Effectiveness of progressive dose-escalation of exenatide (exendin-4) in reducing dose-limiting side effects in subjects with type 2 diabetes

Background Exenatide (exendin‐4) exhibits dose‐dependent glucoregulatory activity, but causes dose‐limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose...

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Vydané v:	Diabetes/metabolism research and reviews Ročník 20; číslo 5; s. 411 - 417
Hlavní autori:	Fineman, Mark S., Shen, Larry Z., Taylor, Kristin, Kim, Dennis D., Baron, Alain D.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Chichester, UK John Wiley & Sons, Ltd 01.09.2004 Wiley
Predmet:	Adolescent Adult Aged Biological and medical sciences Blood Glucose - metabolism Diabetes Mellitus, Type 2 - drug therapy Diabetes. Impaired glucose tolerance dose-escalation Endocrine pancreas. Apud cells (diseases) Endocrinopathies exenatide exendin-4 Female Humans Hypoglycemic Agents - administration & dosage Hypoglycemic Agents - adverse effects incretin mimetic Male Medical sciences Middle Aged mitigation of side effects Nausea - chemically induced Nausea - prevention & control Peptides - administration & dosage Peptides - adverse effects reduction of adverse events type 2 diabetes Venoms - administration & dosage Venoms - adverse effects Endocrinopathy Type 2 diabetes Human incretin mimetic Mimetic dose- escalation Exenatide reduction of adverse events Increasing dose Hypoglycemic agent Secondary effect mitigation of side effects exendin-4
ISSN:	1520-7552, 1520-7560
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Shrnutí:	Background Exenatide (exendin‐4) exhibits dose‐dependent glucoregulatory activity, but causes dose‐limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose‐escalation methodology. Methods In this two‐arm, triple‐blind, multicenter study, 123 subjects with type 2 diabetes were enrolled and randomized; 99 (80.5%) of them completed the study. Subjects in the exenatide‐primed arm received subcutaneous exenatide, starting at 0.02 µg/kg three times a day (TID) and increasing in 0.02 µg/kg per dose increments every 3 days for 35 days. Subjects in the exenatide‐naive arm received placebo TID for 35 days. At the end of this 35‐day regimen, subjects in both arms received the same highest dose of exenatide (0.24 µg/kg TID) for 3 days. Thus, the exenatide‐naive arm received exenatide for the first time on Day 35. Results The exenatide‐primed arm had a lower proportion of subjects experiencing nausea and vomiting in response to exposure to the highest dose of exenatide (27 vs 56% in the exenatide‐naive arm; p = 0.0018). Kaplan–Meier estimates of cumulative incidence were 0.28 in the exenatide‐primed arm, compared with 0.68 in the exenatide‐naive arm (p ≤ 0.001). As predicted by the study design, fewer subjects in the exenatide‐primed arm reported severe nausea (29%) and vomiting (10%) than those in the exenatide‐naive arm (48 and 31%, respectively). In the exenatide‐primed arm, fasting serum glucose progressively declined over the first 35 days of dosing, but was unchanged in the exenatide‐naive arm (placebo phase) during the same interval. Conclusion Gradual dose‐escalation of exenatide successfully reduced the proportion of subjects experiencing dose‐limiting nausea and vomiting, with no loss of glucoregulatory activity, thus demonstrating the value of gradual dose‐escalation in mitigating the gastrointestinal side effects of exenatide. Copyright © 2004 John Wiley & Sons, Ltd.
Bibliografia:	ark:/67375/WNG-VMTJNHGX-T istex:7E0536E2DE9DE2A1F0F5EA1BAC5F0ABCDED705EA ArticleID:DMRR499 ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Undefined-3
ISSN:	1520-7552 1520-7560
DOI:	10.1002/dmrr.499