GLP-1 Receptor Agonists

Glucagon-like peptide-1 receptor agonists also known as GLP-1 agonists, are medications used in the treatment of type 2 diabetes and obesity. They produce their effect by mimicking the effects of the GLP-1 hormone.

Medications belonging to this group include exenatide, liraglutide, semiglutide and dulaglutide.

Background

The history of GLP-1 agonists can be traced back to the early 1990’s where researcher and physician Dr John Eng was working on developing tests that could identify hormones with potential untested benefits. He came across studies, done by researchers in the early 1980’s at the National Institute of Health (NIH).These researchers had noted that poison from certain snakes and lizards could cause swelling of the pancreas.

Of particular interest was the Gila Monster, the largest desert lizard found in the United States (US). The bite of the Lizard is known to cause extreme pain, including a burning sensation and discomfort that can last for hours. Thinking he had designed a test to study the hormones in the lizard’s saliva, he obtained a sample.

In his findings published in 1992 he reported that, contained in the lizard’s saliva was a molecule which had never been documented before. This new molecule had similar properties to the human GLP-1 hormone. Unlike the GLP-1 hormone this new molecule did not breakdown quickly and could potentially be used as medicine. He named this molecule Exendin-4.

Thirteen years later in 2005 after securing a patent for the molecule and partnering with Amylin Pharmaceuticals the first GLP-1 agonist was registered and approved for use in the treatment of type 2 diabetes. It was called Exenatide (Byetta). Exenatide was discontinued in 2024.

In the years that followed other pharmaceutical companies, worked on making improvements on the original molecule. Most of the improvements focused on making the medications stay longer in the body. This has resulted in products that require weekly injections compared to exenatide which requires several injections a day.

How do GLP-1 Agonists work?

GLP-1 Agonists produce their effect by mimicking the actions of the GLP-1 hormone. Once taken into the body these medications :

• Promote insulin production and release by the β-cells of the pancreas.
• Stop α-cells of the pancreas from producing glucagon.
• Slow down the movement of food from the stomach.
• Suppress appetite.
• Cause one to feel fuller for longer.

Factors to consider when using GLP-1 Agonist.

Risk of hypoglycaemia

Treatment induced hypoglycaemia is rare with this group of medications. Use of GLP-1 agonists with other glucose lowering medications may increase risk of hypoglycaemia.

Glycaemic control

Short-acting GLP-1 agonists reduce HbA1c by 0.8% to 1.2%, while long-acting GLP-1 agonists lower HbA1c by 1% to 1.8%.

Effect on weight

GLP-1 agonists cause weight loss. Some medications in this group have been approved for use in the treatment and management of obesity.

Doses used for diabetes treatment differ from those used in weight loss management. Higher doses are used in weight loss when compared to those used in the treatment of diabetes.

Some products with the same active ingredient are marketed under different brand names, based on their approval for either type 2 diabetes or weight loss.

Benefits to heart and kidneys

GLP-1 agonists offer heart and kidney benefits for individuals with Type 2 Diabetes. They reduce the risk of strokes, heart conditions, and death from heart-related issues. Additionally, GLP-1 agonists slow diabetic kidney disease progression and lower blood pressure and cholesterol.

Side effects

Common side effects associated with GLP-1 agonists include nausea, vomiting and diarrhoea. Less common side effects associated with this group of medications include swelling of the pancreas (pancreatitis), bowel obstruction and gastroparesis also known as delayed gastric emptying.

 Eating slowly, having smaller portions, and resting after meals can help reduce side effects.

Box warning

GLP-1 agonists have a black box warning regarding Thyroid cancer; this is based on animal studies.

 A Black Box warning is the strongest safety warning that can be placed on a medication. It is there to warn healthcare professionals and patients about a risk associated with a medication that could cause serious injury or even death.

Cost

Cost remains a challenge for this group of medications as they remain unaffordable for individuals and healthcare systems in low-income settings.

Incretin Dual Agonists

In 2009, researchers found that medications mimicking multiple incretin hormones could enhance weight loss. This was an important development in obesity research.

In 2022 Tirzepatide was approved as the first dual agonist on the market. It works by mimicking the effect of both GLP-1 and GIP hormones.

Tirzepatide reduces HbA1c by 1.7% -2.6%. Studies have reported weight loss of up to 11 kg when used in individual with type 2 diabetes, and a loss of up to 20% of total body weight in individuals without diabetes.

Tirzepatide better lowers blood pressure and cholesterol than semiglutide. It also reduces risk of heart disease, prevents heart-related deaths, and slows progression of kidney disease in those living with type 2 diabetes.

Useful tips when using incretin agonists.

• Women of child bearing age should be on a reliable contraceptive method while on treatment, and for 2 months after stopping treatment.
• Let your Doctor know if you plan to get pregnant or stop using medication at least 2 months before a planned pregnancy.
• Tell your Doctor if you have a family history of Thyroid cancer.