per liter, multiply by 0.0113) were also observed. Finally, semaglutide improved physical QoL by 3.75 points on the SF-36v2 (95% CI, 1.52-5.98; P = .001) but had no significant effect on mental QoL scores or PANSS-6 score. Gastrointestinal symptoms were more frequent in semaglutide-treated patients. A few semaglutide-treated patients were hospitalized more frequently than observed in the placebo-treated group, but the number of serious adverse effects did not differ between groups. Conclusions and Relevance:In this multicenter, double-blinded randomized clinical trial, 30 weeks of administration of semaglutide, up to 1.0 mg/week, was safe, lowered blood glucose (as measured by HbA1c) and weight, and improved physical QoL in SGA-treated patients with schizophrenia, prediabetes, and obesity without worsening mental health. Trial Registration:ClinicalTrials.gov Identifier: NCT05193578.

AIMS:It is well known that patients with type 2 diabetes (T2D) have an increased risk of both ischemic and non-ischemic heart disease. We studied sex differences in the microvascular function and myocardial extracellular fibrosis that underlie cardiac dysfunction. METHODS:In a cross-sectional echocardiography and cardiovascular magnetic resonance imaging study, myocardial extracellular volume fraction (ECV), myocardial blood flow at rest (MBFrest) and during adenosine-induced stress (MBFstress), and the myocardial perfusion reserve (MPR) were determined in 221 patients with T2D without ischemic heart disease and 25 age-matched controls. We investigated sex-related differences in MBF, MPR, ECV, and diastolic and systolic function. RESULTS:Both in unadjusted analyses and after multiple linear regression analyses adjusted for known confounders, women with T2D had higher MBFrest, MBFstress, and ECV than men. The differences in microvascular function resulted in T2D men and women both having lower MPR compared to healthy controls, but the underlying causes differed. Female sex associated with lower lateral e' and higher E/e' independently of MBFstress and ECV. CONCLUSIONS:These findings highlight distinct sex-specific mechanisms of microvascular dysfunction and myocardial remodeling in T2D. Recognizing these differences may be critical for improving risk stratification and guiding targeted preventive strategies in diabetic cardiomyopathy.

Abstract Introduction Cardiovascular magnetic resonance (CMR) research including from our research group, has documented that patients (pts.) with type 2 diabetes (DM2) even without symptoms exhibit subtle to moderately increased myocardial extracellular volume (ECV). ECV is an imaging biomarker of diffuse fibrosis. Also, our prior research has revealed a prevalence of approx. 10% for non-ischemic late gadolinium enhancement (LGE). Intriguingly, these LGE lesions manifested in a distinct pattern, situated in the basal lateral or infero-lateral positions. We postulate that these lesions may represent the end-stage of severe diffuse fibrosis, potentially influenced by factors such as increased shear wall stress. Purpose To investigate if pts. with DM2 with known high global ECV had higher regional ECV in the basal and lateral or infero-lateral AHA segments compared to other segments. Method A case-control study of 20 healthy controls, 20 pts. with DM2 with low ECV (ECV<28%), 20 pts. with DM2 with high ECV (ECV>29%), and 20 pts. with DM2 with non-ischemic LGE (LGE+). Pts. were identified from a cross-sectional cohort of pts. with DM2. All subjects underwent physical examination and extensive CMR with T1 mapping before and after gadolinium contrast, and myocardial perfusion at rest and during adenosine stress. The regional ECV values for the basal and the mid-ventricular short axis slide were analysed using the AHA segments model: segments 1 to 12. Results All groups (grp.) had comparable age and sex distribution. In the DM2 grp. there was a difference between the no. of pts. with DM2 duration >10 years (low ECV 11(55%), high ECV 12(60%), LGE+ 16(80%), however statistically significant. Global ECV were: Controls (mean±sd) 26.7±1.6%, Low ECV 26.3±1.4%, High ECV 32.0±2.9%, LGE+ 29.5±2.6%, p<0.001. Control subjects had regional ECV between 24.4±2% to 27.3±2% (p<0.001), highest values in the septum. The DM2 grp. with low ECV had regional ECV values of 24.5±3% to 29.2±4%, highest values in the basal inferior and septal parts (segments 2-4). The high ECV grp. had regional ECV values between 28.3±4% and 35.3±6 % with very high values in the basal and the mid-ventricular septum, inferior, and inferolateral part (segments 2-5 and 8-11). The DM2 group LGE+ had values between 26.6±3% and 34.5±7%, highest values in the basal slice in the septum, inferior, and infero-lateral parts (segments 2-5). We found no significant difference in the regional myocardial perfusion reserve index. Conclusion This evidence indicates that diffuse fibrosis in DM2 cardiomyopathy tends to concentrate in the septum and inferolateral regions. However, among pts. with non-ischemic LGE lesions, we observed normal ECV in the anterior segments, in contrast to the high ECV group where all segments exceeded normal levels, albeit with notable regional variations. Subsequent investigations should prioritize uncovering the underlying reasons for this specific regional distribution of diffuse fibrosis.AHA segments 1-12 mapsAHA segments 1-12 maps

The significant morbidity and premature mortality of type 2 diabetes mellitus (T2DM) is largely associated with its cardiovascular consequences. Focus has long been on the arterial atheromatosis of DM giving rise to early stroke and myocardial infarctions, whereas less attention has been given to its non-ischemic cardiovascular consequences. Irrespective of ischemic changes, T2DM is associated with heart failure (HF) most commonly with preserved ejection fraction (HFpEF). Largely due to increasing population ages, hypertension, obesity and T2DM, HFpEF is becoming the most prevalent form of heart failure. Unfortunately, randomized controlled trials of HFpEF have largely been futile, and it now seems logical to address the important different phenotypes of HFpEF to understand their underlying pathophysiology. In the early phases, HFpEF is associated with a significantly impaired ability to increase cardiac output with exercise. The lowered cardiac output with exercise results from both cardiac and peripheral causes. T2DM is associated with left ventricular (LV) diastolic dysfunction based on LV hypertrophy with myocardial disperse fibrosis and significantly impaired ability for myocardial blood flow increments with exercise. T2DM is also associated with impaired ability for skeletal muscle vasodilation during exercise, and as is the case in the myocardium, such changes may be related to vascular rarefaction. The present review discusses the underlying phenotypical changes of the heart and peripheral vascular system and their importance for an adequate increase in cardiac output. Since many of the described cardiovascular changes with T2DM must be considered difficult to change if fully developed, it is suggested that patients with T2DM are early evaluated with respect to their cardiovascular compromise.

Purpose (the aim of the study): Two out of three people with osteoarthritis (OA) have comorbidities, i.e., they have multimorbidity. Previous research has demonstrated that a greater number of comorbidities is associated with worsening health status among people with painful knee or hip OA. The aim of the current study was to investigate the association between having hip or knee pain and physical, behavioral, and psychosocial health outcomes among people living with multimorbidity.

AbstractAimsPatients with type 2 diabetes (T2D) have a high prevalence of diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF), which in turn leads to an increased risk of hospitalization and death. However, the factors of risk and their relative importance in leading to higher left ventricular filling pressures are still disputed. We sought to clarify the associations of a wide range of invasive and non‐invasive risk factors with cardiac filling pressures in high‐risk T2D patients.Methods and resultsPatients with T2D at high risk of cardiovascular events were prospectively enrolled in this study. Participants were thoroughly phenotyped including right heart catheterization at rest and during exercise, echocardiography, urinary excretion of albumin (UACR), and quantification of their myocardial blood flow rate (MFR) using cardiac 82Rb‐PET/CT. Of the 37 patients included in the study, 22 (59%) patients met invasive criteria for HFpEF. Only 2 out of 39 variables emerged as independent factors associated with left ventricular filling pressure as assessed by pulmonary capillary wedge pressure (PCWP) at rest; history of hypertension (coefficient: 2.6 mmHg [0.3; 5.0], P = 0.030) and MFR (P = 0.026). We found a significant inverse association between MFR and PCWP with a coefficient of −2.3 mmHg (−4.3; −0.3) in PCWP per integer change of MFR. The MFR ranged from 1.18 to 3.68 in our study, which corresponds to a difference in PCWP of approximately 6 mmHg between patients with the lowest compared to the highest MFR. During exercise, only 2 variables emerged as borderline independent factors associated with PCWP: myocardial flow reserve (coefficient: −4.4 [−9.6; 0.8], P = 0.091) and beta‐blockers use (coefficient: 6.1 [−0.1; 12.4], P = 0.053).ConclusionsIn patients with type 2 diabetes without known HFpEF but risk factors for cardiovascular disease, myocardial blood flow rate was independently associated with PCWP at rest across the range from normal to abnormal left heart filling pressures. A clinically significant difference of 6 mmHg in PWCP was attributable to differences in MFR in patients with the lowest compared with the highest MFR values. This suggests that strategies than attenuate microvascular dysfunction could slow progression of increased left ventricular left heart filling pressures in patients at increased risk.

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.

Abstract Introduction The epicardial adipose tissue (EAT) has unobstructed vascular connection to the myocardium and has a secretome very different from that of other fat depots. The EAT fat pad and its paracrine and vasocrine secretion of pro-inflammatory and profibrotic cytokines is suggested to contribute to heart failure with preserved ejection fraction (HFpEF) pathogenesis albeit via unknown mechanisms. Animal studies and magnetic resonance imaging studies in patients with type 2 diabetes mellitus (T2DM) have documented that important myocardial changes linking diabetic cardiomyopathy to systolic and diastolic dysfunction are myocardial microvascular dysfunction and myocardial fibrosis. Purpose To investigate whether a high volume of EAT is associated with impaired myocardial perfusion reserve (MPR) or disperse fibrosis in patients with T2DM. Methods 198 patients with T2DM but without ischemic heart disease were identified from a cross-sectional cardiovascular magnetic resonance imaging cohort study. 25 healthy controls were included for characterization of baseline characteristics. With gadolinium for contrast, MPR was determined by perfusion sequences and disperse fibrosis was determined from the myocardial extracellular volume (ECV). Volumes of EAT and pericardial adipose tissue (PAT) were determined from cine images. Results The T2DM patients (69% male) had a median age 59 IQR [50, 67] yrs, BMI 30.7 IQR [27.8, 33.7] kg/m2, and EAT of 17.3 IQR [14.2, 22.4] cm2. All patients had normal left ventricle ejection fraction. Compared to the healthy controls, patients with T2DM had higher BMI, abdominal circumference, ECV, EAT, and PAT volumes, and lower MPR (all p<0.001). In univariable regression analysis, EAT and PAT were both associated with higher BMI, abdominal circumference, and age (all p<0.02). In multivariable regression analysis, however, with adjustments for age, sex, BMI, and T2DM-duration, only EAT and MPR were significantly associated (P<0.01), whereas EAT and ECV were not. The PAT volume was not associated with MPR nor ECV. High-sensitive CRP was associated with the EAT volume (p<0.001), but hs-CRP was not associated with MPR or ECV. Conclusion An increased epicardial adipose tissue volume is in patients with T2DM associated with myocardial microvascular dysfunction. Irrespective of a generally heightened inflammatory level, the mechanism by which EAT contribute to development of HFpEF is therefore possibly via an EAT-induced impairment of the myocardial perfusion reserve. Randomized studies targeting a decreased epicardial adipose tissue volume are needed to demonstrate if this will improve myocardial microvascular dysfunction and hence limit development of HFpEF in patients with T2DM.Univariable analysis of EAT and ECVUnivariable analysis of EAT and MPR

Background Patients with diabetes demonstrate early left ventricular systolic dysfunction. Notably reduced global longitudinal strain (GLS) is related to poor outcomes, the underlying pathophysiology is however still not clearly understood. We hypothesized that pathophysiologic changes with microvascular dysfunction and interstitial fibrosis contribute to reduced strain. Methods 211 patients with type 2 diabetes and 25 control subjects underwent comprehensive cardiovascular phenotyping by magnetic resonance imaging. Myocardial blood flow (MBF), perfusion reserve (MPR), extracellular volume (ECV), and 3D feature tracking GLS and global circumferential (GCS) and radial strain (GRS) were quantified. Results Patients (median age 57 [IQR 50, 67] years, 70% males) had a median diabetes duration of 12 [IQR 6, 18] years. Compared to control subjects GLS, GCS, and GRS were reduced in the total diabetes cohort, and GLS was also reduced in the sub-group of patients without diabetic complications compared to control subjects (controls − 13.9 ± 2.0%, total cohort − 11.6 ± 3.0%; subgroup − 12.3 ± 2.6%, all p < 0.05). Reduced GLS, but not GCS or GRS, was associated with classic diabetes complications of albuminuria (UACR ≥ 30 mg/g) [β (95% CI) 1.09 (0.22–1.96)] and autonomic neuropathy [β (95% CI) 1.43 (0.54–2.31)] but GLS was not associated with retinopathy or peripheral neuropathy. Independently of ECV, a 10% increase in MBF at stress and MPR was associated with higher GLS [multivariable regression adjusted for age, sex, hypertension, smoking, and ECV: MBF stress (β (95% CI) − 0.2 (− 0.3 to − 0.08), MPR (β (95% CI) − 0.5 (− 0.8 to − 0.3), p < 0.001 for both]. A 10% increase in ECV was associated with a decrease in GLS in univariable [β (95% CI) 0.6 (0.2 to 1.1)] and multivariable regression, but this was abolished when adjusted for MPR [multivariable regression adjusted for age, sex, hypertension, smoking, and MPR (β (95% CI) 0.1 (− 0.3 to 0.6)]. On the receiver operating characteristics curve, GLS showed a moderate ability to discriminate a significantly lowered stress MBF (AUC 0.72) and MPR (AUC 0.73). Conclusions Myocardial microvascular dysfunction was independent of ECV, a biomarker of myocardial fibrosis, associated with GLS. Further, 3D GLS could be a potential screening tool for myocardial microvascular dysfunction. Future directions should focus on confirming these results in longitudinal and/or interventional studies.

Plasma levels of Vitamin D (25(OH)D) have been suggested as a predictor for developing type 2 diabetes. The purpose of this study was therefore to investigate if a measurement of plasma 25(OH)D could predict the development of type 2 diabetes in a cohort of 222,311 individuals from primary healthcare in Denmark. The CopD-study database containing data from the Copenhagen General Practitioners Laboratory on blood tests conducted from April 2004 to January 2012 was used for identification of the study population. Incident type 2 diabetes was then defined as having at least two redeemed prescriptions of antidiabetics or at least two hospital contacts due to type 2 diabetes or one redeemed prescription and one hospital contact regarding type 2 diabetes. A total of 222,311 individuals were included in the study, of whom 7652 (3.4

IntroductionSubjects 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 analysisWe 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/m2will 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 disseminationThis 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 numberNCT05193578European Clinical Trials Database Number (EudraCT) 2020-004374-22, Regional Ethical Committee number S-20200182.