Semaglutide is making waves in the medical scene with its efficacy in treating patients with type 2 diabetes and obesity. From ordinary people to stars, many are singing their praises for its anti-diabetes brand Ozempic and weight loss brand Wegovy.
While various studies and clinical trials have evidenced semaglutide’s effectiveness, it’s worth understanding how exactly it works. In pharmacology—the study of drugs’ properties and effects—the “mechanism of action” is the biochemical process behind a drug’s efficacy.
In this article, we will be taking a closer look at semaglutide’s structure and nature. Additionally, we will explain how it works to help regulate blood sugar levels and promote weight loss. We will also talk about semaglutide’s clinical efficacy and safety profile, citing important bodies of research. Read on as we uncover semaglutide’s mechanism of action.
What is semaglutide?
First of all, it’s essential that we define semaglutide. What exactly is it?
Definition and classification of semaglutide
In the lower gastrointestinal tract is the hormone GLP-1, which after food consumption produces and secretes insulin from the pancreas. Insulin is a hormone that reduces the amount of glucose, a kind of sugar, in the bloodstream. It also helps facilitate glucose’s movement into the body’s cells, where it will be used or stored as energy.
Semaglutide is classified as a glucagon-like peptide-1 receptor agonist or GLP-1 Ra, used to treat type 2 diabetes and obesity. Basically, GLP-1 Ras mimic how the GLP-1 hormone works. Whenever blood sugar levels are high, semaglutide helps the pancreas release just the right amount of insulin. A GLP-1 Ra also helps slow down the movement of food, reducing appetite and stimulating weight loss.
Early studies
Prior to semaglutide’s FDA approval, scientists conducted countless research to investigate its efficacy on diabetes.
A 2014 study compared the effectiveness of semaglutide on participants who had type 2 diabetes. Those who received semaglutide had a significant drop in their HbA1c levels versus those in the placebo group. HbA1c levels refer to the results of a blood test indicating if they are pre-diabetic or diabetic.
Another study compared the effectiveness of once-weekly semaglutide versus once-daily anti-diabetes medicine liraglutide in patients with type 2 diabetes. Both participants experienced a reduction in their blood sugar levels, with a greater reduction in those who took semaglutide.
Development and approval of semaglutide
After decades of research, scientists have made a breakthrough with the development of GLP-1 Ras such as semaglutide. Here’s a timeline.
1960s: Identification of incretin hormones
- Scientists prove that the gastrointestinal tract secretes incretin hormones, or hormones that reduce blood sugar levels.
1980s-1990s: Discovery of GLP-1 and its role
- Researchers discover GLP-1.
- In the 1990s, studies showed that GLP-1 not only triggered the release of insulin but also inhibited the secretion of glucagon—a hormone that normally increases blood sugar levels for the liver to release glucose in storage.
Early 2000s: GLP-1 and the first GLP-1 receptor agonists
- Scientists begin looking into how GLP-1 could stimulate the secretion of insulin without triggering hypoglycemia, a condition wherein blood sugar levels are lower than normal.
- By the mid-2000s, scientists developed the first GLP-1 Ras, exenatide and liraglutide.
2012: Semaglutide discovery and development
- In 2012, Danish pharmaceutical company Novo Nordisk discover and develop semaglutide.
2017-2021: FDA approvals
- Ozempic, semaglutide’s anti-diabetes brand, received FDA approval in 2017.
- Its other anti-diabetes brand, Rybelsius, received FDA approval in 2019.
- Wegovy, semaglutide’s weight loss drug, gets FDA green light in 2021.
Understanding GLP-1 Receptors
To learn how semaglutide works, you’ll need to understand proteins from a molecular level.
Amino acids and proteins
Amino acids are the building blocks of proteins, which are vital molecules in living organisms. They are tiny compounds with carbon, hydrogen, oxygen, nitrogen, and sometimes sulfur.
For the human body to function properly, it needs 20 different kinds of essential amino acids from food.
Long chains of amino acids form the body’s proteins, which have links to other proteins through covalent peptide bonds. With amino acids, the body can build and repair bones and muscles to produce hormones and enzymes for energy.
G-proteins and insulin
G-proteins are proteins acting like a molecular switch, sending signals from cell receptors to inside the cell. These signals are vital for bodily functions such as cell growth and differentiation, hormonal regulation, immune response, and muscle contraction. Additionally, it’s also essential for relaxation, as well as neurotransmission and the perception of taste and smell.
GLP-1 Receptors react to GLP-1. When GLP-1 binds to GLP-1 receptors, it activates certain cellular actions like insulin secretion and glucagon inhibition. GLP-1 also promotes slow gastric emptying and reduces appetite levels.
GLP-1 receptors are commonly in the pancreas’ beta cells, which produces insulin, and in alpha cells, which inhibits glucagon. They are also in the brain stem’s area postrema which controls vomiting, blood pressure, hunger, and thirst. Such a discovery suggests that treatments involving GLP-1 may also play a role outside of regulating blood sugar levels.
Semaglutide and its mechanism of action
Now, we understand semaglutide’s chemical composition and how it is essential for the body’s functions. We can now discuss how semaglutide creates an effect in the body, concerning treating type 2 diabetes and weight obesity.
Because semaglutide is a GLP-1 receptor agonist, it can replicate the effects of the hormone GLP-1. In this way, it regulates both fasting and post-meal blood sugar levels. Additionally, it also promotes weight loss. Here’s a more comprehensive explanation of how this works.
Activating GLP-1 receptors
Semaglutide binds to and activates GLP-1 receptors in the pancreas’ beta cells, similar to how GLP-1 works. When blood sugar levels are high, it prompts the pancreas to release blood insulin, reducing blood glucose after meals.
Inhibiting glucagon
Another process under semaglutide’s mechanism of action is glucagon inhibition, elevating blood sugar levels and stimulating the release of glucose. As semaglutide prevents the release of glucagon, it controls the body’s overall blood sugar levels.
Slowed down gastric emptying
Studies have shown that semaglutide delayed digestion or gastric emptying, resulting in feeling full long after eating a meal. In fact, participants retained 37% of a solid meal even if it had been four hours since they had eaten. Because people taking semaglutide felt full for longer, they were not as frequently hungry, reducing their appetite and food intake.
Reduced appetite and weight management
As GLP-1 receptors are in both the periphery and central nervous system, the binding of semaglutide triggers altered behavior. In particular, semaglutide was found to reduce food cravings, especially that of fatty foods, in participants suffering from obesity.
As semaglutide curbed a desire for food, so did it increase dopamine reward signaling. Dopamine is a kind of neurotransmitter in the brain that triggers feelings of pleasure, satisfaction, motivation, and learning.
In a 2023 study, researchers rewarded mice with sucrose every time they performed an action they were conditioned with. Each time, the researchers would inject them with semaglutide.
The researchers observed that semaglutide reduced the mice’s rewards while dopamine neuron activity increased in the brain’s ventral tegmental area. This increasingly satiated the mice even when the researchers did not reward them as much.
Pharmacokinetics and Pharmacodynamics of Semaglutide
While we’ve tackled the biochemical process behind semaglutide in the body, it’s also worth looking into its pharmacokinetics and pharmacodynamics. Pharmacokinetics is the study of the body’s reaction to a drug, while pharmacodynamics studies drug’s biochemical and physiological effects.
Absorption, distribution, metabolism, and excretion
A 2017 study looked into how the body processed and excreted a dose of subcutaneous or injected semaglutide. Researchers labeled semaglutide with a radioactive substance and monitored its journey in the bodies of healthy humans, monkeys, and mice.
Next, the researchers measured the amount of radioactivity in the subjects’ blood, urine, and feces. With this, they discovered that semaglutide remained intact in the blood and was metabolized before being excreted. Urinating was the more common form of excreting semaglutide in both humans and animals than defecating.
Proteolytic cleave also played a role in metabolizing semaglutide. Proteolytic cleave is the process wherein peptide bonds between amino acids break apart. Another process, beta-oxidation, wherein fatty acid molecules break down, also metabolized semaglutide.
A separate study showed that after the body absorbs semaglutide, it circulates in the bloodstream before being metabolized and excreted.
Ongoing research
Much is expected of semaglutide given the volume of evidence supporting its safety and efficacy.
Professor Carel le Roux is the director of the Metabolic Medicine Lab at the University College Dublin’s Diabetes Complications Research Centre. According to him, pharmaceutical companies are reversing their approach to testing new medications.
Remember how Novo Nordisk developed semaglutide’s weight loss brands after discovering its secondary weight management benefits? This time around, drug manufacturers are developing drugs for obesity before developing those for diabetes.
“Companies used to first de-risk the treatment by using it for diabetes, and then expand into the disease of obesity,” le Roux said. “What we are now seeing is that companies are doing the opposite. I think you’re going to see drugs designed for obesity being used for people with diabetes and you’re going to see drugs designed for diabetes that will be used for people with obesity. It’s going to be bi-directional.”
By the end of 2024, six obesity clinical trials will have reached completion. These studies aim to support the development of not just GLP-1 drugs. Additionally, these also aim to support monoacylglycerol acyltransferase 2 (MGAT2) inhibitors and calcitonin gene-related peptide (CGRP) inhibitors.
MGAT2 inhibition has been linked to weight loss through the control of gut hormone regulation and energy expenditure. CGRP levels, meanwhile, are typically higher in people with obesity.
What’s ahead
The discovery of GLP-1 has paved the way for the development of effective anti-diabetic and weight-loss drugs such as semaglutide. Understanding GLP-1 receptors’ effects is vital to growing research investigating gut hormones’ role in blood sugar regulation and weight management.
2024 will certainly be a pivotal year in obesity research. This is because pharmaceutical companies will uncover the deeper potential of GLP-1 and enzymes to promote weight loss and diabetes.
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