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Treatment with LY 2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes
Author(s) -
Guzman Cristina B.,
Zhang Xiaotian M.,
Liu Rong,
Regev Arie,
Shankar Sudha,
Garhyan Parag,
Pillai Sreekumar G.,
Kazda Christof,
Chalasani Naga,
Hardy Thomas A.
Publication year - 2017
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12958
Subject(s) - sitagliptin , medicine , endocrinology , placebo , metformin , glycated hemoglobin , type 2 diabetes , glucagon receptor , blood pressure , lipid profile , glucagon , diabetes mellitus , insulin , alternative medicine , pathology
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 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (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. 8 U / L ; P  = .039) and vs placebo (10.7  U/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 (4.9  mm Hg ; P  = .030) and vs placebo (4.3  mm 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.

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