Endocrinol Metab.  2013 Dec;28(4):262-274. 10.3803/EnM.2013.28.4.262.

Clinical Application of Glucagon-Like Peptide 1 Receptor Agonists for the Treatment of Type 2 Diabetes Mellitus

• Cho YM
• Wideman RD
• Kieffer TJ

• KMID: 2169303
• DOI: http://doi.org/10.3803/EnM.2013.28.4.262

Abstract

Glucagon-like peptide 1 (GLP-1) is secreted from enteroendocrine L-cells in response to oral nutrient intake and elicits glucose-stimulated insulin secretion while suppressing glucagon secretion. It also slows gastric emptying, which contributes to decreased postprandial glycemic excursions. In the 1990s, chronic subcutaneous infusion of GLP-1 was found to lower blood glucose levels in patients with type 2 diabetes. However, GLP-1's very short half-life, arising from cleavage by the enzyme dipeptidyl peptidase 4 (DPP-4) and glomerular filtration by the kidneys, presented challenges for clinical use. Hence, DPP-4 inhibitors were developed, as well as several GLP-1 analogs engineered to circumvent DPP-4-mediated breakdown and/or rapid renal elimination. Three categories of GLP-1 analogs, are being developed and/or are in clinical use: short-acting, long-acting, and prolonged-acting GLP-1 analogs. Each class has different plasma half-lives, molecular size, and homology to native GLP-1, and consequently different characteristic effects on glucose metabolism. In this article, we review current clinical data derived from each class of GLP-1 analogs, and consider the clinical effects reported for each category in recent head to head comparison studies. Given the relatively brief clinical history of these compounds, we also highlight several important efficacy and safety issues which will require further investigation.

Keyword

Glucagon-like peptide 1; Diabetes mellitus, type 2; Exenatide; Liraglutide; Exenatide long acting release

MeSH Terms

Blood Glucose
Diabetes Mellitus, Type 2*
Dipeptidyl Peptidase 4
Filtration
Gastric Emptying
Glucagon
Glucagon-Like Peptide 1*
Glucose
Half-Life
Head
Humans
Infusions, Subcutaneous
Insulin
Kidney
Metabolism
Peptides
Plasma
Venoms
Liraglutide
Blood Glucose
Dipeptidyl Peptidase 4
Glucagon
Glucagon-Like Peptide 1
Glucose
Insulin
Peptides
Venoms

Figure

• 

  Fig. 1 Classification of glucagon-like peptide 1 (GLP-1) therapies in clinical use or in development. GLP-1-based therapies either mimic the activity of native GLP-1 (GLP-1 mimetics) or enhance circulating levels of GLP-1 (GLP-1 enhancers). Each of these classes of compounds can be further broken down; examples are given for each type.

• 

  Fig. 2 Schematic of plasma glucagon-like peptide 1 (GLP-1) analog levels and plasma glucose levels with short- versus long (or prolonged)-acting analogs. Plasma levels of representative GLP-1 analogs and corresponding plasma glucose levels are depicted over a 24-hour period. Dashed line and closed circle, short-acting GLP-1 analog; continuous line and open circle, long or prolonged-acting GLP-1 analog.

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