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Aim: To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) in healthy participants. Materials and Methods: This was a double‐blind, placebo‐controlled, Phase 1 study. Overtly healthy adults aged 18 to 65 years with body mass index of 20 to 40 kg/m2 and glycated haemoglobin concentration of 47.5 mmol/mol (<6.5%) were eligible. In Part A, participants received single‐dose orforglipron, with four cohorts receiving escalating doses (0.3‐6 mg). In Part B, participants received 4 weeks of daily repeated oral orforglipron with doses escalating weekly to four different final target doses (2‐24 mg). Results: Ninety‐two participants enrolled and received at least one study drug dose (32 in Part A [mean age 43.4 years] and 60 in Part B [mean age 42.5 years]). The most common adverse events were gastrointestinal tract‐related. Pharmacokinetics were approximately dose proportional, and the mean t1/2 was 24.6 to 35.3 hours after a single dose (0.3‐6 mg). On Day 28, the mean t1/2 was 48.1 to 67.5 hours across the dose range (2‐24 mg). Substantial reductions in body weight of up to 5.4 kg were observed after 4 weeks in orforglipron‐treated participants, compared to a reduction of 2.4 kg with placebo (P < 0.05). Orforglipron decreased fasting glucose levels across Days 1 to 28, and gastric emptying was delayed on Day 28. Conclusions: Orforglipron's long half‐life (25‐68 hours) allows once‐daily oral dosing, without water and food restrictions. Orforglipron had a pharmacodynamic and safety profile similar to that of injectable GLP‐1RAs, which supports continued clinical development. [ABSTRACT FROM AUTHOR]

The novel GIP, GLP-1 and glucagon receptor agonist retatrutide delays gastric emptying Keywords: GIP; GLP-1; glucagon; type 2 diabetes; weight control EN GIP GLP-1 glucagon type 2 diabetes weight control 2784 2788 5 08/03/23 20230901 NES 230901 INTRODUCTION Delayed gastric emptying (GE) is a well-known effect of glucagon-like peptide-1 (GLP-1).[[1]] Similarly, glucagon (GCG) has been shown to slow GE in rodents and humans,[[3]] while glucose-dependent insulinotropic polypeptide (GIP) does not appear to impact GE.[[1]] Retatrutide (LY3437943) is a novel GIP/GLP-1/GCG receptor agonist (RA) under investigation for chronic weight management and its complications. 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. The maximum extent of GE delay observed with retatrutide was similar to that previously noted with tirzepatide.[12] The magnitude of GE inhibition was lower following subsequent retatrutide doses and appeared to be diminishing at Days 30 and 79, despite ongoing dose escalation in the two highest dose retatrutide groups. [Extracted from the article]

Aim: To report the results of a Phase 1b trial evaluating the safety, pharmacokinetics and pharmacodynamics of orforglipron (LY3502970), an oral, non‐peptide glucagon‐like peptide‐1 receptor agonist (GLP‐1RA), in patients with type 2 diabetes (T2D). Materials and Methods: This was a double‐blind, placebo‐controlled Phase 1 study evaluating five different dosing regimens. The first group established that weekly dose escalation of the daily doses of orforglipron was generally well tolerated. This enabled a parallel‐arm design for the four groups following. Participants were randomized 3:1 to daily doses of orforglipron or placebo for 12 weeks. Eligible participants with T2D were aged 18 to 70 years and had glycated haemoglobin (HbA1c) levels ≥53.0 mmol/mol (7.0%) and ≤91.3 mmol/mol (10.5%). Results: A total of 51 participants received orforglipron and 17 received placebo. In the placebo and orforglipron groups, respectively, baseline HbA1c was 8.1% and 8.0%, and baseline body weight was 90.3 and 88.4 kg. The most common adverse events were gastrointestinal‐related, and occurred early in treatment, similar to findings with other GLP‐1RAs. At Week 12, mean t1/2 ranged from 29 to 49 hours. Mean HbA1c change ranged from −1.5% to −1.8% across orforglipron doses, versus −0.4% with placebo, and body weight change was −0.24 to −5.8 kg across orforglipron doses, versus 0.5 kg with placebo. Conclusions: Orforglipron treatment resulted in meaningful reductions in HbA1c and body weight, with an adverse event profile consistent with that of other GLP‐1RAs. Orforglipron may provide a safe and effective once‐daily oral treatment alternative to injectable GLP‐1RAs or peptide oral formulations without water and food restrictions. [ABSTRACT FROM AUTHOR]

In a phase 2 trial of once‐weekly tirzepatide (1, 5, 10, or 15 mg), dulaglutide (1.5 mg), or placebo, the dual glucose‐dependent insulinotropic polypeptide and glucagon‐like peptide‐1 receptor agonist tirzepatide dose‐dependently reduced HbA1c and body weight in patients with type 2 diabetes. In this post hoc analysis, inflammation, endothelial dysfunction, and cellular stress biomarkers were measured at baseline, 4, 12, and 26 weeks to evaluate the additional effects of tirzepatide on cardiovascular risk factors. At 26 weeks, tirzepatide 10 and 15 mg decreased YKL‐40 (also known as chitinase‐3 like‐protein‐1), intercellular adhesion molecule 1 (ICAM‐1), leptin, and growth differentiation factor 15 levels versus baseline, and YKL‐40 and leptin levels versus placebo and dulaglutide. Tirzepatide 15 mg also decreased ICAM‐1 levels versus placebo and dulaglutide, and high‐sensitivity C‐reactive protein (hsCRP) levels versus baseline and placebo, but not dulaglutide. GlycA, interleukin 6, vascular cell adhesion molecule 1, and N‐terminal‐pro hormone B‐type natriuretic peptide levels were not significantly changed in any group. YKL‐40, hsCRP, and ICAM‐1 levels rapidly decreased within 4 weeks of treatment with tirzepatide 10 and 15 mg, whereas the decrease in leptin levels was more gradual and did not plateau by 26 weeks. In this hypothesis‐generating exploratory analysis, tirzepatide decreased several biomarkers that have been associated with cardiovascular risk. [ABSTRACT FROM AUTHOR]

The long‐acting glucagon‐like peptide‐1 receptor agonist dulaglutide acts by stimulating insulin secretion and reducing glucagon levels in a glucose‐dependent manner both in the fasting and postprandial states, resulting in reductions of both fasting glucose (FG) and postprandial glucose (PPG). In contrast, the main mechanism of action of basal insulin is to reduce elevated FG by inhibiting hepatic glucose production. The aim of the present post hoc analysis of the phase 3 AWARD‐2 trial was to investigate whether specific baseline glycaemic patterns respond differentially to dulaglutide compared to insulin glargine (glargine). We categorized participants into four subgroups based on prespecified glucose thresholds and their baseline FG and daily 2‐hour mean PPG: low FG/low PPG; low FG/high PPG; high FG/low PPG; and high FG/high PPG. Changes in glycaemic measures in response to treatment with dulaglutide or glargine were evaluated in each subgroup. At 52 weeks, significant reductions from baseline in glycated haemoglobin (HbA1c) were observed in all subgroups with dulaglutide 1.5 mg and with glargine (all P < .05), except in patients with low FG/low PPG who received glargine. Greater HbA1c reductions were observed with dulaglutide 1.5 mg compared to glargine in all subgroups (all P ≤ .05), except in the low FG/high PPG subgroup. [ABSTRACT FROM AUTHOR]

With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro , LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943. [Display omitted] • LY3437943 has triple agonist activity at the glucagon, GIP, and GLP-1 receptors • LY3437943 caused greater body weight loss in obese mice than tirzepatide • LY3437943 increased energy expenditure through glucagon receptor activation • Safety and tolerability of LY3437943 were similar to other incretin-based drugs Coskun et al. demonstrate that LY3437943, a triple glucagon, GIP, and GLP-1 receptor agonist for the treatment of obesity and type 2 diabetes, can reduce body weight through increased energy expenditure and reduced calorie intake in obese mice. Its safety and tolerability in healthy participants were similar to other incretin-based therapies. [ABSTRACT FROM AUTHOR]

This document summarizes a study on the gastrointestinal side effects of a combination therapy for type 2 diabetes. The study found that when a glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) was used in conjunction with a glucagon-like peptide-1 receptor agonist (GLP-1 RA), there were fewer gastrointestinal adverse events compared to using the GLP-1 RA alone. The study suggests that the GIPRA component of the therapy may improve the tolerability of GLP-1 RA treatment, potentially leading to better effectiveness and adherence. The study acknowledges limitations such as a small number of female participants and limited ethnic diversity. [Extracted from the article]