Retatrutide’s Mechanism of Action: How It Works for Weight Loss

Retatrutide is an investigational medication that’s being studied for weight loss, Type 2 diabetes, and more. And it’s made headlines for its clinical trial results. On average, people receiving the highest dose of the medication have lost about 28% of their starting body weight.

Retatrutide’s mechanism of action, or the way it works, makes it different from existing weight-loss medications. So what exactly sets it apart from the current FDA-approved options? Below, we discuss six ways that retatrutide works for weight loss to explain how it’s unique.

1. Retatrutide acts like three natural hormones

Retatrutide is sometimes called a “triple agonist,” a “GLP-3,” or “the triple G.” This is because it acts like three natural hormones that start with the letter G:

• Glucose-dependent insulinotropic polypeptide (GIP)

• Glucagon-like peptide-1 (GLP-1)

• Glucagon

If “GLP-1” sounds familiar, that’s because several medications mimic that hormone. Other medications that act like GLP-1 include semaglutide (Ozempic, Wegovy) and liraglutide (Victoza, Saxenda). There’s also a medication that acts like both GLP-1 and GIP: tirzepatide (Mounjaro, Zepbound).

If FDA approved, retatrutide will be the first medication in the U.S. to mimic all three hormones. This is the main way it differs from existing weight-loss medications that work similarly.

2. Retatrutide works in your gut to help you feel full

Retatrutide slows down the rate at which food exits your stomach. The process of food exiting the stomach is called gastric emptying. By slowing gastric emptying, it helps you feel fuller for longer. This may cause you to eat less, which can lead to weight loss over time. But it can also contribute to side effects such as nausea and constipation.

Retatrutide affects gastric emptying because it acts like GLP-1. All medications that mimic this hormone have a similar effect on the passage of food through the gut.

But keep in mind that the results of this action are most noticeable when people first start taking medications that act like GLP-1. Research suggests that a GLP-1 medication’s effect on gastric emptying may wear off over time, as the body adjusts to it. More research is needed to say whether people using retatrutide may experience slowed gastric emptying long term.

3. Retatrutide targets areas in your brain that regulate appetite

Retatrutide also affects how your brain regulates appetite. There are receptors (chemical binding sites) for GLP-1 and GIP in your brain. When retatrutide binds to these sites, it reduces your appetite. This can cause you to eat less and lose weight.

Animal studies suggest there may also be glucagon receptors in the brain that play a role in food intake. Scientists are studying whether activating glucagon receptors in humans’ brains has a similar effect.

4. Retatrutide may reduce cravings for certain foods

Retatrutide may help reduce food cravings. It might also lessen “food noise” (constant thoughts about eating). As a result, it may help you consume fewer calories throughout the day.

Medications that act like GLP-1 interfere with dopamine signals in your brain. Dopamine is a chemical messenger that acts like a reward for your brain. When you eat or drink something you’re craving, your brain releases dopamine. And this encourages you to crave (and consume) it again in the future.

By interfering with dopamine signals, retatrutide helps break this cycle. This can give you more control over your dietary choices. So while you can still eat the foods you enjoy, you’re in the driver’s seat — not your cravings.

5. Retatrutide may help your body break down fat cells

Retatrutide may also help break down fat cells. That’s because retatrutide acts like glucagon. This is another way it differs from existing weight-loss medications.

Glucagon is a natural hormone that helps your liver make new glucose (sugar) when needed. But it does more than that. Glucagon also:

• Helps your body break down fat cells

• Speeds up your metabolism

Think of glucagon like a sidekick to GIP and GLP-1. It provides an added metabolism boost to the other hormones’ appetite-balancing and craving-lowering effects.

Good to know: Glucagon can raise blood sugar levels. But GIP and GLP-1 work with your pancreas and liver to help balance your blood sugar. So they help counteract glucagon’s effects on blood sugar levels.

6. Retatrutide may counteract certain hunger hormones that affect weight gain

Retatrutide may also help keep certain hunger hormones in your body in check.

Ghrelin and leptin are two hormones that help you manage hunger and fullness. Ghrelin tells your body that you’re hungry and speeds up gastric emptying. Leptin helps you recognize that you’re full and slows gastric emptying.

When you eat fewer calories, your body increases ghrelin levels and decreases leptin levels. This makes you feel hungrier and signals to your brain that you should eat more. This is why maintaining weight loss can be difficult for many people.

GLP-1 medications, including retatrutide, may help counteract these shifting hormone levels. Research suggests that they help lower ghrelin levels and raise leptin levels, allowing you to feel fuller for longer. This is one reason scientists believe some GLP-1 medications can help people maintain weight loss long term.

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Written by:

Christina Aungst, PharmD, MWC

Christina Aungst, PharmD, MWC is a senior pharmacy editor for GoodRx. She began writing for GoodRx Health in 2019.

Reviewed by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

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