Elsevier

The Lancet

Volume 400, Issue 10366, 26 November–2 December 2022, Pages 1869-1881
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(22)02033-5Get rights and content

Summary

Background

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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