GLP-1/GLP-1RAs: New Options for the Drug Treatment of NAFLD.

Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a global public health concern. Currently, the cornerstone of NAFLD treatment is lifestyle modification and, if necessary, weight loss. However, compliance is a challenge, and this approach alone may not be sufficient to halt and treat the more serious disease development, so medication is urgently needed. Nevertheless, no medicines are approved to treat NAFLD. Glucagon-like peptide-1 (GLP-1) is an enteropeptide hormone that inhibits glucagon synthesis, promotes insulin secretion, and delays gastric emptying. GLP-1 has been found in recent studies to be beneficial for the management of NAFLD, and the marketed GLP-1 agonist drugs have different degrees of effectiveness for NAFLD while lowering blood glucose. In this article, we review GLP-1 and its physiological roles, the pathogenesis of NAFLD, the correlation between NAFLD and GLP-1 signaling, and potential strategies for GLP-1 treatment of NAFLD.

Glucagon: Delivery advancements for hypoglycemia management.

As the 100th anniversary of glucagon's discovery approaches, we reflect on the remarkable journey of understanding its pivotal role in glucose regulation. Advancements in glucagon delivery systems for managing hypoglycemia are unfolding with promise, albeit accompanied by formulation and implementation challenges. Recent developments include non-injectable methods like BAQSIMI® (Nasal glucagon) offers a user-friendly option, but stability, bioavailability, and rapid onset remain formulation hurdles. Closed-loop systems, combining glucagon with insulin, aim to automate glucose control, demanding stable and precise formulations compatible with complex algorithms. However, achieving co-delivery harmony and effective dual-hormone responses poses substantial challenges. Ogluo® and Gvoke HypoPen® are auto-injector pens, a ready-to-use solution that can rapidly control hypoglycemia and eliminate the need for mixing powder and liquid. GlucaGen® Hypokit® and Glucagon Emergency Kits are traditional deliveries that possess complexity during administration and are still widely used in clinical practice. In addition to this advancement, we have covered the recent patents and clinical trials of glucagon delivery. The synergy of patent innovation and clinical validation offers a glimpse into the transformative potential of glucagon delivery yet underscores the intricate path toward widespread adoption and improved diabetes care. Finally, this review will help the formulation scientist, clinicians, healthcare providers, and patient to manage hypoglycemia using glucagon.

Glucagon Enhances Chemotherapy Efficacy By Inhibition of Tumor Vessels in Colorectal Cancer.

Chemotherapy is widely used to treat colorectal cancer (CRC). Despite its substantial benefits, the development of drug resistance and adverse effects remain challenging. This study aimed to elucidate a novel role of glucagon in anti-cancer therapy. In a series of in vitro experiments, glucagon inhibited cell migration and tube formation in both endothelial and tumor cells. In vivo studies demonstrated decreased tumor blood vessels and fewer pseudo-vessels in mice treated with glucagon. The combination of glucagon and chemotherapy exhibited enhanced tumor inhibition. Mechanistic studies demonstrated that glucagon increased the permeability of blood vessels, leading to a pronounced disruption of vessel morphology. Signaling pathway analysis identified a VEGF/VEGFR-dependent mechanism whereby glucagon attenuated angiogenesis through its receptor. Clinical data analysis revealed a positive correlation between elevated glucagon expression and chemotherapy response. This is the first study to reveal a role for glucagon in inhibiting angiogenesis and vascular mimicry. Additionally, the delivery of glucagon-encapsulated PEGylated liposomes to tumor-bearing mice amplified the inhibition of angiogenesis and vascular mimicry, consequently reinforcing chemotherapy efficacy. Collectively, the findings demonstrate the role of glucagon in inhibiting tumor vessel network and suggest the potential utility of glucagon as a promising predictive marker for patients with CRC receiving chemotherapy.

Estimation and Prediction of Glucose Appearance Rate for Use in a Fully Closed-Loop Dual-Hormone Intraperitoneal Artificial Pancreas.

OBJECTIVE: A fully automated artificial pancreas requires a meal estimator and predictions of blood glucose levels (BGL) to handle disturbances during meal times, all without relying on manual meal announcements and user interventions. This study introduces a technique for estimating the glucose appearance rate (GAR) and predicting BGL in people with type 1 diabetes and insulin and glucagon administration. It is demonstrated for intraperitoneal insulin and glucagon delivery but may be adapted to other delivery sites. METHOD: The estimator is designed based on the moving horizon estimation (MHE) approach, where the underlying cost function incorporates prior statistical information on the GAR in subjects over the course of a day. The proposed prediction scheme is developed to predict GAR using estimated states and an intestinal model, which is then used to predict BGL with the help of an animal glucose metabolic model. RESULTS: The intraperitoneal dual-hormone estimator was evaluated on three anesthetized animals, achieving a 21.8% mean absolute percentage error (MAPE) for GAR estimation and a 10.0% MAPE for BGL prediction when the future GAR is known. For a 120-minute prediction horizon, the proposed predictor achieved an 18.0% MAPE for GAR and a 28.4% MAPE for BGL. CONCLUSION: The findings demonstrate the effectiveness and reliability of the proposed estimator and its potential for use in a fully automated artificial pancreas and reducing user interventions. SIGNIFICANCE: This study represents advancements toward the development of a fully automated artificial pancreas, ultimately enhancing the quality of life for people with type 1 diabetes.

Total Pancreatectomy in a Patient Treated with a Sensor-augmented Pump Showing No Evidence of Hyperglycemia or Ketoacidosis without Any Insulin Administration.

Total pancreatectomy results in complete loss of insulin and glucagon. Sensor-augmented pumps (SAPs) allow fine-tuning of the basal insulin rate, which helps avoid both hypo- and hyperglycemic events. We herein report a case of total pancreatectomy treated with a SAP with no evidence of ketoacidosis without any insulin administration during a certain period of time. Furthermore, we observed a sudden drop in blood glucose levels without insulin, which may have been due to glucose effectiveness. Our case is valuable in arguing the concept of glucose effectiveness in the absence of insulin and glucagon.

Double-Blind Multicenter Randomized Clinical Trial Comparing Glucagon vs Placebo in the Resolution of Alimentary Esophageal Impaction.

INTRODUCTION: The aim of this study was to compare the effectiveness of glucagon vs placebo in resolving esophageal foreign body impaction (EFBI), as well as the length of the procedure and adverse events. METHODS: This was a multicenter, randomized, double-blind trial involving consecutive patients diagnosed with alimentary EFBI. Participants were randomized to receive either 1 mg of intravenous glucagon or placebo. All patients underwent upper endoscopy, and adverse events were assessed through a protocolized telephonic interview 7 days later. RESULTS: The study included 72 subjects in the glucagon group and 68 in the placebo group. The foreign body was not identified in 23.6% of subjects in the glucagon group and 20.6% of subjects in the placebo group (difference 3%, 95% confidence interval -10.7% to 16.8%, P = 0.67). The median time required to remove the foreign body was similar in both groups 4 minutes (range 2-10) in the glucagon group and 3.5 minutes (range 2-7) in the placebo group (difference 0.5 minutes, 95% confidence interval -1.3 to 2.3; P = 0.59). The most common adverse event reported in both groups was mild pharyngeal pain. DISCUSSION: Glucagon is no more effective than placebo in resolving EFBI or shortening the time required to remove the foreign body (EUDRA-CT number 2019-004920-40).

A Quantitative Systems Pharmacology Model of the Incretin Hormones GIP and GLP1, Glucagon, Glucose, Insulin, and the Small Molecule DPP-4 Inhibitor, Linagliptin.

In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the "skeleton" structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon, and glucose simultaneously in humans. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is "drug-independent", our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on the glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system.

Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report.

INTRODUCTION: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.

Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children.

CONTEXT: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). METHODS: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2 to 4. RESULTS: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9 mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION: Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.

Comparison of Intranasal and Injectable Glucagon Administration Among Pediatric Population Responders.

Aims: Ease of use and acceptability of nasal versus injectable glucagon (IG) among pediatric responders have been little investigated. This study compared the performance of administering nasal and IG in parents of youth with type 1 diabetes (T1D) and in school workers. Enablers and barriers associated with each glucagon and preferred glucagon administration learning modality were also evaluated. Methods: Three months after watching short pedagogical videos, 30 parents and 30 school workers performed simulated scenarios where they administered both glucagon. Completion time and successful execution of critical steps were collected. Interviews assessed preferred learning modalities, barriers, and enablers associated with each glucagon. Results: Both groups administered nasal glucagon faster than IG (median [interquartile range]: parents 19 [12-29] vs. 97 [71-117] s, P < 0.001; school workers 24 [16-33] vs. 129 [105-165] s, P < 0.001). A lower proportion of participants successfully executed all critical steps for injectable versus nasal glucagon (significant difference for school workers [53% vs. 90%; P = 0.007] but not for parents [68% vs. 83%; P = 0.227]). Nasal glucagon was preferred for ease of use and acceptability. Preferred learning modalities were a combination of videos and workshops, but videos alone could suffice for nasal glucagon. Conclusions: Nasal glucagon is faster to use, more likely to be successfully administered, and more acceptable than IG for parents of children with T1D and school workers. Nasal glucagon training with videos could improve school workers' involvement in severe hypoglycemia management. Clinical Trial number, URL to the registration: NCT05395000, https://clinicaltrials.gov/ct2/show/NCT05395000.

Dasiglucagon for the Treatment of Insulin-induced Hypoglycemia in Patients with Type 1 Diabetes Mellitus: A Meta-analysis

Background: The use of conventional glucagon for managing insulin-induced hypoglycemia is obscured by its chemical instability and the need for reconstitution of the lyophilized powder, leading to delayed rescue. Dasiglucagon, a glucagon analog, may potentially overcome these shortcomings. Aims: To evaluate the efficacy and safety of dasiglucagon in insulin-induced hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Study Design: Meta-analysis. Methods: PubMed/MEDLINE, Scopus, Embase, and Cochrane databases along with clinical trial registries were searched to include data from five randomized controlled trials conducted using dasiglucagon for the treatment of insulin-induced hypoglycemia in T1DM patients published until May 2023. We performed a risk of bias assessment to determine the quality of the included studies and a random-effects model analysis for determining the effect size. Subgroup analysis and meta-regression were done as applicable. Results: The time to recovery (in minutes) with dasiglucagon was earlier than placebo [mean difference (MD): -24.73; 95% confidence interval (CI): -30.94 to -18.52; p < 0.00001) or oral glucose (MD: -15.00; 95% CI: -20.33 to -9.67; p < 0.00001); however, the difference between dasiglucagon and glucagon was not statistically significant (MD: -0.76; 95% CI: -2.19 to 0.66; p = 0.29). Conclusion: Dasiglucagon is safer and more effective than placebo or oral glucose for insulin-induced hypoglycemia in T1DM patients; however, it is not superior to conventional glucagon.

The importance of glucose-dependent insulinotropic polypeptide receptor activation for the effects of tirzepatide.

Tirzepatide is a unimolecular co-agonist of the glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors recently approved for the treatment of type 2 diabetes by the US Food and Drug Administration and the European Medicine Agency. Tirzepatide treatment results in an unprecedented improvement of glycaemic control and lowering of body weight, but the contribution of the GIP receptor-activating component of tirzepatide to these effects is uncertain. In this review, we present the current knowledge about the physiological roles of the incretin hormones GLP-1 and GIP, their receptors, and previous results of co-targeting the two incretin hormone receptors in humans. We also analyse the molecular pharmacological, preclinical and clinical effects of tirzepatide to discuss the role of GIP receptor activation for the clinical effects of tirzepatide. Based on the available literature on the combination of GLP-1 and GIP receptor activation, tirzepatide does not seem to have a classical co-activating mode of action in humans. Rather, in vitro studies of the human GLP-1 and GIP receptors reveal a biased GLP-1 receptor activation profile and GIP receptor downregulation. Therefore, we propose three hypotheses for the mode of action of tirzepatide, which can be addressed in future, elaborate clinical trials.

Glucagon prescribing and prevention of hospitalization for hypoglycemia in a large health system.

AIMS: To examine glucagon prescribing trends among patients at high risk of severe hypoglycemia and assess if a glucagon prescription is associated with lower rates of severe hypoglycemia requiring hospital care. METHODS: Retrospective analysis of electronic health records from a large integrated healthcare system between May 2019 and August 2021. We included adults (≥18 years) with type 1 diabetes or with type 2 diabetes treated with short-acting insulin and/or recent history of hypoglycemia-related emergency department visit or hospitalization. We calculated rates of glucagon prescribing overall and by patient characteristics. We then matched 1:1 those who were and were not prescribed glucagon and assessed subsequent hypoglycemia-related hospitalization. RESULTS: Of 9,200 high risk adults, 2063 (22.4%) were prescribed glucagon. Among patients more likely to be prescribed glucagon were those younger, female, White, living in urban areas, with prior severe hypoglycemia, and with a recent endocrinology specialist visit. In the matched cohort (N = 1707 per arm), 62 prescribed glucagon and 33 not prescribed glucagon were hospitalized for hypoglycemia (adjusted incidence rate ratio 1.71, 95% CI 1.10-2.66; P = 0.018). CONCLUSION: Glucagon prescribing was infrequent with significant racial and rural disparities. Patients with glucagon prescriptions did not have lower rates of hospitalization for hypoglycemia.

Non-severe hypoglycemia in type 1 diabetes: a randomized crossover trial comparing two quantities of oral carbohydrates at different insulin-induced hypoglycemia ranges.

Aims: Non-severe hypoglycemia (NS-H) is challenging for people living with type 1 diabetes (PWT1D) and often results from relative iatrogenic hyper-insulinemia. Current guidelines recommend a one-size-fits-all approach of 15-20 g of simple carbohydrates (CHO) every 15 min regardless of the triggering conditions of the NS-H event. We aimed to test different amounts of CHO to treat insulin-induced NS-H at various glucose ranges. Methods: This is a randomized, four-way, crossover study involving PWT1D, testing NS-H treatment outcomes with 16 g vs. 32 g CHO at two plasma glucose (PG) ranges: A: 3.0-3.5 mmol/L and B: <3.0 mmol/L. Across all study arms, participants consumed an additional 16 g of CHO if PG was still <3.0 mmol/L at 15 min and <4.0 mmol/L at 45 min post-initial treatment. Subcutaneous insulin was used in a fasting state to induce NS-H. Participants had frequent venous sampling of PG, insulin, and glucagon levels. Results: Participants (n = 32; 56% female participants) had a mean (SD) age of 46.1 (17.1) years, had HbA1c at 54.0 (6.8 mmol/mol) [7.1% (0.9%)], and had a diabetes duration of 27.5 (17.0) years; 56% were insulin pump users. We compared NS-H correction parameters between 16 g and 32 g of CHO for range A, 3.0-3.5 mmol/L (n = 32), and range B, <3.0 mmol/L (n = 29). Change in PG at 15 min for A: 0.1 (0.8) mmol/L vs. 0.6 (0.9) mmol/L, p = 0.02; and for B: 0.8 (0.9) mmol/L vs. 0.8 (1.0) mmol/L, p = 1.0. Percentage of participants with corrected episodes at 15 min: (A) 19% vs. 47%, p = 0.09; (B) 21% vs. 24%, p = 1.0. A second treatment was necessary in (A) 50% vs. 15% of participants, p = 0.001; (B) 45% vs. 34% of participants, p = 0.37. No statistically significant differences in insulin and glucagon parameters were observed. Conclusions: NS-H, in the context of hyper-insulinemia, is difficult to treat in PWT1D. Initial consumption of 32 g of CHO revealed some advantages at the 3.0-3.5 mmol/L range. This was not reproduced at lower PG ranges since participants needed additional CHO regardless of the amount of initial consumption. Clinical trial registration: ClinicalTrials.gov, identifier NCT03489967.

Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA.

BACKGROUND: According to current consensus guidelines for type 2 diabetes management, bodyweight management is as important as attaining glycaemic targets. Retatrutide, a single peptide with agonist activity at the glucose-dependent insulinotropic polypeptide (GIP), GLP-1, and glucagon receptors, showed clinically meaningful glucose-lowering and bodyweight-lowering efficacy in a phase 1 study. We aimed to examine the efficacy and safety of retatrutide in people with type 2 diabetes across a range of doses. METHODS: In this randomised, double-blind, double-dummy, placebo-controlled and active comparator-controlled, parallel-group, phase 2 trial, participants were recruited from 42 research and health-care centres in the USA. Adults aged 18-75 years with type 2 diabetes, glycated haemoglobin (HbA1c) of 7·0-10·5% (53·0-91·3 mmol/mol), and BMI of 25-50 kg/m2 were eligible for enrolment. Eligible participants were treated with diet and exercise alone or with a stable dose of metformin (≥1000 mg once daily) for at least 3 months before the screening visit. Participants were randomly assigned (2:2:2:1:1:1:1:2) using an interactive web-response system, with stratification for baseline HbA1c and BMI, to receive once-weekly injections of placebo, 1·5 mg dulaglutide, or retatrutide maintenance doses of 0·5 mg, 4 mg (starting dose 2 mg), 4 mg (no escalation), 8 mg (starting dose 2 mg), 8 mg (starting dose 4 mg), or 12 mg (starting dose 2 mg). Participants, study site personnel, and investigators were masked to treatment allocation until after study end. The primary endpoint was change in HbA1c from baseline to 24 weeks, and secondary endpoints included change in HbA1c and bodyweight at 36 weeks. Efficacy was analysed in all randomly assigned, except inadvertently enrolled, participants, and safety was assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov, NCT04867785. FINDINGS: Between May 13, 2021, and June 13, 2022, 281 participants (mean age 56·2 years [SD 9·7], mean duration of diabetes 8·1 years [7·0], 156 [56%] female, and 235 [84%] White) were randomly assigned and included in the safety analysis (45 in the placebo group, 46 in the 1·5 mg dulaglutide group, and 47 in the retatrutide 0·5 mg group, 23 in the 4 mg escalation group, 24 in the 4 mg group, 26 in the 8 mg slow escalation group, 24 in the 8 mg fast escalation group, and 46 in the 12 mg escalation group). 275 participants were included in the efficacy analyses (one each in the retatrutide 0·5 mg group, 4 mg escalation group, and 8 mg slow escalation group, and three in the 12 mg escalation group were inadvertently enrolled). 237 (84%) participants completed the study and 222 (79%) completed study treatment. At 24 weeks, least-squares mean changes from baseline in HbA1c with retatrutide were -0·43% (SE 0·20; -4·68 mmol/mol [2·15]) for the 0·5 mg group, -1·39% (0·14; -15·24 mmol/mol [1·56]) for the 4 mg escalation group, -1·30% (0·22; -14·20 mmol/mol [2·44]) for the 4 mg group, -1·99% (0·15; -21·78 mmol/mol [1·60]) for the 8 mg slow escalation group, -1·88% (0·21; -20·52 mmol/mol [2·34]) for the 8 mg fast escalation group, and -2·02% (0·11; -22·07 mmol/mol [1·21]) for the 12 mg escalation group, versus -0·01% (0·21; -0·12 mmol/mol [2·27]) for the placebo group and -1·41% (0·12; -15·40 mmol/mol [1·29]) for the 1·5 mg dulaglutide group. HbA1c reductions with retatrutide were significantly greater (p<0·0001) than placebo in all but the 0·5 mg group and greater than 1·5 mg dulaglutide in the 8 mg slow escalation group (p=0·0019) and 12 mg escalation group (p=0·0002). Findings were consistent at 36 weeks. Bodyweight decreased dose dependently with retatrutide at 36 weeks by 3·19% (SE 0·61) for the 0·5 mg group, 7·92% (1·28) for the 4 mg escalation group, 10·37% (1·56) for the 4 mg group, 16·81% (1·59) for the 8 mg slow escalation group, 16·34% (1·65) for the 8 mg fast escalation group, and 16·94% (1·30) for the 12 mg escalation group, versus 3·00% (0·86) with placebo and 2·02% (0·72) with 1·5 mg dulaglutide. For retatrutide doses of 4 mg and greater, decreases in weight were significantly greater than with placebo (p=0·0017 for the 4 mg escalation group and p<0·0001 for others) and 1·5 mg dulaglutide (all p<0·0001). Mild-to-moderate gastrointestinal adverse events, including nausea, diarrhoea, vomiting, and constipation, were reported in 67 (35%) of 190 participants in the retatrutide groups (from six [13%] of 47 in the 0·5 mg group to 12 [50%] of 24 in the 8 mg fast escalation group), six (13%) of 45 participants in the placebo group, and 16 (35%) of 46 participants in the 1·5 mg dulaglutide group. There were no reports of severe hypoglycaemia and no deaths during the study. INTERPRETATION: In people with type 2 diabetes, retatrutide showed clinically meaningful improvements in glycaemic control and robust reductions in bodyweight, with a safety profile consistent with GLP-1 receptor agonists and GIP and GLP-1 receptor agonists. These phase 2 data also informed dose selection for the phase 3 programme. FUNDING: Eli Lilly and Company.

Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of the novel long-acting glucagon analogue HM15136 in overweight and obese patients with co-morbidities.

AIM: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending doses of the novel long-acting glucagon analogue HM15136 in overweight/obese patients with co-morbidities, with and without type 2 diabetes (T2D). MATERIALS AND METHODS: This was a phase 1, double-blind, randomized, placebo-controlled, two-part trial with a 12-week treatment period of once-weekly subcutaneous HM15136 (0.02/0.04/0.06 mg/kg). Part 1 included patients with dyslipidaemia and/or hypertension and no T2D. Part 2 included patients with dyslipidaemia and/or hypertension plus T2D. RESULTS: In part 1, 23/27 (85.2%) patients receiving HM15136 and all patients receiving placebo (9/9 [100%]) experienced a treatment-emergent adverse event (TEAE). Five of 27 (18.5%) patients receiving HM15136 developed anti-HM15136 antibodies. Dose-dependent increases in mean HM15136 serum concentration and fasting plasma glucose (FPG) were observed, as were dose-dependent weight reductions of 0.5%/2.3%/2.6% at doses of 0.02/0.04/0.06 mg/kg, respectively. In part 2, 8/12 (66.7%) patients receiving HM15136 and all patients receiving placebo (4/4 [100.0%]) reported a TEAE. Two (16.7%) patients developed anti-HM15136 antibodies. Dose-dependent increases in mean HM15136 serum concentration were observed. FPG of more than 200 mg/dL was reported in 4/9 (44.4%) and 2/3 (66.7%) patients receiving 0.02 and 0.06 mg/kg, respectively. The 0.06 mg/kg dose was not tolerated in part 2 because of hyperglycaemia. Patients receiving 0.02 mg/kg showed a 0.9% weight reduction. No serious TEAEs leading to discontinuation were reported in either study part. CONCLUSIONS: This study of HM15136 provides a preliminary safety and tolerability profile with initial insights into its efficacy profile.

[Genetic aspects of type 1 glucagon peptide agonists clinical efficacy: A review].

A review of publications devoted to the analysis of genetic polymorphisms of the gene encoding the glucagon-like peptide type 1 receptor and some other genes directly and indirectly involved in the implementation of its physiological action is presented. The aim of the study: to search for information on genes polymorphism that can affect the effectiveness of glucagon-like peptide type 1 agonists. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was based on PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic source eLIBRARY.RU from 1993 to 2022. The several genes polymorphisms (GLP1R, TCF7L2, CNR1, SORCS1, WFS1, PPARD, CTRB1/2) that may affect the course and therapy of type 2 diabetes mellitus, metabolic syndrome and obesity, was described. Single nucleotide substitutions in some regions of these genes can both decrease and increase the clinical efficacy of the treatment of diabetes mellitus and metabolic syndrome with the help of type 1 glucagon-like peptide agonists: exenatide, liraglutide. Data on the role of genetic variations in the structure of the products of these genes in the effectiveness of other type 1 glucacone-like peptide agonists have not been found.

Gaps in glucagon fills among commercially insured patients receiving a glucagon prescription.

Glucagon is critically underutilized, and we explored whether this is due to inadequate glucagon prescribing or the patient's inability to fill prescriptions. Of 216 commercially insured, high-risk individuals with diabetes who were prescribed glucagon in our healthcare system, 142 (65.4%) had a claim indicating its fill within 30 days.

Pharmacokinetics and Safety of Cotadutide, a GLP-1 and Glucagon Receptor Dual Agonist, in Individuals with Renal Impairment: A Single-Dose, Phase I, Bridging Study.

BACKGROUND AND OBJECTIVE: Cotadutide is a balanced glucagon-like peptide-1 and glucagon receptor dual agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes with chronic kidney disease. We evaluated the pharmacokinetics (PK), safety and immunogenicity of a single dose of cotadutide in individuals with varying degrees of renal impairment. METHODS: In this phase I bridging study, individuals 18-85 years of age, with a body mass index of 17-40 kg/m2 and varying degrees of renal function {end-stage renal disease (ESRD; creatinine clearance [CrCl] < 20 mL/min); severe renal impairment (CrCl ≥ 20 to < 30 mL/min); lower moderate renal impairment (CrCl ≥ 30 to < 44 mL/min); upper moderate renal impairment (CrCl ≥ 45 to < 60 mL/min); normal renal function (CrCl ≥ 90 mL/min)} were treated with a single dose of subcutaneous cotadutide 100 µg under fasted conditions in the lower abdomen. The co-primary endpoints were area under the plasma concentration-time curve from time zero to 48 h (AUC48) and the maximum observed plasma concentration (Cmax) for cotadutide. Safety and immunogenicity were secondary endpoints. This trial is registered with ClinicalTrials.gov (NCT03235375). RESULTS: A total of 37 individuals were enrolled in the study (only three enrolled in the ESRD group, therefore this group was excluded from the primary PK analysis). AUC48 and Cmax values for cotadutide were similar across all renal function groups {severe renal impairment vs. normal renal function: AUC48 geometric mean ratio (GMR) 0.99 (90% confidence interval [CI] 0.76-1.29); lower moderate renal impairment versus normal renal function: AUC48 GMR 1.01 (90% CI 0.79-1.30); upper moderate renal impairment versus normal renal function: AUC48 GMR 1.09 (90% CI 0.82-1.43)}. A sensitivity analysis that combined the ESRD and severe renal impairment groups did not show notable changes in the AUC48 and Cmax GMRs. The incidences of treatment-emergent adverse events (TEAE) ranged from 42.9 to 72.7% across all groups and were mostly mild to moderate in severity. Only one patient had a grade III or worse TEAE during the study period. No positive antidrug antibody results were observed. CONCLUSIONS: These results suggest that the PK and tolerability of cotadutide are unaffected by renal function and that dose adjustments may not be required in individuals with renal impairment.

Designer GLP1 poly-agonist peptides in the management of diabesity.

INTRODUCTION: To date, the 21st Century has witnessed key developments in the management of diabesity (a conflation of obesity and Type 2 Diabetes Mellitus [T2D]), including Glucagon Like Peptide 1 (GLP1) receptor agonist therapies, and recently the 'designer' GLP1 Poly-agonist Peptides (GLP1PPs). AREAS COVERED: A PubMed search of published data on the GLP1PP class of therapies was conducted. The gut-brain axis forms complex multi-directional interlinks that include autonomic nervous signaling, components of the gut microbiota (including metabolic by-products and gram-negative cell wall components [e.g. endotoxinaemia]), and incretin hormones that are secreted from the gut in response to the ingestion of nutrients. The development of dual-incretin agonist therapies includes combinations of the GLP1 peptide with Glucose-dependent Insulinotropic Polypeptide (GIP), Glucagon (Gcg), Cholecystokinin (CCK), Peptide YY (PYY), and Glucagon-Like Peptide 2 (GLP2). Triple incretin agonist therapies are also under development. EXPERT OPINION: At the dawn of a new era in the therapeutic management of diabesity, the designer GLP1PP class holds great promise, with each novel combination building on a preexisting palimpsest of clinical data and insights. Future innovations of the GLP1PP class will likely enable medically induced weight loss and glycemic control in diabesity to rival or even out-perform those resulting from bariatric surgery.