5 retatrutide side effects: what we know from clinical trials

Retatrutide is a new, not-yet-approved drug being developed and studied by Eli Lilly for weight loss. Currently, the only way to get retatrutide is through a clinical trial, but since it may soon be available, many people have questions about retatrutide side effects and safety.​

So, what are the side effects of retatrutide? Like other similar weight loss medications, retatrutide primarily causes gastrointestinal issues.

Below, we’ll unpack the most common retatrutide side effects clinical trials have uncovered, plus answer common questions like, “Is retatrutide safe?” and “How long do retatrutide side effects last?”

There isn’t an official side effect profile for retatrutide yet because the drug is still being studied and hasn’t been approved by the United States Food and Drug Administration (FDA). But we know that retatrutide is a triple-hormone receptor agonist. It mimics glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon hormones. 

While retatrutide acts on glucagon too, it makes sense that it would cause similar side effects to GLP-1s like Wegovy (semaglutide) or GLP-1/GIPs like Zepbound (tirzepatide).

Here are the side effects reported by participants in recent retatrutide clinical trials:​

• Nausea

• Vomiting

• Diarrhea

• Constipation

• Dyspepsia (heartburn)

• Decreased appetite

• Abdominal pain

Dysesthesia (abnormal skin sensations) has also been reported. This side effect may feel like burning, tingling, pain, or tightness in the skin without an external cause. Though it feels like a skin issue, dysesthesia is actually a neurological, or nerve-related, side effect.

Remember, this information on retatrutide side effects may change. Until — and unless — the FDA approves retatrutide, the medication’s full side effects and safety profile won't be known.

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Like semaglutide or tirzepatide, retatrutide most commonly causes gastrointestinal symptoms. Here are the five most common retatrutide side effects reported in Phase 2 and Phase 3 clinical trials.

1. Nausea

In the latest Phase 3 clinical trials, nausea was the most frequently reported side effect. It occurred in close to 40% of participants taking 9 mg of retatrutide and 43% of those taking the 12 mg dose.​

Like other GLP-1s, nausea seems more common the higher your dose. And since researchers say the safety profile appears similar to that of other GLP-1s, we might assume nausea will be most frequent during dose escalation.

Fortunately, there are strategies to help manage nausea caused by GLP-1s.

How to manage nausea:

• Eat smaller, but more frequent meals.

• Eat slowly and mindfully, chewing each bite before swallowing.

• Avoid high-fat, greasy foods. Instead, opt for foods that can ease nausea, such as crackers, apple slices, mints, or ginger.

2. Diarrhea

Diarrhea — defined as having watery stool three or more times a day — is a common GLP-1 side effect. Though retatrutide involves other hormones, it is a GLP-1 receptor agonist. And true to form, retatrutide has led to diarrhea in about 35% of people taking 9 mg weekly, and about 33% of people taking 12 mg weekly. 

GLP-1 agonists like retatrutide can change the amount of fluid released in the gut. If you have diarrhea, it’s very important to stay hydrated so that you don’t lose more fluids through your digestive system than you consume.

How to manage diarrhea:

• Drink more water than usual to prevent dehydration.

• Try the BRAT diet — or stick to bland foods like rice or toast — to alleviate stomach cramping.

• Consider limiting or avoiding dairy and greasy foods.

• Temporarily lower your fiber intake until diarrhea improves.

If these tips aren’t helping enough, reach out to your healthcare provider for personalized advice. They may recommend a dose adjustment or an anti-diarrheal medication.

3. Vomiting

In retatrutide clinical trials, about 20% of participants taking retatrutide reported vomiting (compared to zero participants in the placebo group).​

One of the ways retatrutide works is by slowing digestion so that food stays in your stomach longer. That can make vomiting more likely, especially if you’re already feeling nauseated or if you’ve just eaten a large amount of food in one sitting.

How to manage vomiting:

• Eat smaller portions more often, and take smaller bites.

• Don’t lie down immediately after eating.

• Avoid processed, greasy, or rich foods, which can exacerbate nausea.

• Don’t drink fluids during meals. Instead, time your sips 30–60 minutes before and after you eat.

If nausea or vomiting continues despite these tips, contact your health care provider. They may adjust your dose or prescribe medicine to help.

4. Constipation

GLP-1s famously slow down digestion, so it’s no wonder some people start to feel a little stopped up when taking them. In clinical trials, constipation was common, affecting about 22% of people taking 9 mg of retatrutide and 25% of people on 12 mg of retatrutide.

By mimicking the gut hormone GIP, retatrutide might make you feel full fast, causing you to eat and drink less. This can also make bowel movements less frequent, especially if you’re not focusing enough on hydration and fiber.

How to manage constipation:

• Gradually add more fiber-rich foods to your diet, like oats, avocados, and beans.

• Drink lots of water throughout the day.

• Get moving — take a walk, jog around the block — to help get your bowels moving, too. 

You can also consider using an over-the-counter laxative for constipation relief. Check in with a healthcare provider if constipation doesn’t improve.

5. Dysesthesia

In a phase 3 retatrutide clinical trial, some participants experienced mild dysesthesia, which is an unusual skin sensation or skin sensitivity, such as unexplained stinging, burning, or pain. It affected:

• Nearly 9% of people on 9 mg of retatrutide

• Nearly 21% of people on 12 mg of retatrutide

Dysesthesia isn’t the most common retatrutide side effect, but it’s one worth knowing about and monitoring for. Researchers say more studies are needed to understand how and why a GLP-1 — or, in this case, a triple-receptor-agonist — sometimes causes dysesthesia. 

How to manage dysesthesia:

• Tell your healthcare provider what you’re experiencing.

• Avoid scratching or rubbing.

• Try wearing loose-fitting, comfortable clothing.

• Limit alcohol intake.

Research on retatrutide is ongoing, but as with most medications, side effect duration can vary from person to person.

From what we know, retatrutide side effects seem to be dose-dependent. Meaning, the higher the dose, the higher the risk of side effects. Typically, this  also means you’re more likely to experience side effects after dose increases.

If retatrutide is like other GLP-1 medications, side effects should improve with time, as your body gets used to the drug. Don’t hesitate to contact your healthcare provider if side effects don’t go away or are severe enough to interfere with your daily life.  

Since retatrutide is still being studied, we don’t know the full extent of potential serious side effects. GLP-1s in general may have the potential to cause certain rare but serious side effects, so the same may apply to retatrutide. These include:

• Thyroid cancer: It isn’t known if GLP-1s cause thyroid tumors in humans, but for now, anyone with a personal or family history of medullary thyroid carcinoma (a specific kind of thyroid cancer) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) should avoid taking retatrutide. 

• Pancreatitis (inflammation of the pancreas): Anyone on retatrutide should tell their healthcare provider if they experience severe abdominal pain, nausea, fever, or vomiting.

• Gallbladder problems: Likewise, be sure to report gallbladder-related symptoms, such as upper stomach pain, fever, clay-colored stools, or yellowing skin or eyes. 

• Kidney problems: GLP-1s can cause kidney issues, especially if you become dehydrated. If you have kidney problems, make sure your healthcare provider knows, and self-monitor for worsening symptoms.

• Hypoglycemia (low blood sugar): GLP-1s can lower blood sugar, so the risk of hypoglycemia is amplified if you’re taking a diabetes medication such as insulin. Pay attention to unexplained dizziness, lightheadedness, or blurry vision. 

• Serious allergic reactions: Any medication, including retatrutide, can cause serious allergic reactions. Seek urgent medical attention if you have trouble breathing, sudden hives, or swelling in your lips, tongue, or throat.

Currently, retatrutide side effects look similar to those of other GLP-1s. Weight loss medications such as Wegovy (semaglutide), Zepbound (tirzepatide), or Foundayo (orforglipron) can all cause gastrointestinal issues. However, clinical trials suggest that retatrutide is more likely to cause dysesthesia than other medications. 

Below, find a comparison of the official side effect profiles of other GLP-1s and what we know about retatrutide side effects so far. However, these rates aren’t a direct comparison as they come from separate placebo-controlled clinical trials of each drug.

When comparing retatrutide with other weight loss medications like semaglutide or tirzepatide, it’s impossible to overemphasize that retatrutide is still being studied. There is still no official, FDA-approved list of side effects.

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Retatrutide is an investigational triple receptor agonist drug that looks very promising for weight loss. But it’s not without side effects (and it hasn’t been FDA-approved yet). 

• In clinical trials, retatrutide peptide side effects look similar to GLP-1 side effects. The most common side effects are digestive symptoms, such as nausea, diarrhea, vomiting, and constipation.

• Retatrutide may also cause dysesthesia. Up to 21% of retatrutide clinical trial participants have reported strange skin sensations. 

• Rare but serious side effects may occur. Retatrutide is a GLP-1 (along with acting on GIP and glucagon), and GLP-1s have the potential to cause serious side effects such as a specific type of thyroid tumors, pancreatitis, and gallbladder or kidney issues. 

• Contact your healthcare provider if you experience lasting, severe, or worsening side effects on retatrutide. This is especially important during a clinical trial, as trial data helps form a clearer picture of a medication’s safety profile.

• Retatrutide isn’t yet available. It’s still being studied, so the only way to get retatrutide currently is if you’re part of a clinical trial.