Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes

Cristina B. Guzman, Xiaotian M. Zhang, Rong Liu, Arie Regev, Sudha Shankar, Parag Garhyan, Sreekumar G. Pillai, Christof Kazda, Naga Chalasani, Thomas A. Hardy

Research output: Contribution to journalArticle

41 Scopus citations

Abstract

Aims: To evaluate whether treatment with LY2409021, a novel, selective glucagon receptor antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit-risk profile for chronic use in patients with type 2 diabetes (T2D). Methods: Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20mg (n=65), placebo (n=68), or sitagliptin 100mg (n=41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c). Results: A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P<.001) and placebo (4.44%; P<.001), accompanied by significant elevations in alanine aminotransferase levels with LY2409021 vs sitagliptin (6.8U/L; P=.039) and vs placebo (10.7U/L; P<.001). No patients had concomitant elevations in bilirubin levels. LY2409021 treatment showed significant HbA1c reductions vs placebo (LS mean difference -0.77%; P<.001) but not sitagliptin (-0.20%; P=.383). Similar results were observed for fasting plasma glucose. LY2409021 was also associated with significant increases in systolic blood pressure vs sitagliptin (4.9mm Hg; P=.030) and vs placebo (4.3mm Hg; P=.029), as well as significant increases in body weight and total cholesterol. All effects of LY2409021 were reversible. Conclusion: In this cohort of patients with T2D, chronic glucagon receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.

Original languageEnglish (US)
JournalDiabetes, Obesity and Metabolism
DOIs
StateAccepted/In press - 2017

Keywords

  • Fatty liver
  • Glucagon antagonist
  • Randomized trial
  • Type 2 diabetes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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    Guzman, C. B., Zhang, X. M., Liu, R., Regev, A., Shankar, S., Garhyan, P., Pillai, S. G., Kazda, C., Chalasani, N., & Hardy, T. A. (Accepted/In press). Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes, Obesity and Metabolism. https://doi.org/10.1111/dom.12958