GLP-1 drugs for weight loss: How do they work, exactly?

Evan Walker
Evan Walker TheMediTary.Com |
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How do semaglutide drugs like Wegovy, and other GLP-1 analogues, help suppress appetite? Image credit: UCG/Getty Images.
  • GLP-1 analogues, such as semaglutide, are prescribed for people with type 2 diabetes, including those with the condition who have obesity, in order to promote weight loss and improve control of blood sugars.
  • Their use as a treatment for obesity, often off-label, has gained a lot of attention in recent years.
  • The number of potential benefits of these drugs for minimising the risk of other conditions, such as cancer and cardiovascular disease, has also become a focus of research.
  • Researchers have now carried out a review of existing medical literature to summarise our understanding about how, exactly, GLP-1 analogues contribute to reduced calorie consumption.

GLP-1 analogues, such as semaglutide (brand names Ozempic, Wegovy) that were initially licensed for treating type 2 diabetes have received a lot of publicity in the past couple of years, in great part due to their ability to help people lose weight.

The understanding so far has been that GLP-1 analogues work by mimicking the action of a similarly shaped molecule called glucagon-like peptide, which is naturally released by the intestines soon after eating food.

This peptide binds to a specific receptor on the surface of beta cells in the pancreas, causing them to release insulin, and for a long time researchers assumed that GLP-1 analogues only affected insulin release, hence why they were prescribed for type 2 diabetes.

The effect these drugs had on weight did not long go unnoticed, however, as losing fat can help people with type 2 diabetes control their blood sugars better, and even make the condition go into remission.

Studies conducted in recent years have discovered that GLP-1 analogues work in a variety of ways that contribute to weight loss, including by slowing gastric emptying, and by increasing a person’s sense of fullness after eating.

There has been significant research in recent years focused on the other potential benefits of GLP-1 analogues, many of which could be due to the impact they have on body mass index (BMI) and obesity.

People with obesity are more likely to have cancer and cardiovascular disease, and recent research has shown that people who use GLP-1 analogues could have a lower risk of both. It remains unclear however, whether this is due to weight loss or other effects of the drugs.

Dr. Mir Ali, bariatric surgeon and medical director of MemorialCare Surgical Weight Loss Center at Orange Coast Medical Center in Fountain Valley, CA, told Medical News Today:

“As these medications increase in use and popularity, we will likely see more effects as people achieve their weight loss goals; there are still concerns with weight gain after stopping these medications, so more research is needed in order to understand the main reasons for the weight gain.”

Research is now focused on trying to figure out more about how these drugs work. A new review published in the International Journal of Obesity looked at the existing literature on this topic, how studies had been carried out, and how data had been collected on GLP-1 analogue use.

To carry out the review authors searched PubMed for the terms “obesity,” “semaglutide,” “liraglutide,” and “GLP-1 analog.”

Like semaglutide, liraglutide (brand name Saxenda) is a GLP-1 analog.

Researchers found that most of the research done into the effect of GLP-1 analogues on weight loss looked at the initial weight loss phase of action, which tends to last 12–18 months for semaglutide users, rather than the maintenance phase, when weight loss plateaus after this.

So far, researchers have understood that side effects, including gastric upset and nausea, tend to occur at the beginning of treatment, but a review of the available literature suggested that the weight loss in the early stages of using the drug, was not linked to nausea.

While the impact of the drug on reducing eating dropped between 12–18 months, users’ caloric intake was still found to be more restricted than baseline during the so-called maintenance phase after this.

Reviewing studies where people using the drug had been asked about their food cravings and preferences, researchers showed that there was an overall lower desire for dairy and starchy foods, and salty and spicy foods, and also that they wanted a lower number of foods, particularly high-fat, non-sweet foods.

However, macronutrient profiles of what people ate remained the same before and after initiation of the drug. There is still a lack of clarity over whether GLP-1 analogues lead to increased desire for sweeter foods, particularly those containing sucralose.

The authors found that existing research had shown that individuals using exenatide (brand name Byetta) — another GLP-1 analogue — had decreased neuronal responses to pictures of food in parts of the brain regulating appetite and reward. This response was measured through functional magnetic resonance imaging (fMRI).

Research has also shown that semaglutide does not permeate the blood-brain barrier, the layer that “insulates” the brain, protecting it from external agents.

Instead, this drug interrupts signalling that could affect appetite in parts of the central nervous system that are not behind the blood-brain barrier.

Prof. Alex Miras, clinical professor of medicine at Ulster University, United Kingdom, and obesity expert — not involved in this review — told MNT that our understanding of obesity and GLP-1 analogues is limited by the way in which data on diet are collected in these studies.

He noted that studies where the data are self-reported by the participants may have inaccuracies, and argued that the best way to confirm findings is through observational studies, which carry a lower risk of inaccuracies.

I think I think the overall conclusion from this [paper] is that there is some evidence that pharmacotherapy for obesity changes food preferences in some people, he said. “But if we want to find [out] for certain, we should stop asking people what they do, and […] actually observe people as to what they do, and then we will get robust answers.”

“I need to be observing people in a research setting or a clinical research setting, which should be as close to normal life as possible. But with that caveat, we should be studying how these people behave, rather than what they’re telling us,” added Prof. Miras.

Dr. Ali, who was also not involved in this review, noted that a problem affecting a lot of research in this area is that it comes out of smaller studies as double-blind controlled studies “require a lot of time and monetary investment.”

“Obesity is a multifactorial condition; genetics, hormones, activity, environment, socio-economic status all play a role in obesity. Therefore, no one intervention can work for all people suffering from obesity, and that makes it difficult to find the most effective treatment,” he cautioned.

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