LY3437943, a novel triple GIP, GLP-1, and glucagon receptor agonist in people with type 2 diabetes: a phase 1b, multicentre, double-blind, placebo-controlled, randomised, multiple-ascending dose trial
Treating hyperglycaemia and obesity in individuals with type 2 diabetes using multi-receptor agonists can improve short-term and long-term outcomes. LY3437943 is a single peptide with agonist activity for glucagon, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) receptors that is currently in development for the treatment of type 2 diabetes and for the treatment of obesity and associated comorbidities. We investigated the safety, pharmacokinetics, and pharmacodynamics of multiple weekly doses of LY3437943 in people with type 2 diabetes in a 12-week study.
Methods
In this phase 1b, proof-of-concept, double-blind, placebo-controlled, randomised, multiple-ascending dose trial, adults (aged 20–70 years) with type 2 diabetes for at least 3 months, a glycated haemoglobin A1c (HbA1c) value of 7·0–10·5%, body-mass index of 23–50 kg/m2, and stable bodyweight (<5% change in previous 3 months) were recruited at four centres in the USA. Using an interactive web-response system, participants were randomly assigned to receive once-weekly subcutaneous injections of LY3437943, placebo, or dulaglutide 1·5 mg over a 12-week period. Five ascending dose cohorts were studied, with randomisation in each cohort such that a minimum of nine participants received LY3437943, three received placebo, and one received dulaglutide 1·5 mg within each cohort. The top doses in the two highest dose cohorts were attained via stepwise dose escalations. The primary outcome was to investigate the safety and tolerability of LY3437943, and characterising the pharmacodynamics and pharmacokinetics were secondary outcomes. Safety was analysed in all participants who received at least one dose of study drug, and pharmacodynamics and pharmacokinetics in all participants who received at least one dose of study drug and had evaluable data. This trial is registered at ClinicalTrials.gov, NCT04143802.
Findings
Between Dec 18, 2019, and Dec 28, 2020, 210 people were screened, of whom 72 were enrolled, received at least one dose of study drug, and were included in safety analyses. 15 participants had placebo, five had dulaglutide 1·5 mg and, for LY3437943, nine had 0·5 mg, nine had 1·5 mg, 11 had 3 mg, 11 had 3/6 mg, and 12 had 3/6/9/12 mg. 29 participants discontinued the study prematurely. Treatment-emergent adverse events were reported by 33 (63%), three (60%), and eight (54%) participants who received LY3437943, dulaglutide 1·5 mg, and placebo, respectively, with gastrointestinal disorders being the most frequently reported treatment-emergent adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life was approximately 6 days. At week 12, placebo-adjusted mean daily plasma glucose significantly decreased from baseline at the three highest dose LY3437943 groups (least-squares mean difference –2·8 mmol/L [90% CI –4·63 to –0·94] for 3 mg; –3·1 mmol/L [–4·91 to –1·22] for 3/6 mg; and –2·9 mmol/L [–4·70 to –1·01] for 3/6/9/12 mg). Placebo-adjusted sHbA1c also decreased significantly in the three highest dose groups (–1·4% [90% CI –2·17 to –0·56] for 3 mg; –1·6% [–2·37 to –0·75] for 3/6 mg; and –1·2% [–2·05 to –0·45] for 3/6/9/12 mg). Placebo-adjusted bodyweight reduction with LY3437943 appeared to be dose dependent (up to –8·96 kg [90% CI –11·16 to –6·75] in the 3/6/9/12 mg group).
Interpretation
In this early phase study, LY3437943 showed an acceptable safety profile, and its pharmacokinetics suggest suitability for once-weekly dosing. This finding, together with the pharmacodynamic findings of robust reductions in glucose and bodyweight, provides support for phase 2 development.
Funding
Eli Lilly and Company.
Introduction
Weight management in treatment of type 2 diabetes is an accepted component of any treatment regimen in individuals with overweight and obesity. Bodyweight reduction can improve insulin sensitivity and metabolic abnormalities associated with this disease, as well as non-metabolic cardiovascular risk factors.1 When weight loss is a desired treatment goal, select treatments for type 2 diabetes, such as incretins or sodium-glucose cotransporter-2 inhibitors, promote bodyweight reduction and are preferred therapeutic options.2 However, the magnitude of weight loss with these agents is generally modest and pharmacological agents with greater efficacy are needed. Metabolic surgery has well established benefits for people with type 2 diabetes and a high body-mass index (BMI; ≥35 kg/m2), often leading to remission of diabetes and amelioration of many comorbidities associated with obesity.3 Although studies of people after bariatric surgery provide robust evidence for the benefits of substantial weight loss on metabolic disorders, high short-term costs, low patient acceptance, and scalability limit the widespread application of bariatric surgery as a means to reduce the public health impact of obesity.1
Research in context
Evidence before this study
We searched PubMed on Jun 17, 2022, using the terms “glucagon-like peptide-1 receptor agonist”, “GLP-1”, “glucose-dependent insulinotropic polypeptide”, “GIP”, “glucagon” “type 2 diabetes”, “obesity”, “acute bodyweight management”, and “chronic bodyweight management”. English language was the only search restriction. Reference lists of relevant studies were also searched. Our search highlighted that, although there is a rich database for glucagon-like peptide 1 (GLP-1) receptor agonists, there is no evidence for the chronic human use of glucose-dependent insulinotropic polypeptide (GIP) or glucagon receptor agonists as a monotherapy, due to the unavailability of those agonists in clinical practice. In recent years, more clinical data have become available for dual GIP and GLP-1 and GLP-1 and glucagon receptor agonists, indicating that such agonists enable superior management of type 2 diabetes or bodyweight compared with single agents, such as GLP-1 receptor agonists. Previously, we and others reported through preclinical and single-dose clinical evidence that a triple GIP, GLP-1, and glucagon receptor agonist was safe and improved overall metabolic health. The preclinical evidence suggests that a triple GIP, GLP-1, and glucagon receptor agonist can improve lipid metabolism control and provide bodyweight management via increased energy expenditure.
Added value of this study
We report for the first time safety and pharmacodynamic findings with multiple doses of the triple GIP, GLP-1, and glucagon receptor agonist LY3437943 during a 12-week treatment period in people with type 2 diabetes. In this phase 1b, multiple-ascending dose clinical study, safety data indicated that LY3437943 was well tolerated, with the most common adverse events being mild and transient gastrointestinal adverse events. The pharmacokinetics of LY3437943 were dose proportional and its half-life supports once-weekly dosing. Glycated haemoglobin A1c and daily plasma glucose data showed significant improvements in glycaemic control. LY3437943 also showed strong bodyweight-lowering effects that might surpass the efficacy of currently available pharmacological agents approved for treatment of obesity.
Implications of all the available evidence
These multiple-ascending dose study findings motivated us to explore the efficacy of LY3437943 in people with type 2 diabetes (NCT04867785) and with obesity (NCT04881760) in phase 2 clinical trials. The outcomes of these studies will help to determine further clinical explorations in phase 3 trials.
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones essential for typical control of nutrient metabolism. GLP-1 receptor agonists reduce food intake, delay gastric emptying, increase meal-stimulated insulin secretion, and inhibit glucagon secretion in hyperglycaemic or euglycaemic states.4 Short-acting and long-acting GLP-1 receptor agonists can improve glycaemic control and reduce bodyweight in people with type 2 diabetes.1, 2 GIP also enhances meal-stimulated insulin secretion4 and facilitates lipid clearance.5 GIP differs from GLP-1 by stimulating glucagon secretion during fasting and hypoglycaemia.4, 6 The unimolecular GIP and GLP-1 receptor agonist tirzepatide (Mounjaro; Eli Lilly and Company, Indianapolis, IN, USA), which was approved by the US Food and Drug Administration on May 13, 2022, causes significant and clinically meaningful reductions in glycated haemoglobin A1c (HbA1c) and bodyweight, as well as improvements in cardiovascular risk factors, such as blood pressure and lipid profile.7, 8 These improvements were of a significantly greater magnitude with tirzepatide than with the selective GLP-1 receptor agonist semaglutide 1 mg, indicating potential benefit of targeting more than one incretin receptor.8
Glucagon, a peptide hormone produced by pancreatic α cells, has a well established role in glucose metabolism by increasing hepatic glucose output between meals.9 Glucagon can also reduce appetite and increase energy expenditure to reduce bodyweight, reduce gastrointestinal motility, enhance hepatic fatty acid oxidation and lipolysis, and stimulate insulin secretion in hyperglycaemic states.9, 10, 11, 12 Postprandially, glucagon modulates amino acid metabolism and, together with GLP-1 and GIP, mediates proper disposal of nutrient substrates in response to meals.9, 13 Thus, the actions of glucagon, in combination with those of GIP and GLP-1, might have novel metabolic benefits, such as increased energy expenditure and metabolic flexibility, offering a potential new therapeutic approach for people with type 2 diabetes and overweight or obesity. Early preclinical data suggest the potential efficacy of glucagon and GLP-1 co-agonists in bodyweight lowering in rodents.14 Given their distinct effects, an agonist targeting GLP-1, GIP, and glucagon might provide enhanced glycaemic control and weight loss relative to agonists targeting one or two receptors.15, 16, 17 Additionally, the effects of glucagon in the liver and kidney are of interest in individuals with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis and chronic kidney disease, respectively.18, 19
LY3437943 is a 39 amino acid single peptide conjugated to a C20 fatty diacid moiety that possesses agonist activity at the glucagon, GIP, and GLP-1 receptors. LY3437943 is less potent at the human glucagon and GLP-1 receptors compared with native glucagon and GLP-1, and more potent at human GIP compared with native GIP and exhibits an extended pharmacokinetic half-life while providing desired pharmacological properties.17 In mice, LY3437943 promotes bodyweight loss, with glucagon receptor agonism contributing to an increase in energy expenditure while GIP and GLP-1 contribute to reduced food intake.17 In a single-ascending dose study in healthy participants, LY3437943 was well tolerated and showed pronounced effects on weight loss and appetite regulation, albeit within the typical confines of a first-in-human study.17
In this multiple-ascending dose study, we aimed to assess the safety, pharmacokinetics, and pharmacodynamics of LY3437943 in people with type 2 diabetes.
Section snippets
Study design and participants
This phase 1b, double-blind, placebo-controlled, randomised, multiple-ascending dose study was conducted at four centres in the USA. Ethical approval was obtained from Midlands Independent Review Board (KS, USA) and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol is available in the appendix (p 9).
Adults aged 20–70 years with type 2 diabetes for at least 3 months before screening, HbA1c level of 7·0–10·5% at lead-in and
Results
Between Dec 18, 2019 (first patient, first visit), and Dec 28, 2020 (last patient, last visit), 210 people were screened, of whom 72 were enrolled and received at least one dose of study drug (figure 1). Of these enrolled participants, 43 (60%) completed the study. The most common reason for study discontinuation (21 participants) was a medical decision related to COVID-19 by a participant's physician. Discontinuation due to COVID-19 pandemic restrictions largely affected cohorts one and two:
Discussion
The findings from this multiple-ascending dose, phase 1 clinical trial provide initial evidence of the safety and efficacy of the triple GLP-1, GIP, and glucagon receptor agonist LY3437943 in participants with type 2 diabetes. LY3437943 showed a safety profile that is consistent with the safety profile reported with other incretin-based therapeutic agents in early phases of development. The findings suggest that simultaneous agonism on these three receptors is a therapeutic approach that has
Data sharing
Eli Lilly provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the USA and in the EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review
Declaration of interests
SU, TC, MTL, YD, SG, AH, CTB, and ZM are employees and shareholders of Eli Lilly and Company. MKT is an employee and shareholder of Eli Lilly and Company, and reports being industry chair of a steering committee on Accelerating Medicines Partnership-Type 2 Diabetes, and a steering committee member on Accelerating Medicines Partnership-Common Metabolic Diseases. DAD reports research grants and advisory fees from Eli Lilly and Company; research grants from Merck; consulting fees from Intarcia and
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L’histoire du « facteur hyperglycémique » pancréatique a débuté il y a un siècle. Baptisé d’emblée « glucagon » par Murlin, sa découverte a été suivie d’une longue période de silence. Sa caractérisation – origine dans les cellules α des îlots de Langerhans, cristallisation, structure, séquençage et mise au point d’un dosage radio-immunologique par Unger en 1959 – a permis une approche globale des effets du glucagon par l’intermédiaire d’un récepteur spécifique. Trois futurs lauréats du prix Nobel ont été activement impliqués pour comprendre les mécanismes d’action de la seconde hormone pancréatique. Le glucagon est l’hormone d’adaptation au jeûne et aux privations, et est impliqué dans la contre-régulation glycémique. Considéré comme une hormone anti-insuline, le glucagon a rapidement été utilisé pour traiter l’hypoglycémie induite par l’insuline dans le diabète de type 1. La découverte du rôle du glucagon dans la physiopathologie du diabète de type 2 (DT2) a été une étape clé de son histoire. À présent, différentes stratégies ciblant le glucagon, parmi lesquelles les agonistes des récepteurs du GLP-1 ou des récepteurs du glucagon, s’avèrent prometteuses pour traiter le DT2. Par ailleurs, des co-agonistes multiples des récepteurs des incrétines et du glucagon sont en passe d’être développés pour faciliter la perte de poids dans le DT2 et l’obésité en raison de leurs effets sur le métabolisme énergétique.
The story of pancreatic “hyperglycemic factor” began a century ago. Immediately named “glucagon” by Murlin, its discovery was followed by a long period of silence. Its characterization – origin in α cells, islets of Langerhans, crystallization, structure, sequencing and development of a radioimmunoassay by Unger in 1959 – allowed a global approach to the effects of glucagon via a specific receptor. Three future Nobel laureates were actively involved in understanding the mechanisms of action of the second pancreatic hormone. Glucagon is the hormone of adaptation to fasting and deprivation and is involved in glycemic counterregulation. Considered as an anti-insulin hormone, glucagon was soon used to treat insulin-induced hypoglycemia in type 1 diabetes. The discovery of glucagon's role in the pathophysiology of type 2 diabetes (T2D) was a key milestone in its history. Currently, different strategies targeting glucagon, including GLP-1 receptor agonists or glucagon receptor agonists, are showing promise for treating T2D. In addition, multiple co-agonists of incretin and glucagon receptors are being developed to facilitate weight loss in T2D and obesity, because of their effects on energy metabolism.
Tirzepatide, a once-weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial.
Tirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of MACE. The primary analysis is noninferiority for time to first MACE of tirzepatide vs dulaglutide by demonstrating an upper confidence limit <1.05, which will also confirm superiority vs a putative placebo, and also to determine whether tirzepatide produces a greater CV benefit than dulaglutide (superiority analysis).
Over 2 years, 13,299 people at 640 sites in 30 countries across all world regions were randomized. The mean age of randomized participants at baseline was 64.1 years, diabetes duration 14.7 years, HbA1c 8.4%, and BMI 32.6 kg/m2. Overall, 65.0% had coronary disease, of whom 47.3% reported prior myocardial infarction and 57.4% had prior coronary revascularization. 19.1% of participants had a prior stroke and 25.3% had peripheral artery disease. The trial is fully recruited and ongoing.
SURPASS-CVOT will provide definitive evidence as to the CV safety and efficacy of tirzepatide as compared with dulaglutide, a GLP-1 receptor agonist with established CV benefit.
Glucagon-like peptide-1 receptor agonists (GLP1RA) are incretin agents initially designed for the treatment of type 2 diabetes mellitus but because of pleiotropic actions are now used to reduce cardiovascular disease in people with type 2 diabetes mellitus and in some instances as approved treatments for obesity. In this review we highlight the biology and pharmacology of GLP1RA. We review the evidence for clinical benefit on major adverse cardiovascular outcomes in addition to modulation of cardiometabolic risk factors including reductions in weight, blood pressure, improvement in lipid profiles, and effects on kidney function. Guidance is provided on indications and potential adverse effects to consider. Finally, we describe the evolving landscape of GLP1RA and including novel glucagon-like peptide-1-based dual/polyagonist therapies that are being evaluated for weight loss, type 2 diabetes mellitus, and cardiorenal benefit.
Les agonistes du récepteur du GLP-1 (de l’anglais glucagon-like peptide-1) (ARGLP-1) sont des incrétines conçues initialement pour le traitement du diabète de type 2, mais en raison des effets pléiotropiques, ils sont maintenant utilisés pour prévenir les maladies cardiovasculaires chez les personnes atteintes du diabète de type 2 et, dans certains cas, ils sont approuvés dans le traitement de l’obésité. Dans la présente revue, nous vous parlons de la biologie et de la pharmacologie des ARGLP-1. Nous passons en revue les données probantes concernant les bénéfices cliniques sur les événements cardiovasculaires indésirables majeurs en plus de la modulation des facteurs de risque cardiométabolique dont les réductions du poids et de la pression artérielle, l’amélioration des bilans lipidiques et les effets sur la fonction rénale. Des conseils sur les indications et les effets indésirables potentiels à considérer sont fournis. Finalement, nous décrivons le paysage en constante évolution des ARGLP-1 et incluons les nouvelles bithérapies et thérapies polyagonistes du récepteur du GLP-1 en cours d’évaluation pour la perte de poids, le diabète de type 2 et les bénéfices cardiorénaux.
Obesity and its comorbidities, including type 2 diabetes mellitus, cardiovascular disease, heart failure and non-alcoholic liver disease are a major health and economic burden with steadily increasing numbers worldwide. The need for effective pharmacological treatment options is strong, but, until recently, only few drugs have proven sufficient efficacy and safety. This article provides a comprehensive overview of obesity and its comorbidities, with a special focus on organ-specific pathomechanisms. Bariatric surgery as the so far most-effective therapeutic strategy, current pharmacological treatment options and future treatment strategies will be discussed. An increasing knowledge about the gut-brain axis and especially the identification and physiology of incretins unfolds a high number of potential drug candidates with impressive weight-reducing potential. Future multi-modal therapeutic concepts in obesity treatment may surpass the effectivity of bariatric surgery not only with regard to weight loss, but also to associated comorbidities.