Advances in the clinical measurement of glucagon: from diagnosis to therapy.

Glucagon has many functions: it promotes glucose production, fatty acid oxidation, thermogenesis, energy consumption, lipolysis, and myocardial contraction, and suppresses lipogenesis, appetite, and gastrointestinal motility. Which of these functions are physiological and which are pharmacological is not fully understood. Although the Mercodia sandwich ELISA provides significantly higher specificity of glucagon measurement than does conventional competitive RIA, it cannot provide accurate plasma glucagon values in the presence of elevated cross-reacting plasma glicentin. This occurs in patients post-pancreatectomy or bariatric surgery and in around 30% of outpatients suspected for glucose intolerance who have not had surgery. Thus, our newly developed sandwich ELISA with higher specificity and higher sensitivity than the Mercodia sandwich ELISA is needed for accurate measurements of plasma glucagon in diabetic patients. It is expected that the new sandwich ELISA will contribute to personalized medicine for diabetes by its use in clinical tests to accurately diagnose the conditions of diabetic patients in order to design better individual treatment strategies. Meanwhile, clinical trials are being conducted worldwide to apply glucagon/GLP-1 receptor dual agonists and glucagon/GLP-1/GIP receptor triagonists to the treatment of obesity, fatty liver, and diabetes. Most clinical trials have shown that both types of drugs have stronger effects on weight reduction, improving fatty liver, and glucose tolerance than do the single GLP-1 receptor agonists. Glucagon is expected to be used as a new diagnostic marker and in a new therapeutic strategy based on a true understanding of its physiological and pharmacological functions.

Investigational and emerging gastric inhibitory polypeptide (GIP) receptor-based therapies for the treatment of obesity.

INTRODUCTION: One billion people live with obesity. The most promising medications for its treatment are incretin-based therapies, based on enteroendocrine peptides released in response to oral nutrients, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The mechanisms by which GLP-1 receptor agonism cause weight reduction are becoming increasingly understood. However, the mechanisms by which GIP receptor-modulating medications cause weight loss remain to be clarified. AREAS COVERED: This review describes GLP-1 and GIP physiology and explores the conflicting data regarding GIP and weight management. It details examples of how to reconcile the contradictory findings that both GIP receptor agonism and antagonism cause weight reduction. Specifically, it discusses the concept of 'biased agonism' wherein exogenous peptides cause different post-receptor signaling patterns than native ligands. It discusses how GIP effects in adipose tissue and the central nervous system may cause weight reduction. It describes GIP receptor-modulating compounds and their most current trials regarding weight reduction. EXPERT OPINION: Effects of GIP receptor-modulating compounds on different tissues have implications for both weight reduction and other cardiometabolic diseases. Further study is needed to understand the implications of GIP agonism on not just weight reduction, but also cardiovascular disease, liver disease, bone health and fat storage.

Excessive accumulation of epicardial adipose tissue promotes microvascular obstruction formation after myocardial ischemia/reperfusion through modulating macrophages polarization.

BACKGROUND: Owing to its unique location and multifaceted metabolic functions, epicardial adipose tissue (EAT) is gradually emerging as a new metabolic target for coronary artery disease risk stratification. Microvascular obstruction (MVO) has been recognized as an independent risk factor for unfavorable prognosis in acute myocardial infarction patients. However, the concrete role of EAT in the pathogenesis of MVO formation in individuals with ST-segment elevation myocardial infarction (STEMI) remains unclear. The objective of the study is to evaluate the correlation between EAT accumulation and MVO formation measured by cardiac magnetic resonance (CMR) in STEMI patients and clarify the underlying mechanisms involved in this relationship. METHODS: Firstly, we utilized CMR technique to explore the association of EAT distribution and quantity with MVO formation in patients with STEMI. Then we utilized a mouse model with EAT depletion to explore how EAT affected MVO formation under the circumstances of myocardial ischemia/reperfusion (I/R) injury. We further investigated the immunomodulatory effect of EAT on macrophages through co-culture experiments. Finally, we searched for new therapeutic strategies targeting EAT to prevent MVO formation. RESULTS: The increase of left atrioventricular EAT mass index was independently associated with MVO formation. We also found that increased circulating levels of DPP4 and high DPP4 activity seemed to be associated with EAT increase. EAT accumulation acted as a pro-inflammatory mediator boosting the transition of macrophages towards inflammatory phenotype in myocardial I/R injury through secreting inflammatory EVs. Furthermore, our study declared the potential therapeutic effects of GLP-1 receptor agonist and GLP-1/GLP-2 receptor dual agonist for MVO prevention were at least partially ascribed to its impact on EAT modulation. CONCLUSIONS: Our work for the first time demonstrated that excessive accumulation of EAT promoted MVO formation by promoting the polarization state of cardiac macrophages towards an inflammatory phenotype. Furthermore, this study identified a very promising therapeutic strategy, GLP-1/GLP-2 receptor dual agonist, targeting EAT for MVO prevention following myocardial I/R injury.

A chemical modification of a peroxisome proliferator-activated receptor pan agonist produced a shift to a new dual alpha/gamma partial agonist endowed with mitochondrial pyruvate carrier inhibition and antidiabetic properties.

New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.

Evaluating the Efficacy and Safety of Tirzepatide on Glycaemic and Non-glycaemic Outcomes in Diabetes: A Systematic Review of Meta-Analyses.

Tirzepatide is a novel once-a-week dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, recently approved for type 2 diabetes mellitus (T2DM) and obesity. A systematic review of the literature published in multiple meta-analyses on Tirzepatide with emphasis on its effect on glycaemic and non-glycaemic parameters was conducted. We systematically searched the electronic databases PubMed and Google Scholar up to August 2023 for meta-analyses that compared Tirzepatide with placebo or active antihyperglycaemic drugs in subjects with T2DM. Various parameters for efficacy and safety, with their point estimates and confidence intervals, such as glycated haemoglobin (HbA1c), fasting serum glucose (FSG), body weight, lipid, and cardiovascular outcomes were assessed. Six meta-analyses fulfilled the pre-specified criteria and were included in the study. In all the studies, Tirzepatide treatment at different doses resulted in a significant reduction in HbA1c and FSG levels along with a significant reduction in weight compared with active control and placebo groups. Tirzepatide significantly reduced levels of triglycerides and increased high-density lipoprotein (HDL) cholesterol, whether used as monotherapy or add-on therapy. The studies suggested the cardiovascular safety of Tirzepatide as there was no increase in major adverse cardiovascular events (MACE). The drug shows lesser hypoglycemia but predominant gastrointestinal adverse effects such as nausea, vomiting, and diarrhoea. In conclusion, Tirzepatide shows superior glycaemic control and weight loss in patients with T2DM with beneficial effects on lipids, without an increased risk of hypoglycemia and cardiovascular events.

Dual and Triple Incretin-Based Co-agonists: Novel Therapeutics for Obesity and Diabetes.

The discovery of long-acting incretin receptor agonists represents a major stride forward in tackling the dual epidemic of obesity and diabetes. Here we outline the evolution of incretin-based pharmacotherapy, from exendin-4 to the discovery of the multi-incretin hormone receptor agonists that look set to be our next step toward curing diabetes and obesity. We discuss the multiagonists currently in clinical trials and the improvement in efficacy each new generation of these drugs bring. The success of these agents in preclinical models and clinical trials suggests a promising future for multiagonists in the treatment of metabolic diseases, with the most recent glucose-dependent insulinotropic peptide receptor:glucagon-like peptide 1 receptor:glucagon receptor (GIPR:GLP-1R:GCGR) triagonists rivaling the efficacy of bariatric surgery. However, further research is needed to fully understand how these therapies exert their effect on body weight and in the last section we cover open questions about the potential mechanisms of multiagonist drugs, and the understanding of how gut-brain communication can be leveraged to achieve sustained body weight loss without adverse effects.

Efficacy and safety of Mazdutide on weight loss among diabetic and non-diabetic patients: a systematic review and meta-analysis of randomized controlled trials.

Background: Overweight and obesity are increasing global public health problems. Mazdutide is a new dual agonist drug that can potentially reduce weight and blood glucose levels simultaneously. However, the synthesis of evidence on the efficacy and safety of this drug is scarce. Therefore, this study aimed to synthesize evidence on the efficacy and safety of Mazdutide compared to placebo on weight reduction among adults with and without diabetes. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Data were retrieved from six electronic databases: PubMed, Web of Science, Scopus, Cochrane Library, ClinicalTrial.gov, and Google Scholar, and manually searched from the included references. The data were synthesized using a random effect model. This analysis was performed in the R programming language using the Meta package. Results: A total of seven RCTs involving 680 participants were included in this study. Mazdutide was more effective in reducing body weight (mean difference [MD]= -6.22%, 95% confidence interval [CI]: -8.02% to -4.41%, I2 = 90.0%), systolic blood pressure (MD = -7.57 mmHg, 95% CI: -11.17 to -3.98 mmHg, I2 = 46%), diastolic blood pressure (MD = -2.98 mmHg, 95% CI: -5.74 to -0.22 mmHg, I2 = 56%), total cholesterol (MD = -16.82%, 95% CI: -24.52 to -9.13%, I2 = 61%), triglycerides (MD = -43.29%, 95% CI: -61.57 to -25.01%, I2 = 68%), low-density lipoprotein (MD= -17.07%, 95% CI: -25.54 to -8.60%, I2 = 53%), and high-density lipoprotein (MD = -7.54%, 95% CI: -11.26 to -3.83%, I2 = 0%) than placebo. Mazdutide was associated with reduced hemoglobin A1c (HbA1c) and fasting plasma glucose in participants with type 2 diabetes. In the subgroup and meta-regression analyses, weight reduction was more significant in non-diabetics compared to diabetics, and in those who received a longer treatment duration (24 weeks) than in those on shorter durations (12-20 weeks). Participants who received Mazdutide had a higher risk of transient mild or moderate gastrointestinal side effects. Conclusion: Mazdutite appears to be effective in weight reduction among patients with and without diabetes, and it has an advantage over other associated comorbidities. However, it was associated with mild or moderate gastrointestinal side effects. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=403859, identifier CRD42023403859.

Polyagonists in Type 2 Diabetes Management.

PURPOSE OF THE REVIEW: This review summarizes the new developments in polyagonist pharmacotherapy for type 2 diabetes. RECENT FINDINGS: Several dual- and triple-agonists targeting different pathogenic pathways of type 2 diabetes have entered clinical trials and have led to significant improvements in glycaemia, body weight, fatty liver, and cardio-renal risk factors, with variable adverse event profiles but no new serious safety concerns. Combining agents with complementary and synergistic mechanisms of action have enhanced efficacy and safety. Targeting multiple pathogenic pathways simultaneously has led to enhanced benefits which potentially match those of bariatric surgery. Tirzepatide, cotadutide, BI456906, ritatrutide, and CagriSema have entered phase 3 clinical trials. Outcomes from published clinical studies are reviewed. Efficacy-safety profiles are heterogeneous between agents, suggesting the potential application of precision medicine and need for personalized approach in pharmacological management of type 2 diabetes and obesity. Polyagonism has become a key strategy to address the complex pathogenesis of type 2 diabetes and co-morbidities and increasing number of agents are moving through clinical trials. Heterogeneity in efficacy-safety profiles calls for application of precision medicine and need for judicious personalization of care.

Identification of Crocetin as a Dual Agonist of GPR40 and GPR120 Responsible for the Antidiabetic Effect of Saffron.

Crocin, a glycoside of crocetin, has been known as the principal component responsible for saffron's antidiabetic, anticancer, and anti-inflammatory effects. Crocetin, originating from the hydrolytic cleavage of crocin in biological systems, was subjected to ligand-based virtual screening in this investigation. Subsequent biochemical analysis unveiled crocetin, not crocin, as a novel dual GPR40 and GPR120 agonist, demonstrating a marked preference for GPR40 and GPR120 over peroxisome proliferator-activated receptors (PPAR)γ. This compound notably enhanced insulin and GLP-1 secretion from pancreatic ß-cells and intestinal neuroendocrine cells, respectively, presenting a dual mechanism of action in glucose-lowering effects. Docking simulations showed that crocetin emulates the binding characteristics of natural ligands through hydrogen bonds and hydrophobic interactions, whereas crocin's hindered fit within the binding pocket is attributed to steric constraints. Collectively, for the first time, this study unveils crocetin as the true active component of saffron, functioning as a GPR40/120 agonist with potential implications in antidiabetic interventions.

Discovery of 7-Azanorbornane-Based Dual Agonists for the Delta and Kappa Opioid Receptors through an In Situ Screening Protocol.

In medicinal chemistry, the copper-catalyzed click reaction is used to prepare ligand candidates. This reaction is so clean that the bioactivities of the products can be determined without purification. Despite the advantages of this in situ screening protocol, the applicability of this method for transmembrane proteins has not been validated due to the incompatibility with copper catalysts. To address this point, we performed ligand screening for the µ, δ, and κ opioid receptors using this protocol. As we had previously reported the 7-azanorbornane skeleton as a privileged scaffold for the G protein-coupled receptors, we performed the click reactions between various 7-substituted 2-ethynyl-7-azanorbornanes and azides. Screening assays were performed without purification using the CellKeyTM system, and the putative hit compounds were re-synthesized and re-evaluated. Although the "hit" compounds for the µ and the δ receptors were totally inactive after purifications, three of the four "hits" for the κ receptor were true agonists for this receptor and also showed activities for the δ receptor. Although false positive/negative results exist as in other screening projects for soluble proteins, this in situ method is effective in identifying novel ligands for transmembrane proteins.

Incretin Mimetics Restore the ER-Mitochondrial Axis and Switch Cell Fate Towards Survival in LUHMES Dopaminergic-Like Neurons: Implications for Novel Therapeutic Strategies in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that afflicts more than 10 million people worldwide. Available therapeutic interventions do not stop disease progression. The etiopathogenesis of PD includes unbalanced calcium dynamics and chronic dysfunction of the axis of the endoplasmic reticulum (ER) and mitochondria that all can gradually favor protein aggregation and dopaminergic degeneration. OBJECTIVE: In Lund Human Mesencephalic (LUHMES) dopaminergic-like neurons, we tested novel incretin mimetics under conditions of persistent, calcium-dependent ER stress. METHODS: We assessed the pharmacological effects of Liraglutide-a glucagon-like peptide-1 (GLP-1) analog-and the dual incretin GLP-1/GIP agonist DA3-CH in the unfolded protein response (UPR), cell bioenergetics, mitochondrial biogenesis, macroautophagy, and intracellular signaling for cell fate in terminally differentiated LUHMES cells. Cells were co-stressed with the sarcoplasmic reticulum calcium ATPase (SERCA) inhibitor, thapsigargin. RESULTS: We report that Liraglutide and DA3-CH analogs rescue the arrested oxidative phosphorylation and glycolysis. They mitigate the suppressed mitochondrial biogenesis and hyper-polarization of the mitochondrial membrane, all to re-establish normalcy of mitochondrial function under conditions of chronic ER stress. These effects correlate with a resolution of the UPR and the deficiency of components for autophagosome formation to ultimately halt the excessive synaptic and neuronal death. Notably, the dual incretin displayed a superior anti-apoptotic effect, when compared to Liraglutide. CONCLUSIONS: The results confirm the protective effects of incretin signaling in ER and mitochondrial stress for neuronal degeneration management and further explain the incretin-derived effects observed in PD patients.

A novel PPARß/FFA1 dual agonist Y8 promotes diabetic wound healing.

BACKGROUND: Diabetes ulcer is one of the leading causes of disability and death in diabetics. Y8 [(2-(2-fluoro-4-((4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)methoxy) phenoxy)acetic acid)], a dual agonist of peroxisome proliferation activated receptorß (PPARß) and free fatty acid receptor 1 (FFA1/FFAR1/GPR40), a new compound molecule with the potential for diabetes ulcer treatment. OBJECTIVE: To research the effect of the dual target agonist Y8 and its mechanism of action in the treatment of diabetic ulcers. METHODS: We have established a wound model in diabetic mice. After treatment with Y8, wound healing was evaluated by tissue pathology, reactive oxygen species (ROS) levels, and gene expression testing. Under high sugar conditions, the mechanism of Y8 affecting fibroblasts' proliferation and keratinocytes' migration is further studied. RESULTS: We found that Y8 accelerated wound healing and shortened healing time in diabetic mice. Granulation tissue generation and extracellular matrix (ECM) deposition were significantly increased in Y8-treated mice. Mechanistically, Y8 promotes keratinocyte proliferation by activating PPARß and migration of keratinocytes by triggering FFA1 in vitro. In addition, Y8 also decreased ROS levels in fibroblasts in vitro and in vivo by activating PPARß, reducing their release of superoxide anions. CONCLUSION: Our results suggest that PPARß/FFA1 dual agonist Y8 has the effect of promoting the healing of diabetic ulcer wounds in vivo and in vitro, and its therapeutic effect is better than that of single-target agonists.

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.

A phase 2, adaptive randomized, double-blind, placebo-controlled, multicenter, 52-week study of HM15211 in patients with biopsy-confirmed non-alcoholic steatohepatitis - Study design and rationale of HM-TRIA-201 study.

Non-alcoholic steatohepatitis (NASH) is a multifactorial disease with an increasing prevalence worldwide due to the obesity pandemic. HM15211 (efocipegtrutide), a novel, long-acting glucagon-like peptide-1/glucagon/glucose-dependent insulinotropic polypeptide triple incretin agonist has shown promising efficacy in in vitro, preclinical rodent models of NASH and phase 1 studies with manageable toxicity. Though liver biopsy is recommended for grading and staging of NASH, its invasive nature necessitates innovative approaches in clinical trials that decrease the burden of patients otherwise subjected to this invasive procedure. We report an innovative study design of phase 2 study of HM15211. METHODS: HM-TRIA-201 is a multicenter, randomized, double-blind, 52-week, placebo-controlled, parallel-group adaptive design study of 217 patients with biopsy-proven NASH. The primary endpoint is the proportion of patients with complete resolution of steatohepatitis (defined as Non-alcoholic fatty liver disease Activity Score of 0-1 for inflammation, 0 for ballooning, and any other value for steatosis) on overall histopathological reading and no worsening of liver fibrosis on NASH Clinical Research Network fibrosis score. An interim analysis is planned after 15 patients/group complete 26 weeks of treatment, after which one HM15211 dose group will be discontinued based on safety and efficacy risk-to-benefit analysis; patients of the dropped dosing arm will be re-randomized into 2 remaining HM15211 groups. CONCLUSION: The adaptive design study of HM15211 minimizes the number of patients to be exposed to a liver biopsy while optimizing the sample size of patients exposed to safe and effective doses of HM15211 to inform ideal dose for further clinical development in NASH.

A Multiplex Molecular Cell-Based Sensor to Detect Ligands of PPARs: An Optimized Tool for Drug Discovery in Cyanobacteria.

Cyanobacteria produce a wealth of secondary metabolites. Since these organisms attach fatty acids into molecules in unprecedented ways, cyanobacteria can serve as a novel source for bioactive compounds acting as ligands for Peroxisome Proliferator-Activated Receptors (PPAR). PPARs (PPARα, PPARß/δ and PPARγ) are ligand-activated nuclear receptors, involved in the regulation of various metabolic and cellular processes, thus serving as potential drug targets for a variety of pathologies. Yet, given that PPARs' agonists can have pan-, dual- or isoform-specific action, some controversy has been raised over currently approved drugs and their side effects, highlighting the need for novel molecules. Here, we expand and validate a cell-based PPAR transactivation activity biosensor, and test it in a screening campaign to guide drug discovery. Biosensor upgrades included the use of different reporter genes to increase signal intensity and stability, a different promoter to modulate reporter gene expression, and multiplexing to improve efficiency. Sensor's limit of detection (LOD) ranged from 0.36-0.89 nM in uniplex and 0.89-1.35 nM in multiplex mode. In triplex mode, the sensor's feature screening, a total of 848 fractions of 96 cyanobacteria extracts were screened. Hits were confirmed in multiplex mode and in uniplex mode, yielding one strain detected to have action on PPARα and three strains to have dual action on PPARα and -ß.

Dual GIP/GLP-1 receptor agonists: New advances for treating type-2 diabetes.

Glucagon-like peptide-1 (GLP-1) receptor agonists currently occupy a privileged place in the management of type-2 diabetes (T2D). Dual glucose-dependent insulinotropic polypeptides (GIP/GLP-1) have been recently developed. Tirzepatide is the most advanced unimolecular dual GIP/GLP-1 receptor agonist to be used as once weekly subcutaneous injection in T2D and recently received approval by the European Medicines Agency. Because of the complementarity of action of the two incretins, tirzepatide showed better dose-dependent (5, 10 and 15mg) efficacy (greater reduction in HbA1c and body weight) than placebo, basal insulin or two GLP-1 analogues (dulaglutide and semaglutide) in the SURPASS program. Its cardiovascular protective effect is currently being assessed versus dulaglutide in the SURPASS-CVOT study. Finally, studies for the treatment of obesity (SURMOUNT program) and metabolic-associated fatty liver disease (MAFLD) are also ongoing. Gastrointestinal tolerance of tirzepatide appears comparable to that of GLP-1 analogues, except for higher incidence of diarrhea. Other original molecules have been built, including triple GIP/GLP-1/glucagon receptor agonists. The risk/benefit ratio will decide whether dual (or triple) receptor agonists should replace pure GLP-1 receptor agonists for the management of T2D in the near future, with a significant role in the pharmacotherapy of obesity.

Activity-balanced GLP-1/GDF15 dual agonist reduces body weight and metabolic disorder in mice and non-human primates.

Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its weight-lowering potential in animals. The molecule, QL1005, is engineered via fusing GLP-1 and GDF15 analogs by a peptide linker and conjugating it to a fatty acid for time-action extension. In vitro, the potency of QL1005 is superior to the GLP-1 analog semaglutide. In obese mice, QL1005 induces reductions in body weight, food intake, insulin, fasting glucose, and triglycerides. Notably, these metabolic effects come as a result of activities emanating from both GLP-1 and GDF15, in an individual pathway-balanced fashion. In a cynomolgus monkey model of obesity, QL1005 reduces body weight, food intake, insulin, and glucose in a dose-dependent manner with limited incidence of GI side effects. Altogether, this long-acting, dual GLP-1/GDF15 molecule demonstrates the promise of poly-pharmaceutical approaches in metabolic drug discovery and development.

Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple-ascending-dose phase 1b trial.

Background: Mazdutide (also known as IBI362 or LY3305677), a novel once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist, achieved 12-week body weight loss up to 6.4% at doses up to 6 mg in Chinese adults with overweight or obesity. We further explored the safety and efficacy of mazdutide dosed up to 9 mg and 10 mg. Methods: In this randomised, placebo-controlled, multiple-ascending-dose phase 1b trial, we enrolled adults (aged 18-75 years, both inclusive) with overweight (body-mass index [BMI] ≥24 kg/m2) accompanied by hyperphagia and/or at least one obesity-related comorbidity or obesity (BMI ≥28 kg/m2) from five hospitals in China. Eligible participants were randomly assigned (2:1) within each cohort by using an interactive web-response system to receive once-weekly subcutaneous mazdutide or placebo for 12 weeks in the 9 mg cohort (3 mg weeks 1-4; 6 mg weeks 5-8; 9 mg weeks 9-12) and for 16 weeks in the 10 mg cohort (2.5 mg weeks 1-4; 5 mg weeks 5-8; 7.5 mg weeks 9-12; 10 mg weeks 13-16). The participants, investigators, study site personnel involved in treating and assessing participants in each cohort and sponsor personnel were masked to treatment allocation. The primary outcomes were safety and tolerability of mazdutide, assessed from baseline to end of follow-up in all participants who received at least one dose of the study treatment. The secondary outcomes included the change from baseline to week 12 or week 16 in body weight, waist circumference and BMI. This trial is registered with ClinicalTrials.gov, NCT04440345. Findings: Between Mar. 1, 2021 and Mar. 26, 2021, a total of 24 participants were enrolled, with eight randomly assigned to mazdutide and four to placebo in each cohort. One participant receiving mazdutide and two receiving placebo in the 10 mg cohort withdrew consent and quitted the study. No serious adverse event was reported. All treatment-emergent adverse events (TEAEs) were mild or moderate in severity and most commonly-reported TEAEs were upper respiratory tract infection, diarrhoea, decreased appetite, nausea, urinary tract infection, abdominal distension and vomiting. The mean percent change from baseline to week 12 in body weight were -11.7% (SE 1.5) for participants receiving mazdutide in the 9 mg cohort and -1.8% (1.6) for participants receiving placebo (estimated treatment difference [ETD]: -9.8%; 95% confidence interval [CI]: -14.4, -5.3; P = 0.0002). The mean percent change from baseline to week 16 in body weight were -9.5% (SE 1.7) for participants receiving mazdutide in the 10 mg cohort and -3.3% (1.9) for participants receiving placebo (ETD: -6.2%; 95% CI: -11.5, -0.9; P = 0.024). In addition, compared with placebo, mazdutide achieved more profound reductions in waist circumference and BMI. Interpretation: Mazdutide dosed up to 9 mg and 10 mg was both well tolerated and showed a favourable safety profile. High-dose mazdutide showed promising 12-week body weight loss, holding great potential for the treatment of moderate-to-severe obesity. A larger and longer phase 2 trial will further evaluate the efficacy and safety of high-dose mazdutide in Chinese adults with obesity. Funding: Innovent Biologics, Inc.

Tirzepatide: A Novel, Once-weekly Dual GIP and GLP-1 Receptor Agonist for the Treatment of Type 2 Diabetes.

Gastrointestinal hormones are currently used to treat type 2 diabetes mellitus (T2D). Incretin preparations with gastric inhibitory polypeptide (GIP) activity or glucagon-like peptide-1 (GLP-1) provide new means for controlling blood glucose levels, body weight, and lipid metabolism. GIP, an incretin, has not been used due to lack of promising action against diabetes. However, recent studies have shown that GIP has an important effect on glucagon and insulin secretion under normoglycaemic conditions. Co-existence of GIP with GLP-1 and glucagon signalling leads to a stronger effect than that of GLP-1 stimulation alone. The development of a GIP/GLP-1R unimolecular dual agonist with affinity for both GIP and GLP-1 receptors is under investigation, and the drug is expected to be clinically available in the near future. Tirzepatide, a GIP/GLP-1R unimolecular dual agonist, regulates metabolism via both peripheral organs and the central nervous system. The SURPASS phase III clinical trials conducted for tirzepatide comprise 10 clinical trials, including five global trials and the global SURPASS-CVOT trial, with >13,000 patients with T2D (ClinicalTrials.gov Identifier: NCT04255433). The clinical application of tirzepatide as a therapy for T2D may provide new insights into diabetic conditions and help clarify the role of GIP in its pathogenesis.

Efficacy of glucagon-like peptide-1 and estrogen dual agonist in pancreatic islets protection and pre-clinical models of insulin-deficient diabetes.

We study the efficacy of a glucagon-like peptide-1 (GLP-1) and estrogen dual agonist (GLP1-E2) in pancreatic islet protection. GLP1-E2 provides superior protection from insulin-deficient diabetes induced by multiple low-dose streptozotocin (MLD-STZ-diabetes) and by the Akita mutation in mice than a GLP-1 monoagonist. GLP1-E2 does not protect from MLD-STZ-diabetes in estrogen receptor-α (ERα)-deficient mice and fails to prevent diabetes in Akita mice following GLP-1 receptor (GLP-1R) antagonism, demonstrating the requirement of GLP-1R and ERα for GLP1-E2 antidiabetic actions. In the MIN6 ß cell model, GLP1-E2 activates estrogen action following clathrin-dependent, GLP-1R-mediated internalization and lysosomal acidification. In cultured human islet, proteomic bioinformatic analysis reveals that GLP1-E2 amplifies the antiapoptotic pathways activated by monoagonists. However, in cultured mouse islets, GLP1-E2 provides antiapoptotic protection similar to monoagonists. Thus, GLP1-E2 promotes GLP-1 and E2 antiapoptotic signals in cultured islets, but in vivo, additional GLP1-E2 actions in non-islet cells expressing GLP-1R are instrumental to prevent diabetes.