Targeting the GLP-1 Receptor: Genetics and a New Option for Weight Loss

Key takeaways:
~ GLP-1 receptor agonists (e.g., Wegovy (semaglutide), liraglutide) are now approved for weight loss for teens and adults.
~ These medications work by binding to the GLP-1 receptor and reducing appetite.
~ Genetic variants can affect the response to GLP-1 agonists for weight loss.

Losing weight can be challenging for most people. It is easy to become frustrated and lose motivation for a specific diet or exercise program. Cravings can torpedo your best-laid eating plans. The GLP-1 agonists seem to be effective because they don’t rely on willpower or require a specific diet – instead, the weekly injections just make you feel full.

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GLP-1 agonists: Who do they work for?

GLP-1 receptor agonists work by increasing the levels of the hormone GLP-1 in the body, which helps to increase the body’s sensitivity to insulin and reduce hunger.

An agonist is a type of drug or other agent that binds to a receptor on a cell and triggers a physiological response. Agonists stimulate receptors to produce an action, while antagonists block or inhibit the action of agonists.

GLP-1 agonists bind to the GLP-1 receptor and stimulate it to produce a physiological response, such as an increase in insulin sensitivity or appetite suppression.

Two GLP-1 receptor agonists (RAs) currently approved for weight loss are liraglutide and semaglutide. These drugs are typically prescribed to adults, and now teens, who are obese (BMI above 30).

Interestingly, GLP-1 RAs work better for weight loss in people without diabetes. Clinical trials show that semaglutide works a little bit better than liraglutide for most people in promoting weight loss.[ref]

What do GLP-1 receptor agonists do?

GLP-1RAs work by increasing the levels of the hormone glucagon-like peptide-1 (GLP-1) in the body.

GLP-1 increases the body’s sensitivity to insulin, the hormone responsible for controlling blood sugar levels. GLP 1 agonists can also help reduce hunger and slow down the rate of food digestion, making them an important tool in weight management.

GLP-1 is released in response to food intake. When you eat carbohydrates or certain proteins, the stomach releases the glucagon-like peptide-1 (GLP-1) hormone, which triggers the release of insulin from the pancreas. This helps to regulate blood sugar levels in the body. GLP-1 also helps to suppress appetite and slow down the rate of food digestion, which can lead to weight loss.

The receptor for GLP-1 is the GLP-1 receptor (GLP1R), a G-protein coupled receptor. The GLP-1 receptor is a type of cell surface receptor that binds to GLP-1, triggering a signaling cascade that leads to various effects, including the stimulation of insulin secretion, the inhibition of gastric emptying, and the promotion of satiety.

How does a GLP-1 agonist work for weight loss

By binding to the GLP-1 receptor, GLP-1 RAs mimic the effects of having eaten and released GLP1. In other words, you’ll feel full and won’t be driven to eat as much.

GLP-1 receptors are located in the brain, and GLP1 is created in the brain in preproglucagon neurons. Researchers have found that these preproglucagon neurons are naturally activated, specifically after large meals. But, a recent mouse study showed that semaglutide doesn’t really target these preproglucagon neurons and instead acts more on the peripheral systems.[ref]

GLP-1 receptors are also found on pancreatic beta cells, triggering insulin release. It also targets other cells in the pancreas to stop the glucagon signal for generating glucose in the liver.[ref]

In clinical trials, GLP-1 RAs improved lipid profiles, increased satiety and slower gastric emptying, reduced inflammation, and had neuroprotective effects.[ref] The slowing of gastric emptying and reducing inflammation may also play a role in weight loss – along with the decrease in appetite.

Which GLP-1 Agonists are Approved for Weight Loss?

There are currently two GLP-1 receptor agonists approved for weight loss: liraglutide (Saxenda) and semaglutide (Ozempic, Wegovy).

Liraglutide is an injectable drug taken once a day, while semaglutide is an injectable drug taken once a week.

Who is Eligible for GLP-1 Agonists for Weight Loss?

GLP-1 agonists are typically prescribed to adults over the age of 18 who are overweight or obese with a body mass index (BMI) above 30. However, these drugs may also be prescribed to adults with a BMI of 27 or higher if they have other health conditions such as type 2 diabetes or high cholesterol.

Talk to your doctor to see if you are eligible and whether it is the best option for you.

The FDA also just approved semaglutide for adolescents (ages 12 and up) with an initial BMI at or above the 95th percentile for their age and sex.[ref]

Clinical trial in adolescents:

A recent clinical trial showed that teens who were overweight or obese also lost weight on semaglutide. The trial ran for a little over a year and showed an average decrease in BMI of 16% (compared to 0.6% for placebo). To put that into perspective, if starting BMI was 32, a 16% reduction would bring it down to 27. Gastrointestinal adverse events were reported in 62% of the group taking semaglutide, compared to 42% in the placebo group.[ref]

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Lifehacks:

The GLP-1 receptor agonists are prescription medications. Talk with your doctor and see what your insurance will cover. The out-of-pocket cost without insurance is listed as around $1600/month, so this is definitely something you want to investigate thoroughly and make sure your insurance will cover it.

If you don’t have a GP, several online telemedicine websites now offer GLP-1 agonists for weight loss. There is a cost for the initial online exam, where you’ll video chat with a medical professional, and then some charge a monthly fee for follow-ups and for the prescription.

What about safety?

This type of medication is FDA approved, but that doesn’t mean it is totally benign. You’ll need to decide for yourself how the health benefits of weight loss stack up against the risk of serious side effects.

Side effects associated with GLP-1 agonists include:

Common side effects of GLP-1 agonists include nausea, vomiting, diarrhea, constipation, abdominal pain, headache, dizziness, and fatigue. Most gastrointestinal side effects occur during the first month. In rare cases, GLP-1 agonists may cause serious side effects, including allergic reactions, pancreatitis, gallbladder disease, and kidney disease.[ref][ref]

Obviously, talk with your doctor about the risk vs. benefits of GLP-1RAs for your specific situation.

No impact on bone fractures: If osteoporosis is a concern, the GLP-1 receptor agonists were shown not to increase fracture rates.[ref]

Benefit for CVD: In a huge cardiovascular disease study, GLP-1 RAs were shown to be associated with a lower risk of heart attacks and strokes.[ref]

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