How do GLP-1s, GLP-1/GIP dual agonists, and triple agonists work for weight loss?

Lately, everybody is raving about drugs like Ozempic® and Wegovy® and how effective these and other GLP-1 medications are for weight loss. But it can be hard to find legitimate information about these medications and whether they might be right for you. And with so many GLP-1 medications* available now, things can get a little confusing. So we’re explaining a bit about each, including how they help aid weight loss. 

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Now, here’s how each GLP-1 helps aid in weight loss.

What are GLP-1 and GIP?

In case you’re not familiar, glucagon-like peptide-1 (GLP-1) is a peptide hormone your body naturally makes in your small intestine and colon. Another gut peptide hormone your body makes is glucose-dependent insulinotropic polypeptide (GIP), which is produced in the small intestine. Both are released in response to eating nutrients—specifically amino acids, glucose, dietary fiber, and fatty acids in food. 

One of the many effects of GLP-1 and GIP is helping regulate blood glucose levels by promoting insulin secretion–known as the incretin effect. This helps to lower blood sugar levels. GLP-1 also delays gastric emptying (digestion) and decreases secretion of glucagon, another hormone involved in regulating blood glucose. Both GLP-1 and GIP play a role in making and breaking down lipids such as cholesterol and triglycerides. They can also affect how your body metabolizes and stores fat. GIP receptors are abundant in fat, and it’s thought that they help prevent fat buildup in the body. 

How GLP-1 medications work for weight loss 

GLP-1s are a class of medications approved by the U.S. Food and Drug Administration (FDA) to treat type 2 diabetes and obesity. GLP-1 medications work by mimicking the actions of your natural GLP-1, binding to cells throughout your body that have GLP-1 receptors, and ultimately lowering blood sugar. Weight loss was initially observed as a side effect of GLP-1 medications in clinical trials testing the drugs for type 2 diabetes. Now researchers are working to understand the mechanism of how GLP-1s work in the body for weight loss.

What we do know is that GLP-1 medications slow digestion, leading you to feel more satiated, so you might eat less—and drop pounds. Interestingly, research suggests that GLP-1 may be impaired in some people with obesity, even if they have a normal glucose tolerance. This may help explain why GLP-1 drugs are so effective in helping some people with obesity lose weight. 

There are currently six GLP-1 medications:

• Exenatide, taken twice daily: This was the first FDA-approved GLP-1. Sold under the brand name Byetta®, it’s approved to treat type 2 diabetes.  
• Exenatide extended-release (ER), taken weekly: FDA-approved under the brand name Bydureon® to treat type 2 diabetes. 
• Liraglutide, taken daily: FDA-approved under the brand name Saxenda® for chronic weight management alongside diet and exercise in adults with a body mass index (BMI) of 30 or higher or a BMI of 27 or higher with a weight-related medical condition or in children ages 12 years and older with obesity who weigh at least 132 pounds. It’s also FDA-approved under the brand name Victoza® to treat type 2 diabetes and to reduce the risk of adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease. 
• Dulaglutide, taken weekly: FDA–approved to improve A1C levels in patients with type 2 diabetes who have established cardiovascular disease or multiple cardiovascular risk factors under the brand name Trulicity®.
• Semaglutide, taken weekly: Possibly the most well-known of them all, FDA-approved under the brand names Ozempic for type 2 diabetes and to reduce the risk of a major adverse cardiovascular event in adults with type 2 diabetes or an established cardiovascular disease and Wegovy for obesity. 
• Oral semaglutide, taken daily: Branded under Rybelsus®, it’s FDA-approved to treat type 2 diabetes.

All GLP-1s listed are injections except for oral semaglutide. 

How GLP-1/GIP dual agonists work for weight loss

GLP-1/GIP dual agonists (or "co-agonists") mimic the actions of two peptide hormones, GLP-1 and GIP. Like GLP-1 medications, co-agonists can lower blood sugar. And—with the addition of GIP—their ability to reduce appetite may be enhanced.

GLP-1/GIP dual agonists are thought to be more effective at lowering blood glucose and body weight than GLP-1s alone. That’s because dual agonists increase the chance of binding to either receptor in your body. And since they can target multiple signaling pathways simultaneously, dual agonist drugs may also lead to improved metabolic action. In fact, recent clinical trials have shown that people with type 2 diabetes who have taken a dual agonist had the following markers improve significantly:

• body weight
• fasting and after-eating glucose levels
• insulin sensitivity
• total cholesterol

The only GLP-1/GIP dual agonist currently on the market is tirzepatide, branded under Mounjaro®. Mounjaro can help you feel fuller faster and help regulate blood glucose levels, cravings, and appetite. That said, it’s been shown to be extremely effective for weight loss, too. Mounjaro is FDA-approved to treat type 2 diabetes alongside diet and exercise. But it can also be prescribed off-label for weight reduction because substantial evidence supports its effectiveness. Off-label prescribing is a common practice among clinicians to prescribe an FDA-approved drug at different doses or for conditions other than what the drug is approved for.

How tri-agonists work for weight loss

Tri-agonists are just like co-agonists but with the addition of glucagon receptor agonists. Adding glucagon means the medication can bind not only to GLP-1 and GIP receptors (and mimic the actions of these hormones) but also to glucagon receptors. Glucagon is a peptide hormone secreted by the pancreas that helps regulate blood sugar. Since glucagon signals your liver to convert stored glucose to energy and metabolize fats and amino acids, it may help increase your resting metabolic rate. It’s also thought to decrease appetite and increase satiety.

Retatrutide, a GIP/GLP-1/Glucagon receptor agonist (GGG tri-agonist) in development by Eli Lilly and Company, isn’t on the market yet. Currently, this GGG tri-agonist is in phase two clinical trials to determine its efficacy in the treatment of obesity and type 2 diabetes. 

What are the side effects of GLP-1 and GIP medications?

Not everyone experiences side effects from GLP-1 and GIP medications. When side effects do occur, they tend to be minor and include symptoms such as nausea, vomiting, gastrointestinal issues, and diarrhea. Headaches, dizziness, slightly increased heart rate, infections, hypoglycemia, and upper respiratory congestion may also occur. Since most GLP-1 and GIP medications are administered through subcutaneous injections, there is a possibility of experiencing itchiness and redness at the injection site. 

If you have a family history of medullary thyroid cancer, multiple endocrine neoplasias, or acute pancreatitis, it is advisable to avoid using GLP-1 drugs. GIP-1s and GIPs are not appropriate for pregnant women and individuals with severe gastrointestinal conditions such as gastroparesis and inflammatory bowel disease.

Bottom line

Weight loss medications aren’t for everyone. They’re meant to be taken long-term alongside lifestyle changes, and under a healthcare provider’s supervision. It’s up to you and your healthcare provider to determine if GLP-1s are right for you. Since there are multiple causes for obesity, your doctor might recommend weight-loss medications that aren’t GLP-1s. That’s why Found provides a comprehensive set of prescription medications in addition to behavior change support and access to clinicians trained in obesity medicine. 

GLP-1*

GLP-1 prescriptions, filled through your local pharmacy, are now available as part of Found's weight-loss toolkit. While GLP-1s are effective for weight loss, they are not clinically appropriate for everyone. Eligibility for a GLP-1 is based on a thorough evaluation of your medical history, eating behavior, lab work, and insurance coverage. If a GLP-1 is not appropriate for you, our providers will work with you to determine an effective medication for your health profile.

About Found

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