TY - JOUR
T1 - Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years
AU - Klonoff, David C.
AU - Buse, John B.
AU - Nielsen, Loretta L.
AU - Guan, Xuesong
AU - Bowlus, Christopher
AU - Holcombe, John H.
AU - Wintle, Matthew E.
AU - Maggs, David G.
PY - 2008/1
Y1 - 2008/1
N2 - Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of ≥ 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 μg exenatide, or 10 μg exenatide for 30 weeks, followed by 5 μg exenatide BID for 4 weeks, then 10 μg exenatide BID for ≥ 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/m2, 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 ≤ 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 ≥ 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.
AB - Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of ≥ 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 μg exenatide, or 10 μg exenatide for 30 weeks, followed by 5 μg exenatide BID for 4 weeks, then 10 μg exenatide BID for ≥ 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/m2, 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 ≤ 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 ≥ 3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.
KW - ALT
KW - AST
KW - Exenatide
KW - Exendin-4
KW - HDLC
KW - Incretin mimetic
KW - LDL-C
KW - NAFLD
KW - Triglycerides
KW - Type 2 diabetes
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U2 - 10.1185/030079907X253870
DO - 10.1185/030079907X253870
M3 - Article
C2 - 18053320
AN - SCOPUS:38549162147
VL - 24
SP - 275
EP - 286
JO - Current Medical Research and Opinion
JF - Current Medical Research and Opinion
SN - 0300-7995
IS - 1
ER -