Recombinant glucagon-like peptide-1 (7-36 amide) lowers fasting serum glucose in a broad spectrum of patients with type 2 diabetes.
OBJECTIVE
To evaluate the safety and efficacy of various doses of recombinant glucagon-like peptide-1 (7-36) amide (rGLP-1) administered subcutaneously (s. c.) via bolus injection or continuous infusion to lower fasting serum glucose (FSG) levels in subjects with type 2 diabetes treated by diet, hypoglycemic drugs, or insulin injection.


METHODS
rGLP-1 was administered s. c. to 40 type 2 diabetics currently treated by diet, sulfonylurea (SU), metformin, or insulin in a double-blind, placebo-controlled, cross-over trial; preexisting treatments were continued during the study. In the bolus injection protocol, 32 subjects (8 from each of the 4 treatment groups) received 0.0, 0.5, 1.0, and 1.5 nmol rGLP-1/kg per injection (two injections, two hours apart, beginning one hour after the evening meal) in a randomized order on separate days. In the continuous s. c. infusion protocol, 40 subjects received rGLP-1 at 0.0, 1.5, 2.5, 3.5, and 4.5 pmol/kg/min for 10-12 hours overnight starting one hour after the evening meal. Fasting bloods were taken the morning after for glucose, insulin, and glucagon measurements.


RESULTS
In the diet, SU, and metformin cohorts, bolus rGLP-1 injections produced modest reductions in mean FSG levels, averaging 17.4 mg/dl (7.3-27.5; 95 % CI) at the highest dose (p < 0.001 vs. placebo). Reductions in FSG levels were greater by continuous infusion at up to 30.3 mg/dl (18.8 - 41.8; 95 % CI; p < 0.001 vs. placebo). The greatest reduction in mean FSG occurred in the SU cohort (up to 43.9 mg/dl, 24.7 - 63.1; 95 % CI; p < 0.001). rGLP-1 infusions resulted in significant increases in fasting plasma insulin and decreases in fasting plasma glucagon levels. There were no serious adverse events; GI-related symptoms were dose-related and more commonly associated with injections.


CONCLUSIONS
rGLP-1 (7-36) amide dose-dependently lowered FSG in a broad spectrum of type 2 diabetics when added to their existing treatment. Subcutaneous infusion was more effective than injection, and the combination with SU was more effective than with metformin.
Ehlers
M R
MR
Restoragen, Inc., Lincoln, Nebraska, USA. marioe@pacbio.com
Klaff
L J
LJ
D'Alessio
D A
DA
Brazg
R
R
Kay
H D
HD
Harley
R E
RE
Mathisen
A L
AL
Schneider
R
R
D001786:Blood Glucose / Q000032:analysis*; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005215:Fasting; D005934:Glucagon / Q000097:blood; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage / Q000097:blood; D008687:Metformin / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D010919:Placebos; D011994:Recombinant Proteins / Q000008:administration & dosage; D013453:Sulfonylurea Compounds / Q000008:administration & dosage
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D010919:Placebos; D011994:Recombinant Proteins; D013453:Sulfonylurea Compounds; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin