Glucagon-like Peptide-1 Receptor Agonists Semaglutide Research Articles

Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system

Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.

Semaglutide as a promising treatment for hypothalamic obesity: a six-month case series on four females with craniopharyngioma.

Patients with hypothalamic pathology often develop hypothalamic obesity, causing severe metabolic alterations resulting in increased morbidity and mortality. Treatments for hypothalamic obesity have not proven very effective, although the glucagon-like peptide-1 receptor agonist semaglutide has been shown to have positive effects. We examined semaglutide's effect on weight loss in a sample of patients with hypothalamic obesity. Four female patients with hypothalamic obesity resulting from treatment of craniopharyngiomas were treated with semaglutide for six months. Whole Body Dual-energy x-ray absorptiometry scans were performed, and blood samples drawn at baseline and after six months. Semaglutide dosages were increased monthly along with tracking of body weight and eating behavior (Three Factor Eating Questionnaire, TFEQ-R18). BMI was reduced in all cases, with an average of 7.9 BMI (range: 6.7 to 10.1) corresponding to a weight loss of 17.0% (range: 11.3-22.4%) or 20.2kg (range 16.2kg to 23.4kg). We found a comparable reduction in total fat mass (17.2%, p = 0.006) and lean mass (16.0%, p = 0.05), whereas bone mass was unchanged (2.6%, p = 0.12). All cases reported an increase in energy levels, improved mobility and physical activity. Unfavorable eating behaviors were reduced after 1 month of treatment (emotional eating - 41 points, p = 0.02, uncontrolled eating - 23 points, p = 0.11). HbA1c and total cholesterol were significantly reduced (p = 0.014 for both). Semaglutide is a promising and safe treatment option for HO, that improves eating behavior, reduces weight, and improves metabolic markers.

Glucagon-like peptide-1 receptor agonist semaglutide reduces atrial fibrillation incidence: A systematic review and meta-analysis.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are new anti-hyperglycaemic drugs with proven cardiovascular (CV) benefit in diabetic and non-diabetic patients at high CV risk. Despite a neutral class effect on arrhythmia risk, data on semaglutide suggest a possible drug-specific benefit in reducing atrial fibrillation (AF) occurrence. To perform a meta-analysis of randomized clinical trials (RCTs) to assess the risk of incident AF in patients treated with semaglutide compared to placebo. Ten RCTs were included in the analysis. Study population encompassed 12,651 patients (7285 in semaglutide and 5366 in placebo arms), with median follow-up of 68 months. A random effect meta-analytic model was adopted to pool relative risk (RR) of incident AF. Semaglutide reduces the risk of AF by 42% (RR .58, 95% CI .40-.85), with low heterogeneity across the studies (I2 0%). At subgroup analysis, no differences emerged between oral and subcutaneous administration (oral: RR .53, 95% CI .23-1.24, I2 0%; subcutaneous: RR .59, 95% CI .39-.91, I2 0%; p-value .83). In addition, meta-regression analyses did not show any potential influence of baseline study covariates, in particular the proportion of diabetic patients (p-value .14) and body mass index (BMI) (p-value .60). Semaglutide significantly reduces the occurrence of incident AF by 42% as compared to placebo in individuals at high CV risk, mainly affected by type 2 diabetes mellitus. This effect appears to be consistent independently of the route of administration of the drug (oral or subcutaneous), the presence of underlying diabetes and BMI.

Effectiveness of switching from dipeptidyl peptidase-4 inhibitor to oral glucagon-like peptide-1 receptor agonist in Japanese participants with type 2 diabetes mellitus: Prospective observational study using propensity score matching.

Recently, the development of the oral glucagon-like peptide-1 receptor agonist semaglutide has drawn a great deal of attention. This study aimed to compare the effectiveness of oral glucagon-like peptide-1 receptor agonist semaglutide and dipeptidyl peptidase-4 (DPP-4) inhibitors on glycaemic control and several metabolic parameters in patients with type 2 diabetes mellitus over a 6-month period. Fifty-nine participants were included, and we compared various clinical parameters between before and after switching from DPP-4 inhibitors to oral semaglutide in 'study 1' (pre-post comparison) and set the control group using the propensity score matching method in 'study 2'. In 'study 1', 6 months after the switching, the glycated haemoglobin value was significantly reduced from 7.5% to 7.0%, and the body mass index was also decreased from 29.7 kg/m2 to 28.8 kg/m2. Such effects were more clearly observed in participants whose glycaemic control was poor. In 'study 2', after 1:1 propensity score matching, 51 participants from each group were matched, and glycaemic control as well as body weight management were improved in the switching group compared with the DPP-4 inhibitor continuation group over the 6-month observation period. In this study, including obese participants with poor glycaemic control, switching DPP-4 inhibitors to oral semaglutide showed more beneficial effects on both glycaemic and weight control, irrespective of age, body weight and diabetes duration. Therefore, we should bear in mind that it would be better to start using an oral semaglutide in clinical practice, particularly in obese participants with poor glycaemic control with DPP-4 inhibitors.

Comprehensively prognostic and immunological analyses of GLP-1 signaling-related genes in pan-cancer and validation in colorectal cancer.

Background: Glucagon-like peptide-1 (GLP-1) has crucial impact on glycemic control and weight loss physiologically. GLP-1 receptor agonists have been approved for treatment of diabetes and obesity. Emerging evidence suggests that GLP-1 receptor agonists exert anticancer effect in tumorigenesis and development. However, the role and mechanism of GLP-1 signaling-related genes in pan-cancer still need further study. Methods: We comprehensively investigated the aberrant expression and genetic alterations of GLP-1 signaling-related genes in 33 cancer types. Next, GLP-1 signaling score of each patient in The Cancer Genome Atlas were established by the single-sample gene set enrichment analysis. In addition, we explored the association of GLP-1 signaling score with prognostic significance and immune characteristics. Furthermore, qRT-PCR and immunohistochemistry staining were applied to verify the expression profiling of GLP-1 signaling-related genes in colorectal cancer (CRC) tissues. Wound-healing assays and migration assays were carried out to validate the role of GLP-1 receptor agonist in CRC cell lines. Results: The expression profiling of GLP-1 signaling-related genes is commonly altered in pan-cancer. The score was decreased in cancer tissues compared with normal tissues and the lower expression score was associated with worse survival in most of cancer types. Notably, GLP-1 signaling score was strongly correlated with immune cell infiltration, including T cells, neutrophils, dendritic cells and macrophages. In addition, GLP-1 signaling score exhibited close association with tumor mutation burden, microsatellite instability and immunotherapy response in patients with cancer. Moreover, we found that the expression of GLP-1 signaling-related genes ITPR1 and ADCY5 were significantly reduced in CRC tissues, and GLP-1 receptor agonist semaglutide impaired the migration capacity of CRC cells, indicating its protective role. Conclusion: This study provided a preliminary understanding of the GLP-1 signaling-related genes in pan-cancer, showing the prognosis significance and potential immunotherapeutic values in most cancer types, and verified the potential anticancer effect of GLP-1 receptor agonist in CRC.

The glucagon-like peptide-1 receptor agonist semaglutide in diabetic kidney disease: A new kid on the block to afford maximal kidney protection.

The glucagon-like peptide-1 receptor agonist semaglutide in diabetic kidney disease: A new kid on the block to afford maximal kidney protection.

#2496 Effect of semaglutide on kidney outcomes in people with overweight or obesity and established cardiovascular disease in the SELECT trial

Abstract Background and Aims Obesity is an important risk factor for declining kidney function and albuminuria. Secondary analyses of cardiovascular outcome trials in people with type 2 diabetes suggest that the glucagon-like peptide-1 receptor agonist semaglutide has the potential to reduce kidney function deterioration. Semaglutide reduced the primary endpoint of major adverse cardiovascular events by 20% in the randomised controlled SELECT trial in people with overweight or obesity without diabetes. The present report is the prespecified analysis on secondary and exploratory kidney outcomes in SELECT. Method The main kidney endpoint was the time from randomisation to first occurrence of a 5-component nephropathy composite comprising: death from kidney causes; initiation of chronic kidney replacement therapy (dialysis or transplantation); onset of persistent estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2; persistent ≥50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria. Persistence was defined as at least two measures at least 4 weeks apart. Patients were randomised to once-weekly subcutaneous semaglutide 2.4 mg or placebo. Blood and urine samples for eGFR and urinary albumin-to-creatinine ratio (UACR) were collected at screening, at 20, 52, 104, 156, 208 weeks of follow-up and at the end of treatment. Analyses were of in-trial data and used Cox regression and mixed models for repeated measures. Results A total of 8803 patients were assigned to semaglutide and 8801 to placebo. The median follow-up was 182 weeks. The main composite nephropathy endpoint occurred in fewer of those assigned semaglutide (1.8% [155/8803]) than placebo (2.2% [198/8801]): hazard ratio 0.78 [95% confidence interval (CI) 0.63, 0.96]; p = 0.02 (Fig. 1). This effect on the main endpoint was driven by the treatment effect on onset of macroalbuminuria and, to a lesser extent, persistent ≥50% reduction in eGFR. At the prespecified 104-week time point, eGFR had declined less in the semaglutide than placebo arm, giving a treatment effect of 0.75 mL/min/1.73 m2 [95% CI 0.43, 1.06]; p < 0.001 (Fig. 2A). The treatment effect on eGFR at 104 weeks was 0.57 mL/min/1.73 m2 [95% CI 0.26, 0.89] among those with eGFR ≥60 mL/min/1.73 m2 (N = 15 638) at baseline and was 2.19 mL/min/1.73 m2 [95% CI 1.00, 3.38] in those with eGFR <60 mL/min/1.73 m2 (N = 1908) at baseline. At 104 weeks the proportionate increase in UACR was less in the semaglutide than the placebo arm, with a treatment effect of –10.7% [95% CI –13.2, –8.2]; p < 0.001 (Fig. 2B). The treatment effect on UACR at 104 weeks was –8.1% [95% CI –10.6, –5.6], –27.2% [95% CI –35.3, –18.1] and –31.4% [95% CI –54.9, 4.3] in those with normo- (N = 14 848), micro- (N =1968) and macroalbuminuria (N = 325) at baseline, respectively. Semaglutide was not associated with any excess of acute kidney injury, regardless of baseline eGFR. Conclusion These prespecified secondary analyses suggest a beneficial effect of once-weekly subcutaneous semaglutide 2.4 mg on a composite kidney endpoint in people with overweight or obesity and established cardiovascular disease. Significant benefits for both eGFR and UACR were found, including clinically relevant lesser eGFR decline in those with baseline eGFR <60 mL/min/1.73 m2.

Risk of Stroke in Real-World US Individuals with Type2 Diabetes Receiving Semaglutide or a Dipeptidyl Peptidase4 Inhibitor.

People with type2 diabetes (T2D) have a higher risk of stroke and worse outcomes than those without T2D. Pooled data from randomized controlled trials indicate that the glucagon-like peptide1 receptor agonist semaglutide is associated with stroke risk reduction in people with T2D at high cardiovascular risk. We compared real-world stroke risk in people with T2D or T2D plus atherosclerotic cardiovascular disease (ASCVD) initiating either semaglutide or a dipeptidyl peptidase4 inhibitor (DPP4i). Adults (≥ 18years old) in a US claims database with a claim indicating initiation of either semaglutide or a DPP4i (index date) during the index period (1 January 2018-30 September 2020), a diagnosis code for T2D on or before the index date and at least 12months' continuous enrolment in the database pre-index were included and propensity score matched 1:1 on baseline demographic and clinical characteristics. The primary outcome was time to first stroke event during follow-up. Healthcare resource utilization was also compared between groups. The analysis included 17,920 matched pairs with T2D and 4234 matched pairs with T2D and ASCVD. The groups were well matched on baseline characteristics. People initiating semaglutide had a lower risk of stroke over short-term follow-up than those initiating a DPP4i (T2D: hazard ratio 0.63 [95% confidence interval 0.41-0.95], p = 0.029; T2D plus ASCVD: 0.45 [0.24-0.86], p = 0.015). Semaglutide was also associated with a lower rate of inpatient, outpatient and emergency room visits compared with a DPP4i. This proof-of-concept analysis indicates that semaglutide has the potential to reduce the risk of stroke in people with T2D when prescribed in clinical practice.

Maternal GLP-1 receptor activation inhibits fetal growth.

Glucagon-like peptide 1 (GLP-1) regulates food intake, insulin production, and metabolism. Our recent study demonstrated that pancreatic α-cells-secreted (intraislet) GLP-1 effectively promotes maternal insulin secretion and metabolic adaptation during pregnancy. However, the role of circulating GLP-1 in maternal energy metabolism remains largely unknown. Our study aims to investigate systemic GLP-1 response to pregnancy and its regulatory effect on fetal growth. Using C57BL/6 mice, we observed a gradual decline in maternal blood GLP-1 concentrations. Subsequent administration of the GLP-1 receptor agonist semaglutide (Sem) to dams in late pregnancy revealed a modest decrease in maternal food intake during initial treatment. At the same time, no significant alterations were observed in maternal body weight or fat mass. Notably, Sem-treated dams exhibited a significant decrease in fetal body weight, which persisted even following the restoration of maternal blood glucose levels. Despite no observable change in placental weight, a marked reduction in the placenta labyrinth area from Sem-treated dams was evident. Our investigation further demonstrated a substantial decrease in the expression levels of various pivotal nutrient transporters within the placenta, including glucose transporter one and sodium-neutral amino acid transporter one, after Sem treatment. In addition, Sem injection led to a notable reduction in the capillary area, number, and surface densities within the labyrinth. These findings underscore the crucial role of modulating circulating GLP-1 levels in maternal adaptation, emphasizing the inhibitory effects of excessive GLP-1 receptor activation on both placental development and fetal growth.NEW & NOTEWORTHY Our study reveals a progressive decline in maternal blood glucagon-like peptide 1 (GLP-1) concentration. GLP-1 receptor agonist injection in late pregnancy significantly reduced fetal body weight, even after restoration of maternal blood glucose concentration. GLP-1 receptor activation significantly reduced the placental labyrinth area, expression of some nutrient transporters, and capillary development. Our study indicates that reducing maternal blood GLP-1 levels is a physiological adaptation process that benefits placental development and fetal growth.

OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

ObjectiveDual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonists are therapeutic agents with an interesting liver-specific mode of action suitable for metabolic complications. In this study, dual GLP-1 and glucagon receptor agonist OXM-104 is compared head-to-head with the once-daily dual GLP-1 and glucagon receptor agonist cotadutide and GLP-1 receptor agonist semaglutide to explore the metabolic efficacy of OXM-104. MethodsThe in vitro potencies of OXM-104, cotadutide and semaglutide were assessed using reporter assays. In addition, in vivo efficacy was investigated using mouse models of diet-induced obesity (DIO mice), diabetes (db/db mice) and diet-induced NASH mice (MS-NASH). ResultsOXM-104 was found to only activate the GLP-1 and glucagon with no cross-reactivity at the (GIP) receptor. Cotadutide was also found to activate the GLP-1 and glucagon receptors, whereas semaglutide only showed activity at the GLP-1 receptor. OXM-104, cotadutide, and semaglutide elicited marked reductions in body weight and improved glucose control. In contrast, hepatoprotective effects, i.e., reductions in steatosis and fibrosis, as well as liver fibrotic biomarkers, were more prominent with OXM-104 and cotadutide than those seen with semaglutide, demonstrated by an improved NAFLD activity score (NAS) by OXM-104 and cotadutide, underlining the importance of the glucagon receptor. ConclusionThese results show that dual GLP-1 and glucagon receptor agonism is superior to GLP-1 alone. OXM-104 was found to be a promising therapeutic candidate for the treatment of metabolic complications such as obesity, type 2 diabetes and NASH.

Reducing BMI below the obesity threshold in adolescents treated with once-weekly subcutaneous semaglutide 2.4 mg.

To examine how improvement in body mass index (BMI) with the glucagon-like peptide-1 receptor agonist, semaglutide, translated to changes in BMI category in a post-hoc analysis of the double-blind, phase 3a randomized controlled STEP TEENS trial (NCT04102189). Adolescents with obesity received once-weekly subcutaneous semaglutide 2.4 mg or placebo, plus lifestyle intervention which comprised counseling in healthy nutrition and a goal of 60 minutes of moderate- to high-intensity physical activity per day. Achievement of an improvement in BMI category and attainment of normal weight or overweight BMI category by week 68 were analyzed using logistic regression models. In the overall population, 44.9% of participants receiving semaglutide achieved normal weight or overweight BMI category versus 12.1% receiving placebo at week 68 (odds ratio: 22.7; 95% confidence interval [CI]: 7.6-67.9). The proportion of semaglutide-treated participants in obesity class III decreased from 37.3% to 13.6%, but increased with placebo. The odds ratio for achieving an improvement of ≥1 BMI category was significantly greater with semaglutide versus placebo (23.5; 95% CI: 9.9-55.5); an improvement of ≥1 BMI category was seen in 73.7% of participants receiving semaglutide compared with 19.0% with placebo. Semaglutide was highly effective in reducing BMI category. While on treatment, most trial participants' BMI improved by ≥1 category and > 40% reached a category below the obesity threshold. This article is protected by copyright. All rights reserved.

A phase IIa active-comparator-controlled study to evaluate the efficacy and safety of efinopegdutide in patients with non-alcoholic fatty liver disease

This study assessed the effects of the glucagon-like peptide-1 (GLP-1)/glucagon receptor co-agonist efinopegdutide relative to the selective GLP-1 receptor agonist semaglutide on liver fat content (LFC) in patients with non-alcoholic fatty liver disease (NAFLD). This was a phase IIa, randomized, active-comparator-controlled, parallel-group, open-label study. A magnetic resonance imaging-estimated proton density fat fraction assessment was performed to determine LFC at screening and Week 24. Participants with an LFC of ≥10% at screening were randomized 1:1 to efinopegdutide 10mg or semaglutide 1mg, both administered subcutaneously once weekly for 24 weeks. Participants were stratified according to the concurrent diagnosis of type 2 diabetes mellitus (T2DM). Both drugs were titrated to the target dose over an 8-week time period. The primary efficacy endpoint was relative reduction from baseline in LFC (%) after 24 weeks of treatment. Among 145 randomized participants (efinopegdutide n= 72, semaglutide n= 73), 33.1% had T2DM. At baseline, mean BMI was 34.3kg/m2 and mean LFC was 20.3%. The least squares (LS) mean relative reduction from baseline in LFC at Week 24 was significantly (p <0.001) greater with efinopegdutide (72.7% [90% CI 66.8-78.7]) than with semaglutide (42.3% [90% CI 36.5-48.1]). Both treatment groups had an LS mean percent reduction from baseline in body weight at Week 24 (efinopegdutide 8.5% vs. semaglutide 7.1%; p= 0.085). Slightly higher incidences of adverse events and drug-related adverse events were observed in the efinopegdutide group compared with the semaglutide group, primarily related to an imbalance in gastrointestinal adverse events. In patients with NAFLD, treatment with efinopegdutide 10mg weekly led to a significantly greater reduction in LFC than semaglutide 1mg weekly. EudraCT: 2020-005136-30; NCT:04944992. Currently, there are no approved therapies for non-alcoholic steatohepatitis (NASH). The weight loss associated with glucagon-like peptide-1 (GLP-1) receptor agonists has been shown to decrease hepatic inflammation in patients with NASH. In addition to reducing liver fat content (LFC) indirectly through weight loss, glucagon receptor agonism may also reduce LFC by acting on the liver directly to stimulate fatty acid oxidation and reduce lipogenesis. This study demonstrated that treatment of patients with non-alcoholic fatty liver disease with the GLP-1/glucagon receptor co-agonist efinopegdutide (10mg weekly) led to a significantly greater reduction in LFC compared to treatment with the GLP-1 receptor agonist semaglutide (1mg weekly), suggesting that efinopegdutide may be an effective treatment for NASH.

A Lipopolysaccharide Mouse Model Mirrors Neuroinflammatory Transcriptional Signatures of Human AD, and the Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Attenuates Neuroinflammation in this Model (P1-6.007)

<h3>Objective:</h3> We aimed to investigate the molecular effects of semaglutide on lipopolysaccharide (LPS) induced hippocampal neuroinflammation in mice and further to compare human gene expression signatures in Alzheimer’s disease (AD) brain tissue with those induced by LPS. <h3>Background:</h3> Neuroinflammation is part of the pathophysiology in AD. AD neuroimaging studies highlight increased inflammation, while genome wide association studies indicate that many AD-associated genes are expressed in glial cells. The glucagon-like peptide-1 receptor agonist semaglutide is currently being investigated in two phase 3a randomized, placebo-controlled trials in people with early Alzheimer’s disease (evoke/evoke+). <h3>Design/Methods:</h3> Mice were treated daily with subcutaneous semaglutide (30nmol/kg) or vehicle for 28 days, and LPS or vehicle was administered on days 15–17. RNA-sequencing and immunohistochemistry were performed to assess transcriptional and morphological changes in the hippocampus at Day 19 and Day 28 (Day 2 and 11 post-LPS, respectively). RNA-sequencing analyses included differentially expressed gene analysis, weighted gene co-regulated network analysis, pathway analysis and gene set enrichment analysis on published human AD datasets. <h3>Results:</h3> Semaglutide treatment significantly decreased the area of ionized calcium binding adaptor molecule 1 (Iba1) positive microglia (quantitative assessment) and attenuated co-expressed inflammatory genes vs vehicle in LPS-treated mice (p&lt;0.01) on Day 28. Pathway analysis was consistent with an overall dampening of inflammatory processes in mice treated with LPS and semaglutide. The mouse LPS model mirrored the transcriptional signatures identified in people with AD in data of human hippocampal subtype transcriptional signatures, suggesting that semaglutide could potentially alleviate homologous inflammatory molecular processes in humans. <h3>Conclusions:</h3> In an LPS-induced neuroinflammation mouse model, semaglutide reduced hippocampal neuroinflammation as measured by transcriptional changes and microglial area (Iba1). This could represent a novel mechanism whereby semaglutide may affect neuronal integrity and function, and thereby AD pathophysiology. <b>Disclosure:</b> Dr. Ludwig has nothing to disclose. Dr. Rausch has nothing to disclose. Dr. Secher has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Secher has received personal compensation for serving as an employee of Novo Nordisk. Dr. Secher has stock in Novo Nordisk. Dr. Bentsen has received personal compensation for serving as an employee of Novo Nordisk. An immediate family member of Dr. Bentsen has stock in Novo Nordisk. Dr. Hansen has received personal compensation for serving as an employee of Neumirna Therapeutics. Dr. Hansen has received intellectual property interests from a discovery or technology relating to health care. Dr. Bjerregaard has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Niss has nothing to disclose. Kristoffer L Egerod has nothing to disclose. Dr. Hansen has received personal compensation for serving as an employee of Novo Nordisk A/S. Dr. Hansen has stock in Novo Nordisk A/S. Dr. Dalgaard has received personal compensation for serving as an employee of Novo Nordisk. Dr. Merkestein has received personal compensation for serving as an employee of Novo Nordisk A/S. Dorte Holst has nothing to disclose. Charles Pyke has nothing to disclose. Mrs. Wichern has received personal compensation for serving as an employee of Gubra ApS. Dr. Polex-Wolf has received personal compensation for serving as an employee of Novo Nordisk A/S. Tune H Pers has nothing to disclose. Lotte B Knudsen has nothing to disclose.

Improved metabolic efficacy of a dual amylin and calcitonin receptor agonist when combined with semaglutide or empagliflozin

Pharmacotherapies for obesity and type 2 diabetes (T2D) are thought to bridge the gap between lifestyle modification and the weight loss obtained with bariatric surgery. Although the effect of monotherapies, namely amylin and glucagon-like peptide-1 receptor (GLP-1R) agonists, has shown great potential, combination therapy is now becoming a strategy to optimize efficacy for weight management while minimizing adverse effects. This study investigated a dual amylin and calcitonin receptor agonist (DACRA); KBP-066A in combination with the GLP-1R agonist semaglutide or the sodium-glucose co transporter-2 inhibitor (SGLT2i) empagliflozin for anti-obesity and anti-diabetic treatment. The effect of KBP-066A, semaglutide, and empagliflozin alone and in combination was studied with respect to their impact on body weight, food intake, and glucose metabolism in high-fat diet (HFD) and Zucker diabetic fatty (fa/fa) (ZDF) rats. Treatment with KBP-066A and semaglutide lowered body weight by 13% and 9.7%.In contrast, a combination of both KBP-066A + semaglutide reduced body weight by 21% in HFD rats demonstrating superiority compared to monotherapies alone. A combination of KBP-066A with semaglutide or empagliflozin significantly lowered fasting blood glucose, and HbA1C (%) levels in ZDF rats. The complementary action by KBP-066A to GLP-1R agonist and SGLT2i on BW, food intake and glucose control endorsed the potential of DACRAs as an add-on therapy to therapeutic options for T2D and obesity.

Nephroprotective Properties of the Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) Receptor Agonists.

Diabetes mellitus is the leading cause of chronic kidney disease, and about 30–40% of patients with diabetes will develop kidney disease. Incretin hormones have received attention during the past three decades not only as a pharmacotherapy for the treatment of type 2 diabetes, but also for their cardiorenometabolic effects. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Additional to the pancreas, receptors for GLP-1 are widely distributed in various organs, causing positive effects on endothelial function and vascular atherogenesis. Along with glycemic control and weight reduction, GLP-1 receptor agonists also strongly improve cardiovascular and renal outcomes in patients with type 2 diabetes. Recently, a dual GIP and GLP-1 receptor agonist has been approved for the treatment of type 2 diabetes. Compared to GLP-1 receptor agonist semaglutide, dual GIP and GLP-1 receptor agonist tirzepatide showed a superior reduction in hemoglobin A1c and body weight. Preliminary results also suggest that tirzepatide improves kidney outcomes in adults with type 2 diabetes with increased cardiovascular risk. In this review, we present the nephroprotective properties of dual GIP and GLP-1 receptor agonists as a new drug to treat type 2 diabetes.

FC 123: Baseline Characteristics of the Flow Trial Population: Kidney Outcomes Trial With Once-Weekly Semaglutide in People With Type 2 Diabetes and Chronic Kidney Disease

Abstract BACKGROUND AND AIMS Chronic kidney disease (CKD) in type 2 diabetes (T2D) is the most common cause of kidney failure. Despite treatment advances, there is still a large unmet need to prevent CKD progression, which can increase the risk for cardiovascular (CV) disease and kidney failure. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have beneficial effects on glycaemic control and body weight. Some agents have also shown CV benefit and can be used in people with T2D regardless of CKD status (except in end-stage renal disease). CV outcomes trials have suggested that GLP-1RAs may have kidney-protective effects, reducing albuminuria and preserving estimated glomerular filtration rate (eGFR). FLOW (NCT03819153) is a dedicated kidney outcomes trial designed to evaluate the effect of the once-weekly (OW) GLP-1RA semaglutide on major kidney outcomes in subjects with T2D and CKD; we report the blinded baseline characteristics of the FLOW trial population. METHOD FLOW is an ongoing randomized, double-blinded, multinational, phase 3b trial in which 3535 subjects with T2D with an eGFR ≥25–≤75 mL/min/1.73 m², and urine albumin-to-creatinine ratio (UACR) &amp;gt;100 to &amp;lt;5000 mg/g were randomly assigned 1:1 to OW semaglutide 1.0 mg or placebo, as add-on to standard-of-care (including maximum labelled/tolerated renin–angiotensin–aldosterone system inhibitors). The primary endpoint is the time to first occurrence of kidney failure (as measured by persistent eGFR &amp;lt;15 mL/min/1.73 m² or initiation of chronic dialysis or kidney transplantation); ≥50% persistent eGFR reduction compared with baseline; and kidney or CV death. RESULTS Baseline characteristics from FLOW are shown in the Table 1. Overall, mean eGFR at baseline was 47.0 mL/min/1.73 m2 with 79.6% of subjects having an eGFR of &amp;lt;60 mL/min/1.73 m2. Median UACR at baseline was 567 mg/g, and 68.5% of subjects had macroalbuminuria (≥300 mg/g). According to Kidney Disease: Improving Global Outcomes categories, 24.8% of subjects were classified as high risk and 68.2% of subjects were classified as very high risk for CKD progression (Figure 1). CONCLUSION The FLOW trial will evaluate the efficacy and safety of semaglutide on kidney outcomes in subjects with T2D and high risk of kidney disease progression, a group for which additional therapies are urgently required.

Effects of switching from a dipeptidyl peptidase-4 inhibitor to oral semaglutide on glucose metabolism in patients with type 2 diabetes: protocol for a multicentre, prospective, randomised, open-label, parallel-group comparison study (the SWITCH-SEMA 2 study)

IntroductionIncretin-based therapies exert antihyperglycaemic effects in patients with type 2 diabetes (T2D) in a blood glucose concentration-dependent fashion. The first-in-class oral glucagon-like peptide-1 receptor agonist semaglutide has potent effects on...

Glucagon-Like Peptide-1 Receptor Agonist Semaglutide Improves Eating Behavior and Glycemic Control in Japanese Obese Type 2 Diabetic Patients.

We evaluated time-course changes and the relationship between eating behavior and glycemic profile during the treatment of 34 obese type 2 diabetic patients with the glucagon-like peptide-1 receptor agonist (GLP1-RA) semaglutide. Changes in dietary habits were evaluated using the Japan Society for the Study of Obesity questionnaire. Semaglutide improved body weight and hemoglobin A1C (HbA1c) 3 and 6 months after treatment. In addition, semaglutide led to marked improvements in the total scores for eating behavior items on the questionnaire. In particular, changes in the scores regarding the sensation of hunger, food preference, eating style, regularity of eating habits and emotional eating behavior were significantly improved during semaglutide treatment. By contrast, there were no significant changes in the scores for the recognition of weight and constitution and external eating behavior. Furthermore, changes in the scores regarding the sensation of hunger and food preference were correlated with changes in HbA1c after semaglutide treatment. Multivariable regression analyses showed that the change in the sensation of hunger was related to HbA1c during treatment. In conclusion, the GLP1-RA semaglutide regulates eating behavior, and, in particular, the sensation of hunger is closely related to the improvement in HbA1c by semaglutide in obese patients with type 2 diabetes.

Blocking C3d+/GFAP+ A1 Astrocyte Conversion with Semaglutide Attenuates Blood-Brain Barrier Disruption in Mice after Ischemic Stroke.

Astrocytes play an essential role in the modulation of blood-brain barrier function. Neurological diseases induce the transformation of astrocytes into a neurotoxic A1 phenotype, exacerbating brain injury. However, the effect of A1 astrocytes on the BBB dysfunction after stroke is unknown. Adult male ICR mice (n=97) were subjected to 90-minute transient middle cerebral artery occlusion (tMCAO). Immunohistochemical staining of A1 (C3d) and A2 (S100A10) was performed to characterize phenotypic changes in astrocytes over time after tMCAO. The glucagon-like peptide-1 receptor agonist semaglutide was intraperitoneally injected into mice to inhibit A1 astrocytes. Infarct volume, atrophy volume, neurobehavioral outcomes, and BBB permeability were evaluated. RNA-seq was adopted to explore the potential targets and signaling pathways of A1 astrocyte-induced BBB dysfunction. Astrocytic C3d expression was increased, while expression of S100A10 was decreased in the first two weeks after tMCAO, reflecting a shift in the astrocytic phenotype. Semaglutide treatment reduced the expression of CD16/32 in microglia and C3d in astrocytes after ischemic stroke (p<0.05). Ischemia-induced brain infarct volume, atrophy volume and neuroinflammation were reduced in the semaglutide-treated mice, and neurobehavioral outcomes were improved compared to control mice (p<0.05). We further demonstrated that semaglutide treatment reduced the gap formation of tight junction proteins ZO-1, claudin-5 and occludin, as well as IgG leakage three days following tMCAO (p<0.05). In vitro experiments revealed that A1 astrocyte-conditioned medium disrupted BBB integrity. RNA-seq showed that A1 astrocytes were enriched in inflammatory factors and chemokines and significantly modulated the TNF and chemokine signaling pathways, which are closely related to barrier damage. We concluded that astrocytes undergo a phenotypic shift over time after ischemic stroke. C3d+/GFAP+ astrocytes aggravate BBB disruption, suggesting that inhibiting C3d+/GFAP+ astrocyte formation represents a novel strategy for the treatment of ischemic stroke.

Possibilities of a new glucagon-like peptide-1 receptor agonist Semaglutide in improving left ventricular diastolic function in a patient with arterial hypertension and type 2 diabetes mellitu

The emergence of new classes of glucose-lowering drugs that can further reduce cardiovascular risk (CVR) have fundamentally changed the approach to the management of patients with type 2 diabetes mellitus. The most significant changes concerned the strategy of choosing glucose-lowering therapy with a change in priorities from the glycemia level to CVR, which plays a key role in choosing a class of antidiabetic drugs. At the same time, the mechanisms responsible for lowering CVR remain largely unclear. Of undoubted interest is the study of effects of a new glucagon-like peptide-1 receptor agonist, Semaglutide, on the preclinical stage of diastolic dysfunction. The article presents a clinical case of the use of Semaglutide in a patient with arterial hypertension and type 2 diabetes mellitus.