If you've been paying attention to the news, you’ve probably heard about weight loss drugs like Wegovy and Zepbound, 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 Mounjaro), 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 agonists for weight loss?
Glucagon-like peptide-1 (GLP-1) is a hormone 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 slow gastric emptying, 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 metabolized 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 hormone (increase insulin, decrease glucagon, increase satiety, slow down gastric 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:
- Byetta™ (exenatide)
- Bydureon Bcise® (exenatide extended release)
- Ozempic (semaglutide)
- Rybelsus® (semaglutide, oral form)
- Trulicity® (dulaglutide)
- 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:
- Zepbound (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, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. (5, 6, 7) They 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 originally used 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 gastric acid secretion and gastric emptying, thereby reducing postprandial glucose (the amount of glucose in the blood after eating) as well as helping people feel fuller, longer. (2) It has been thought that this slowing down of gastric 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 a GLP-1s can result in weight loss 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 these medications are discontinued, weight is regained and improvements in markers of cardiovascular risk, like blood pressure, are lost. (12, 13, 14) Because of this, most prescribing information recommends staying on GLP-1s long-term 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, it should not be overlooked. 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 a prerequisite 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 may be used to combat 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. 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 glycemic 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.
Gastrointestinal issues tend to be the most common side effects when taking these medications. In a “real-life” cohort study of 175 patients taking semaglutide, 49% experienced adverse side effects including nausea and vomiting (37%), diarrhea (9%), fatigue (6%), constipation (6%), and abdominal pain (5%). (21) These side effects tended to be mild to moderate and stabilized after dose-escalation was stopped but 3% of people ended up discontinuing 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 clinical trials is enticing, real-world application of these medications does not always produce the same results. (22)
Additionally, current contraindications include anyone with a personal or family history of medullary thyroid cancer or diagnosed with multiple endocrine neoplasia syndrome type 2. The medication should be stopped at least two months before a planned pregnancy and should also be stopped prior to any surgery due to its effects on gastric emptying. (20)
When it comes down to it, if you are someone with obesity or type 2 diabetes, whether you should take a GLP-1 medication is a conversation reserved for you and your doctor. A focus on lifestyle, including healthy blood glucose, 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
It is possible to achieve similar effects of GLP-1s through diet and lifestyle. (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 gastric emptying, especially after a meal. This is one of the reasons why they are so effective for weight loss. This slow-down 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 gastric emptying and more stable post-meal glucose delays hunger after eating and increases satiety. An alternative way to do this 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-glycemic foods) and foods that promote satiety (like protein and fiber), similar to what a GLP-1 receptor agonist would do.
Eating a diet that is low in carbohydrates or focusing on low-glycemic foods can have similar effects to a GLP-1 medication (24), including:
- Eating slow-to-digest carbohydrates 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 less glucose spikes and less insulin secretion. (24)
- Low-glycemic 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)
- Low-glycemic diets may also reduce ghrelin (the hunger hormone) and increase adiponectin (a protein involved in cells response to insulin as well as fatty acid breakdown). (24)
- Low glycemic diets have been shown to increase GLP-1 naturally. (24)
If you do decide to take a GLP-1 medication, a focus on lifestyle, including healthy blood glucose, is a good idea in conjunction with these medications. Appetite changes induced by these medications may cause your eating patterns to shift and tastes for foods to change. (25)
Additionally, with any weight loss strategy, it’s important to pay attention to the foods you eat to minimize the loss of lean mass (aka muscle) while losing fat. Prioritizing 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:
“Weight care is important for most of us in the United States. Three out of four adults live with excess weight or obesity and prevalence among children and adolescents is growing. 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 fueling 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 maximize 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 loss journey and even enhance adherence to a low-carb or low-glycemic approach to nutrition. (26)
Additionally, a CGM can give you insight that can help to improve the quality of your diet, not just the quantity of what you are 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-glycemic diet versus those who did not have access to CGM their data. (26) Another small study found that having access to glucose data in real-time actually changed the participants preference for food, preferring a lower glycemic option over a higher glycemic option after the study. (27) This can impact your overall health and how you feel day-to-day, prioritizing your health beyond just weight loss. Being aware of foods that promote satiety and reduce glucose spikes can support weight loss goals, complementing lifestyle changes whether you choose to use a medication or not.
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