Semaglutide Treatment Research Articles

Real-world retrospective study in elderly patients aged 65 years and older with type 2 diabetes mellitus treated with daily oral semaglutide (SEMA-elderly).

This real-world, retrospective cohort study aimed to assess the efficacy, safety and tolerability of oral semaglutide-the first GLP-1 receptor agonist available in oral form-in patients aged 65 years and older with type 2 diabetes mellitus (T2DM). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline (V1) to six months (V3). Secondary endpoints included change in body weight, proportion of patients achieving HbA1c <7%, proportion of patients achieving both an HbA1c reduction of ≥1% and a body weight reduction of ≥5%. Exploratory endpoints were also assessed, including evaluations at three months (V2). One hundred and one patients (mean age 74.7 ± 6.1 years) started oral semaglutide treatment. Mean HbA1c decreased significantly from V1 to V3 (change: -0.44%, p < 0.001), with reductions already evident at V2. The proportion of patients achieving an HbA1c ≤7% increased from 36.6% at V1 to 61.7% at V3. At V3, 9.6% of patients achieved an HbA1c reduction of ≥1% and a weight loss of ≥5%. Body weight decreased from a baseline mean of 76.8-73.7 kg at V3 (p < 0.001). Body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and systolic blood pressure decreased significantly from V1 to V3, with changes already evident at V2. Eleven patients (10.9%) reported adverse events. Seven patients (6.9%) discontinued treatment. Oral semaglutide effectively improves glycaemic control and weight management in elderly patients with T2DM while improving lipid and cardiovascular parameters and proving to be safe and well tolerated.

Real-world effectiveness of Semaglutide treatment on weight loss maintenance after weight loss in patients with obesity or overweight and diabetes

PurposeTo report data on the real-world effectiveness and safety of injectable (IS) and oral (OS) therapies in obese or overweight diabetes (T2DM) patients on glycometabolic control, weight loss (WL) and weight maintenance after the use of semaglutide.Methods175 subjects with obesity or overweight and T2DM were retrospectively assessed. Of these, 129 (75F, 54 M; mean age 61.2 ± 9.8 years) patients were treated with IS and 46 (24F, 22 M; mean age 65.7 ± 12.8 years) with OS for T2DM and WL. At baseline, mean weight (mW) was 101.8 ± 24.6 kg and 95.2 ± 15.0 kg; mean body mass index (mBMI) was 36.7 ± 8.7 kg/m2 and 34.3 ± 5.3 kg/m2.ResultsAfter 6 months, in the IS group, 127 patients had a mW and mBMI reduction of − 10.4 ± 8.1 kg and − 3.9 ± 3.0 kg/m2. 46 patients in the OS group had a mW and mBMI reduction of − 6.7 ± 5.3 kg and − 2.6 ± 2.1 kg/m2. After 12 months, 102 patients in the IS group achieved a mW and mBMI reduction of − 9.3 ± 7.5 kg and − 3.4 ± 2.6 kg/m2. 44 patients in the OS group of treatment had a mW and mBMI reduction of − 10.7 ± 6.5 kg and − 3.9 ± 2.4 kg/m2.After 24 months, 92 patients in the IS group of therapy achieved a mW and mBMI reduction of − 15.9 ± 11.4 kg and − 5.8 ± 3.7 kg/m2.There was a mean percentage reduction of glycated hemoglobin (HBA1C) of − 1.9 ± 1.4%, − 1.5 ± 1.9%, and − 1.5 ± 1.7% after 6, 12 and 24 months in the IS group. In the OS group there was a mean reduction of − 1.5 ± 1.6% after 6 months and of − 0.8 ± 0.6% after 12 months of therapy.ConclusionsSemaglutide induces WL maintenance after 12 and 24 months of treatment. Our results show a comparable effectiveness of IS and OS in T2DM patients with obesity or overweight. IS and OS treatment provide significant WL that allows reaching the glycometabolic therapeutic goal in a short time.Level of Evidence Level II

Weight loss and body composition after compounded semaglutide treatment in a real world setting.

Clinical trials have shown efficacy of semaglutide for weight loss, but further study is needed in less controlled environments including impacts on body composition. This retrospective study included individuals who participated in a weight management programme at a commercial wellness studio receiving once-weekly compounded semaglutide/cyanocobalamin injections from June 2023 to January 2024. Once-weekly semaglutide/cyanocobalamin injected subcutaneously starting at 0.25 mg/0.125 mg and titrated to a maximum dose of 2.4 mg/0.24 mg. The primary endpoint was weight loss at 3 months, with secondary analyses including weight loss percentage, weight loss by body mass index (BMI) class and body composition changes including changes in total fat mass, lean body mass, skeletal muscle mass and trunk adiposity. A total of 94 individuals were analysed (81F/13M), age in years mean (SD) = 46.57 (10.60). After 3 months, average weight loss was 4.11 (2.77) kg or 4.57% (2.96%). Individuals lost fat mass (2.67 (2.37) kg) and trunk fat mass (1.10 (1.36) kg), while also losing small amounts of lean mass (1.43 (1.41) kg) and skeletal muscle mass (0.88 (0.81) kg). As a proportion of total weight, fat mass decreased while lean muscle mass and skeletal muscle mass increased. This study demonstrates that meaningful weight loss is achievable on semaglutide/cyanocobalamin outside of a closely controlled environment. In addition, body composition improved with losses in fat mass and gains in overall proportion of lean muscle and skeletal muscle.

A Bioequivalence Study of Two Formulations of Oral Semaglutide in Healthy Participants.

The glucagon-like peptide-1 (GLP-1) analogue semaglutide is approved as an oral formulation for the treatment of type 2 diabetes. This study aimed to confirm bioequivalence between a new, second-generation (2G) oral semaglutide formulation (1.5, 4 and 9mg) and the initially approved first-generation (1G) formulation (3, 7 and 14mg). This was a randomised, multicentre, open-label, full replicate crossover study to confirm bioequivalence between 2G and 1G oral semaglutide formulations at steady-state (SS) in healthy participants (NCT05227196). Participants were recruited to three groups. In each group, participants were randomised to one of two alternating sequences comparing once-daily oral semaglutide treatment of 9 and 14mg (group 1), 4 and 7mg (group 2) or 1.5 and 3mg (group 3) at SS. Treatment duration was 20weeks, comprising four 5-week steady-state periods on alternating formulations. Repeated 24-h blood sampling at the end of each steady-state period supported pharmacokinetic analysis. Co-primary endpoints were area under the semaglutide plasma concentration-time curve during a dosing interval at SS (AUC0-24h,SS) and maximum semaglutide plasma concentration at SS (Cmax, 0-24h,SS). Bioequivalence for co-primary endpoints was assessed using European Medicines Agency (EMA), U.S. Food and Drug Administration (FDA) and Japan Pharmaceuticals and Medical Devices Agency (PMDA) criteria. Safety was monitored. A total of 222, 201 and 123 participants were recruited into groups 1, 2 and 3, respectively. The prespecified EMA, FDA and PMDA bioequivalence criteria were met for 2G versus 1G oral semaglutide for all three dose levels (1.5 vs 3mg, 4 vs 7mg and 9 vs 14mg). The safety profile of 2G oral semaglutide was consistent with 1G oral semaglutide. The 2G oral semaglutide formulation was confirmed as bioequivalent to 1G oral semaglutide, with no new safety concerns identified. ClinicalTrials.gov identifier, NCT05227196.

Effectiveness for adding or switching from other incretin-related drugs to oral semaglutide in type 2 diabetes.

This study aimed to evaluate and compare the effectiveness of oral semaglutide after adding to or switching from incretin-related drugs by assessing the changes in HbA1c and body weight (BW) in participants with type 2 diabetes in clinical settings. A total of 368 participants were divided into groups according to antidiabetic medications before oral semaglutide treatment; incretin-related drug-naïve (naïve), switching from dipeptidyl peptide-4 inhibitors (DPP-4i) or glucagon-like peptide-1 receptor agonist (GLP-1 RA) groups. Adjusted mean changes in HbA1c and BW at 6 months after oral semaglutide administration were compared among the three groups. Similar analyses were performed in the GLP-1 RAs group between GLP-1RAs before switching. Mean change of HbA1c in DPP-4i and GLP-1 RA groups was -0.67% (95% confidence interval [CI]: -0.79 to -0.54) and -0.13% (95% CI: -0.40 to 0.15), respectively, which were significantly smaller than incretin-related drug-naïve group; -0.85% (95% CI: -1.08 to -0.62). Mean change in BW between the naïve and DPP-4i groups had no differences; however, these changes were lower in the GLP-1 RA group than in the naïve group. Mean change in HbA1c between pretreatment with GLP-1 RAs had no differences; however, the mean change in BW in the dulaglutide group was significantly higher than that in the injectable semaglutide group. Oral semaglutide reduced HbA1c levels and BW after adding or switching from other incretin-related drugs in Japanese participants with type 2 diabetes.

Intrapatient Changes in CT-Based Body Composition After Initiation of Semaglutide (Glucagon-Like Peptide-1 Receptor Agonist) Therapy.

BACKGROUND. The long-acting glucagon-like peptide-1 receptor agonist semaglutide is used to treat type 2 diabetes or obesity in adults. Clinical trials have observed associations of semaglutide with weight loss, improved control of diabetes, and cardiovascular risk reduction. OBJECTIVE. The purpose of this study was to evaluate intrapatient changes in body composition after initiation of semaglutide therapy by applying an automated suite of CT-based artificial intelligence (AI) body composition tools. METHODS. This retrospective study included adult patients who were receiving semaglutide treatment and who, between January 2016 and November 2023, underwent abdominopelvic CT within both 5 years before and 5 years after initiation of semaglutide. An automated suite of previously validated CT-based AI body composition tools was applied to scans obtained before semaglutide initiation (hereafter, presemaglutide scans) and scans obtained after semaglutide initiation (hereafter, postsemaglutide scans) to quantify visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area, skeletal muscle area and attenuation, intermuscular adipose tissue (IMAT) area, liver volume and attenuation, and trabecular bone mineral density (BMD). Patients with weight loss of 5 kg or more and those with weight gain of 5 kg or more between the scans were compared. RESULTS. The study included 241 patients (151 women and 90 men; mean age, 60.4 ± 12.4 [SD] years). In the weight-loss group (n = 67), the postsemaglutide scan, compared with the presemaglutide scan, showed a decrease in VAT area (309.4 vs 341.1 cm2, p < .001), SAT area (371.4 vs 410.7 cm2, p < .001), muscle area (179.2 vs 193.0, p < 0.001), and liver volume (2379.0 vs 2578 HU, p = .009) and an increase in liver attenuation (74.5 vs 67.6 HU, p = .03). In the weight-gain group (n = 48), the postsemaglutide scan, compared with the presemaglutide scan, showed an increase in VAT area (334.0 vs 312.8, p = .002), SAT area (485.8 vs 448.8 cm2, p = .01), and IMAT area (48.4 vs 37.6, p = .009) and a decrease in muscle attenuation (5.9 vs 13.1, p < .001). Other comparisons were not statistically significant (p > .05). CONCLUSION. Patients using semaglutide who lost versus gained weight showed distinct patterns of changes in CT-based body composition measures. Those with weight loss had overall favorable shifts in measures related to cardiometabolic risk. A decrease in muscle attenuation in those with weight gain is consistent with decreased muscle quality. CLINICAL IMPACT. Among patients using semaglutide, automated CT-based AI tools provide biomarkers of changes in body composition beyond those that are evident by standard clinical measures.

Cardiovascular Events in Adults with Type2 Diabetes and ASCVD Initiating Once-Weekly Semaglutide vs DPP-4is in the USA.

Glucagon-like peptide1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in trials involving high-risk patients with type2 diabetes (T2D), while dipeptidyl peptidase4 inhibitors (DPP-4is) have not. However, DPP-4is are still commonly prescribed in patients with T2D and atherosclerotic cardiovascular disease (ASCVD). This study compared time to occurrence of cardiovascular events, health care resource utilization (HCRU), and medical costs in patients with T2D and ASCVD who initiated once-weekly semaglutide vs a DPP-4i. Two separate observational cohort analyses were conducted using Optum's de-identified Clinformatics® Data Mart Database (CDM) and Komodo Healthcare Map™ (January 1, 2018 to September 30, 2022). Patients had T2D and ASCVD and received semaglutide or a DPP-4i. Baseline characteristics were balanced using inverse probability of treatment weighting. After weighting, the CDM analysis included 14,461 semaglutide users and 38,630 DPP-4i users and the Komodo Healthcare Map analysis included 48,303 semaglutide users and 109,179 DPP-4i users. In CDM, semaglutide users had significantly decreased risk of stroke (hazard ratio [HR], 0.54), myocardial infarction (HR 0.64), and their composite (HR 0.59) vs DPP-4is. Semaglutide users also had fewer ASCVD-related and all-cause hospitalizations and outpatient visits and lower ASCVD-related and all-cause hospitalization and total medical costs. Results from Komodo Health were generally consistent with those from CDM. Semaglutide users had significantly reduced risk of cardiovascular outcomes, HCRU, and medical costs compared with DPP-4is. This corroborates results from prior studies of once-weekly GLP-1 RAs and reinforces the important role of semaglutide treatment for patients with T2D and ASCVD. Graphical abstract available for this article.

GLP-1 Agonist Promotes Proliferation of Neuroendocrine Neoplasm Cells Expressing GLP-1 Receptors

Semaglutide is a glucagon-like peptide 1 (GLP-1) analog that binds to GLP-1 receptors (GLP-1R) on beta-cells and neuronal cells and is used for treating type 2 diabetes and obesity. Insulin-secreting pancreatic neuroendocrine neoplasms have been reported to express high levels of GLP-1R protein, raising the possibility that GLP-1 receptor agonists could promote tumor growth. Our goal was to quantify GLP-1R expression levels in 6 neuroendocrine neoplasm cellular models and determine their proliferative response to semaglutide treatment. Gene expression of GLP-1R in neuroendocrine neoplasm cells (BON, GOT1, NT-3, NEC913, NEC1452, and NEC1583) was measured by quantitative polymerase chain reaction. Protein expression was determined by immunofluorescent staining and Western blotting. Neuroendocrine neoplasm cells were incubated with semaglutide, and cell growth was measured using a cell viability assay. Mice harboring GOT1 xenografts were treated with semaglutide, and tumor volumes were measured. BON, NEC1452, and NEC1583cells expressed significantly lower levels of GLP-1R transcript and protein than GOT1, NT-3, and NEC913cells. GOT1 and NT-3 showed the highest response to semaglutide treatment, with a 19% and 22% increase in growth. Semaglutide promotes tumor growth in mice with GOT1 xenografts by 72%. The impact of the GLP-1 receptor agonist semaglutide on neuroendocrine cancer growth is understudied. Our data revealed that 50% of neuroendocrine neoplasm cell lines tested expressed GLP-1R, and semaglutide treatment promoted their growth. These results indicate a potential risk in the use of semaglutide in patients with neuroendocrine neoplasms expressing GLP-1R. Investigations into a larger set of neuroendocrine neoplasms would be important because they are highly heterogeneous.

Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota-gut--brain axis in obese mice.

Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.

Semaglutide-induced weight loss improves mitochondrial energy efficiency in skeletal muscle.

Glucagon-like peptide 1 receptor agonists (e.g. semaglutide) potently induce weight loss and thereby reducing obesity-related complications. However, weight regain occurs when treatment is discontinued. An increase in skeletal muscle oxidative phosphorylation (OXPHOS) efficiency upon diet-mediated weight loss has been described, which may contribute to reduced systemic energy expenditure and weight regain. We set out to determine the unknown effect of semaglutide on muscle OXPHOS efficiency. C57BL/6J mice were fed a high-fat diet for 12 weeks before receiving semaglutide or vehicle for 1 or 3 weeks. The rate of ATP production and O2 consumption were measured by a high-resolution respirometry and fluorometry to determine OXPHOS efficiency in skeletal muscle at these 2 timepoints. Semaglutide treatment led to significant reductions in fat and lean mass. Semaglutide improved skeletal muscle OXPHOS efficiency, measured as ATP produced per O2 consumed (P/O) in permeabilized muscle fibers. Mitochondrial proteomic analysis revealed changes restricted to two proteins linked to complex III assembly (Lyrm7 and Ttc1, p <0.05 without multiple corrections) without substantial changes in the abundance of OXPHOS subunits. These data indicate that weight loss with semaglutide treatment increases skeletal muscle mitochondrial efficiency. Future studies could test whether it contributes to weight regain.

Semaglutide promotes the transition of microglia from M1 to M2 type to reduce brain inflammation in APP/PS1/tau mice

A growing number of studies show that the diabetes drug Semaglutide is neuroprotective in Alzheimer’s disease (AD) animal models, but its mode of action is not fully understood. In order to explore the mechanism of Semaglutide, 7-month-old APP/PS1/tau transgenic (3xTg) mice and wild-type (WT) mice were randomly divided into four groups: control group (WT + PBS), AD model group (3xTg + PBS), Semaglutide control group (WT + Semaglutide) and Semaglutide treatment group (3xTg + Semaglutide). Semaglutide (25 nmol/kg) or PBS was administered intraperitoneally once every two days for 30 days, followed by behavioral and molecular experiments. The results show that Semaglutide can improve working memory and spatial reference memory of 3xTg-AD mice, promote the release of anti-inflammatory factors and inhibit the production of pro-inflammatory factors in the cortex and hippocampus, and reduce Aβ deposition in the hippocampal CA1 region of 3xTg mice. Semaglutide can inhibit the apoptosis of BV2 cells induced by Aβ1-42 in a dose-dependent manner and promote the transformation of microglia from M1 to M2, thereby exerting anti-inflammatory and neuroprotective effects. Therefore, we speculate that Semaglutide shows an anti-inflammatory effect by promoting the transformation of microglia from M1 to M2 type in the brain of 3xTg mice, and thus exerts a neuroprotective effect.

Oral Semaglutide Use in Type2 Diabetes: A Pooled Analysis of Clinical and Patient-Reported Outcomes from Seven PIONEER REAL Prospective Real-World Studies.

Oral semaglutide is a glucagon-like peptide1 receptor agonist (GLP-1RA) approved for improving glycemic control in adults with type2 diabetes (T2D). The PIONEER REAL program evaluates clinical and patient-reported outcomes of oral semaglutide treatment as part of routine clinical practice across 13 countries. Here, data from Canada, Denmark, Italy, the Netherlands, Sweden, Switzerland, and the UK are pooled and analyzed to address treatment satisfaction as well as glycated hemoglobin (HbA1C) and body weight changes in relevant subgroup analyses. This pooled analysis encompasses seven country-specific, non-interventional, multicenter, phase4, prospective, single-arm clinical studies assessing the use of oral semaglutide in adults with T2D. Primary endpoint was the change in HbA1C from baseline to end of study (EOS), and secondary endpoints included changes in body weight and treatment satisfaction. For the analyses, results were stratified by age, T2D duration, and oral semaglutide dose at EOS as well as baseline HbA1C, body weight, and body mass index. Oral semaglutide treatment was initiated by 1615 participants. At EOS, 1222 (76%) participants out of the 1483 (92%) who completed the study were on treatment. Estimated changes in HbA1C and body weight from baseline to week38 were - 1.0%-point (95%CI - 1.08 to - 0.97; P < 0.0001) and - 5.0% (CI - 5.37 to - 4.72; P < 0.0001). Treatment satisfaction increased significantly during the study. Shorter T2D duration interacted with higher HbA1C reduction and body weight loss. Interaction was also observed between higher baseline HbA1C and more pronounced decrease in HbA1C. No significant interactions were detected between clinical outcomes and age or physician setting. The PIONEER REAL pooled analysis shows that people initiating oral semaglutide treatment experience improved glycemic control and body weight loss across age groups and T2D duration. This occurs regardless of specialist or primary care practice setting and is accompanied by an increased treatment satisfaction. NCT04559815 (Canada), NCT04537637 (Denmark), NCT05230615 (Italy), NCT04601740 (the Netherlands), NCT04601753 (Sweden), NCT04537624 (Switzerland), NCT04862923 (UK).

Abstract 4137914: Eligibility for Semaglutide in US Adults with Diabetes and Potentially Preventable Cardiovascular Events Projected from the SUSTAIN-6 Trial

Background: The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) trial showed cardiovascular disease (CVD) benefits of semaglutide therapy in patients with type 2 diabetes mellitus (T2DM). Purpose: To estimate the number of US adults with T2DM that may be eligible for semaglutide based on SUSTAIN-6 eligibility criteria and the number of preventable CVD events from semaglutide treatment based on observed CVD event reductions in SUSTAIN-6. Methods: We included US adults with T2DM from the National Health and Nutrition Examination Survey (NHANES) 2011– 2020 who had eligibility criteria from SUSTAIN-6. This included an HbA1c&gt;7.0%, age &gt; 50 with established CVD, heart failure, or chronic kidney disease or an age &gt; 60 with at least one CVD risk factor. We estimated the number of primary composite and secondary CVD endpoints that would occur based on SUSTAIN-6 treated and placebo published event rates, with the difference indicating the number of preventable events (and annualized based on median 2.1 year follow-up time). Results: Among 5002 (projected to 34.0 million [M]) adults we identified with T2DM, we estimated 1,132 (6.9 million) (20.3%) to fit SUSTAIN-6 eligibility criteria. Compared to SUSTAIN-6 trial participants, our sample was slightly older, had a higher proportion of Black participants, shorter duration of diabetes, lower HbA1c and diastolic blood pressure, but similar body mass index and systolic blood pressure. Prior history of ischemic heart disease, myocardial infarction, and stroke were also less common in our NHANES sample. From SUSTAIN-6 semaglutide and placebo primary composite CVD event rates of 6.6% and 8.9%, respectively, we estimated 456,060 and 614,990 events would occur, respectively, for a total of 159,930 preventable CVD events, or 75,681 on an annualized basis. We similarly estimated annualized preventable events for secondary outcomes as shown in the Figure. Conclusion: Semaglutide may prevent many fatal and non-fatal CVD events if provided to US adults meeting SUSTAIN-6 eligibility criteria. More efforts are needed to educate the healthcare providers on the CVD benefits from newer diabetes therapies, including semaglutide.

Abstract 4137917: Eligibility and Preventable CVD Events in US Adults with Cardiovascular Disease and Overweight or Obesity: Projections from the SELECT Trial

Background: The Trial to Evaluate Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT) showed cardiovascular disease (CVD) benefits of semaglutide therapy in patients with preexisting CVD and overweight or obesity. Purpose: To estimate the number of US adults with CVD and overweight or obesity that may be eligible for semaglutide based on SELECT eligibility criteria and the number of preventable CVD events from semaglutide treatment based on observed CVD event reductions in SELECT. Methods: We included US adults from the National Health and Nutrition Examination Survey (NHANES) 2011-2020 who had eligibility criteria from SELECT. This included patients aged &gt; 45 years who had preexisting CVD and a BMI of &gt; 27kg/m 2 but no history of diabetes. Using NHANES sample weighting, we estimated the number of SELECT-eligible US adults and primary composite and secondary CVD endpoints that would occur based on SELECT treated and placebo published event rates, with the difference indicating the number of preventable events (and annualized based on mean 3.3-year follow-up). Results: Among 8783 (projected to 77.9 million [M]) adults with overweight or obesity, we estimated 493 (4.1 million) (5.61%) to fit SELECT eligibility criteria. Compared to SELECT trial participants, our sample had a higher proportion of Black participants and was older with higher levels of diastolic blood pressure, total, LDL and HDL-cholesterol, and lower BMI, HbA1c, eGFR and triglycerides. Prior myocardial infarction was less common, but stroke was more common in our sample. From SELECT semaglutide and placebo primary composite CVD event rates of 6.5% and 8.0%, respectively, we estimated 79949 and 98399 CVD events would occur annually, the difference being 18450 potentially preventable CVD events. Moreover, we similarly estimated 104,549 and 357,928 annual preventable cases of diabetes and pre-diabetes, respectively. The Figure shows the estimated number of primary and secondary CVD outcomes that could be prevented annually. Conclusion: Semaglutide may prevent many fatal and non-fatal CVD events, as well as incident cases of diabetes and pre-diabetes if provided to US adults meeting SELECT eligibility criteria. More efforts are needed to educate clinicians and patients on the benefits of semaglutide 2.4mg in those with preexisting CVD and overweight or obesity.

Semaglutide Reduces Cardiomyocyte Damage Caused by High-Fat Through HSDL2.

Obesity-induced inflammation and oxidative stress can cause damage to cardiomyocytes. Semaglutide has the potential to reduce glucose levels and weight, while hydroxysteroid dehydrogenase-like protein 2 (HSDL2) also plays a role in regulating lipid metabolism. This study aimed to investigate the expression of oxidative stress markers and HSDL2 in myocardium and serum under high-fat conditions, in order to elucidate the mechanism of obesity-induced myocardial injury and evaluate the impact of semaglutide on myocardial injury through HSDL2. Mouse models of obesity were established with semaglutide treatment. Palmitic acid-cultured mouse cardiomyocytes with HSDL2 knockout were used, as well as palmitic acid-induced high-fat environment models followed by semaglutide treatment. The levels of inflammatory and oxidative stress markers in serum and cardiomyocytes were measured. Additionally, the expression of HSDL2 and autophagy levels in different cell groups were assessed to evaluate the effect of semaglutide on high-fat diet-induced cardiomyocyte injury mediated by HSDL2. Obesity increased oxidative stress, which was alleviated by intervention with semaglutide. Furthermore, semaglutide down-regulated HSDL2 expression in obese individuals. Moreover, palmitic acid-induced oxidative stress and autophagy were reduced when using cells with knocked out HSDL2 gene. These findings suggest that semaglutide may mitigate cardiomyocyte injury caused by a high-fat diet through regulation of HDLSDSLEP-1 expression. These discoveries are expected to unveil novel molecular mechanisms and provide new targets for clinical treatment.

Semaglutide modulates pro-inflammatory neutrophil phenotype induced by supraphysiological levels of the adipokine FABP4 in patients with cardiovascular disease

Abstract Background Increased adiposity is a risk factor for cardiovascular disease (CVD). Adipose tissue is an endocrine organ that releases proteins with pro-inflammatory effects. One of them is FABP4, which levels are increased after adipogenesis. Insulin resistance is linked to supraphysiological levels of this biomarker. Therapies to reduce body weight and improve insulin response, such as the GLP-1 receptor agonists, like semaglutide, have been shown to benefit patients with CVD and obesity, who have a high pro-inflammatory neutrophil profile. Purpose To study the FABP4 effects on neutrophils from patients with cardiovascular disease and cellular models and its possible modulation by semaglutide. Methods We included 11 patients undergoing open heart surgery. Neutrophils from blood were isolated by single-step centrifugation, counted, and same number were treated with FABP4 (100 ng/mL), semaglutide (1nM) or both. Finally, their phenotype was assessed using flow cytometry (FACS). The same treatment conditions were used on differentiated HL-60 cells (dHL-60) to test their phenotype and functionality based on a) oxidative burst capacity using dihydrorhodamine 123 and b) adhesion to coronary artery endothelial cells. At the end, neutrophils phenotype was tested on patients with obesity and diabetes under semaglutide treatment for 6 months, according to clinical practice. Neutrophils phenotype was determined by FACS and FABP4/C5a plasma levels by immunofluorescence assay. Results FABP4 reduced neutrophils’ CD88 (p=0.006) and CXCR2 (p=0.02) levels. This was also verified in dHL60 cells (p=0.01). In these cells, we were also able to observe a CD11b increment after FABP4 treatment (p=0.04), modulated by semaglutide (p=0.02). This phenotype increased the neutrophil-coronary adhesion (p=0.03). Their oxidative burst capacity was attenuated after semaglutide treatment. In addition, 32% of patients underwent semaglutide treatment reduced plasmatic FABP4 (p=0.03) levels and increased CD88 (p=0.01). We confirmed that CD88 modulation does not lead to a change in plasma C5a. Conclusions High FABP4 levels reduce CD88 of neutrophils from patients with cardiovascular disease and enhance their adhesion to coronary endothelial cells. Modulation of the FABP4 effects by semaglutide treatment might suggest a protective mechanism against adiposity/coronary endothelial inflammation.

Semaglutide modulates adipogenic differentiation and extracellular acidification in epicardial (EAT) and subcutaneous (SAT) adipose tissue stromal cells from patients with cardiovascular disease

Abstract Backround Cardiovascular disease (CVD) is the main cause of death in the world. One of the known risk factors is the epicardial fat (EAT) accumulation, which is around the myocardium and coronaries playing a paracrine role over them. Although mature and functional adipocytes are involved in energy balance and glucose metabolism, the hypertrophic state increases the production of fatty acid binding protein 4 (FABP4), which is a pro-inflammatory adipokine, with consequences on extracellular acidification. Recent data shows that glucagon-like peptide receptor agonists 1 (GLP1ra) drug improves the insulin response and reduces EAT thickness. Although GLP1ra has a direct effect on hypothalamus for reducing food intake, this drug might play a direct role on adipogenesis process in this fat stromal cells. Purpose Our study aims to demonstrate the effect of semaglutide on adipogenesis and metabolism in epicardial and subcutaneous stromal cells from patients with cardiovascular disease. Methods The study was approved by the Galician Research Ethics Committee, and subcutaneous adipose tissue (SAT) and EAT samples from 17 patients were obtained undergoing open-heart surgery with informed consent. Stromal cells from biopsies were isolated and cultured. Adipogenesis was induced for 15 days with or without 1 nM semaglutide, given by Novo-Nordisk (Bagsværd, Denmark), using an adipogenesis cocktail. Cells were lysed and RNA was isolated for RT-qPCR. Target genes were amplified for Glucagon like peptide 1- receptor (GLP1R), differentiation, adipogenesis, glucose metabolism and cellular markers. Extracellular acidification rate was measured with glycolytic rate assay on Seahorse. Lipids accumulation was tested by AdipoRed staining. Results Stromal cells from both tissues express GLP1R but higher differentiation factor (PGC1α) was detected in SAT compared to EAT (p=0.02), as well as adipogenesis induction. After semaglutide treatment, we observed a downregulation of FABP4 and GLUT1 in EAT (p=0.01 and p=0.02, respectively). Despite FABP4 was not modulated on SAT, there was a reduction of PGC1α levels. (p=0.02). Since glitazones upregulate PGC1α, which is used for adipogenesis induction, these results might suggest the counteract mechanism of semaglutide. The metabolism assay showed that semaglutide reduces extracellular acidification rate in EAT cells (p=0.04) and oxidative glycolysis with semaglutide treatment (p=0.003) but not in SAT cells. Conclusions Semaglutide reduces adipogenesis, through modulation of PGC1α transcription factor in EAT from patients with cardiovascular disease and extracellular acidification and oxidative glycolysis. These results might help to understand one of the mechanisms associated with EAT reduction in patients with semaglutide treatment.

Baseline patient reported outcomes in patients with peripheral artery disease and type 2 diabetes from STRIDE: a phase 3, 52-week, randomised, double-blind, placebo-controlled trial

Abstract Introduction Lower extremity peripheral artery disease (PAD) is caused by atherosclerotic steno-occlusive arterial lesions in the lower extremities and can lead to intermittent claudication, severe functional impairment and reduced health-related quality of life (HRQoL). People living with type 2 diabetes (T2D) are at higher risk of developing PAD than those without T2D. The most common clinical manifestation of PAD, functional impairment, can be stratified based on severity using Fontaine classification (stages I-IV). There are a limited number of therapies approved for the management of PAD related functional impairment and no glucose-lowering medication has been shown to improve functional capacity in people with PAD and T2D. STRIDE is a phase 3 clinical trial investigating once-weekly subcutaneous (s.c.) semaglutide treatment in people with PAD (Fontaine IIa claudication) and T2D. Purpose To report the patient-reported outcomes (PROs) at baseline from STRIDE and elucidate the impact that PAD has on the functional capacity and HRQoL in this early-stage symptomatic PAD population with T2D. Methods STRIDE enrolled 792 participants with PAD (Fontaine IIa claudication) and T2D who were randomised to receive either 1 mg once-weekly s.c. semaglutide or placebo for 52 weeks. The primary outcome of STRIDE is the change in maximum walking distance at week 52 on a constant load treadmill. Baseline PRO assessments included two Patient Global Impression of Severity (PGI-S) questions and three patient-reported questionnaires: the six items version of the Vascular Quality of Life questionnaire (VascuQoL-6), the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Short Form 36 (SF-36). Results Baseline responses to both PGI-S questions showed that two thirds of patients reported a moderate-to-severe limitation in their ability to walk (64.9%) and reported that the impact of poor blood circulation in their legs on their HRQoL was also moderate-to-severe (62.5%) (Figure 1A and B). The baseline VascuQoL-6 median score was 15 (score range: 6-24, with a low score indicating more severe impact) and details of impact on the six domains are presented in Table 1. Baseline responses to the WIQ indicated that 20.1% of participants found the degree of difficulty to walk 200 meters either ‘much difficulty’ or were ‘unable to do so’ and 21.8% reported the same when climbing 2 flights of stairs. The secondary supportive outcome assessed in the SF-36 questionnaire was the domain physical functioning where a median baseline value of 38.09 was observed (score range: 19.03-57.60, with a low score indicating more impact). Conclusion Participants in STRIDE, characterized as having early-stage symptomatic PAD, have reported moderate-to-high impact on their physical functioning and HRQoL at baseline. These findings highlight the need for better therapies that improve the functional capacity and HRQoL in people with PAD and T2D.

Semaglutide improves contractile function in isolated human atrium

Abstract Background Recently, the results of the STEP-HFpEF trial were announced, in which high-dose treatment with the antidiabetic glucagon-like-peptide 1 agonist semaglutide resulted in a significant improvement of HFpEF-associated symptoms and reduction of NT-proBNP levels. Interestingly, treatment effects were independent of initial body weight and left-ventricular ejection fraction, sparking interest regarding the precise mechanism of action. Purpose We tested the effects of acute semaglutide treatment in isolated human right-atrial trabeculae. Methods Trabeculae were prepared from right atrial appendage biopsies from 32 patients undergoing elective coronary artery bypass grafting and/or valve surgery. Regular contractions were elicited by electrical field stimulation (1Hz, 5V/50ms, 37°C). Paired experiments were performed simultaneously per patient with a control group and one exposed to semaglutide (100 or 300nM). Developed tension was analysed at steady state after 30 min. Arrhythmias were defined as deviations from baseline not arising from electrical stimulation. L-type calcium channel blockade was achieved with nifedipine (2µM) in some experiments. Rapid cooling contraction was elicited to assess sarcoplasmic reticulum Ca2+ content (RCC1) by rapidly superfusing the trabeculae with chilled solution (2°C). After a short rewarming period of 10s to 37°C, RCC was repeated to assess the Na+/Ca2+ exchanger function (RCC2). Statistical analysis was conducted using paired t-test or Wilcoxon test as appropriate (for 2 groups) and one-way ANOVA with test for trend (for &amp;gt;2 groups). Results Exposure to semaglutide increased developed tension by over 3-fold in human atrial trabeculae in a dose-dependent manner: from 3.14±1.14 for control to 5.43±2.35mN/mm2 for 100nM semaglutide (p=0.03 vs. control) to 12.5±3.53 for 300nM semaglutide (p=0.004 vs. control, mean±SEM, fig. A-D, p=0.005 for linear trend). L-type calcium channel blockade with nifedipine blunted developed tension overall but did not abolish the effect of semaglutide (fig. E, p=0.02). In contrast, the developed tensions upon RCC1 and RCC2 were increased by semaglutide (300nM) compared to control, while the ratio of RCC2:RCC1 was elevated by semaglutide, indicating both increased SR Ca2+ reuptake and less external Ca2+ removal in the presence of semaglutide (fig. H-J). Relaxation time to 50% of baseline was unaltered (not shown), while relaxation time to 90% of baseline was mildly prolonged by semaglutide at 300 nM (fig. F). No increase in the rate of arrhythmias was observed by semaglutide treatment (fig. G). Conclusion Acute exposure of human atrial trabeculae to semaglutide results in a strong positive inotropic effect in a dose-dependent manner without increasing the propensity for arrhythmias. This effect is most likely due to increased SR Ca2+ reuptake. Treatment of heart failure patients with high-dose semaglutide can improve atrial function, which may ameliorate symptoms.

Effects of prognostic nutritional index and obesity on 1-year mortality in patients with acute heart failure

Abstract Background Increased body mass index (BMI) has paradoxically been linked to improved survival rates among patients with acute heart failure (AHF). However, the impact of different nutritional statuses on this obesity paradox on 1-year mortality remains unclear. The prognostic nutritional index (PNI) is a simple tool to assess nutrition status. Recently, landmark findings such as the STEP-HFpEF (Semaglutide Treatment Effect in People With Obesity and HFpEF) trial showed at 1-year, semaglutide not only reduced weight considerably, but also significantly improved health-related quality of life, functional status, and CRP levels. Also, the semaglutide effects on heart disease and stroke in patients with overweight or obesity (SELECT) trial demonstrated a 20% reduction in cardiovascular outcomes. Purpose To investigate the association between obesity and AHF on all-cause mortality according to nutritional status. Methods The cohort study comprised 7258 patients with a cardiopulmonary condition, all of whom were admitted and included on-site at the Emergency Department (ED) in a large University Hospital in Denmark, between March 2020 and March 2022. The follow-up time was at least 365 days. 408 patients with AHF were identified by chart review by trained cardiologists for analysis. PNI was calculated according to the formula: 10×serum albumin (g/ dL) + 5×total lymphocyte count×109/L. A value ≥ 38 is considered well-nourished, and a value &amp;lt; 38 is considered malnourished. Patients were divided into High-PNI (≥38) and Low-PNI (&amp;lt;38) according to cut-off value of PNI. The Kaplan-Meier (KM) curves were used to analyze cumulative survival in each subgroup, and the log-rank test was used to compare differences between groups. Cox regression models were used to analyze associa­tions between BMI, nutritional status and outcomes, expressed as hazard ratios (HR) and relative 95% confi­dence intervals (CI). Results Amongst 408 hospitalized AHF patients, 384 (mean age 75.6 ±11.7) with available PNI scores were enrolled into this study. 55.7% (n=214) were male, 56.4% (n=93) died in the Low-PNI group and 34.2% (n=75) died in the High-PNI group within 1 year. After adjusting for potential confounders in the High-PNI population, compared with the under/normal and overweight BMI group, obesity was negatively associated with 1-year mortality, with adjusted HR of 0.47, 95% CI (0.24–0.94), P = 0.033. However, this correlation disappeared in the Low-PNI group (obese BMI: HR 1.2, 95% CI 0.71–2.1, P = 0.457). In addition, those who were overweight in the Low-PNI group had an 80% increase in 1-year risk of death. Conclusion Obesity (BMI&amp;gt;30) was associated with reduced 1-year mortality only in AHF-patients with good nutritional status. However, this association disappeared in malnourished patients. Consequently, additional research is essential to formulate weight loss recommendations for malnourished obese patients with AHF.