Semaglutide & Tirzepatide Side Effects: Complete Guide to Contraindications

Understanding GLP-1 Medication Side Effects

GLP-1 receptor agonists like semaglutide and tirzepatide are among the most effective weight loss medications available today. Cora Health providers prescribe both medications and monitor patients throughout treatment. Like all prescription medications, they carry potential side effects ranging from mild and manageable to rare but serious. Understanding these effects before starting treatment helps you make informed decisions and recognize when to contact your provider.

Side effect prevalence: the numbers across the FDA-approved clinical trials

The exact frequency of GLP-1 side effects is well-documented in the pivotal clinical trials that supported FDA approval. The numbers below come from the original Phase III trials published in the New England Journal of Medicine.

Semaglutide 2.4 mg (Wegovy) — from STEP 1 (Wilding et al., NEJM 2021), 1961 participants: - Nausea: 44.2% (vs 16.1% placebo) - Diarrhea: 31.5% (vs 15.9% placebo) - Vomiting: 24.8% (vs 6.2% placebo) - Constipation: 23.4% (vs 9.5% placebo) - Treatment discontinuation due to adverse events: 7.0% (vs 3.1% placebo) - Serious adverse events: 9.8% (vs 6.4% placebo); most considered unrelated to study drug

Tirzepatide 15 mg (Zepbound) — from SURMOUNT-1 (Jastreboff et al., NEJM 2022), 2539 participants: - Nausea: 29.6% at 15 mg dose (vs 9.5% placebo) - Diarrhea: 23.0% at 15 mg dose (vs 7.3% placebo) - Vomiting: 12.2% at 15 mg dose (vs 1.7% placebo) - Constipation: 17.1% at 15 mg dose (vs 5.8% placebo) - Treatment discontinuation due to adverse events: 6.2% at 15 mg dose (vs 2.6% placebo)

Critical context: these figures reflect studies of the FDA-approved branded products only. Per the U.S. Food and Drug Administration, "Compounded drugs are not FDA-approved. This means the FDA does not review these drugs to evaluate their safety, effectiveness, or quality before they are marketed" (FDA — Compounding and the FDA: Questions and Answers). Side effect rates for compounded semaglutide and compounded tirzepatide have not been formally measured in equivalent trials. Mechanistically the same molecule should produce similar effects, but this is not a substitute for trial-based evidence. Individual results vary.

Common Side Effects of Semaglutide

The most frequently reported side effects of semaglutide are gastrointestinal in nature, particularly during dose escalation phases. These typically improve as your body adjusts to the medication.

• Nausea — affects up to 44% of patients, most common in the first 4–8 weeks
• Vomiting — reported in about 24% of patients during initial titration
• Diarrhea — occurs in approximately 30% of users
• Constipation — affects up to 24% of patients
• Abdominal pain or discomfort
• Decreased appetite (desired effect, but can be excessive in some)
• Fatigue, especially in the first few weeks
• Headache during dose increases
• Injection site reactions (redness, swelling, itching)

Common Side Effects of Tirzepatide

Tirzepatide's dual GLP-1 and GIP receptor activity produces a similar side effect profile to semaglutide, though some studies suggest slightly higher rates of GI symptoms due to its dual mechanism. In clinical trials (SURMOUNT program), the following were most commonly reported:

• Nausea — approximately 29.6% of participants at the 15mg dose per SURMOUNT-1 (NEJM 2022); rates were higher in earlier titration phases
• Diarrhea — approximately 30% across all doses
• Vomiting — reported in 20–25% during titration
• Constipation — affects roughly 17% of patients
• Decreased appetite and early satiety
• Dyspepsia (indigestion)
• Abdominal pain
• Hair thinning (telogen effluvium) — often temporary
• Injection site reactions

Serious Warnings and Black Box Alerts

Both semaglutide and tirzepatide carry a black box warning regarding thyroid C-cell tumors. The FDA-approved prescribing information for Wegovy (semaglutide) states the warning verbatim:

"WARNING: RISK OF THYROID C-CELL TUMORS. In rodents, semaglutide causes thyroid C-cell tumors. It is unknown whether WEGOVY causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as the human relevance of semaglutide-induced rodent thyroid C-cell tumors has not been determined. WEGOVY is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)."

(Source: FDA-approved Wegovy prescribing information.) The equivalent boxed warning appears in the FDA-approved prescribing information for Zepbound (tirzepatide).

Other serious but rare risks documented in the FDA-approved labels include: - Acute pancreatitis — discontinue immediately if suspected; symptoms include severe persistent abdominal pain radiating to the back. - Acute kidney injury — often secondary to dehydration from GI side effects; particularly relevant in patients with pre-existing renal disease. - Serious hypersensitivity reactions — including anaphylaxis and angioedema. - Diabetic retinopathy complications — primarily documented in type 2 diabetes patients with pre-existing retinopathy. - Acute gallbladder disease — cholelithiasis and cholecystitis reported in clinical trials. - Suicidal ideation — currently under post-market FDA review; contact your provider immediately if you experience mood changes or thoughts of self-harm.

These serious adverse events are rare in clinical trials of the FDA-approved branded products. Compounded medications are not FDA-approved and have not been independently evaluated for these specific safety signals at trial scale; serious adverse event rates for compounded versions are not formally measured.

Contraindications: Who Should Not Take These Medications

Certain individuals should not use GLP-1 receptor agonists. Your Cora physician reviews your health history specifically to screen for these contraindications during the assessment process.

• Personal or family history of medullary thyroid carcinoma (MTC)
• Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
• Known hypersensitivity to semaglutide or tirzepatide or any excipients
• Pregnancy or active breastfeeding (discontinue at least 2 months before attempting conception)
• Severe gastrointestinal disease (e.g., gastroparesis)
• History of pancreatitis (use with caution or avoid)
• Severe renal impairment (eGFR < 15 mL/min)
• Concurrent use of other GLP-1 receptor agonists

Practical Tips for Managing Side Effects

Most GI side effects are manageable with lifestyle adjustments. Clinical experience suggests the following strategies significantly reduce discomfort:

• Eat smaller, more frequent meals — avoid large portions that overwhelm your slowed gastric emptying
• Stay well-hydrated — sip water throughout the day, especially if experiencing vomiting or diarrhea
• Avoid high-fat, greasy, or spicy foods in the first weeks of treatment
• Inject on a consistent day and time each week
• Ask your provider about anti-nausea options (e.g., ginger supplements, prescription ondansetron) if nausea is severe
• Do not rush through dose escalation — slower titration dramatically reduces side effects
• Avoid lying down immediately after eating

When to Contact Your Provider Immediately

While most side effects are mild, certain symptoms require prompt medical attention. Contact your Cora provider or seek emergency care if you experience:

• Severe abdominal pain that radiates to the back (possible pancreatitis)
• Persistent vomiting that prevents you from keeping down fluids
• Signs of allergic reaction: rash, swelling of the face or throat, difficulty breathing
• Vision changes
• Signs of dehydration: dizziness, dark urine, rapid heartbeat
• Unusual changes in mood or thoughts of self-harm
• A lump or swelling in the neck, hoarseness, or trouble swallowing

Sources & verification

All side-effect prevalence figures, contraindications, and boxed-warning language in this article are sourced from FDA-approved prescribing information and peer-reviewed Phase III clinical trials published in the New England Journal of Medicine. Article last verified 2026-05-12.

• FDA-approved Wegovy (semaglutide 2.4 mg) prescribing information: accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf
• FDA-approved Zepbound (tirzepatide) prescribing information: accessdata.fda.gov/drugsatfda_docs/label/2023/217806s000lbl.pdf
• FDA-approved Ozempic (semaglutide for type 2 diabetes) prescribing information: accessdata.fda.gov/drugsatfda_docs/label/2020/209637s003lbl.pdf
• FDA — "Compounding and the FDA: Questions and Answers" (regulatory status of compounded medications): fda.gov/drugs/human-drug-compounding/compounding-and-fda-questions-and-answers
• STEP 1 (Wilding et al., NEJM 2021); foundational Phase III trial for semaglutide 2.4 mg weight management — 14.9% mean weight loss, full adverse event profile in supplementary appendix: nejm.org/doi/full/10.1056/NEJMoa2032183
• SURMOUNT-1 (Jastreboff et al., NEJM 2022); foundational Phase III trial for tirzepatide 5/10/15 mg weight management — 22.5% mean weight loss at 15 mg, full adverse event profile in supplementary appendix: nejm.org/doi/full/10.1056/NEJMoa2206038
• CDC — Adult Obesity Facts (41.9% US prevalence per NHANES 2017–March 2020): cdc.gov/obesity/adult-obesity-facts
• FDA Adverse Event Reporting System (FAERS) — public dashboard for adverse event reports for any drug, including post-market surveillance signals: fda.gov FAERS public dashboard
• Cora Health Compounded vs Brand-Name GLP-1 Comparison (internal sister article): /blog/compounded-vs-brand-glp1
• Cora Health 2026 GLP-1 Telehealth Industry Report (12-provider pricing and methodology): /blog/cora-2026-glp1-industry-report