GLP-1 receptor agonists for weight loss: What are they?

If you've been paying attention to the news, you’ve probably heard about weight loss drugs like Wegovy® and Mounjaro®, which are in a class of medications called GLP-1 receptor agonists (for the purpose of this article, we will refer to these medications as GLP-1s).  While these drugs were originally developed to treat people with type 2 diabetes and come by different names (for example, Ozempic® or Saxenda®), some are approved to treat obesity due to their significant effects on body weight. 

In this article, we’ll delve into the science behind GLP-1s, exploring how they work in the body, what the clinical evidence shows, and their potential as a treatment for obesity along with alternative treatment options that don’t require medication. 

What are GLP-1 receptor agonists for weight loss? 

Glucagon-like peptide-1 (GLP-1) is a hormone naturally produced in cells of the intestine. 

Its main action is to stimulate the release of insulin in response to rising glucose levels after eating a meal. It also blocks the release of glucagon, which is a hormone that works opposite of insulin to raise blood glucose by promoting the release of glucose from the liver into the bloodstream. This results in a reduction of glucose spikes after eating. ¹ 

GLP-1 also acts in the brain and gastrointestinal (GI) tract to reduce appetite and how quickly the stomach empties, resulting in increased satiety after meals and a reduction in food intake. ² 

When naturally produced in the body in response to food intake, GLP-1 is rapidly metabolised and inactivated by the enzyme dipeptidyl peptidase IV (DPP-4) even before the hormone has left the gut. ¹ 

This is where GLP-1 receptor agonists come in. An agonist is a substance that mimics the action of a hormone to produce a response. 

Scientists were able to develop a GLP-1 receptor agonist, which means the molecule can bind with GLP-1 receptors and produce the same physiological actions as the natural hormone (increase insulin, decrease glucagon, increase satiety, slow down stomach emptying), without being rapidly degraded by DPP-4. 

GLP-1 isn’t the only gut hormone with glucose-lowering effects (called incretin hormones) that scientists have targeted. Glucose-dependent insulinotropic polypeptide (GIP) also lowers glucose and was discovered to have an additive effect when administered with GLP-1. ^3,4 

One such drug (tirzepatide) on the market today targets the effects of two incretins and is a dual GIP and GLP-1 receptor agonist. Most of the GLP-1s are injectable medications and approved for people with type 2 diabetes. However, three drugs have been approved by the FDA for the treatment of obesity when used with diet and exercise. 

GLP-1 receptor agonists for type 2 diabetes

• Bydureon® (exenatide) 
• Ozempic® (semaglutide) 
• Rybelsus® (semaglutide, oral form) 
• Wegovy® (semaglutide) 
• Trulicity® (dulaglutide) 
• Lyxumia® (lixisenatide) 
• Victoza® (liraglutide) 
• Mounjaro® (tirzepatide)  

All GLP-1 medications approved for type 2 diabetes require a prescription and should only be considered with the help of your doctor. 

GLP-1 receptor agonists for obesity and excess weight with weight-related medical conditions

• Mounjaro® (tirzepatide) 
• Wegovy® (semaglutide) 
• Saxenda® (liraglutide) 

Tirzepatide, semaglutide, and liraglutide for weight management also require a prescription. They have been approved for weight management in people with a BMI of 30 or higher or those with a BMI of 27 or higher who also have one weight-related comorbidity such as hypertension, dyslipidaemia, obstructive sleep apnoea, or cardiovascular disease. ^5,6,7

These drugs are taken as once-weekly (semaglutide and tirzepatide) or once-daily (liraglutide) injections in combination with diet and exercise to promote weight loss. (8) Beyond weight management, one drug (semaglutide) is approved to lower risk of major cardiovascular events such as death, heart attack, and stroke in people with excess weight or obesity and known heart disease. (9) 

Why are GLP-1 agonists used for weight loss? 

Along with GLP-1 medication’s effect on insulin and glucagon as mentioned, they also play a significant role in the central and peripheral nervous system and GI tract. 

While doctors originally used them for their ability to reduce both fasting and after-meal glucose levels in people with diabetes, GLP-1s have also been found to reduce food intake by direct interaction with GLP-1 receptors in the brain that regulate appetite. ²

These medications also inhibit meal-stimulated stomach acid secretion and stomach emptying, thereby reducing postprandial glucose (the amount of glucose in the blood after eating) as well as helping people feel fuller for longer. ² 

It has been thought that this slowing down of stomach emptying after meals may be more important to regulate postprandial glucose than GLP-1 medication’s effect on insulin and glucagon because nutrients take longer to reach the small intestine, thereby reducing the postprandial glucose spike. ² 

While a medication for weight loss might sound appealing, these drugs are not intended for those who are just looking to drop a few pounds. 

Clinical trials have found that for people with a significant amount of weight to lose, the use of GLP-1s can result in weight loss of around 15% of body weight as well as improvements in cardiovascular risk factors such as better blood pressure and plasma levels of LDL, HDL, and triglycerides. ^10,11 

However, clinical trials showed that once people stop taking these medications, they regain weight and lose improvements in markers of cardiovascular risk, like blood pressure. ^12,13,14 Because of this, most prescribing information recommends long-term use of GLP-1s to sustain weight loss and other health benefits. ¹⁵ 

Additionally, studies of GLP-1s show that between 10-50% of the total weight lost comes from lean body mass. ¹⁶ While this is in line with other methods of weight loss such as a reduced calorie diet or bariatric surgery, we shouldn’t overlook it. 

Maintaining lean body mass (aka muscle) during weight loss is crucial because it helps preserve metabolic rate, supports physical function, and contributes to a healthier body composition. All of these are essential when it comes to keeping a healthy metabolism and promoting long-term weight management success. 

Whether pursuing weight loss via medication, surgery, or diet and lifestyle, incorporating physical activity is essential for any obesity treatment; exercise helps to preserve as much lean mass as possible while also losing fat. ¹⁰ 

Eating sufficient protein and incorporating strength training are other strategies that doctors may recommend to combat the loss of lean mass when losing weight. ^17,18 

Emerging research is starting to look at strategies that support the discontinuation of these medications while also sustaining weight loss and the other positive metabolic effects achieved while taking them. 

For instance, one recent study published in Diabetes Therapy showed that carbohydrate-restricted nutrition therapy (aka a very low-carb diet) supported via telemedicine allowed patients on GLP-1s to stop the medication while sustaining both weight loss as well as improvements in glycaemic control. ¹⁹ 

What are the side effects of GLP-1 agonists?

GLP-1s represent a substantial therapeutic advancement in the treatment of excess weight and obesity. 

Many weight loss medications of the past have come with serious side effects that don’t always outweigh the reductions in fat mass. ²⁰ While these medications can offer significant benefits for some, others may not want a pharmacological approach due to personal, medical, or cultural preferences or needs. 

GI issues tend to be the most common side effects when taking these medications. In a “real life” study of 175 patients taking semaglutide, 49% experienced adverse side effects including nausea and vomiting (37%), diarrhoea (9%), fatigue (6%), constipation (6%), and abdominal pain (5%). ²¹ 

These side effects tended to be mild-to-moderate and stabilised after dose-escalation was stopped, but 3% of people ended up stopping the medication due to side effects and 9% required the dose to be reduced or not escalated to the max dose. ²¹

One thing to also note is that while the significant weight loss seen in well-controlled clinical trials is enticing, real-world application of these medications does not always produce the same results. ²² 

Additionally, people shouldn’t use GLP-1s if they have a personal or family history of medullary thyroid cancer or a diagnosis of multiple endocrine neoplasia syndrome type 2. People should stop taking the medication at least two months before a planned pregnancy and should also stop it before any surgery due to its effects on the emptying of the stomach. ²⁰ 

When it comes down to it, if you’re someone with obesity or type 2 diabetes, whether you should take a GLP-1 medication or not is a conversation reserved for you and your doctor. 

A focus on lifestyle, including healthy glucose levels, attention paid to hunger and fullness, and physical activity is useful for anyone trying to manage their weight, whether on these medications or not. 

Diet and lifestyle changes that mimic GLP-1 agonists

Research involving people with type 2 diabetes suggests that it’s possible to achieve similar effects to GLP-1s through diet and lifestyle changes. ²³ 

While their original action of helping to regulate glucose after meals was the reason these medications were first approved for people with diabetes, they also persistently slow stomach emptying, especially after a meal. This is one of the reasons why they’re so effective for weight loss. 

This slowdown delays the time glucose enters your system, allowing insulin to more easily match the glucose consumed and reduce the overall insulin demand. ²⁴ The slowed stomach emptying and more stable post-meal glucose subsequently delays hunger after eating and increases satiety. An alternative way to get the same effect would be to choose foods that help you avoid these glucose spikes in the first place and eat foods that are slower to absorb (like low-glycaemic foods) and foods that promote satiety (like protein and fibre). Eating a diet that is low in carbs or focusing on low-glycaemic foods can have similar effects to a GLP-1 medication ²⁴.

Here's how: 

• Eating slow-to-digest carbs such as non-starchy vegetables, beans and legumes, or whole grains results in lower postprandial glucose and insulin. ²⁴ 
• Protein and fat digest more slowly, leading to fewer glucose spikes and less insulin secretion. ²⁴ 
• Low-glycaemic diets have been shown to decrease leptin (a hormone that promotes fullness and helps regulate metabolism). A decrease in leptin suggests an improvement in leptin resistance, which is common in obesity, meaning your body can better regulate appetite and metabolism. ²⁴ 
• A low-glycaemic diet may reduce ghrelin (the hunger hormone) and increase adiponectin (a protein involved in insulin responses as well as fatty acid breakdown). ²⁴ 
• Low-glycaemic diets have been shown to increase natural levels of the GLP-1 hormone. ²⁴ 

If you do decide to take a GLP-1 medication, focusing on your lifestyle alongside, including healthy glucose levels, is a good idea. Appetite changes induced by these medications may cause your eating patterns to shift and tastes for foods to change. ²⁰ 

Additionally, with any weight management strategy, it’s important to pay attention to the foods you eat to minimise the loss of lean mass (aka muscle) while losing fat. Prioritising protein, strength training, and eating foods that help keep your glucose steady are key components to help maintain a healthy metabolism while losing weight. 

A final note from Lingo

Lingo’s Director of Clinical Research, Amy McKenzie, PhD, has studied the interaction of GLP-1s and nutrition. She said: 

“The role of GLP-1s or any other medication in weight care is a decision only a person and their doctor can make, but regardless of whether we choose to include medication in a weight care plan, nutrition plays a foundational role. 

With medication like GLP-1s, which have the power to significantly reduce food intake, we need to be sure we’re fuelling the body with adequate protein, vitamins, and minerals to support maintaining our muscle – it’s critical as we age. 

On the other hand, research shows that reducing glucose exposure through diet changes can help some people achieve as much weight loss as a medication could do for them and it can help them transition off the medication if they can’t be or don’t want to be on it for a lifetime. 

So no matter where we are in our weight journeys, getting our fuel right is key.” 

Whether you choose to use a GLP-1 medication or not, focusing on lifestyle is essential to maximise benefits, with or without medication support. 

Using a continuous glucose monitor (CGM) like Lingo can offer valuable data on your unique response to foods. This understanding can help to guide nutrition and exercise to support your weight management journey and even enhance adherence to a low-carb or low-glycaemic approach to nutrition. ²⁵ 

Additionally, a CGM can give you insights that can help to improve the quality of your diet, not just the quantity of what you’re eating. In a study of 40 adults, it was found that those who were wearing a CGM and able to see the data in real-time were able to better adhere to a low-glycaemic diet versus those who did not have access to their CGM data. ²⁵ 

Another small study found that having access to glucose data in real-time actually changed the participants preference for food, preferring a low-glycaemic option over a high-glycaemic option after the study. ²⁶ This can impact your overall health and how you feel day-to-day, prioritising your health beyond just weight loss. 

Being aware of foods that promote satiety and reduce glucose spikes can support weight management goals, complementing lifestyle changes whether you choose to use a medication or not. 

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