Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies

IF 6.3 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2026-01-01 Epub Date: 2025-12-12 DOI:10.1016/j.molmet.2025.102298

William Roell, Jorge Alsina-Fernandez, Hongchang Qu, Tamer Coskun, Charles Benson, Axel Haupt, Ronan P. Kelly, Libbey O'Farrell, Kyle W. Sloop, James P. Steele, James Ficorilli, Ajit Regmi, Mallikarjuna Rettiganti, Shweta Urva, Kieren J. Mather, Edward Pratt

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引用次数: 0

Abstract

Background

Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood.

Objectives

To characterize the preclinical and in-human effects of a long-acting GIPR agonist monotherapy in healthy participants and patients with type 2 diabetes (T2D).

Methods

A long-acting GIPR agonist (LY3537021) was characterized in vitro and in Long-Evans diet-induced obese rats and Wistar rats. Next, a phase 1, randomized, placebo-controlled, single ascending dose (SAD)/multiple ascending dose (MAD) study explored the safety, tolerability, pharmacokinetics, and pharmacodynamics of LY3537021 in healthy participants and participants with T2D in Singapore.

Results

In vitro, LY3537021 demonstrated potency greater than native GIP and selectivity for the GIPR. In vivo in rats, chronic treatment with LY3537021 resulted in weight loss and improved glycemic control during a glucose tolerance test. The phase 1 clinical study enrolled 85 healthy participants and patients with T2D (SAD, n = 47 [aged 25–64 years]; MAD, n = 38 [aged 25–69 years]; average baseline BMI was 25.9–27.0 kg/m² across the arms). During the MAD part, dose-dependent decreases in mean body weight were observed in all LY3537021 dose groups, regardless of T2D status, and persisted at 35 days after the last dose. For example, participants with T2D treated with 25 mg of LY3537021 lost a mean of 3.14 kg of body weight compared with 0.36 kg in the placebo group (p < 0.05) at day 57. Transient reductions in fasting glucose were observed in these participants, but the reductions were not sustained and not significantly different from placebo at day 29. The time to maximum observed drug concentrations varied across cohorts (8–96 h), and the half-life was estimated at approximately 12 days for non-T2D and T2D cohorts with the 25-mg dose, supporting once-weekly administration. There was no delay in gastric emptying following a single subcutaneous dose of 0.3–25 mg LY3537021. LY3537021 was well tolerated with infrequent gastrointestinal adverse events.

Conclusions

In vivo studies demonstrated that LY3537021 reduced body weight and improved glycemia during a glucose challenge in rats. The phase 1 study demonstrated that the long-acting GIPR agonist LY3537021 was well tolerated, induced weight loss, and improved glucose control in humans. These observations better define the therapeutic benefit of long-acting GIPR agonists and support a distinct contribution of GIP agonism to the benefits observed with multi-agonist peptides that act via the GIPR. Future studies are needed in more diverse populations and in cohorts with overweight/obesity to confirm these findings.

ClinicalTrials.gov

NCT04586907.

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长效GIPR激动剂LY3537021可降低T2D患者的体重和空腹血糖：临床前开发和1期随机递增剂量研究

背景：tizepatide是一种单分子双葡萄糖依赖性胰岛素性多肽(GIP)/胰高血糖素样肽-1 （GLP-1）受体(R)激动剂，在降低血糖和体重方面具有优于选择性GLP-1R激动剂的优势，但GIP对这些作用的贡献尚未完全了解。目的：研究一种长效GIPR激动剂单药治疗在健康参与者和2型糖尿病（T2D）患者中的临床前和体内效应。方法：对一种长效GIPR激动剂LY3537021进行体外及Long-Evans饮食诱导的肥胖大鼠和Wistar大鼠的实验研究。接下来，在新加坡进行了一项随机、安慰剂对照、单次递增剂量(SAD)/多次递增剂量（MAD）的1期研究，探讨了LY3537021在健康参与者和T2D参与者中的安全性、耐受性、药代动力学和药效学。结果：LY3537021体外效价高于天然GIP，对GIPR具有选择性。在大鼠体内，在葡萄糖耐量试验中，LY3537021慢性治疗导致体重减轻和血糖控制改善。该1期临床研究招募了85名健康参与者和T2D患者（SAD, n=47[25-64岁]；MAD, n=38[25-69岁]；两组平均基线BMI为25.9-27.0 kg/m2）。在MAD部分，所有LY3537021剂量组均观察到平均体重的剂量依赖性下降，无论T2D状态如何，并持续到最后一次给药后35天。例如，接受25毫克LY3537021治疗的T2D参与者平均体重减轻3.14公斤，而安慰剂组平均体重减轻0.36公斤(结论：体内研究表明，LY3537021在大鼠葡萄糖挑战期间降低体重并改善血糖。该i期研究表明，长效GIPR激动剂LY3537021耐受性良好，可诱导体重减轻，并改善人体血糖控制。这些观察结果更好地定义了长效GIPR激动剂的治疗益处，并支持了GIP激动剂对通过GIPR作用的多激动剂肽所观察到的益处的独特贡献。未来的研究需要在更多样化的人群和超重/肥胖人群中进行，以证实这些发现。临床试验：GOV: NCT04586907。

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.