| Abstract | BACKGROUND: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A(1c) (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of > or = 3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety. METHODS: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5 mug exenatide, or 10 mug exenatide for 30 weeks, followed by 5 mug exenatide BID for 4 weeks, then 10 mug exenatide BID for > or = 3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas. RESULTS: 217 patients (64% male, age 58 +/- 10 years, weight 99 +/- 18 kg, BMI 34 +/- 5 kg/m(2), A1C 8.2 +/- 1.0% [mean +/- SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (-1.1 +/- 0.1% [mean +/- SEM]) were sustained to 3 years (-1.0 +/- 0.1%; p < 0.0001), with 46% achieving A1C < or = 7%. Exenatide progressively reduced body weight from baseline (-5.3 +/- 0.4 kg at 3 years; p < 0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n = 116) had reduced ALT (-10.4 +/- 1.5 IU/L; p < 0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (-6.1 +/- 0.6 kg vs. -4.4 +/- 0.5 kg; p = 0.03), however weight change was minimally correlated with baseline ALT (r = -0.01) or ALT change (r = 0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n = 151). Triglycerides decreased 12% (p = 0.0003), total cholesterol decreased 5% (p = 0.0007), LDL-C decreased 6% (p < 0.0001), and HDL-C increased 24% (p < 0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison. CONCLUSION: Adjunctive exenatide treatment for > or = 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction. |
| Authors | David C Klonoff, John B Buse, Loretta L Nielsen, Xuesong Guan, Christopher L Bowlus, John H Holcombe, Matthew E Wintle, David G Maggs
(Affiliation: Diabetes Research Institute, Mills-Peninsula Health Services, San Mateo, CA, USA.)
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| Journal | Current medical research and opinion
(Curr Med Res Opin)
Vol. 24
Issue 1
Pg. 275-86
(Jan 2008)
ISSN: 1473-4877 England |
| PMID | 18053320
(Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Biomarkers, Pharmacological
- Hemoglobin A, Glycosylated
- Hypoglycemic Agents
- Peptides
- Placebos
- Venoms
- hemoglobin A1c protein, human
- exenatide
|
| Topics |
- Aged
- Biomarkers, Pharmacological
(metabolism)
- Blood Pressure
(drug effects)
- Body Weight
(drug effects)
- Cardiovascular Diseases
(etiology, prevention & control)
- Diabetes Mellitus, Type 2
(drug therapy, etiology, metabolism, physiopathology)
- Female
- Follow-Up Studies
- Hemoglobin A, Glycosylated
(metabolism)
- Humans
- Hypoglycemic Agents
(pharmacology, therapeutic use)
- Liver
(drug effects, enzymology, metabolism)
- Male
- Middle Aged
- Obesity
(etiology, prevention & control)
- Peptides
(pharmacology, therapeutic use)
- Placebos
- Risk Factors
- Time Factors
- Venoms
(pharmacology, therapeutic use)
|
