How Does Wegovy Work?

Overview

Global incidence of overweight and obesity has risen, reaching 38% in 2020, and is projected to reach 51% in 2035. Obesity, however, is difficult to treat, as it is a complex disease with multiple factors, including genetics and environment.¹ There are several medicinal treatments available for weight loss, including Orlistat, Liraglutide (also known as Saxenda^®), and semaglutide (also known as Wegovy^®).² 

Wegovy has been gaining more traction in recent media, and it is important to know how it works and how it is administered, along with the possible side effects before conferring with a GP. 

Developed by Novo Nordisk,³ Wegovy is a medicine used alongside lifestyle changes to treat obesity for certain body mass index (BMI) ranges. 

How is obesity defined?

Obesity, according to the NHS, is a term used for people who have excess body fat. Numerically, obesity is defined as having a BMI equal to or greater than 30 Kg/m².¹ BMI is calculated by ‘dividing a person’s weight by the square of their height.¹ 

An excess of fat can lead to other health problems (i.e. comorbidities). These comorbidities include higher probability of type 2 diabetes (T2D), cardiovascular diseases, and lower life expectancy.¹ The equation¹ is shown below. 

As BMI only accounts for mass without taking into consideration the type of mass (i.e. muscle mass vs fat), it can be considered inaccurate if the fitness level of the individual is not accounted for. Muscle is denser than fat, therefore the same volume occupied by muscle has a greater mass than that of fat. As such, those with large amounts of muscle can be technically classified as obese according to the BMI but are actually at a healthy weight. 

Nevertheless, for the general population, calculating BMI is an efficient method of estimating the amount of fat in the human body. The table below shows BMI ranges and their classifications below:

The NHS also notes that those of Asian ethnic descent, Black African, or Black-Caribbean descent may be susceptible to health conditions in lower BMI ranges. Consequently, medical practitioners will also consider ethnicity before assigning a particular weight loss drug to an individual.

A simple overview of hunger

Before understanding the mechanism whereby Wegovy works, it is necessary to understand what causes hunger. For the human body to carry out necessary functions, it requires energy generally obtained from food.^4,5 When the body requires more energy, organs such as the pancreas, stomach, intestines, and others send signals – generally as hormones.

These signals bind to macromolecules (receptors) that allow proteins (ligands) to bind to them and cause a specific effect.⁶ These effects include indicating to the brain that it is ‘hungry.⁵ Likewise, once enough food has been consumed, signals are also sent to the brain to signal that the body is full. 

Obesity is generally due to the overconsumption of energy in comparison to its expenditure and can be influenced by genetics or environment, or both.⁷ These factors change the ability the body is able to metabolise at the biological level and therefore increases the likelihood of obesity occurring.

In relation to signalling pathways, these genetic and/or environmental factors disrupt and or decrease the body’s sensitivity to hormones that would otherwise tell the brain and body that it is full.⁷ Due to the significant number of hormones involved in the hunger/satiety pathway, researchers are interested in finding potential medicinal targets and their mechanism of action.

One way to target these pathways is to design analogue drugs. An analogue drug is designed chemically and pharmacologically similar to a ‘naturally occurring’ (i.e. endogenous) protein, or hormone.⁸ By designing drugs similar to hormones that signal the brain to ‘stop eating,’ weight loss can be achieved.³

How does wegovy work?

Wegovy functions similarly to glucagon-like peptide-1 (GLP-1), a hormone involved in decreasing appetite. This is achieved by controlling the overall levels of sugar (glucose) in the body through increasing insulin secretion, inhibiting glucagon, suppressing hepatic gluconeogenesis (glucose production in the liver) production, and delaying gastric emptying (i.e. where digested contents from the stomach are sent into the small intestine).^9,10,11,12 Wegovy is an agonist, binding to the same receptor (GLP1R) as GLP-1, and performs these same functions. 

A more detailed overview of hunger

Insulin is a hormone that maintains glucose levels and is secreted after eating, although other factors may change the amount secreted.¹³ GLP-1 is involved in up to 70% of insulin secretion, and therefore the design of an analogue through Wegovy allows major control of insulin. 

In obese individuals, glucose-dependent insulin resistance can occur,³ where insulin has a reduced effect. When insulin has a reduced effect, it can cause hormones, such as glucagon, to hypersecrete.¹⁴ Simultaneously, as insulin concentrations fall and glucagon increases, the rate of hepatic gluconeogenesis also increases,¹⁵ therefore leading to hyperglycaemia (high blood sugar) and thus leads to comorbidities such as T2D. 

What makes wegovy efficient?

Compared to the endogenous GLP-1, Wegovy has been designed to be more effective with its structure being 94% identical to GLP-1.² These slight alterations allow for better binding to the receptor as well as being less susceptible to degradation. Overall, these two factors lead to a longer half-life (i.e., the duration at which the drug reaches half its concentration in the body)¹⁶ of the drug, which is also the reason why it is administered once a week subcutaneously (via injection).^2,3 

Since the drug is present in the body for longer durations compared to GLP-1, it will activate GLP-1 receptors for longer periods of time. Consequently, pathways involving insulin and glucagon, as well as hepatic gluconeogenesis, are controlled more effectively.² This leads to reduced appetite and weight loss.^{2,3,9,10,11,12} 

Lifestyle changes

Clinical trials have shown that Wegovy has the potential for patients to lose 5% to 15% of their weight with lifestyle changes.³ These lifestyle changes are a necessity alongside Wegovy to achieve weight loss. 

Wegovy treatment is limited to two years, and aims to reduce individuals to healthy weights, and should be discontinued once achieved. To maintain a healthy weight post-medication, diet and exercise are necessary.

Side effects of wegovy

According to the FDA, the following side effects were shown in 5% or more of the clinical trial patients:

Who can and cannot take wegovy?

Requirements to be eligible for wegovy

Wegovy is a prescription-only medicine. It is taken as an injection once a week. According to the NHS, Wegovy can only be taken under the following circumstances:

• You have health problems due to your weight
• Your BMI is 35 OR 32.5 if you are of South Asian, East Asian, Middle Eastern, African, or African-Caribbean descent
• Your BMI is 30–35 OR BMI is 27.5–32.5 if you are of South Asian, East Asian, Middle Eastern African or African-Caribbean descent AND you have other criteria (e.g. diabetes, hypertension) [for all ethnic groups]

Ineligible candidates for wegovy

According to Novo Nordisk: 

• Wegovy cannot be taken for patients who are pregnant or breastfeeding, as the effects are still unknown (i.e. possible harm to the baby)
• Patients who have problems with their pancreas and/or kidneys
• Patients who have had T2D alongside diabetic retinopathy
• Patients who have had depression, suicidal ideation, or other mental health issues
• Patients who are already taking GLP-1-like medicine

Novo Nordisk have stated that during clinical trials on rats, the active ingredient, semaglutide, was shown to cause tumours in thyroid parafollicular cells (C cells) in doses used clinically in humans. It is not clear whether Wegovy can cause medullary thyroid cancer (cancer of the thyroid C cells) [MTC] as it has yet to be seen in humans. Therefore, patients with a family history of MTC are suggested not to take Wegovy.

As an additional consideration, semaglutide (Ozempic) was originally trialled and then approved for T2D, and it was found that those with T2D and obesity were losing weight. Consequently, a different study was conducted to see if semaglutide could be used solely to treat obesity rather than for T2D. This was approved and branded as Wegovy. It is important to note: that Wegovy and Ozempic are NOT the same – they have the same ingredient (semaglutide), but are given at different doses to treat obesity or T2D, respectively.¹² They should not be taken together. 

Summary

As obesity rates continue to rise, it may be beneficial to look at possible treatment options available. Depending on an individual’s ethnic background and BMI, Wegovy can be used to suppress appetite and aid in weight loss. Wegovy is an analogue of the glucagon-like peptide-1 hormone (GLP-1) that binds to the same receptor (GLP1R) and performs similar functions in increasing insulin secretion, inhibiting glucagon and suppressing hepatic gluconeogenesis.

It is important to recognise that Wegovy should be used alongside lifestyle changes, especially since obesity is a complex disease that involves a multitude of factors. For the medicine to be especially effective, these lifestyle changes must be continued to maintain a healthy weight post-medication.