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

31 Citations (Scopus)

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

Fingerprint

Glucagon Receptors
Type 2 Diabetes Mellitus
Fats
Liver
Placebos
Therapeutics
Blood Pressure
Transaminases
Least-Squares Analysis
Glucose
Fasting
Safety
Metformin
Glycosylated Hemoglobin A
Alanine Transaminase
Bilirubin
Cholesterol
Body Weight
Magnetic Resonance Imaging
Sitagliptin Phosphate

Keywords

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

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

Guzman, C. B., Zhang, X. M., Liu, R., Regev, A., Shankar, S., Garhyan, P., ... 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

Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. / Guzman, Cristina B.; Zhang, Xiaotian M.; Liu, Rong; Regev, Arie; Shankar, Sudha; Garhyan, Parag; Pillai, Sreekumar G.; Kazda, Christof; Chalasani, Naga; Hardy, Thomas A.

In: Diabetes, Obesity and Metabolism, 2017.

Research output: Contribution to journalArticle

Guzman, Cristina B. ; Zhang, Xiaotian M. ; Liu, Rong ; Regev, Arie ; Shankar, Sudha ; Garhyan, Parag ; Pillai, Sreekumar G. ; Kazda, Christof ; Chalasani, Naga ; Hardy, Thomas A. / Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. In: Diabetes, Obesity and Metabolism. 2017.
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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.",
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T1 - Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes

AU - Guzman, Cristina B.

AU - Zhang, Xiaotian M.

AU - Liu, Rong

AU - Regev, Arie

AU - Shankar, Sudha

AU - Garhyan, Parag

AU - Pillai, Sreekumar G.

AU - Kazda, Christof

AU - Chalasani, Naga

AU - Hardy, Thomas A.

PY - 2017

Y1 - 2017

N2 - 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.

AB - 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.

KW - Fatty liver

KW - Glucagon antagonist

KW - Randomized trial

KW - Type 2 diabetes

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