How do the “G” meds used for weight loss differ? GLP-1s, GIPs and GGGs explained

Wondering about the differences between all the new medications being prescribed for weight loss? From GLP-1 receptor-agonist meds like Ozempic® or Wegovy® and GLP-1/GIP dual agonists to the triple agonists on the horizon–it can get confusing. You’ve come to the right place. Here’s a primer on GIP vs. GLP-1 medications and what they do.

First, a little about gut peptides

Let’s start at the beginning. Gut peptides (gastrointestinal hormones) are chains of amino acids that endocrine cells release into your bloodstream. From there, they travel to receptors throughout the body. They do a lot: 

• regulate insulin secretion

• stimulate the gallbladder to release bile

• help with digestion and nutrient absorption

• keep food moving through and out of the body (known as gut motility)

• help regulate appetite and satiety (fullness) 

Some gut peptides you may have heard of: 

• glucagon-like peptide 1 (GLP-1)

• glucose-dependent insulinotropic polypeptide (GIP)

• ghrelin (the “hunger hormone”)

Gut peptides like GLP-1 and GIP lower blood sugar levels, which is also known as the incretin effect. It works like this: After you eat, gut peptides begin stimulating insulin secretion in response to the typical rise in blood glucose post-meal. GLP-1 and GIP are the two primary incretin hormones that are naturally produced in your small intestine. GLP-1 is also produced in the colon. The hormones are made by your intestinal cells and released from your gut in response to nutrient ingestion (specifically glucose, dietary fiber, protein, and fatty acids from the food you eat). 

What are GLP-1 receptor agonists?

Called GLP-1 RAs or GLP-1 meds for short, glucagon-like peptide-1 receptor agonists are a class of drugs used to treat type 2 diabetes and obesity. These medications mimic what your natural GLP-1 hormone does: boosting insulin secretion, delaying gastric emptying (i.e., slowing digestion), decreasing the release of glucagon (another hormone that controls blood glucose), and increasing satiety. They may also protect cardiovascular function. The synthetic hormones bind to the GLP-1 receptors in your body just like your natural GLP-1 would. GLP-1 receptor agonists improve glycemic control and help reduce body weight in people with type 2 diabetes. 

Weight loss was a common side effect originally observed in the clinical trials for GLP-1 receptor agonists. It’s not fully understood how these receptor agonists cause weight loss, but we know that GLP-1 reduces hunger and slows digestion, so they may make you feel fuller longer. And as a result, you may eat less—and lose weight. GLP-1s are meant to be taken long-term, alongside lifestyle changes including more physical activity and a balanced food intake, and under a healthcare provider’s supervision. A well-known GLP-1 RA, semaglutide, is approved by the FDA for the treatment of type 2 diabetes under the brand names Ozempic and Rybelsus®. It’s FDA-approved for the treatment of obesity under the brand name Wegovy.

What are GLP-1/GIP dual agonist drugs?

GLP-1/GIP dual agonists combine GLP-1 and GIP into a single molecule. Dual agonists are thought to be more effective at lowering blood sugar and weight loss than GLP-1 RAs alone. This is because the GLP-1 and GIP agonists can bind to either receptor in the body.

Dual agonist drugs may also lead to a superior metabolism because the medication targets multiple signaling pathways simultaneously. (Metabolism is the result of many chemical reactions in your body’s cells that convert food into energy. And signaling pathways are a series of chemical reactions through which a group of molecules in a cell work together to control a cell’s function.) The addition of GIP may also help prevent fat storage; GIP receptors are abundant in fat and affect how your body metabolizes fat. Plus, GIP may stimulate GLP-1’s response in decreasing appetite. 

Recent clinical trials show that GLP-1/GIP dual agonists can significantly improve body weight, fasting and after-meal blood glucose levels, insulin sensitivity, and total cholesterol. Tirzepatide sold under the brand name Mounjaro® and Zepbound is the first GLP-1/GIP dual agonist approved by the FDA. Mounjaro is FDA-approved for type 2 diabetes, but it is also used off-label for weight loss. Zepbound has received FDA approval for weight loss.

GLP-1 and GLP-1/GIP medications do have some known potential side effects. The most common are nausea, vomiting, diarrhea, and acid reflux. More serious but less common side effects include pancreatitis, gallbladder disease, and worsening of diabetic eye disease. And those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasias should not use them. Find detailed side effects and risk information for specific medications by name here.

What are triple agonist medications? 

Medical weight loss is not only about GLP-1 vs. GIP, as triple agonists are in the works too. The triple agonist that is currently in development, and so is not yet available outside of clinical trials, is a GLP-1/GIP and glucagon receptor agonist (a GGG triagonist). Retatrutide is meant to bind to GIP, GLP-1, and glucagon receptors. Glucagon is a peptide hormone secreted by the pancreas. It stimulates glucose production in the liver to help regulate blood sugar. And since glucagon is involved with the liver and how it metabolizes fats and amino acids, it may increase your resting metabolic rate. And just like the single and dual agonist medications, a GGG triagonist may decrease appetite and help you feel fuller after eating. 

As of June 2023, Eli Lilly and Company–the pharmaceutical company behind Mounjaro–has published Phase 2 clinical trial results for retatrutide in The New England Journal of Medicine. The trial focused on treating obesity, showing an average weight loss of 17.5% at 24 weeks and 24.2% at 48 weeks at the highest dosage prescribed for adults with obesity and overweight. Moving ahead, Phase 3 clinical trials will assess its efficacy and tolerability for chronic weight management, obstructive sleep apnea, and knee osteoarthritis in people with obesity and overweight. 

A recap of GIP vs. GLP-1 and GGG medications

All GLP-1 medications mimic the naturally occurring gut hormone GLP-1 in an effort to help lower blood sugar and decrease appetite. Dual agonists and triple agonists aim to build on that. Dual agonists (which target GLP-1 and GIP receptors) can also help prevent fat storage. Triple agonists that are being developed to target three Gs (GLP-1, GIP, and glucagon) may also help increase metabolism. Some GLP-1 medications are FDA-approved to treat type 2 diabetes and used off-label for weight loss, while others are approved specifically to treat obesity.

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