What is the origin of Glucagon-like peptide-1 (GLP-1) medication?

From the Guidelines

GLP-1 medications originated from the discovery of glucagon-like peptide-1, a hormone naturally produced in the intestines that stimulates insulin release in response to food intake, with the first breakthrough coming in 2005 when exenatide (Byetta), derived from Gila monster saliva, was approved as the first GLP-1 receptor agonist for treating type 2 diabetes. The development of these medications began in the 1980s when researchers identified GLP-1's role in glucose regulation 1. Scientists found that the lizard's saliva contained exendin-4, a protein similar to human GLP-1 but with a longer duration of action. This discovery led to the development of synthetic GLP-1 analogs that resist rapid breakdown in the body, allowing for effective blood sugar control with once-daily or once-weekly injections.

Key Points

• The first GLP-1 receptor agonist, exenatide, was approved in 2005 for the treatment of type 2 diabetes 1.
• GLP-1 receptor agonists have been shown to be effective in reducing the risk of major adverse cardiovascular events (MACE) and have benefits beyond glucose control, including weight loss and improved kidney outcomes 1.
• The development of GLP-1 medications has expanded to include weight management due to their effects on appetite regulation and gastric emptying.
• Numerous GLP-1 medications have been developed, including liraglutide, semaglutide, and dulaglutide, which have demonstrated statistically significant reductions in the hazard ratio for the first occurrence of the 3-point MACE composite of non-fatal myocardial infarction, non-fatal stroke or CV death 1.

Benefits and Risks

• GLP-1 receptor agonists have been shown to have a 12% reduction in 3-point MACE, 12% reduction in CV death, 11% reduction in all-cause mortality, 9% reduction in fatal/non-fatal MI, 16% reduction in fatal/non-fatal stroke, 9% reduction in heart failure hospitalization, and 17% reduction for a broad kidney composite outcome mainly driven by effects on albuminuria 1.
• The most common adverse effects of GLP-1 receptor agonists are gastrointestinal in nature, including nausea, vomiting, and diarrhea 1.

From the FDA Drug Label

Exenatide is a synthetic peptide, glucagon-like peptide-1 (GLP-1) receptor agonist, that was originally identified in the lizard Heloderma suspectum. VICTOZA contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist The origin of GLP-1 medication is:

• Exenatide: originally identified in the lizard Heloderma suspectum 2
• Liraglutide: an analog of human GLP-1 3

From the Research

Origin of GLP-1 Medication

The origin of GLP-1 medication can be traced back to the discovery of the glucagon-like peptide-1 (GLP-1) hormone.

• GLP-1 is a multifaceted hormone with broad pharmacological potential, including glucose-dependent stimulation of insulin secretion, decrease of gastric emptying, and inhibition of food intake 4.
• The first GLP-1 receptor agonist, exenatide, was approved in 2005 for the treatment of type 2 diabetes 5.
• Exenatide is a synthetic version of exendin-4, a compound found in the venom of the Gila monster 6.
• Since then, several other GLP-1 receptor agonists have been developed, including liraglutide, lixisenatide, and semaglutide, which have been shown to be effective in improving glycemic control and reducing body weight in patients with type 2 diabetes 5, 7, 6, 8.

Development of GLP-1 Receptor Agonists

The development of GLP-1 receptor agonists has involved the modification of the natural GLP-1 hormone to create synthetic versions with improved pharmacokinetic and pharmacodynamic properties.

• Short-acting GLP-1 receptor agonists, such as exenatide and lixisenatide, have a shorter duration of action and primarily delay gastric emptying, while long-acting GLP-1 receptor agonists, such as liraglutide and semaglutide, have a longer duration of action and affect both fasting and postprandial glucose levels 5, 6.
• The development of GLP-1 receptor agonists has also involved the creation of once-weekly and once-daily formulations, which have improved patient adherence and persistence 5, 6.

Clinical Use of GLP-1 Receptor Agonists

GLP-1 receptor agonists are currently used in the treatment of type 2 diabetes and have been shown to be effective in improving glycemic control, reducing body weight, and decreasing the risk of major adverse cardiovascular events 5, 7, 8.

• GLP-1 receptor agonists have been recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, due to their efficacy and safety profile 5.
• The choice of GLP-1 receptor agonist depends on individual patient factors, such as the presence of cardiovascular disease, renal impairment, and patient preference 6.