Glucagon Receptor Research Articles

Effect of survodutide, a glucagon and GLP-1 receptor dual agonist, on weight loss: a meta-analysis of randomized controlled trials.

Considering the increasing prevalence of obesity/overweight, its treatment or prevention with new interventions can greatly help health and reduce its adverse effects in people. One of these new interventions is investigating the effect of Survodutide as a dual agonist of glucagon and GLP-1 receptors, which seems to be able to influence weight loss processes in different ways. In this study, we investigated the effect of injectable Survodutide on weight loss. In order to identify all randomized controlled trials that investigated the effects of Survodutide on factores related to obesity, a systematic search was conducted in the original databases using predefined keywords until August 2024. The pooled weighted mean difference and 95% confidence intervals were computed using the random-effects model. The Findings from 18 treatment arms with 1029 participants indicated significant reductions in weight (WMD: -8.33kg; 95% CI: -10.80, -5.86; I2 = 99.6%), body mass index (BMI) (WMD:-4.03kg/m2; 95% CI: -4.86, -3.20; I2 = 72.7%), and waist circumferences (WC) (WMD: -6.33cm; 95% CI: -8.85 to -3.81; I2 = 99.5%) following the Survodutide injection compared to the control group. Subgroup analysis reveals that longer interventions (more than 16 weeks) and higher doses (more than 2mg/week) of Survodutide are associated with more significant reductions in weight and WC. These results were also observed in the meta-regression analysis. The results of this meta-analysis show that Survodutide is effective in reducing weight, BMI and waist circumference, especially with longer interventions and higher doses.

Innovative Glucagon-Based Therapies for Obesity

Abstract Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21 (FGF21), and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities.

Oxyntomodulin physiology and its therapeutic development in obesity and associated complications.

Incretins, such as glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP), have advanced the treatment landscape of obesity to a new pinnacle. As opposed to singular incretin effects, oxyntomodulin (OXM) activates glucagon receptors (GCGR) and glucagon-like peptide-1 receptors (GLP1R), demonstrating a more dynamic range of effects that are more likely to align with evolving 'health gains' goals in obesity care. Here, we will review the molecular insights from their inception to recent developments and challenges. This review will discuss the physiological actions of OXM, primarily appetite regulation, energy expenditure, and glucose homeostasis. Finally, we will shed light on the development of OXM-based therapies for obesity and associated complications, and outline important considerations for more translational efforts.

Survodutide for treatment of obesity: rationale and design of two randomized phase 3 clinical trials (SYNCHRONIZE™-1 and -2).

The objective of this study was to describe the rationale and design of two multinational phase 3 clinical trials of survodutide, an investigational glucagon and glucagon-like peptide-1 receptor dual agonist for the treatment of obesity with or without type 2 diabetes (T2D; SYNCHRONIZE-1 and -2). In these ongoing double-blind trials, participants were randomized to once-weekly subcutaneous injections of survodutide or placebo added to lifestyle modification. Survodutide doses are uptitrated to 3.6 or 6.0 mg, and dose flexibility is permitted. Participants (n = 726) in SYNCHRONIZE-1 (NCT06066515) have a baseline BMI ≥ 30 kg/m2 or ≥27 kg/m2 with at least one obesity-related complication but without T2D; participants (n = 755) in SYNCHRONIZE-2 (NCT06066528) have a baseline BMI ≥ 27 kg/m2 and T2D. The primary endpoints are percentage change in body weight and proportion of participants achieving ≥5% body weight reduction from baseline to week 76. Secondary endpoints include change in systolic blood pressure and measures of glycemia. A SYNCHRONIZE-1 substudy is evaluating changes in body composition and liver fat content using magnetic resonance imaging. These trials are designed to provide robust evaluation of the efficacy, safety, and tolerability of survodutide for the treatment of obesity in the presence or absence of T2D.

Glucagon receptor activation contributes to the development of kidney injury.

The underlying causes of diabetic kidney disease are still largely unknown. New insights into the contributing causes of diabetic nephropathy are important to prevent this complication. Hyperglycemia and hypertension are some of the risk factors for diabetic nephropathy. However, the incidence of diabetic nephropathy is increasing despite efforts to normalize blood glucose levels and blood pressure. Therefore, other factors should be investigated as causes of diabetic nephropathy. We investigated whether long-term increased plasma levels of glucagon contribute to the development of pathophysiological changes in kidney function as seen in patients with diabetic nephropathy. Using mouse models of chronic activation and inactivation of glucagon receptor signaling, we investigated whether glucagon is involved in changes in renal function, renal structure, and transcriptional changes. We found several histopathological changes in the kidney, such as thickening of the parietal layer of Bowman's capsule, glomerular mesangial cell expansion, and significant albuminuria in the mice with activated glucagon receptor signaling. Opposite effects on mesangial area expansion and the development of albuminuria were demonstrated in mice with glucagon receptor inactivation. RNA sequencing data revealed that transcription of genes related to fatty acid metabolism, podocytes, Na+-K+-ATPase, and sodium/glucose transport was significantly changed in mice with activated glucagon receptor signaling. These data implicate that glucagon receptor signaling is involved in the development of kidney injury, as seen in type 2 diabetes, and that glucagon receptor is a potential therapeutic target in the treatment of diabetes. NEW & NOTEWORTHY This study suggests that the glucagon receptor is a potential therapeutic target in the treatment of diabetic kidney disease. We show, in mice, that long-term treatment with a glucagon analog showed not only pathophysiological changes and changes in renal function but also transcriptional changes in the kidneys, whereas opposite effects were demonstrated in mice with glucagon receptor inactivation. Therefore, the use of glucagon in a treatment regimen requires investigation of possible metabolic and renal abnormalities.

Triple-hormone receptor agonist retatrutide significantly improves lipoprotein and apolipoprotein profiles in participants with obesity or overweight

Abstract Background In a phase 2 study in participants who have obesity or overweight but not type 2 diabetes (T2D) (n=338), retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, reduced body weight, glycated hemoglobin, triglycerides (TG), LDL-C and VLDL-C. Purpose To better understand the effects of RETA on the serum lipid profile we analyzed changes in apolipoprotein levels and distribution and size of lipoprotein particles. Methods Adult participants with obesity (BMI ≥30 kg/m2), or overweight (BMI ≥ 27 kg/m2 and < 30 kg/m2) with a weight-related comorbidity, and without T2D were randomized to receive RETA 1, 4, 8, 12 mg or placebo for 48 weeks. Lipids panel (including calculated non-HDL-C), apolipoproteins (apo) and NMR lipoprotein profiles were measured at baseline, 24 and 48 weeks in fasting plasma samples. Data were analyzed using a mixed model for repeated measures after log transformation. Results RETA dose-dependently reduced non-HDL-C up to 22.2% and 26.9% and apoB up to 19.6% and 24.2% at 24 and 48 weeks, respectively (Figure). At 48 weeks, RETA reduced TG and apoC-III levels up to 40.6% and 38.0%, respectively. RETA greatly reduced the total number of TG-rich lipoprotein particles (TRLP) and all subfractions of TRLP (large, medium and small) at 48 weeks (Table). Since the reduction in large and medium TRLP was greater than the reduction in small TRLP, the average size of TRLP was smaller following treatment with RETA. RETA reduced the number of total and highly atherogenic small LDL particles (LDLP), while total and small HDL particles (HDLP) were only slightly reduced. The average size of HDLP increased following treatment with RETA. At 48 weeks, the NMR-derived lipoprotein insulin resistance score was dose-dependently decreased by 27.4%, 31.7% and 32.5% with 4 mg, 8 mg and 12 mg, respectively, following RETA treatment. Conclusions RETA treatment for 48 weeks dose-dependently reduced levels of non-HDL-C and apoB and the number of total and small LDL particles, suggesting an improvement in atherogenic lipoprotein profile and cardiovascular risk in subjects who have obesity or overweight but not T2D.

Reduction of triglyceride-rich lipoproteins with retatrutide in type 2 diabetes may be explained by concurrent reduction in ANGPTL3/8 levels

Abstract Background/Introduction In the recent phase 2 study (NCT04867785) in patients with type 2 diabetes (T2D), retatrutide, an agonist of glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide 1 (GLP-1), and glucagon receptors, reduced triglycerides (TG) and non-high-density lipoprotein cholesterol (non-HDL-C) up to 35.0% and 20.7%, respectively. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating inhibitor of lipoprotein lipase (LPL), and its serum levels have been shown to be directly correlated with TG and low-density lipoprotein cholesterol (LDL-C). Purpose In the aforementioned phase 2 study, we examined the effects of retatrutide on circulating ANGPTL3/8 complex concentrations to help understand the mechanism by which retatrutide reduced TG and non-HDL-C. Methods Patients with T2D were randomly assigned to receive once-weekly injections of placebo, 1.5 mg dulaglutide, or retatrutide doses of 0.5 mg, 4 mg, 8 mg, or 12 mg. Fasting serum samples were collected at baseline, week 2, week 4, week 8, week 12, week 16, and week 24, and ANGPTL3/8 levels were measured at all time points using a sensitive and selective immunoassay. Plasma PCSK9 levels were also measured at baseline and 24 weeks. Data were analyzed using a mixed model for repeated measures with log-transformation. Results Baseline ANGPTL3/8 levels (mean 26.3 ng/mL, IQR 17.4-33.0 ng/mL) were not different among all study groups. Mean percent changes of ANGPTL3/8 from baseline at week 24 were -1.3%, -12.0%, -48.7% and -51.0% in 0.5 mg, 4 mg, 8 mg and 12 mg retatrutide groups, respectively (Figure). Percent changes of ANGPTL3/8 in 8 mg and 12 mg retatrutide groups were significantly different from placebo group (p < 0.0001). Mean percent changes of PCSK9 levels from baseline to 24 weeks were not different from placebo for any treatment arm (+6.2%, -3.9%, -3.8% and -9.6% for retatrutide 0.5 mg, 4 mg, 8 mg and 12 mg groups, respectively, and -1.5% for dulaglutide and -6.5% for placebo). Conclusions In patients with T2D, retatrutide dose-dependently decreased serum concentrations of ANGPTL3/8, the most potent circulating LPL inhibitor. These data suggest that retatrutide may reduce TG-rich lipoproteins by decreasing ANGPTL3/8 levels.

Identification of immune feature genes and intercellular profiles in diabetic cardiomyopathy

BACKGROUND Diabetic cardiomyopathy (DCM) is a multifaceted cardiovascular disorder in which immune dysregulation plays a pivotal role. The immunological molecular mechanisms underlying DCM are poorly understood. AIM To examine the immunological molecular mechanisms of DCM and construct diagnostic and prognostic models of DCM based on immune feature genes (IFGs). METHODS Weighted gene co-expression network analysis along with machine learning methods were employed to pinpoint IFGs within bulk RNA sequencing (RNA-seq) datasets. Single-sample gene set enrichment analysis (ssGSEA) facilitated the analysis of immune cell infiltration. Diagnostic and prognostic models for these IFGs were developed and assessed in a validation cohort. Gene expression in the DCM cell model was confirmed through real time-quantitative polymerase chain reaction and western blotting techniques. Additionally, single-cell RNA-seq data provided deeper insights into cellular profiles and interactions. RESULTS The overlap between 69 differentially expressed genes in the DCM-associated module and 2483 immune genes yielded 7 differentially expressed immune-related genes. Four IFGs showed good diagnostic and prognostic values in the validation cohort: Proenkephalin (Penk) and retinol binding protein 7 (Rbp7), which were highly expressed, and glucagon receptor and inhibin subunit alpha, which were expressed at low levels in DCM patients (all area under the curves > 0.9). SsGSEA revealed that IFG-related immune cell infiltration primarily involved type 2 T helper cells. High expression of Penk (P < 0.0001) and Rbp7 (P = 0.001) was detected in cardiomyocytes and interstitial cells and further confirmed in a DCM cell model in vitro . Intercellular events and communication analysis revealed abnormal cellular phenotype transformation and signaling communication in DCM, especially between mesenchymal cells and macrophages. CONCLUSION The present study identified Penk and Rbp7 as potential DCM biomarkers, and aberrant mesenchymal-immune cell phenotype communication may be an important aspect of DCM pathogenesis.

Glucagon and glucagon-like peptide-1 dual agonist therapy: A possible future towards fatty kidney disease.

Obesity is a growing epidemic affecting approximately 40% of the adult population in developed countries with major health consequences and comorbidities, including diabetes mellitus and insulin resistance, metabolically associated fatty liver disease, atherosclerotic cardiovascular and cerebrovascular diseases and chronic kidney disease. Pharmacotherapies targeting significant weight reduction may have beneficial effects on such comorbidities, though such therapeutic options are highly limited. In this narrative review, we aim to evaluate current knowledge regarding dual agonist therapies and potential implications for managing fatty kidney and chronic kidney disease. Glucagon-like peptide-1 agonists and sodium-glucose cotransporter-2 inhibitors are two novel classes of glucose-lowering medications with potential implications and beneficiary effects on renal outcomes, including estimated glomerular filtration rate, albuminuria and chronic kidney disease progression. Recently, dual agonist therapies targeting glucagon-like peptide-1 and glucagon receptors, namely survodutide and cotadutide, have been evaluated in managing metabolically associated fatty liver disease, a well-established example of visceral obesity. Fatty kidney is another novel concept implicated in the pathophysiology of chronic kidney disease among patients with visceral obesity.

The First Triple Agonist for Antiobesity: Retatrutide

The prevalence of individuals with overweight and obesity has increased by 18% since 1990 and it is projected that by 2030, nearly 50% of US adults will have obesity. Lifestyle modifications, such as diet and exercise, typically lead to approximately 3–5% weight loss, whereas 5–15% weight loss is necessary to significantly impact obesity-associated comorbidities and improve overall health outcomes. In addition to lifestyle modifications, pharmacotherapy has been utilized as an adjunctive treatment to increase weight loss and improve health outcomes. The Food and Drug Administration has currently approved 6 drugs to treat overweight and obesity, with the recently approved drugs surging in popularity after demonstrating superior weight loss outcomes. Additionally, a number of agents are in the pipeline, offering promise of unprecedented degrees of weight loss. One such drug is retatrutide, which is a triple agonist targeting the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor, and glucagon receptor. Phase 1 and 2 clinical trials have demonstrated the safety, tolerability, and pharmacokinetics of retatrutide in patients with obesity and/or type 2 diabetes. The pharmacokinetics of retatrutide were dose proportional and its mean half-life of approximately 6 days supported a once-weekly dosing. The safety profile was similar to GLP-1R agonists and glucose-dependent insulinotropic polypeptide receptor/GLP-1R co-agonists, with gastrointestinal disorders being the most common adverse effects reported. Each trial demonstrated greater weight loss with retatrutide treatment in comparison to placebo, with greatest efficacy at higher doses. Overall, these clinical trials have demonstrated the superior efficacy of retatrutide as a weight loss medication in patients with overweight and obesity.

7792 Efficacy of Retatrutide for Weight Reduction and Its Cardiometabolic Effects Among Adults: A Systematic Review and Meta-Analysis

Abstract Disclosure: D.C. Lopez: None. J.T. Pajimna: None. M.D. Milan: None. G.V. Jasul: None. G. Orpilla: None. I. Zapanta: None. B. Serquiña: None. G. Dychiao: None. Background: Obesity remains to be a global health challenge and it is associated with several complications such as diabetes, cardiovascular disease, fatty liver disease, and reduced life expectancy. Although lifestyle modifications are the mainstay for weight management, long term maintenance of weight loss can be a challenge for many affected adults. There have been proven safe and effective pharmacologic interventions but these remain limited to date. One of the novel anti-obesity drugs, retatrutide, is a single peptide with agonist activity at the GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptors. The aim of this systematic review and meta-analysis is to evaluate the effectiveness of this triple-hormone receptor agonist, Retatrutide, in weight reduction and assess its cardiometabolic effects in adults. Methodology: An extensive electronic database search was done to identify studies published from inception until December 2023. All randomized controlled trials (RCT) that evaluated the use of retatrutide for adult patients were included. The Cochrane Risk of Bias 2.0 tool was used to assess the risk of bias of each study. Meta-analysis was conducted to determine weight reduction and glycemic control using random effects model which was reported at 95% confidence interval. Statistical heterogeneity was assessed using I2 statistics and random effects analysis and sensitivity analysis were done to control for the heterogeneity. Results: A total of 3 eligible RCTs were included in the study, all of which had risk of bias ranging from low to unclear. Of these articles, in 2 RCTs involving 353 participants with type 2 diabetes mellitus, retatrutide showed significant weight reduction by 11.89kg as compared to placebo (MD -11.89; 95% CI -13.53 to -10.25) and decreased glycosylated hemoglobin (HbA1C) by 1.64% as compared to placebo (MD: -1.64%, 95% CI [-2.38, -0.89]). Using direct comparison, retatrutide 12mg reduced body weight by 11.83kg as compared to dulaglutide 1.5mg with significant difference (MD -11.83; 95% CI -18.50 to -5.16), and retatrutide showed slight decrease in HbA1C by 0.61% as compared to dulaglutide (MD -0.66; 95% CI -0.66 to -0.56). In another 1 RCT involving 338 non-diabetic adult patients with obesity, retatrutide decreased least-squares mean percentage in body weight by 24.2% and 83% of participants who received retatrutide achieved weight reduction of 15% or more at 48 weeks. Conclusion: The use of retatrutide may result in substantial reductions in mean body weight and HbA1C as compared to controls in adult patients, with low to moderate certainty of evidence. In addition, retatrutide showed marked decrease in body weight but with modest glucose lowering effect when compared to a single GLP1 agonist drug. Presentation: 6/3/2024

6494 GLP-1/GIP/Glucagon Triagonist Improves Glycemic Control via Gαq Signaling Pathway and TRPM5 Activation

Abstract Disclosure: N. Khajavi: None. P.C. Schreier: None. P. Beyerle: None. P.S. Reinach: None. A. Breit: None. I. Boekhoff: None. T.D. Müller: Grant Recipient; Self; Novo Nordisk. Speaker; Self; Novo Nordisk. Stock Owner; Self; Novo Nordisk. T. Gudermann: None. Cutting-edge research on obesity and diabetes strives to pioneer innovative drug combinations targeting various dysfunctional metabolic regulatory pathways. The single-molecule triagonist has been developed to directly interact with the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and the glucagon receptor (GcgR). It provides a breakthrough in the treatment of obesity and type 2 diabetes because of greater efficacy compared to conventional single-agonist therapy. While the triagonist is already undergoing phase two clinical trials, the downstream mechanism requires further study. Previously, we showed that triagonist elicits transient rises in intracellular Ca2+ concentration that augment glucose-induced rises in insulin secretion in murine (MIN6) and human (1.1B4) pancreatic β cell lines. Although Gαs signaling is known as the main mediator of both GLP-1 and GIP signaling, our research indicates that the superior effect of the triagonist on insulin secretion is not solely dependent on the activation of the classical Gαs pathway and the exchange factor activated by cAMP (EPAC) signaling. Instead, we report that the triagonist enhances glucose-induced rises in insulin secretion via Gαq signaling and its downstream effector, the TRPM5 channel. This involvement is evident, as blocking Gαq signaling with a specific blocker, YM254890, reduced triagonist-induced rises in insulin secretion in mouse pancreatic islets. Similarly, blocking TRPM5 with the TPPO blocker attenuated triagonist-induced increases in insulin secretion and Ca2+ signaling in mouse pancreatic islets. Strikingly, both blockers had no remarkable impact on GLP-1- and GIP-induced rises in insulin secretion. Our in vivo analysis demonstrates that the triagonist improves glucose tolerance in diet-induced obese wild-type mice, but this effect was absent in TRPM5 knockout mice. Notably, the triagonist augments glucose-induced insulin secretion in isolated islets of wild-type mice more than treatment with GLP1 and GIP mono-agonists. Furthermore, this enhanced response is absent in TRPM5 knockout islets. Recent studies propose that persistent membrane depolarization of β cells leads to a switch from Gαs to Gαq signaling, which is a major amplifying pathway of insulin secretion under diabetic conditions. Our study shows that the enhancing effect of the triagonist, acting as a biased agonist, on insulin secretion is dependent on TRPM5 activation through the Gαq signaling pathway. Presentation: 6/2/2024

Potential allosteric pockets identification of glucagon receptor based on molecular dynamics simulations

Glucagon receptor (GCGR) is an important target for the treatment of type 2 diabetes mellitus. Although several small molecules with antagonistic activity have been discovered, so far, only one small molecule binding site has been resolved. To discover more novel allosteric pockets and allosteric molecules, we started with the unique full-length inactive conformation of GCGR and applied all-atom molecular dynamics (MD) simulations to obtain extensive dynamic conformations of the GCGR/glucagon complex. For the first time, MDpocket, FTMove and FTMap were used to detect allosteric pockets in simulation trajectories, selecting 4 stable pockets with a total of 14 structures as templates for virtual screening. From the results of virtual screening, 14 compounds were ultimately selected after a series of filtering steps. The cAMP accumulation assay indicated that compound gs6 has antagonistic activity, and MD simulations further revealed the allosteric mechanism of gs6. We are the first to identify new allosteric pockets and allosteric molecules in simulation trajectories of the GCGR/glucagon complex, providing a reference for research on other G-protein-coupled receptors (GPCR). However, there is still considerable room for improvement, such as using more simulation methods to obtain a richer set of dynamic conformations.

Interruption of glucagon signaling augments islet non-alpha cell proliferation in SLC7A2- and mTOR-dependent manners.

Dysregulated glucagon secretion and inadequate functional beta cell mass are hallmark features of diabetes. While glucagon receptor (GCGR) antagonism ameliorates hyperglycemia and elicits beta cell regeneration in pre-clinical models of diabetes, it also promotes alpha and delta cell hyperplasia. We sought to investigate the mechanism by which loss of glucagon action impacts pancreatic islet non-alpha cells, and the relevance of these observations in a human islet context. We used zebrafish, rodents, and transplanted human islets comprising six different models of interrupted glucagon signaling to examine their impact on delta and beta cell proliferation and mass. We also used models with global deficiency of the cationic amino acid transporter, SLC7A2, and mTORC1 inhibition via rapamycin, to determine whether amino acid-dependent nutrient sensing was required for islet non-alpha cell growth. Inhibition of glucagon signaling stimulated delta cell proliferation in mouse and transplanted human islets, and in mouse islets. This was rapamycin-sensitive and required SLC7A2. Likewise, gcgr deficiency augmented beta cell proliferation via SLC7A2- and mTORC1-dependent mechanisms in zebrafish and promoted cell cycle engagement in rodent beta cells but was insufficient to drive a significant increase in beta cell mass in mice. Our findings demonstrate that interruption of glucagon signaling augments islet non-alpha cell proliferation in zebrafish, rodents, and transplanted human islets in a manner requiring SLC7A2 and mTORC1 activation. An increase in delta cell mass may be leveraged for future beta cell regeneration therapies relying upon delta cell reprogramming.

Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index≥27kg/m2 and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events. This global CV outcomes trial is currently enrolling, with a target recruitment of 4,935 participants. SYNCHRONIZE-CVOT is the first trial that will determine the CV safety and efficacy of survodutide in people with obesity and increased CV risk. (A Study to TesttheEffect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity [SYNCHRONIZE-CVOT]; NCT06077864).

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials

PurposeThis study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis. MethodsRelevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software. ResultsTwenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (−22.10 % in body weight and − 17.00 cm in waist circumference), retatrutide 8 mg (−20.70 % and − 15.90 cm), and tirzepatide 15 mg (−16.53 % and − 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable. ConclusionRetatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

The deubiquitinase OTUB1 inhibits gluconeogenesis by stabilizing YWHAB

Hepatic gluconeogenesis plays a crucial role in maintaining glucose homeostasis and serves as a potential therapeutic target for type 2 diabetes, while its underlying mechanisms are not fully understood. This study elucidates the role of the deubiquitinase OTU domain-containing ubiquitin aldehyde binding protein 1 (OTUB1) in gluconeogenesis. We found that hepatic OTUB1 expression is reduced in both db/db mice and patients with type 2 diabetes. Deletion of hepatic OTUB1 significantly elevates fasting blood glucose levels and increases the expression of key gluconeogenic genes. Conversely, overexpression of OTUB1 in hepatocytes mitigates diabetic hyperglycemia and enhances insulin sensitivity. It is known that the tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein β (YWHAB) functions as an inhibitor of hepatic gluconeogenesis by interacting with forkhead box protein O (FOXO1) and glucagon receptor (GPCR), but its own modification mechanism remains unclear. Our findings indicate that OTUB1 interacts with YWHAB and deubiquitinates it through a catalytic process, which in turn suppresses gluconeogenesis. Therefore, OTUB1 plays a pivotal role in inhibiting hepatic gluconeogenesis, highlighting its potential as a therapeutic target for type 2 diabetes.

Incretin hormone agonists: Current and emerging pharmacotherapy for obesity management.

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management.

Dietary protein defends lean mass and maintains the metabolic benefits of glucagon receptor agonism in mice

ObjectiveGlucagon has long been proposed as a component of multi-agonist obesity therapeutics due to its ability to induce energy expenditure and cause weight loss. However, chronic glucagon-receptor agonism has been associated with a reduction in circulating amino acids and loss of lean mass. Importantly, it is currently not known whether the metabolic benefits of glucagon can be maintained under contexts that allow the defence of lean mass. MethodsWe investigate the metabolic effects of the long-acting glucagon receptor agonist, G108, when administered to obese mice at low-doses, and with dietary protein supplementation. ResultsDietary protein supplementation can only fully defend lean mass at a low dose of G108 that is sub-anorectic and does not reduce fat mass. However, in this context, G108 is still highly effective at improving glucose tolerance and reducing liver fat in obese mice. Mechanistically, liver RNA-Seq analysis reveals that dietary protein supplementation defends anabolic processes in low-dose G108-treated mice, and its effects on treatment-relevant glucose and lipid pathways are preserved. ConclusionGlucagon-mediated energy expenditure and weight loss may be mechanistically coupled to hypoaminocidemia and lean mass loss. However, our data suggest that glucagon can treat MAFLD at doses which allow full defence of lean mass given sufficient dietary protein intake. Therefore, proportionate glucagon therapy may be safe and effective in targeting hepatocytes and improving in glycaemia and liver fat.

241 - Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial

241 - Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial