Liraglutide Mechanism of Action: For Weight Loss and Diabetes

Liraglutide mechanism of action for weight loss (obesity) and diabetes is detailed here. It belongs to the class of medicine called GLP-1 analog and is available under the brand names Saxenda and Victoza.

It is available as an injection for daily administration into the skin. The two main indications of the use of liraglutide are obesity and diabetes.

Liraglutide Mechanism of Action:

Liraglutide is a long-acting analog of GLP-1 (Glucagon-like peptide). Other GLP-1 analogs include:

• Semaglutide (Rybelsus, Ozempic, and Wegovy)
• Dulaglutide (Trulicity)
• Exenatide (Byetta)

Glucagon-like peptides are also called incretins.

There are two incretins of clinical importance in the body, namely:

• GLP (Glucagon-like peptide) and
• GIP (Gastric inhibitory peptides).

Tirzepatide (Mounjaro) is a newly approved diabetes and obesity drug that has dual GLP/ GIP effects.

“Incretins” word has been derived from INtestinal seCRETion of INSulin. These are gut hormones that are secreted by the enteroendocrine cells of the gastrointestinal tract when a food stimulus is sensed by the body.

Incretins were discovered when scientists found out that insulin secretion in response to a glucose load administered intravenously is less compared to when the same amount of glucose is administered orally.

Liraglutide Mechanism of Action in Diabetes:

Liraglutide is a long-acting analog of GLP-1. It is used in patients with diabetes because of the following main mechanisms:

• It causes the release of insulin in a glucose-dependent manner.
• It inhibits the release of glucagon in a glucose-dependent manner.
• It inhibits gastric emptying.

Liraglutide activates the Beta-cells of the pancreas to release insulin in response to elevated blood sugars.

Thus, in individuals with normal blood glucose, its effect on insulin is blunted. Insulin in turn directly causes the shift of glucose into the body cells reducing blood glucose.

Liraglutide also inhibits the release of glucagon in a glucose-dependent way. Glucagon normally is involved in the production of glucose, inhibition of glucose breakdown, inhibition of glycogen synthesis, and glycogen breakdown.

When glucagon production is inhibited, all these mechanisms are inhibited resulting in a reduction in plasma glucose.

Liraglutide (Victoza and Saxenda) also inhibits gastric emptying. This effect is important as it reduces the glucose load being poured into the blood rapidly.

Slow stomach movements cause a slow release of food into the intestine and a gradual absorption occurs. A gradual absorption of the food does not cause a rapid spike of glucose in the blood.

GLP-1 analogs, including liraglutide, cause early satiety. Patients may complain of fullness all the time and not feeling like eating. Liraglutide also inhibits beta-cell apoptosis and preserves pancreatic function.

Do You Know: GLP-1 analogs were first isolated from the venom of GILA MONSTER!

Liraglutide Mechanism of Action for weight loss:

Liraglutide has direct and indirect effects on appetite. The endogenous GLP-1 is secreted by the L-cells of the intestine.

The receptors for GLP-1 are present in the islet cells of the pancreas, upper gastrointestinal tract, and the afferent nerve endings in the gastrointestinal tract. It is also secreted in the brain and the appetite centers present in the hypothalamus.

In the brain, it directly suppresses appetite and stimulates the nausea center in the area postrema of the hypothalamus.

The CNS appetite and vomiting center are also activated as a result of the stretch of the stomach.

When food enters the stomach, it is stretched and the afferent neuronal receptors are activated that excite the receptors in the brain’s satiety center. Thus, early satiety and nausea are the early side effects (or effects) of the drug.

Indirectly, it delays gastric emptying into the intestine. Food remains in the stomach for a longer time than usual. This may cause weight loss via three mechanisms:

• Stomach fullness causes the feeling of being full and reduces appetite.
• Delayed gastric emptying causes a slow food transit and hence the nutrient load in the blood is less. Thus, little insulin is released which could blunt the weight-gaining effect of insulin.
• Stomach stretch causes the activation of brain appetite and satiety centers that directly suppresses the appetite.

In clinical trials (The LEAD and SCALE Trials), liraglutide resulted in a weight loss exceeding 5% in two-thirds of the patients and greater than 10% weight loss was observed in one-third of the patients [Ref].

Because of its weight-losing effects, it is also available in combination with Insulin Degludec by the name of Xultophy. The combination has better efficacy and is weight neutral.

In Conclusion:

Liraglutide is an incretin mimetic drug that causes the release of insulin in a glucose-dependent manner. It also inhibits the release of glucagon and suppresses the appetite center.