| Abstract | 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. |
| Authors | John B Buse, David C Klonoff, Loretta L Nielsen, Xuesong Guan, Christopher L Bowlus, John H Holcombe, David G Maggs, Matthew E Wintle
(Affiliation: Division of Endocrinology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA.)
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| Journal | Clinical therapeutics
(Clin Ther)
Vol. 29
Issue 1
Pg. 139-53
(Jan 2007)
ISSN: 0149-2918 United States |
| PMID | 17379054
(Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Biological Markers
- Hemoglobin A, Glycosylated
- Hypoglycemic Agents
- Peptides
- Sulfonylurea Compounds
- Venoms
- exenatide
- Metformin
- Aspartate Aminotransferases
- Alanine Transaminase
|
| Topics |
- Aged
- Alanine Transaminase
(drug effects, metabolism)
- Aspartate Aminotransferases
(drug effects, metabolism)
- Biological Markers
- Blood Pressure
(drug effects)
- Diabetes Mellitus, Type 2
(drug therapy)
- Dose-Response Relationship, Drug
- Double-Blind Method
- Drug Administration Schedule
- Female
- Follow-Up Studies
- Hemoglobin A, Glycosylated
(drug effects)
- Humans
- Hypoglycemic Agents
(administration & dosage, adverse effects, pharmacology)
- Insulin-Secreting Cells
(drug effects)
- Liver Function Tests
- Male
- Metformin
(therapeutic use)
- Middle Aged
- Obesity
(drug therapy)
- Peptides
(administration & dosage, adverse effects, pharmacology)
- Sulfonylurea Compounds
(therapeutic use)
- Venoms
(administration & dosage, adverse effects, pharmacology)
- Weight Loss
(drug effects)
|
