A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes.
OBJECTIVE
To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long-acting glucagen-like peptide-1 analogue, administered once weekly to subjects with type 2 diabetes.


METHODS
This was a placebo-controlled, parallel-group, subject- and investigator-blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once-weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C-peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed.


RESULTS
Once-weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2-h post-test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses ≥1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C-peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events).


CONCLUSIONS
LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent.
Eli Lilly and Company, Erl Wood, Surrey, UK. barringtonph@lilly.com
P
P
Barrington
J Y
JY
Chien
H D H
HD
Showalter
K
K
Schneck
S
S
Cui
F
F
Tibaldi
B
B
Ellis
T A
TA
Hardy
D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005215:Fasting / Q000097:blood; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives*; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D019518:Postprandial Period; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D045162:Thiazolidinediones / Q000627:therapeutic use; D016896:Treatment Outcome
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D045162:Thiazolidinediones; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D008687:Metformin; C555680:dulaglutide