Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes.
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.
['Guzman|Cristina B|CB|', 'Zhang|Xiaotian M|XM|', 'Liu|Rong|R|', 'Regev|Arie|A|', 'Shankar|Sudha|S|', 'Garhyan|Parag|P|', 'Pillai|Sreekumar G|SG|0000-0001-7385-4953', 'Kazda|Christof|C|', 'Chalasani|Naga|N|', 'Hardy|Thomas A|TA|']
D000328:Adult D000368:Aged D001713:Biphenyl Compounds D003924:Diabetes Mellitus, Type 2 D005234:Fatty Liver D005260:Female D006801:Humans D007003:Hypoglycemia D050356:Lipid Metabolism D008099:Liver D008297:Male D008875:Middle Aged D018027:Receptors, Glucagon
type 2 diabetes fatty liver glucagon antagonist randomized trial