Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials.
BACKGROUND
Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA(1c)) and weight in 30-week placebo-controlled trials. Some patients were followed up in open-label extensions to provide 'real-world' exenatide clinical experience.


OBJECTIVE
The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM.


METHODS
For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-microg exenatide, 10-microg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials.


RESULTS
A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean [SD] age, 57 [10] years; mean [SD] weight, 100[19] kg; sex, 63% male; mean [SD] body mass index, 34 [6] kg/m(2); mean [SD] HbA(1c), 8.3% [1.0%]) completed 2 years of exenatide treatment. Reductions in mean (SE) HbA(1c) from baseline to week 30 (-0.9% [0.1%]) were sustained through 2 years (-1.1% [0.1%]; P < 0.05 vs baseline), with 50% of the population achieving HbA(1c) < or = 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (-2.1 [0.2] kg), with progressive reductions after 2 years (-4.7 [0.3] kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 [47%]; normal: female < or =19 IU/L; male < or =30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 [53%]) had a mean (SEM) reduction of ALT (-11 [1] IU/L from baseline 38 [1] IU/1; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline (P = 0.04). However, weight change was minimally correlated with baseline ALT (r = -0.09) or ALT change (r = 0.31). Also, homeostasis model assessment of the beta-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea.


CONCLUSIONS
In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA(1c), progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.
Buse
John B
JB
Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.
Klonoff
David C
DC
Nielsen
Loretta L
LL
Guan
Xuesong
X
Bowlus
Christopher L
CL
Holcombe
John H
JH
Maggs
David G
DG
Wintle
Matthew E
ME
D000368:Aged; D000410:Alanine Transaminase / Q000187:drug effects / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000187:drug effects / Q000378:metabolism; D015415:Biomarkers; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D000077270:Exenatide; D005260:Female; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D008111:Liver Function Tests; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D009765:Obesity / Q000188:drug therapy; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D014688:Venoms / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015431:Weight Loss / Q000187:drug effects
D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D015415:Biomarkers; D000077270:Exenatide; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D010455:Peptides; D013453:Sulfonylurea Compounds; D014688:Venoms