Evaluation of efficacy and safety of the glucagon receptor antagonist LY2409021 in patients with type 2 diabetes: 12-and 24-week phase 2 studies

Diabetes Care

Volumn 39, Issue 7, 2016, Pages 1241-1249

  Kazda, Christof M ^a   Ding, Ying ^a   Kelly, Ronan P ^b   Garhyan, Parag ^a   Shi, Chunxue ^c   Lim, Chay Ngee ^a   Fu, Haoda ^a   Watson, David E ^a   Lewin, Andrew J ^d   Landschulz, William H ^a   Deeg, Mark A ^a   Moller, David E ^a   Hardy, Thomas A ^a  

^a ELI LILLY AND COMPANY   (United States)

^b NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

^c SYNEOS HEALTH   (United States)

^d NATIONAL RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADOMEGLIVANT; ALANINE AMINOTRANSFERASE; ALKALINE PHOSPHATASE; ASPARTATE AMINOTRANSFERASE; BILIRUBIN; GAMMA GLUTAMYLTRANSFERASE; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; GLUCOSE; HEMOGLOBIN A1C; INSULIN; METFORMIN; PLACEBO; AMINOTRANSFERASE; ANTIDIABETIC AGENT; BIPHENYL DERIVATIVE; GLUCAGON RECEPTOR; GLUCOSE BLOOD LEVEL; GLYCOSYLATED HEMOGLOBIN; HEMOGLOBIN A1C PROTEIN, HUMAN;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; ATRIAL FIBRILLATION; BILIRUBIN BLOOD LEVEL; CELLULITIS; CONFERENCE PAPER; CONTROLLED STUDY; DISEASE SEVERITY; DOUBLE BLIND PROCEDURE; DRUG EFFICACY; DRUG SAFETY; DRUG TOLERABILITY; FEMALE; GAMMA GLUTAMYL TRANSFERASE BLOOD LEVEL; GLUCAGON BLOOD LEVEL; GLYCEMIC CONTROL; HEADACHE; HUMAN; HYPERTRANSAMINASEMIA; HYPOGLYCEMIA; INCIDENCE; INSULIN BLOOD LEVEL; MAJOR CLINICAL STUDY; MALE; MULTICENTER STUDY; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; PHASE 2 CLINICAL TRIAL; PROTEIN BLOOD LEVEL; RANDOMIZED CONTROLLED TRIAL; SINGLE BLIND PROCEDURE; TREATMENT WITHDRAWAL; ANTAGONISTS AND INHIBITORS; BLOOD; CLINICAL TRIAL; DIABETES MELLITUS, TYPE 2; GLUCOSE BLOOD LEVEL; METABOLISM; MIDDLE AGED; YOUNG ADULT;

ADULT; AGED; BIPHENYL COMPOUNDS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 2; DOUBLE-BLIND METHOD; FEMALE; GLUCAGON-LIKE PEPTIDE 1; HEMOGLOBIN A, GLYCOSYLATED; HUMANS; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; MALE; MIDDLE AGED; RECEPTORS, GLUCAGON; TRANSAMINASES; YOUNG ADULT;

EID: 84975815650     PISSN: 01495992     EISSN: 19355548     Source Type: Journal    
DOI: 10.2337/dc15-1643     Document Type: Conference Paper

References (37)

1. Woerle HJ, Szoke E, Meyer C, et al. Mechanisms for abnormal postprandial glucose metabolism in type 2 diabetes. Am J Physiol Endocrinol Metab 2006;290:E67-E77
2. Sloop KW, Michael MD, Moyers JS. Glucagon as a target for the treatment of type 2 diabetes. Expert Opin Ther Targets 2005;9:593-600
3. Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 2012; 122:4-12
4. Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. Abnormal alpha-cell function in diabetes. Response to carbohydrate and protein ingestion. N Engl J Med 1970;283:109-115
5. Hollander PM, Asplin CM, Palmer JP. Glucose modulation of insulin and glucagon secretion in nondiabetic and diabetic man. Diabetes 1982; 31:489-495
6. Ward WK, Best JD, Halter JB, Porte D Jr. Prolonged infusion of somatostatin with glucagon replacement increases plasma glucose and glucose turnover in man. J Clin Endocrinol Metab 1984;58:449-453
7. Dunning BE, Gerich JE. The role of alpha-cell dysregulation in fasting and postprandial hyper-glycemia in type 2 diabetes and therapeutic implications. Endocr Rev 2007;28:253-283
8. Gastaldelli A, Baldi S, Pettiti M, et al. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 2000;49:1367-1373
9. Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 2000;85:4053-4059
10. Bagger JI, Knop FK, Holst JJ, Vilsbøll T. Glu-cagon antagonism as a potential therapeutic target in type 2 diabetes. Diabetes Obes Metab 2011;13:965-971
11. Tham LS, Abu-Raddad EJ, Lim CN. The glu-cagon receptor antagonist LY2409021 attenuates increases in hepatic glucose output (HGO) and blood glucose during hyperglucagonemia in healthy male patients (Abstract 416-PP). Diabetes 2011;60(Suppl. 1):A115
12. Kelly RP, Garhyan P, Raddad E, et al. Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes. Diabetes Obes Metab 2015;17:414-422
13. Kelly RP, Garhyan P, Reynolds VL, et al. Glucagon receptor antibody LY2786890 reduced glucose levels in type 2 diabetes mellitus patients (Abstract 106-LB). Diabetes 2015;64(Suppl. 1A):LB27
14. Engel SS, Xu L, Andryuk PJ, et al. Efficacy and tolerability of MK-0893, a glucagon receptor antagonist (GRA), in patients with type 2 diabetes (T2DM) (Abstract 309-OR). Diabetes 2011;60 (Suppl. 1):A85
15. Ruddy M, Pramanik B, Lunceford J, et al. Inhibition of glucagon-induced hyperglycemia predicts glucose lowering efficacy of a glucagon receptor antagonist, MK-0893, in type 2 diabetes (T2DM) (Abstract 311-OR). Diabetes 2011; 60(Suppl. 1):A85-A86
16. Kazierad DJ, Bergman A, Tan B, Somayaji V, Lee DS, Rolph T. Pharmacokinetics (PK) and pharmacodynamics (PD) of PF-06291874 (PF), a glucagon receptor antagonist, in subjects with T2DM (Abstract 1202-P). Diabetes 2015; 64(Suppl. 1):A310-A311
17. Vajda EG, Logan D, Lasseter K, et al. Phar-macokinetics and pharmacodynamics of the glucagon receptor antagonist LGD-6972 in a multi-dose clinical trial (Abstract 1193-P). Diabetes 2015;64(Suppl. 1):A308
18. Morgan E, Smith A, Watts L, et al. ISIS-GCGRRX, an antisense glucagon receptor antagonist, caused rapid, robust, and sustained improvements in gly-cemic control without changes in BW, BP, lipids, or hypoglycemia in T2DM patients on stable metfor-min therapy (Abstract 109-LB). Diabetes 2014; 63(Suppl. 1A):LB28
19. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998;15:539-553
20. Sloan JH, Siegel RW, Ivanova-Cox YT, Watson DE, Deeg MA, Konrad RJ. A novel high-sensitivity electrochemiluminescence (ECL) sandwich immunoassay for the specific quantitative measurement of plasma glucagon. Clin Biochem 2012;45:1640-1644
21. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003;26(Suppl. 1):S5-S20
22. Petersen KF, Sullivan JT. Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 2001;44:2018-2024
23. Baron AD, Schaeffer L, Shragg P, Kolterman OG. Role of hyperglucagonemia in maintenance of increased rates of hepatic glucose output in type II diabetics. Diabetes 1987;36: 274-283
24. Whalley NM, Pritchard LE, Smith DM, White A. Processing of proglucagon to GLP-1 in pancreatic a-cells: is this a paracrine mechanism enabling GLP-1 to act on b-cells? J Endocrinol 2011;211:99-106
25. Longuet C, Robledo AM, Dean ED, et al. Liver-specific disruption of the murine glucagon receptor produces a-cell hyperplasia: evidence for a circulating a-cell growth factor. Diabetes 2013;62:1196-1205
26. Ali S, Lamont BJ, Charron MJ, Drucker DJ. Dual elimination of the glucagon and GLP-1 receptors in mice reveals plasticity in the incretin axis. J Clin Invest 2011;121:1917-1929
27. Gu W, Winters KA, Motani AS, et al. Gluca-gon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor. Am J Physiol Endocrinol Metab 2010;299:E624-E632
28. Lefèbvre PJ, Paquot N, Scheen AJ. Inhibiting or antagonizing glucagon: making progress in diabetes care. Diabetes Obes Metab 2015;17: 720-725
29. Gelling RW, Du XQ, Dichmann DS, et al. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci USA 2003;100:1438-1443
30. Yu R, Dhall D, Nissen NN, Zhou C, Ren SG. Pancreatic neuroendocrine tumors in glucagon receptor-deficient mice. PLoS One 2011;6: e23397
31. Eli Lilly and Company. A study of LY2409021 on blood pressure and pulse rate in participants with type 2 diabetes mellitus. In: ClinicalTrials.gov [Internet]. Bethesda, MD, National Library of Medicine, 2014. Available from http://clinicaltrials.gov/show/NCT02091362 NLM Identifier NCT02091362. Accessed 17 March 2016
32. Sinclair EM, Yusta B, Streutker C, et al. Glu-cagon receptor signaling is essential for control of murine hepatocyte survival. Gastroenterol-ogy 2008;135:2096-2106
33. Conarello SL, Jiang G, Mu J, et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 2007;50:142-150
34. Eli Lilly and Company. A phase 2, double-blind, placebo-controlled trial to evaluate the safety and efficacy of LY2409021 compared to sitagliptin in subjects with type 2 diabetes mel-litus. In: ClinicalTrials.gov [Internet]. Bethesda, MD, National Library of Medicine, 2014. Available from http://clinicaltrials.gov/show/NCT02111096 NLM Identifier NCT00004451. Accessed 12 January 2016
35. Liang Y, Osborne MC, Monia BP, et al. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes 2004;53: 410-417
36. Hancock AS, Du A, Liu J, Miller M, May CL. Glu-cagon deficiency reduces hepatic glucose production and improves glucose tolerance in adult mice. Mol Endocrinol 2010;24:1605-1614
37. Sloop KW, Cao JX, Siesky AM, et al. Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligo-nucleotide inhibitors. J Clin Invest 2004;113: 1571-1581