Journal
DIABETOLOGIA
Volume 56, Issue 9, Pages 1878-1883Publisher
SPRINGER
DOI: 10.1007/s00125-013-2953-6
Keywords
Autonomic nervous system; Gastrointestinal adverse events; Glucagon-like peptide-1 (GLP-1); Glucagon-like peptide-1 (GLP-1) receptor agonists; Incretin mimetics; Subcutaneous adipose tissue
Categories
Funding
- Berlin-Chemie/Menarini
- Eli Lilly Co.
- Merck, Sharp Dohme
- Novartis Pharma
- AstraZeneca
- Boehringer Ingelheim
- GlaxoSmithKline
- MetaCure
- Roche Pharma
- Novo Nordisk Pharma
- Tolerx Inc.
- Amylin Pharmaceuticals
- Bristol-Myers Squibb
- Diartis Pharmaceuticals
- Hoffmann-LaRoche
- Intarcia Therapeutics
- MannKind Corp.
- Merck Sharp Dohme
- NovoNordisk
- Sanofi, Takeda
- Wyeth Research
- Sanofi
- Takeda
- Berlin-Chemie
- BMS
- Eli Lilly
- Novartis
- Roche
- Sanofi-Aventis
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Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are incretin-derived glucose-lowering agents that have been used for the treatment of type 2 diabetes since 2007. Agents such as exenatide (short-acting and once weekly preparations), liraglutide, taspoglutide, albiglutide and lixisenatide lower fasting glucose and HbA(1c) upon subcutaneous injection, leading to glycaemic control that is equivalent to, or better than, that observed with other oral glucose-lowering agents or bedtime insulin. However, varying proportions of patients report nausea and vomiting, adverse events that typically narrow the therapeutic dose range. Furthermore, GLP-1 RAs reduce fasting glucose to a clinically meaningful extent, but not into the normal range. In contrast, where GLP-1 is administered as a short-term intravenous infusion, a full normalisation of glucose concentrations (approximately 5 mmol/l) has been observed without any risk of gastrointestinal side effects. Subcutaneous infusions or injections of GLP-1 are much less effective. The present analysis relates the proportion of patients who report nausea following treatment with GLP-1 and GLP-1 RAs to the clinical effectiveness of the treatment (represented by the fasting glucose concentration achieved with treatment). The results suggest that GLP-1 RAs injected into the subcutaneous compartment do not exploit the full potential inherent in GLP-1 receptor activation. Reasons for this may include modifications of the peptide molecules in the subcutaneous environment or high local concentrations triggering side effects through GLP-1 receptors on autonomic nerves in subcutaneous adipose tissue. Elucidation of the mechanisms underlying differential responses to GLP-1/GLP-1 RAs administered intravenously vs subcutaneously may help to develop improved agents or modes of administration that are more effective and have fewer side effects.
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