Understanding Zepbound Side Effects: A Comprehensive Guide for Patients and Clinicians

Nearly 70% of American adults have obesity or are classified as overweight, with many facing weight-related health conditions. Losing just 5-10% of body weight can reduce cardiovascular risk, but achieving and maintaining weight loss is a significant challenge for many Americans.

In late 2023 Zepbound (tirzepatide) was FDA-approved as a weight loss drug as well as a drug to lower blood sugar in type 2 diabetics. As more patients consider Zepbound, it’s necessary for both healthcare professionals and patients to understand its potential side effects and strategies for managing them. 

This guide provides an overview of Zepbound, its mechanism, common and serious side effects, and best practices for monitoring and addressing them.

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What is Zepbound?

Zepbound (tirzepatide) is a dual-acting drug that targets both GLP-1 and GIP receptors.

How is Zepbound (Tirzepatide) Different from Ozempic (Semaglutide)? 

Both Ozempic (semaglutide) and Zepbound (tirzepatide) work by activating GLP-1 receptors, which helps increase insulin release, decrease appetite, slow down stomach emptying, and reduce glucagon (a hormone that raises blood sugar). 

Together, these actions help people feel fuller and eat less, supporting weight loss.

Zepbound has an additional effect because it also targets GIP receptors. This dual action improves insulin sensitivity, boosts a hormone called adiponectin that aids in metabolism, and supports the function of pancreatic cells that produce insulin. 

By combining GLP-1 and GIP effects, Zepbound may be especially effective for managing both obesity and type 2 diabetes compared to medications that only target GLP-1 receptors.

Zepbound’s Mechanism of Action

As a dual GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) receptor agonist, Zepbound enhances insulin secretion, reduces glucagon release (glucagon is a hormone that raises blood sugar by releasing glucose from the liver), reduces appetite and slows gastric emptying, which leads to better blood sugar control and weight reduction. 

This dual action makes Zepbound particularly effective for patients with type 2 diabetes and those struggling with obesity.

FDA Approval and Clinical Indications

Approved by the FDA in late 2023, Zepbound is indicated for chronic weight management:

• In adults with a body mass index (BMI) of 30 or greater (obesity)

• or in adults with a BMI of 27 or greater (overweight) with at least one weight-related comorbidity such as hypertension, high cholesterol or type 2 diabetes. 

Clinical trials show Zepbound provides greater reductions in weight and blood sugar than semaglutide, offering a significant new option for patients with obesity and type 2 diabetes.

Common Zepbound Side Effects

While Zepbound shows promise in reducing weight and blood sugar, as a pharmaceutical it carries its own profile of side effects.

Mild Side Effects

Patients on Zepbound often report mild side effects, typically gastrointestinal in nature, including:

• Nausea: common, especially when starting the medication or increasing the dose.

• Vomiting and Diarrhea: may occur as the body adjusts to the medication.

• Decreased Appetite: while contributing to weight loss, it may also cause discomfort or food aversion.

• Constipation and Acid Reflux: these gastrointestinal side effects have also been reported.

• Headache and Dizziness: some patients experience mild headaches or dizziness as their bodies adapt.

Frequency and Severity

These mild side effects are most common but generally manageable, and often subside as treatment continues. 

Patients may notice improvement over time, particularly if they begin with a lower dose and gradually increase it as tolerated.

Managing Mild Side Effects

For mild gastrointestinal symptoms, patients can try simple remedies:

• Herbal Remedies: while often helpful, herbal supplements should always be discussed with your doctor.

• Ginger: drinking ginger tea or taking ginger supplements may help ease nausea.

• Chamomile Tea: known for its calming effects on the digestive system, chamomile tea can help relieve bloating, gas, and mild stomach discomfort. Patients may find it especially soothing in the evening.

• Peppermint: drinking peppermint tea or using peppermint oil capsules may help alleviate symptoms of nausea, vomiting, and stomach cramps. Peppermint is particularly effective for relieving gas and is best used after meals.

• Acupuncture: acupuncture has shown effectiveness in reducing nausea and vomiting across various conditions including postoperative and chemotherapy-related cases. Research is exploring whether acupuncture may also help patients with GLP-1-associated nausea and vomiting as well.

• Dietary Adjustments: eating smaller, more frequent meals can help manage nausea and reduce stomach discomfort.

Serious Zepbound Side Effects

While common side effects include symptoms of gastrointestinal distress, Zepbound also carries the risk of more serious side effects.

Severe Side Effects

Although less common, Zepbound can cause serious side effects that require prompt medical attention:

• Allergic Reactions: swelling, rash, or difficulty breathing can indicate an allergic reaction and requires immediate medical care.

• Cardiovascular Issues: in rare cases, Zepbound may increase heart rate or lead to arrhythmias, particularly in patients with a history of heart disease.

• Kidney Issues: dehydration from severe nausea or vomiting may lead to acute kidney injury.

• Pancreatitis: Inflammation of the pancreas can be signaled by severe abdominal pain and requires immediate medical intervention.

• Eyes: in people with diabetic retinopathy, symptoms may temporarily worsen with quick blood sugar improvements.

• Gallbladder Problems: rapid weight loss may increase the risk of gallstones (cholelithiasis) or gallbladder inflammation (cholecystitis).

• Blood Sugar: mild risk of low blood sugar (hypoglycemia), particularly in those using insulin or certain diabetes medications.

• Suicidal Behavior and Ideation: The FDA’s HIGHLIGHTS OF PRESCRIBING INFORMATION also report a recommendation to monitor for suicidal thoughts or behaviors, and to discontinue Zepbound if symptoms develop.

Zepbound Black Box Warning

Zepbound carries a black box warning:

• Thyroid C-Cell Tumors: animal studies have shown a potential for developing medullary thyroid carcinoma (MTC) with tirzepatide, although it’s unknown if this risk applies to humans. Tirzepatide is contraindicated for patients with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type-2 (MEN-2).

Who is at Risk for Severe Side Effects?

Patients with certain risk factors may be more susceptible to severe side effects:

• Age: older adults may experience side effects more intensely or have higher sensitivity to the medication.

• Pre-existing Conditions: those with heart, kidney, gallbladder or liver issues may be at greater risk.

• Medication Interactions: patients taking other medications should consult their provider about potential interactions that could amplify side effects.

• Hypersensitivity Reactions: those with previous severe hypersensitivity reactions to GLP-1 receptor agonists (e.g., anaphylaxis, swelling) should use caution.

• People with a personal or family history of medullary thyroid carcinoma, or patients with multiple endocrine neoplasia syndrome type-2 (MEN-2) should not use tirzepatide.

Managing and Reporting Zepbound Side Effects

It’s important to self-monitor for signs of side effects, especially when beginning Zepbound. This may help inform the appropriate dose for an individual.

Monitoring Side Effects

Both healthcare professionals and patients should be vigilant about monitoring for side effects, especially in the early stages of treatment. 

Regular follow-up visits are recommended to check how well the treatment is working (like monitoring HbA1c levels and weight), see how well the patient is tolerating it, and adjust the dose if needed. These visits usually start as soon as 4 weeks into treatment.

Day-to-Day Management

Patients using Zepbound for weight management can monitor their symptoms and response to natural therapies. 

• Tracking Symptoms: keeping a diary of any symptoms can help patients and providers address issues proactively.

• Staying Hydrated: adequate hydration may minimize or prevent kidney issues and gastrointestinal side effects.

• Natural Remedies: as discussed, patients can try herbal support such as ginger, peppermint or chamomile, along with acupuncture, small meals, and dietary adjustments.

When to Seek Medical Attention

Patients should seek medical care if they experience severe or persistent side effects:

• Seek immediate medical help if you experience severe abdominal pain, as this may be a sign of acute pancreatitis, a serious side effect of tirzepatide.

• Contact your doctor if you notice any changes in vision, especially if you have diabetic retinopathy, as rapid blood sugar control can temporarily worsen these symptoms.

• If you experience signs of a severe allergic reaction, such as swelling (angioedema) or difficulty breathing (anaphylaxis), seek urgent medical care.

Interactions and Contraindications

Certain drugs may interact with Zepbound, or Zepbound may reduce the efficacy of certain drugs. Zepbound is also contraindicated in certain individuals.

Drug Interactions

Certain medications or substances can interact with Zepbound, potentially increasing the risk of side effects:

• Use with Insulin or Insulin Secretagogues: Zepbound lowers blood sugar levels, so starting it may require reducing the dose of insulin or medications that increase insulin levels to prevent hypoglycemia.

• Impact on Oral Medications: Zepbound slows gastric emptying, which can affect how other oral medications are absorbed. Patients on drugs with narrow therapeutic windows (like warfarin) or those that require specific concentration levels should be monitored closely.

• Hormonal Contraceptives: oral hormonal contraceptives may be less effective with Zepbound. Patients should switch to non-oral contraceptives or add a barrier method for 4 weeks after starting Zepbound and after each dose increase. Non-oral hormonal contraceptives are not affected by Zepbound.

Contraindications

Zepbound is not recommended for certain individuals:

• Personal or Family History of Medullary Thyroid Carcinoma: animal studies suggest a risk of thyroid tumors with similar drugs.

• MEN-2 Syndrome: Zepbound is contraindicated in patients with multiple endocrine neoplasia syndrome type 2.

Zepbound in Special Populations

Certain people may need additional consideration when determining whether Zepbound is appropriate for their condition.

Pregnancy and Breastfeeding

Pregnancy: Zepbound is not recommended during pregnancy due to potential fetal harm. Pregnant patients should stop Zepbound if pregnancy is detected. There is a registry to monitor outcomes; healthcare providers or patients can report to Eli Lilly at 1-800-545-5979.

Lactation: no data exists on Zepbound's presence in breast milk or its effects on breastfeeding infants. Weigh the benefits of breastfeeding against potential risks from Zepbound.

Reproductive Potential

Zepbound may reduce the effectiveness of oral hormonal contraceptives. Patients should use a non-oral contraceptive or add a barrier method for 4 weeks after starting Zepbound and after each dose increase.

Pediatric and Geriatric Populations

Children: Zepbound’s safety and effectiveness have not been established for individuals under 18.

Geriatric Use: Zepbound appears as effective and safe in patients over 65 as in younger adults, based on clinical trial data.

Liver or Kidney Disease

Kidney Impairment: no dosage change is needed, but monitor kidney function in patients who experience side effects related to fluid loss.

Liver Impairment: no dosage adjustment is required for patients with liver impairment, as studies show no significant impact on drug levels.

Long-Term Use and Side Effects

Zepbound may be used long-term for weight and blood sugar management. Certain considerations may apply:

Chronic Use Considerations

Sustained Efficacy: Tirzepatide supports ongoing glycemic control and weight loss as a second-line diabetes therapy, with periodic dose adjustments based on patient response and tolerance to optimize results.

Long-term Risks: chronic users should be aware of risks like pancreatitis (similar to GLP-1 drugs), potential dehydration-related kidney issues, and thyroid cancer risks for those with certain thyroid conditions (like MEN-2).

Organ-Specific Cautions: gastrointestinal side effects (e.g., delayed gastric emptying) and kidney function need close monitoring, especially in those with existing health issues that may increase risks.

Periodic Monitoring

Key Tests: regular HbA1c and weight checks help track effectiveness and catch early side effects.

Follow-Up Frequency: check-ups are advised every 4 to 12 weeks to adjust doses and address any side effects.

‍Thyroid Monitoring: routine thyroid monitoring isn’t necessary for all, but high-risk patients (those with thyroid nodules or elevated calcitonin) may need additional screening.

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Key Takeaways

High Rates of Obesity: about 70% of American adults are overweight or obese, increasing their risk for heart disease. Losing 5-10% of body weight can help reduce this risk but is hard to maintain.

FDA Approval of Zepbound: approved in 2023, Zepbound (tirzepatide) helps with weight loss and blood sugar control in type 2 diabetes, offering unique benefits over similar medications.

Importance of Monitoring: both patients and healthcare providers should watch for side effects, especially early on, and use strategies to manage them.