Dual Receptor Agonist Research Articles

Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial

Obesity is a widespread and chronic condition that requires long-term management; research into additional targets to improve treatment outcomes remains a priority. This study aimed to investigate the safety, tolerability, and efficacy of glucagon receptor-GLP-1 receptor dual agonist survodutide (BI 456906) in obesity management. In this randomised, double-blind, placebo-controlled, dose-finding phase 2 trial conducted in 43 centres in 12 countries, we enrolled participants (aged 18-75 years, BMI ≥27 kg/m2, without diabetes) and randomly assigned them by interactive response technology (1:1:1:1:1; stratified by sex) to subcutaneous survodutide (0·6, 2·4, 3·6, or 4·8 mg) or placebo once-weekly for 46 weeks (20 weeks dose escalation; 26 weeks dose maintenance). The primary endpoint was the percentage change in bodyweight from baseline to week 46. Primary analysis included the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of trial medication and who had analysable data for at least one efficacy endpoint) and was based on the dose assigned at randomisation (planned treatment), including all data censored for COVID-19-related discontinuations; the sensitivity analysis was based on the actual dose received during maintenance phase (actual treatment) and included on-treatment data. Safety analysis included all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov (NCT04667377) and EudraCT (2020-002479-37). Between March 30, 2021, and Nov 11, 2021, we enrolled 387 participants; 386 (100%) participants were treated (0·6 mg, n=77; 2·4 mg, n=78; 3·6 mg, n=77; 4·8 mg, n=77; placebo n=77) and 233 (60·4%) of 386 completed the 46-week treatment period (187 [61%] of 309 receiving survodutide; 46 [60%] of 77 receiving placebo). When analysed according to planned treatment, mean (95% CI) changes in bodyweight from baseline to week 46 were -6·2% (-8·3 to -4·1; 0·6 mg); -12·5% (-14·5 to -10·5; 2·4 mg); -13·2% (-15·3 to -11·2; 3·6 mg); -14·9% (-16·9 to -13·0; 4·8 mg); -2·8% (-4·9 to -0·7; placebo). Adverse events occurred in 281 (91%) of 309 survodutide recipients and 58 (75%) of 77 placebo recipients; these were primarily gastrointestinal in 232 (75%) of 309 survodutide recipients and 32 (42%) of 77 placebo recipients. All tested survodutide doses were tolerated, and dose-dependently reduced bodyweight. Boehringer Ingelheim.

Tirzepatide prevents neurodegeneration through multiple molecular pathways

BackgroundSeveral evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders.MethodsWe investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures.ResultsFor the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level.ConclusionsWe demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy.Graphical

Cotadutide (GLP-1/Glucagon dual receptor agonist) modulates hypothalamic orexigenic and anorexigenic neuropeptides in obese mice

The hypothalamic neuropeptides linked to appetite and satiety were investigated in obese mice treated with cotadutide (a dual receptor agonist of glucagon-like peptide 1 (GLP-1R)/Glucagon (GCGR)). Twelve-week-old male C57BL/6 mice were fed a control diet (C group, n = 20) or a high-fat diet (HF group, n = 20) for ten weeks. Each group was further divided, adding cotadutide treatment and forming groups C, CC, HF, and HFC for four additional weeks. The hypothalamic arcuate neurons were labeled by immunofluorescence, and protein expressions (Western blotting) for neuropeptide Y (NPY), proopiomelanocortin (POMC), agouti-related protein (AgRP), and cocaine- and amphetamine-regulated transcript (CART). Cotadutide enhanced POMC and CART neuropeptides and depressed NPY and AGRP neuropeptides. In addition, gene expressions (RT-qPCR) determined that Lepr (leptin receptor) and Calcr (calcitonin receptor) were diminished in HF compared to C but enhanced in CC compared to C and HFC compared to HF. Besides, Socs3 (suppressor of cytokine signaling 3) was decreased in HFC compared to HF, while Sst (somatostatin) was higher in HFC compared to HF; Tac1 (tachykinin 1) and Mc4r (melanocortin-4-receptor) were lower in HF compared to C but increased in HFC compared to HF. Also, Glp1r and Gcgr were higher in HFC compared to HF. In conclusion, the findings are compelling, demonstrating the effects of cotadutide on hypothalamic neuropeptides and hormone receptors of obese mice. Cotadutide modulates energy balance through the gut-brain axis and its associated signaling pathways. The study provides insights into the mechanisms underlying cotadutide's anti-obesity effects and its possible implications for obesity treatment.

Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline–trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial

New treatments with new mechanisms are urgently needed for people with schizophrenia. Xanomeline is a dual M1 and M4-preferring muscarinic receptor agonist that does not block D2 dopamine receptors, unlike all currently approved treatments for schizophrenia. Xanomeline-trospium (KarXT) combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium chloride with the goal of ameliorating xanomeline-related adverse events associated with peripheral muscarinic receptors. The EMERGENT-2 trial aimed to assess the efficacy and safety of KarXT in people with schizophrenia experiencing acute psychosis. EMERGENT-2 was a randomised, double-blind, placebo-controlled, flexible-dose, 5-week, inpatient, phase 3 trial in people with schizophrenia. Participants were adults aged 18-65 years with a diagnosis of schizophrenia who had a recent worsening of psychosis warranting hospital admission, a Positive and Negative Syndrome Scale (PANSS) score of 80 or higher, and a Clinical Global Impression-Severity score of 4 or higher. The participants were recruited from 22 inpatient sites in the USA, and were randomly assigned (1:1) to KarXT or placebo twice per day. Participants randomly assigned to KarXT received 50 mg xanomeline and 20 mg trospium twice per day for the first 2 days and then 100 mg xanomeline and 20 mg trospium twice per day for days 3-7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg xanomeline and 30 mg trospium twice per day and the option to return to 100 mg xanomeline and 20 mg trospium based on tolerability. The primary endpoint was change from baseline to week 5 in PANSS total score. Efficacy analyses used the modified intention-to-treat population (all randomly assigned participants who received at least one trial medication dose and had at least one post-baseline PANSS assessment). Least squares mean change from baseline, SE, and least squares mean difference between the KarXT and placebo groups at week 5, along with the 95% CI and two-sided p values were calculated for the primary and secondary continuous efficacy endpoints. Safety analyses included all participants receiving at least one trial medication dose and used descriptive statistics. This trial is registered with ClinicalTrials.gov (NCT04659161). From Dec 16, 2020, to April 13, 2022, of 407 people who were screened, 252 participants meeting enrolment criteria were randomly assigned to the KarXT (n=126) or placebo (n=126). Baseline PANSS total scores were 98·3 (KarXT; n=126) and 97·9 (placebo; n=125). The trial met the primary endpoint with a mean change from baseline to week 5 in PANSS total score that favoured KarXT (-21·2 points, SE 1·7) versus placebo (-11·6 points, 1·6; least squares mean difference -9·6; 95% CI -13·9 to -5·2; p<0·0001, Cohen's d effect size=0·61). All secondary endpoints were also met, and favoured KarXT versus placebo (p<0·05). The most common adverse events with KarXT versus placebo were constipation (27 [21%] vs 13 [10%]), dyspepsia (24 [19%] vs 10 [8%]), headache (17 [14%] vs 15 [12%]), nausea (24 [19%] vs seven [6%]), vomiting (18 [14%] vs one [1%]), hypertension (12 [10%] vs one [1%]), dizziness (11 [9%] vs four [3%]), gastro-oesophageal reflux disease (eight [6%] vs zero [0%]), and diarrhoea (seven [6%] vs four [3%]). Treatment-emergent adverse event rates of extrapyramidal motor symptoms (KarXT, zero [0%] vs placebo, zero [0%]), akathisia (one [1%] vs one [1%]), weight gain (zero [0%] vs one [1%]), and somnolence (six [5%] vs five [4%]) were similar between the KarXT and placebo groups, as were adverse event-related discontinuation rates (nine [7%] vs seven [6%]). In the EMERGENT-2 trial, KarXT was effective in reducing positive and negative symptoms and was generally well tolerated. These results support the potential for KarXT to represent a new class of effective and well tolerated antipsychotic medicines based on activating muscarinic receptors, not the D2 dopamine receptor-blocking mechanism of all current antipsychotic medications. Results from additional trials, including the identical EMERGENT-3 trial and the 52-week, open-label EMERGENT-4 and EMERGENT-5 trials, will provide additional information on the efficacy and safety of KarXT in people with schizophrenia. Karuna Therapeutics.

A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity

Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. We evaluated the efficacy and safety of 24-week treatment of mazdutide up to 6 mg in Chinese overweight adults or adults with obesity, as an interim analysis of a randomised, two-part (low doses up to 6 mg and high dose of 9 mg), double-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov, NCT04904913). Overweight adults (body-mass index [BMI] ≥24 kg/m2) accompanied by hyperphagia and/or at least one obesity-related comorbidity or adults with obesity (BMI ≥ 28 kg/m2) were randomly assigned (3:1:3:1:3:1) to once-weekly mazdutide 3 mg, 4.5 mg, 6 mg or matching placebo at 20 hospitals in China. The primary endpoint was the percentage change from baseline to week 24 in body weight. A total of 248 participants were randomised to mazdutide 3 mg (n = 62), 4.5 mg (n = 63), 6 mg (n = 61) or placebo (n = 62). The mean percentage changes from baseline to week 24 in body weight were −6.7% (SE 0.7) with mazdutide 3 mg, −10.4% (0.7) with 4.5 mg, −11.3% (0.7) with 6 mg and 1.0% (0.7) with placebo, with treatment difference versus placebo ranging from −7.7% to −12.3% (all p < 0.0001). All mazdutide doses were well tolerated and the most common adverse events included diarrhoea, nausea and upper respiratory tract infection. In summary, in Chinese overweight adults or adults with obesity, 24-week treatment with mazdutide up to 6 mg was safe and led to robust and clinically meaningful body weight reduction.

Discovery of a CB2 and 5-HT1A receptor dual agonist for the treatment of depression and anxiety

Cannabinoid CB2R agonists have gained considerable attention as potential novel therapies for psychiatric disorders due to their non-psychoactive nature, in contrast to CB1R agonists. In this study, we employed molecular docking to design and synthesize 23 derivatives of cannabidiol (CBD) with the aim of discovering potent CB2R agonists rather than CB2R antagonists or inverse agonists. Structure-activity relationship (SAR) investigations highlighted the critical importance of the amide group at the C-3′ site and the cycloalkyl group at the C-4′ site for CB2R activation. Interestingly, three CBD derivatives, namely 2o, 6g, and 6h, exhibited substantial partial agonistic activity towards the CB2 receptor, in contrast to the inverse agonistic property of CBD. Among these, 2o acted as a CB2R and 5-HT1AR dual agonist, albeit with some undesired antagonist activity for CB1R. It demonstrated significant CB2R partial agonism while maintaining a level of 5-HT1AR agonistic and CB1R antagonistic activity similar to CBD. Pharmacokinetic experiments confirmed that 2o possesses favorable pharmacokinetic properties. Behavioral studies further revealed that 2o elicits significant antidepressant-like and anxiolytic-like effects while maintaining a good safety profile.

Dose–response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist, compared with placebo and open-label semaglutide in people with type 2 diabetes: a randomised clinical trial

Aims/hypothesisThe aim of this study was to assess the dose–response effects of the subcutaneous glucagon receptor/glucagon-like peptide-1 receptor dual agonist survodutide (BI 456906) on HbA1c levels and bodyweight reduction.MethodsThis Phase II, multicentre, randomised, double-blind, parallel-group, placebo-controlled study, conducted in clinical research centres, assessed survodutide in participants aged 18–75 years with type 2 diabetes, an HbA1c level of 53–86 mmol/mol (7.0–10.0%) and a BMI of 25–50 kg/m2 on a background of metformin therapy. Participants were randomised via interactive response technology to receive survodutide (up to 0.3, 0.9, 1.8 or 2.7 mg once weekly [qw; dose group (DG) 1–4, respectively] or 1.2 or 1.8 mg twice weekly [DG 5 and 6, respectively]), placebo or semaglutide (up to 1.0 mg qw). Participants and all those involved in the trial conduct/analysis were blinded; the semaglutide arm was open-label. The primary endpoint was absolute change from baseline in HbA1c after 16 weeks’ treatment. The key secondary endpoint was relative change from baseline in bodyweight after 16 weeks’ treatment.ResultsA total of 413 participants were randomised (DG1, n=50; DG2, n=50; DG3, n=52; DG4, n=50; DG5, n=51; DG6, n=50; semaglutide, n=50; placebo, n=60). The full analysis set comprised 411 treated participants (DG6, n=49; placebo, n=59). Adjusted mean (95% CI) HbA1c decreased from baseline (mean ± SD 64.7±9.2 mmol/mol [8.07±0.84%] after 16 weeks’ treatment: DG1 (n=41), −9.92 mmol/mol (−12.27, −7.56; −0.91% [−1.12, −0.69]); DG2 (n=46), −15.95 mmol/mol (−18.27, −13.63; −1.46% [−1.67, −1.25]); DG3 (n=36), −18.72 mmol/mol (−21.15, −16.29; −1.71% [−1.94, −1.49]); DG4 (n=33), −17.01 mmol/mol (−19.59, −14.43; −1.56% [−1.79, −1.32]); DG5 (n=44), −17.84 mmol/mol (−20.18, −15.51; −1.63% [−1.85, −1.42]); DG6 (n=36), −18.38 mmol/mol (−20.90, −15.87; −1.68% [−1.91, −1.45]). The mean reduction in HbA1c was similar with low-dose survodutide (DG2: −15.95 mmol/mol [−1.46%]; n=46) and semaglutide (−16.07 mmol/mol [−1.47%]; n=45). Mean (95% CI) bodyweight decreased dose-dependently up to −8.7% (−10.1, −7.3; DG6, n=37); survodutide ≥1.8 mg qw produced greater bodyweight reductions than semaglutide (−5.3% [−6.6, −4.1]; n=45). Adverse events (AEs) were reported for 77.8% of survodutide-treated participants (mainly gastrointestinal), 52.5% receiving placebo and 52.0% receiving semaglutide.Conclusions/interpretationSurvodutide reduced HbA1c levels and bodyweight after 16 weeks’ treatment in participants with type 2 diabetes. Dose-related gastrointestinal AEs could be mitigated with slower dose escalations.Trial registrationClinicalTrials.gov NCT04153929 and EudraCT 2019-002390-60.FundingBoehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany.Graphical

Newer pharmacological interventions directed at gut hormones for obesity.

The objective is to review the newer pharmacological interventions for obesity, specifically single, dual and triple incretin receptor agonists that are either available or in the pipeline for treatment of obesity. The three incretin receptor targets are glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and glucagon. There are several approved single or dual incretin agonists which can be administered subcutaneously daily (e.g., liraglutide) or weekly (e.g., semaglutide, dulaglutide, and exenatide QW), and other experimental dual or triple incretin agonists. Analogues of amylin, peptide YY and oxyntomodulin, as well as the combination of a GLP1R agonist and GIPR antagonist also are in development. Oral semaglutide (administered daily) is approved for type 2 diabetes mellitus and is on track for regulatory review for obesity. The review includes specifically perspectives on the effects of these mechanisms and pharmacological agents on gastric emptying, which contribute to satiation and weight loss, in addition to the established evidence on effects on central mechanisms controlling appetite. In the future, it is anticipated that small molecule GLP-1 receptor agonists (e.g., oral danuglipron) will be developed for treating obesity. These pharmacological agents are having significant impact on glycaemic control and obesity and on their co-morbidities.

The novel GLP-1/GIP dual agonist DA3-CH improves rat type 2 diabetes through activating AMPK/ACC signaling pathway.

Type 2 diabetes mellitus (T2DM) accounts for more than 95% of all diabetes. DA3-CH is a novel dual receptor agonist of glucagon like peptide-1 (GLP-1) and glucose dependent insulin stimulating polypeptide (GIP). The regulatory role of DA3-CH in T2DM has not been reported. T2DM rat model was established successfully with high sugar and fat feed and streptomycin (STZ) induction. The mRNA and protein expression were measured with RT-PCR and western blotting. The apoptosis level in the pancreatic tissue was evaluated with Tunel staining. Blood glucose, fat, and oxidative stress indicators were measured. DA3-CH greatly improved T2DM symptoms by reducing blood glucose, blood fat, pancreatic tissue injury, apoptosis, and oxidative stress condition. The inactivation of Adenylate activated protein kinase (AMPK)/acetyl CoA carboxylase (ACC) signaling pathway in T2DM rats was promoted by DA3-CH. The influence of DA3-CH was significantly reversed by Com-C, the inhibitor of AMPK/ACC signaling pathway. DA3-CH might improve T2DM through targeting AMPK/ACC signaling pathway. This study might provide a novel therapeutic strategy for the prevention and treatment of T2DM through targeting DA3-CH and AMPK/ACC signaling pathway.

FRI483 Changes In Thyroid Function Test With Tirzepatide Use In Patients With Hypothyroidism

Abstract Disclosure: G.K. Yu: None. S. Nakhle, M.D.: None. N.J. Vernetti: None. A. Chao, DO: None. Background: Incretin hormone Glucacon-like peptide-1 receptor agonist (GLP-1RA) has been established to treat type 2 diabetes or obesity. A novel dual-receptor agonist to GIPR/GLP-1R, tirzepatide has been approved for type 2 diabetes mellitus treatment and has shown greater weight loss compared to GLP1-RA. Also, since GLP-1 and GIP have effects on multiple organs/tissue including the gut, tirzepatide may have additional effects on levothyroxine absorption. Method: We retrospectively reviewed the charts of patients with hypothyroidism and newly given prescriptions of tirzepatide (Mounjaro) at our outpatient clinic from July 1, 2022, to Nov 30, 2022. Baseline thyroid function test results and follow-up test results were reviewed. Result: A total of seventy patients’ data were identified and reviewed. Patients with insufficient data, early termination of the therapy, and patients whose levothyroxine doses were adjusted at the same time of tirzepatide initiation were excluded. A total of 17 patients on stable dose of levothyroxine replacement who had lab prior to starting tirzepetide and repeated lab within 4 to 8 weeks after that were found and included in the study. TSH of 5/17 patients (29%) was suppressed below the normal range at 6 weeks. TSH of 11/17 patients (65%) decreased compared to baseline. The mean baseline TSH was 2.288. Repeat test was done in 4-8 weeks, (mean 53.28 days, median 47 days), and mean TSH was 1.569. Conclusion: We were able to review only seventeen patients’ thyroid function tests, but there was TSH reduction in 65 % of patients, and 5(29%) out of 17 patients had suppressed TSH in 6-8 weeks (mean 53.28 days, median 47 days). Our results suggest monitoring TSH early after starting tirzepatide might be necessary to avoid iatrogenic hyperthyroidism. We suspect factors other than weight loss play a role in the thyroid hormone level because of early changes in TSH prior to achieving significant weight loss. Presentation: Friday, June 16, 2023

Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets.

Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.

Emerging therapeutic options for non-alcoholic fatty liver disease: A systematic review.

Non-alcoholic fatty liver disease (NAFLD) has become a prevalent cause of chronic liver disease and ranks third among the causes of transplantation. In the United States alone, annual medical costs are approximately 100 billion dollars. Unfortunately, there is no Federal Drug Administration (FDA)-approved medication for its treatment. However, various clinical trials are investigating several therapeutic classes that could potentially treat NAFLD. It is valuable to have a compilation of the data available on their efficacy. To assess the efficacy of cyclophilin inhibitors, fibroblast growth factor 21 analogs (FGF21), and dual and pan peroxisome proliferator-activated receptor (PPAR) agonists for treating NAFLD. A comprehensive literature search using keywords including cyclophilin inhibitor, FGF agonist, pan-PPAR agonists, dual-PPAR agonist, NAFLD, non-alcoholic steatohepatitis, and fatty liver was conducted on October 29, 2022, in PubMed, EMBASE, Cochrane Library, Scopus and Web of Science. Animal and human research, case reports, and published articles in English from all countries with patients aged 18 and above were included. Only articles with a National Institutes of Health (NIH) Quality Assessment score of five or higher out of eight points were included. Articles that were narrative or systematic reviews, abstracts, not in English, focused on patients under 18 years old, did not measure outcomes of interest, were inaccessible, or had a low NIH Quality Assessment score were excluded. Each article was screened by two independent researchers evaluating relevance and quality. Resources were scored based on the NIH Quality Assessment Score; then, pertinent data was extracted in a spreadsheet and descriptively analyzed. Of the 681 records screened, 29 met the necessary criteria and were included in this review. These records included 12 human studies and 17 animal studies. Specifically, there were four studies on cyclophilin inhibitors, four on FGF agonists/analogs, eleven on pan-PPAR agonists, and ten on dual-PPAR agonists. Different investigational products were assessed: The most common cyclophilin inhibitor was NV556; FGF agonists and analogs was Efruxifermin; pan-PPAR agonists was Lanifibranor; and dual-PPAR agonists was Saroglitazar. All classes were found to be statistically efficacious for the treatment of NAFLD, with animal studies demonstrating improvement in steatosis and/or fibrosis on biopsy and human studies evidencing improvement in different metabolic parameters and/or steatosis and fibrosis on FibroScan (P < 0.05). The data analyzed in this review showed clinically significant improvement in individual histological features of NAFLD in both animal and human trials for all four classes, as well as good safety profiles (P < 0.05). We believe this compilation of information will have positive clinical implications in obtaining an FDA-approved therapy for NAFLD.

Obesity wars: hypothalamic sEVs a new hope.

There are currently several pharmacological therapies available for the treatment of obesity, targeting both the central nervous system (CNS) and peripheral tissues. In recent years, small extracellular vesicles (sEVs) have been shown to be involved in many pathophysiological conditions. Because of their special nanosized structure and contents, sEVs can activate receptors and trigger intracellular pathways in recipient cells. Notably, in addition to transferring molecules between cells, sEVs can also alter their phenotypic characteristics. The purpose of this review is to discuss how sEVs can be used as a CNS-targeted strategy for treating obesity. Furthermore, we will evaluate current findings, such as the sEV-mediated targeting of hypothalamic AMP-activated protein kinase (AMPK), and discuss how they can be translated into clinical application.

Engineering a potent and long-acting GLP-1/Y2 receptor dual agonist as a multi-agonist therapy for diabetes and obesity

Novel dual agonists for the glucagon-like peptide-1 (GLP-1) and Y2 receptor hold the potential for enhanced efficacy over GLP-1 receptor (GLP-1R) agonists in treating obesity and diabetes. In this study, we aimed to improve the stability and increase the drug development success rate of our previously identified GLP-1/Y2 receptor dual agonist, 6q. To achieve this, we first optimized the structure of the linker within 6q. Additionally, we explored various fatty acid albumin binders to further enhance the stability of 6q. These binders were mainly selected from approved or clinically developed GLP-1R agonists or GLP-1-based multi-agonists. Through this process, we were able to identify a lead peptide, xGLP/PYY-6, that exhibited comparable in vitro potency toward the GLP-1 and Y2 receptors as 6q but with significantly improved stability compared to 6q. In Kunming and DIO mice, xGLP/PYY-6 showed a comparable hypoglycemic effect to semaglutide, and a significantly better effect on inhibiting food intake than semaglutide. In a chronic study in DIO mice, xGLP/PYY-6 exhibited significant metabolic benefits, as reflected by regulation of lipid levels, improved glucose tolerance, weight loss, decreased hepatocellular vacuolation, and the reversal of steatosis effects caused by xGLP/PYY-6. These results indicate the potential of developing xGLP/PYY-6 as an antiobesity, lipid regulation, antisteatotic, and antidiabetic agent.

Efficacy and safety of the dual GIP and GLP-1 receptor agonist tirzepatide for weight loss: a meta-analysis of randomized controlled trials.

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist approved for type 2 diabetes. We performed a meta-analysis to assess tirzepatide's weight reduction efficacy and safety. We searched PubMed, Embase, and Cochrane for randomized controlled trials published from inception to July 2022, comparing tirzepatide with placebo for the co-primary endpoints of absolute and percent change in weight. Mean difference (MD) and odds ratio (OR) were calculated for continuous and binary outcomes, respectively. Review Manager 5.4.1 and RStudio were used for the statistical analysis, and RoB-2 (Cochrane) to assess the risk of bias. Of 397 search results, 6 studies (4036 participants) ranging from 12 to 72 weeks were included. Pooled analysis showed that tirzepatide 5 mg, 10 mg, and 15 mg were more effective than placebo, with MD in body weight of -7.7 kg (95% CI -11.0, -4.4; p < 0.001), -11.6 kg (95% CI -18.8, -4.3; p = 0.002), and -11.8 kg (95% CI -17.4, -6.2; p < 0.001), respectively, and MD in percent change in weight of -8.1% (95% CI -11.0, -5.2; p < 0.001), -11.9% (95% CI -18.1, -5.6; p < 0.001), and -12.4% (95% CI -17.2, -7.5; p < 0.001), respectively. Tirzepatide also reduced BMI and waist circumference. Adverse events were more common with tirzepatide with respect to nausea (OR 4.2; 95% CI 2.4, 7.5; p < 0.001), vomiting (OR 7.0; 95% CI 4.3, 11.4; p < 0.001), and diarrhea (OR 2.8; 95% CI 1.6, 4.9; p < 0.001) (15 mg dose), when compared with placebo. The results support that tirzepatide leads to substantial weight reduction and constitutes a valuable therapeutic option for weight management, despite an increase in gastrointestinal symptoms. CRD42022348576.

Novel Dual Incretin Receptor Agonists in the Spectrum of Metabolic Diseases with a Focus on Tirzepatide: Real Game-Changers or Great Expectations? A Narrative Review.

The prevalence of metabolic diseases including type 2 diabetes (T2D), obesity and non-alcoholic fatty liver disease (NAFLD) increases globally. This highlights an unmet need for identifying optimal therapies for the management of these conditions. Tirzepatide is a novel dual incretin receptor agonist (twincretin) that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. The aim of this narrative review was to examine the impact of novel twincretins, focusing on tirzepatide, on the management of a wide spectrum of metabolic diseases. Data from preclinical and clinical trials have shown that twincretins significantly reduce blood glucose levels in T2D, and tirzepatide is the first agent of this class that has been approved for the management of T2D. Additionally, the beneficial impact of tirzepatide on weight reduction has been corroborated in several studies, showing that this agent can achieve substantial and sustained weight loss in obese patients with or without T2D. Data also suggest that tirzepatide could be a promising drug for hepatic steatosis reduction in individuals with NAFLD. The remarkable effects of tirzepatide on glycaemic control, weight loss and liver-related outcomes have posed new research questions that are likely to lead to further advancements in the treatment of T2D, obesity and related metabolic disorders.

1668-P: Differentiated Metabolic Effects of DA-1726, a Balanced GLP1R/GCGR Dual Agonist

DA-1726 is a novel oxyntomodulin analogue preparing for phase I clinical trials for obesity. In this study, the pharmacological effect of DA-1726 compared to other competitor peptides was evaluated. DA-1726 showed superior efficacy compared to other glucagon-like peptide-1 receptor (GLP1R)/glucagon receptor (GCGR) dual agonist (Cotadutide; COTA) in reducing body weight (14.4% for DA-1726 and 6.4% for COTA vs. DIO control at 30 nmol/kg, p&amp;lt;0.05) and improving plasma glucose, insulin, and HOMA-IR (-91% for DA-1726 vs. -52% for COTA) in diet-induced obese mice. In addition, superior plasma triglyceride (TG) reduction and similar reduction of total cholesterol (T-CHO) compared to COTA were confirmed by DA-1726. These data suggested that the balanced dual agonist DA-1726 was superior to a GLP1R-biased dual agonist in metabolic effects. Meanwhile, enhanced glucagon action of GLP1R/GCGR dual agonists may increase the risk of hyperglycemia when GLP1R agonism is reduced. Thus, DA-1726 was injected for 3 weeks and glucose tolerance test was performed at 72-h after the last dosing. DA-1726 did not impair glucose tolerance even at minimal plasma concentrations during repeated dosing up to 100 nmol/kg. In the case of repeated dosing of 100 nmol/kg, the plasma drug concentration at 72-h after the final injection is similar to the concentration that induces about 50% activation of receptors under 4% human albumin condition. In a comparative study with a GLP1R/glucose-dependent insulinotropic polypeptide receptor (GIPR) dual agonist (Tirzepatide; TIR), DA-1726 showed a similar maximum efficacy on weight loss (31.2% for DA-1726 and 31.3% for TIR vs. DIO control, p&amp;lt;0.05). However, DA-1726 was more efficacious in improving plasma metabolic parameters such as glucose, TG, and T-CHO compared to TIR, indicating differential metabolic effects caused by GCGR agonism. Taken together, these data suggest that DA-1726 is a well-balanced GLP1R/GCGR dual agonist that effectively reduces body weight and glycemic control. Disclosure Y.Chae: None. I.Jung: None. T.Kim: None. S.Lee: None. M.Kim: Employee; Dong-A ST. H.Kim: None.

208-OR: Comparable Improvement in NAFLD, Weight Loss, and Lipid Metabolism in Rats Treated with Dual GLP-1–GIP Receptor Agonist (Tirzepatide) and Gastric Sleeve

Background: Bariatric surgery is increasingly utilized as a weight management and metabolic control procedure, hence the name metabolic Surgery. Metabolic surgery is currently considered as an effective procedure for the treatment of diabetes providing a phenomenal hope for a long-lasting remission of diabetes. The use of combined GIPR and GLP-1R activation has recently emerged as a novel therapeutic tool in the treatment of T2D that produces profound weight loss, glycemic control, and lipid lowering. Tirzepatide (LY3298176) is a novel dual GIP and GLP-1 receptor agonist. Objectives: The aim of this study is to evaluate the difference between GLP-1/GIP receptor agonist (Tirzepatide) treatment vs bariatric surgery on weight loss, NAFLD, insulin signaling and insulin resistance in SD rats. Methods: Sprague-Dawley rats between the age of 4-6 weeks were either placed on regular rat chow diet (n=7) or cafeteria diet "high-fat/carbohydrate diet" ad libitum (n=42). After 21 weeks, rats on high fat diet were divided into either Obese control (n=6) gastric sleeve (n=6), Semaglutide 10nM/Kg (n=6), or various concentrations of Tirzepatide (10nM/Kg (n=6), 50nM/Kg (n=6) or 100nM/Kg (n=6). The treatments lasted for six weeks before animals were euthanized. Weight, OGTT, as well as liver biopsy analysis and gene expression analysis was performed. Results: Gastric sleeve resulted in about 15.5 % weight loss compared to 10.7% in Semaglutide, and 5.0%, 14.9% and 17.7% in the 10, 50 and 100 nM/Kg Tirzepatide groups. Glucose tolerance was improved after all treatments. NAFLD was also improved in all treatment with surgery and 100 nM/Kg Tirzepatide showing highest improvement. Additionally, gene expression of lipid metabolism markers such as ANGPTL3 and 8 were markedly reduced in all treatments. Conclusions: Tirzepatide is a novel dual GIP and GLP-1 receptor agonist that can lead to improved metabolic conditions similar to sleeve gastrectomy. Disclosure J.Abubaker: None. M.Abu-farha: None. S.Alsabah: None. I.Al-khairi: None. P.T.Cherian: None. N.A.Abukhalaf: None. H.Arefanian: None. C.Dsouza: None. S.Al-sabah: None. F.Al-mulla: None.

130-OR: Tirzepatide Attenuates Hepatic Insulin Resistance and Glucagon Action Independent of Weight Loss and GIP Action in Diet-Induced Obese Mice

As a dual GLP-1 receptor and GIP agonist, Tirzepatide (TZP) induces weight loss and improves glycemic control in patients with type 2 diabetes. Here, we performed insulin clamp and glucagon clamp under euglycemic conditions in male C57BL/6J mice fed a high-fat diet (HFD; 12 weeks) after once-daily treatment with TZP (3 nmol/kg) or GIP (25 nmol/kg) for 5 days (n=5). TZP and GIP caused HFD-fed mice to lose 10~15% of weight, but their fat mass remained 7-fold higher than chow-fed controls (C) (Fig. 1). Insulin clamp showed that GIP caused a 37% decrease in hepatic insulin action in chow-fed mice (Fig. 2). In HFD-fed mice, TZP induced significant increases in hepatic insulin action (4-fold) and glucose turnover (25%) compared to GIP, restoring insulin sensitivity to levels comparable to controls (Fig. 2-3). TZP also increased glucose metabolism in brown fat (1,528±155 vs. 798±166 nmol/g/min in GIP). Glucagon clamp showed that TZP significantly reduced hepatic glucose production (HGP) by ~50% compared to controls and GIP (Fig. 4). CONCLUSION: These data indicate that TZP improves insulin action and reduces hepatic glucagon action in obese mice while GIP causes hepatic insulin resistance in lean mice. Our findings suggest that TZP’s glycemic control may involve amelioration of insulin resistance and glucagon resistance, independent of weight loss and GIP action in the liver. Disclosure B.Kim: None. L.A.Tauer: None. X.Hu: None. J.K.Kim: None. Funding National Institutes of Health (5U2CDK093000)

#3000 EFFICACY AND SAFETY OF COTADUTIDE, A DUAL GLP1-GLUCAGON RECEPTOR AGONIST, IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND T2DM

Abstract Background and Aims Cotadutide is a dual GLP1-glucagon receptor agonist under development for NASH and CKD with T2DM. Incretin-based therapies have been shown to promote improvements in albuminuria while the addition of glucagon has been suggested to provide hepatic benefits; the renal benefits of dual GLP1-glucagon receptor agonism are unknown but kidney and liver are the organs with highest expression of glucagon receptor. We sought to evaluate the efficacy and safety of cotadutide in patients with CKD and T2DM. Method In this randomised, double-blind, phase 2b study, patients with T2DM and CKD on insulin and/or oral therapy including ≥ 40% treated with SGLT-2i (HbA1c ≥ 6.5 and ≤ 10.5%), eGFR ≥ 20 and &amp;lt; 90 ml/min/1.73m2 and BMI ≥ 25 (23 in Japan) kg/m2 were treated for 26 weeks. Participants were randomised (n = 45 per arm) to receive once-daily SC cotadutide titrated up to 100, 300 or 600 µg, or placebo. The primary endpoint was percentage change in UACR (log-transformed) at 14 weeks. Secondary endpoints evaluated urinary albumin creatinine ratio (UACR) at 26 weeks, safety and tolerability. Changes in renal function was evaluated as an exploratory endpoint. Results A total of 248 Participants were randomised. Approximately 47% were on SGLT-2i and 97% were on ACE inhibitors or ARBs at baseline. The primary endpoint was met. Dose dependent reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 µg of cotadutide, -39.9% (95% CI -52,5, -23.9) and -46.0% (95% CI -57.1, -32.1) vs placebo (P &amp;lt;0.001). In patients on background SGLT2i therapy, similar reductions in UACR from baseline were observed after 26 weeks treatment with 300 and 600 µg of cotadutide, - 31.2% (95% CI – 51.9, -1.5) and - 48.7% (95% CI -64.1, - 26.6) vs placebo (P = 0.01 and &amp;lt;0.001 respectively). There was no observed change in eGFR early in dosing. At 26 weeks, an increase in eGFR (+5.5 ml/min/1.73m2) was observed with 600 µg of cotadutide (p = 0.028). A statistically significant, modest reduction in serum uric acid was observed as an exploratory endpoint at 26 weeks in the 100 and 600 µg arms (- 0.54 mg/dL, p = 0.03 and 0.76 mg/dL, p = 0.001 respectively) but not the 300 µg arm (- 0.32 mg/dL, p = 0.17). No significant changes in urine KIM-1 were observed. A significant increase in pulse rate was observed (+4.8 bpm), alongside a numerical reduction in systolic BP (-8.3 mmHg) at 600 µg on office-based measures. SAEs were balanced across all arms and there were fewer AE-related discontinuations at 100 and 300 ug versus placebo, but more discontinuations at 600 µg. Conclusion In patients with CKD with T2DM, cotadutide promoted clinically important effects on UACR on top of standard of care with an acceptable tolerability profile. The results suggest cotadutide has potential to provide benefit to patients with CKD and T2DM. Larger studies will be required to evaluate this.