Semaglutide Safety Information

Absolute Contraindications

Certain conditions absolutely preclude the use of semaglutide due to unacceptable safety risks. These contraindications are based on clinical trial data, post-marketing surveillance, and theoretical concerns from preclinical studies.

Personal or Family History of Medullary Thyroid Carcinoma (MTC)

Semaglutide carries a boxed warning regarding thyroid C-cell tumors based on rodent studies showing dose-dependent increases in thyroid C-cell adenomas and carcinomas, including medullary thyroid carcinoma. While the relevance to humans remains uncertain (human C-cells express minimal GLP-1 receptors compared to rodents), the severity of MTC and the inability to definitively rule out human risk led to this contraindication.

Anyone with personal history of MTC should never use semaglutide. Additionally, first-degree relatives (parents, siblings, children) of people with MTC should not use semaglutide due to potential hereditary risk. Before prescribing semaglutide, healthcare providers should specifically ask about personal and family history of thyroid cancer.

Multiple Endocrine Neoplasia Syndrome Type 2 (MEN2)

MEN2 is a hereditary condition caused by mutations in the RET proto-oncogene that dramatically increases risk of medullary thyroid carcinoma, pheochromocytoma, and parathyroid tumors. People with MEN2 have near-certain risk of developing MTC, often at young ages. Given the theoretical thyroid cancer risk with GLP-1 agonists, semaglutide is absolutely contraindicated in anyone with known or suspected MEN2.

MEN2 should be suspected in anyone with family history of MTC, pheochromocytoma, or hyperparathyroidism, particularly if occurring at young ages or in multiple family members. Genetic testing for RET mutations can confirm or rule out MEN2 in at-risk individuals.

Known Hypersensitivity to Semaglutide

Anyone with known serious hypersensitivity reaction (anaphylaxis, angioedema, severe rash) to semaglutide or any of its components should not use the medication. While serious allergic reactions are rare, they can be life-threatening. Previous allergic reaction to other GLP-1 agonists is a relative contraindication, as cross-reactivity may occur, though it's not absolute as the molecular structures differ.

Pregnancy

Semaglutide is contraindicated during pregnancy due to potential teratogenic effects observed in animal studies. In pregnant rats and rabbits, semaglutide caused embryo-fetal mortality, structural abnormalities, and growth alterations at exposures below the maximum recommended human dose. While animal findings don't always translate to humans, the potential risks outweigh any benefits during pregnancy.

Women of reproductive potential should use effective contraception while taking semaglutide. If pregnancy is planned, semaglutide should be discontinued at least 2 months before conception attempts (5 half-lives to ensure complete elimination). If pregnancy occurs while taking semaglutide, the medication should be discontinued immediately and the patient should contact their healthcare provider. For women with diabetes, alternative glucose-lowering medications safe in pregnancy (insulin, metformin) should be used.

Relative Contraindications and Precautions

Certain conditions require careful consideration and may preclude semaglutide use or require enhanced monitoring and precautions.

History of Pancreatitis

While not an absolute contraindication, history of pancreatitis warrants extreme caution with semaglutide. GLP-1 agonists have been associated with increased pancreatitis risk, and people with prior pancreatitis have substantially elevated recurrence risk. The decision to use semaglutide in someone with pancreatitis history should involve careful risk-benefit assessment, consideration of alternative treatments, and informed patient consent.

If semaglutide is used in someone with pancreatitis history, patients should be educated about pancreatitis symptoms (severe persistent abdominal pain radiating to the back, nausea, vomiting) and instructed to discontinue semaglutide and seek immediate medical care if these occur. Some experts recommend avoiding semaglutide entirely in people with pancreatitis history, particularly if recent or recurrent.

Severe Gastrointestinal Disease

Conditions affecting gastrointestinal motility or function may be exacerbated by semaglutide's delayed gastric emptying effects. These include gastroparesis, severe gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), and history of bowel obstruction. Semaglutide should be used cautiously if at all in these populations, with close monitoring for symptom worsening.

Gastroparesis deserves special mention. Pre-existing gastroparesis (whether diabetic or idiopathic) is likely to worsen with semaglutide due to its gastric emptying effects. Symptoms may become intolerable, and severe gastroparesis can lead to malnutrition and dehydration. Most experts recommend avoiding semaglutide in people with established gastroparesis. If symptoms of gastroparesis develop during semaglutide treatment (severe nausea, vomiting, early satiety, bloating), the medication should be discontinued.

Severe Renal Impairment

While no dose adjustment is required for mild to moderate renal impairment, data in severe renal impairment (eGFR <15 mL/min/1.73m² or end-stage renal disease requiring dialysis) are limited. Semaglutide can be used in this population but requires enhanced monitoring for adverse effects, particularly dehydration and electrolyte disturbances from gastrointestinal side effects. Acute kidney injury has been reported with semaglutide, usually in the context of severe dehydration.

Diabetic Retinopathy

The SUSTAIN-6 trial found increased risk of diabetic retinopathy complications with semaglutide, particularly in people with pre-existing retinopathy and those with rapid HbA1c reduction. This finding led to recommendations for ophthalmologic screening before starting semaglutide in people with diabetes and pre-existing retinopathy. If retinopathy is present, more frequent ophthalmologic monitoring may be warranted, and glucose lowering should be gradual rather than rapid.

History of Eating Disorders

Semaglutide's appetite suppression effects may be problematic in people with history of eating disorders, particularly anorexia nervosa or bulimia nervosa. The medication could potentially trigger relapse or exacerbate disordered eating patterns. Additionally, people with eating disorders may be at higher risk for gastroparesis. Use in this population requires careful psychiatric assessment, close monitoring, and often coordination with eating disorder specialists.

Depression and Suicidal Ideation

While comprehensive analysis has not confirmed increased risk of depression or suicidal ideation with semaglutide, anyone with history of depression, particularly with suicidal ideation or attempts, should be monitored closely. Any worsening of mood, emergence of suicidal thoughts, or behavioral changes should prompt immediate psychiatric evaluation. The benefits of weight loss on mood must be weighed against potential risks in vulnerable individuals.

Gallbladder Disease

Active gallbladder disease (symptomatic gallstones, cholecystitis) is not an absolute contraindication but requires consideration. Semaglutide may worsen symptoms or precipitate complications. History of gallbladder disease increases risk of recurrence. Some experts recommend cholecystectomy (gallbladder removal) before starting semaglutide in people with symptomatic gallstones, though this is not universally accepted.

Pre-Treatment Evaluation

Before initiating semaglutide, comprehensive evaluation helps identify contraindications, assess baseline status, and establish monitoring parameters.

Medical History

Detailed medical history should specifically address:

• Personal or family history of medullary thyroid carcinoma or MEN2
• History of pancreatitis (acute or chronic)
• Gastrointestinal disorders (gastroparesis, GERD, IBD, bowel obstruction)
• Kidney disease and current renal function
• Diabetic complications (retinopathy, neuropathy, nephropathy)
• Cardiovascular disease
• Gallbladder disease
• Eating disorders
• Depression or suicidal ideation
• Pregnancy plans or current pregnancy status
• Current medications, particularly insulin, sulfonylureas, and oral contraceptives
• Allergies to medications

Physical Examination

Baseline physical examination should include:

• Weight, height, and BMI calculation
• Blood pressure and heart rate
• Waist circumference
• Thyroid palpation (checking for nodules or enlargement)
• Abdominal examination
• Cardiovascular examination
• Assessment for signs of diabetic complications if applicable

Laboratory Testing

Recommended baseline laboratory tests include:

• HbA1c (if diabetes or prediabetes)
• Fasting glucose
• Comprehensive metabolic panel (kidney function, electrolytes, liver enzymes)
• Lipid panel
• Thyroid function tests (TSH, free T4)
• Pregnancy test for women of reproductive potential
• Consider: lipase/amylase (baseline for pancreatitis monitoring), calcitonin (controversial - not routinely recommended but some providers check)

Additional Evaluations

Depending on individual circumstances:

• Ophthalmologic examination for people with diabetes, especially if retinopathy suspected
• Abdominal ultrasound if gallbladder disease suspected
• Gastric emptying study if gastroparesis suspected
• Psychiatric evaluation if significant mental health concerns
• Nutritional assessment, particularly for older adults or those at malnutrition risk

Safe Initiation and Dose Escalation

Proper initiation and dose escalation are crucial for minimizing side effects and optimizing adherence.

Standard Dose Escalation Schedule

For diabetes (Ozempic):

• Weeks 1-4: 0.25 mg once weekly
• Weeks 5+: 0.5 mg once weekly (maintenance dose for most patients)
• If additional glycemic control needed after ≥4 weeks: increase to 1 mg once weekly
• If still inadequate after ≥4 weeks on 1 mg: consider increasing to 2 mg once weekly

For weight management (Wegovy):

• Weeks 1-4: 0.25 mg once weekly
• Weeks 5-8: 0.5 mg once weekly
• Weeks 9-12: 1 mg once weekly
• Weeks 13-16: 1.7 mg once weekly
• Week 17+: 2.4 mg once weekly (maintenance dose)

Rationale for Gradual Escalation

The gradual dose escalation serves multiple purposes. First, it allows tolerance to develop to gastrointestinal side effects, which are most pronounced when starting treatment or increasing doses. Second, it provides opportunity to assess individual response and tolerability before committing to higher doses. Third, it reduces risk of severe adverse events. Clinical trials that used this escalation schedule had lower discontinuation rates than studies using faster escalation.

Managing Dose Escalation Challenges

If intolerable side effects occur during dose escalation:

• Delay dose increase by 1-2 weeks to allow more time for tolerance development
• Consider smaller dose increments (though this requires off-label dosing)
• Implement side effect management strategies (dietary modifications, anti-nausea medications)
• If side effects persist, may need to remain at lower dose or discontinue

Some people never tolerate the full target dose. This is acceptable—treatment should be individualized based on response and tolerability. A lower dose that is tolerated and provides benefit is preferable to a higher dose that causes intolerable side effects and leads to discontinuation.

Injection Technique

Proper injection technique is important for safety and efficacy:

• Inject subcutaneously in abdomen, thigh, or upper arm
• Rotate injection sites to prevent lipodystrophy
• Allow medication to reach room temperature before injecting (reduces injection site reactions)
• Use proper technique: pinch skin, insert needle at 90-degree angle, inject slowly, hold for 6 seconds before withdrawing
• Dispose of needles properly in sharps container
• Never share pens or needles between people

Timing and Consistency

Semaglutide can be injected at any time of day, with or without meals. However, consistency is important—inject on the same day each week. If a dose is missed, inject as soon as remembered if within 5 days of the missed dose. If more than 5 days have passed, skip the missed dose and resume the regular schedule. Never double up doses to make up for a missed dose.

Ongoing Monitoring

Regular monitoring helps detect adverse effects early, assess treatment response, and guide dose adjustments.

Clinical Monitoring

At each follow-up visit (typically every 1-3 months initially, then every 3-6 months once stable):

• Weight and BMI
• Blood pressure and heart rate
• Assessment of side effects (gastrointestinal symptoms, injection site reactions, etc.)
• Review of glucose monitoring data if applicable
• Assessment of dietary intake and nutritional status
• Evaluation of physical activity
• Mental health screening
• Medication adherence assessment

Laboratory Monitoring

Recommended laboratory monitoring schedule:

• HbA1c: Every 3 months until stable, then every 6 months (if diabetes)
• Comprehensive metabolic panel: Every 3-6 months (monitor kidney function, electrolytes, liver enzymes)
• Lipid panel: Every 6-12 months
• Consider lipase/amylase if abdominal pain develops
• Thyroid function: Annually or if symptoms develop

Glucose Monitoring

For people with diabetes:

• Self-monitoring of blood glucose frequency depends on diabetes regimen
• Those on insulin or sulfonylureas need more frequent monitoring due to hypoglycemia risk
• Continuous glucose monitoring can be valuable for detecting hypoglycemia and assessing glycemic patterns
• Target glucose ranges should be individualized based on age, comorbidities, and hypoglycemia risk

Specialized Monitoring

Depending on individual risk factors:

• Ophthalmologic examination: Annually for people with diabetes, more frequently if retinopathy present
• Thyroid ultrasound: If thyroid nodule palpated or symptoms develop (not routine screening)
• Abdominal imaging: If gallbladder symptoms develop
• Gastric emptying study: If severe gastroparesis symptoms develop
• Psychiatric evaluation: If mood changes or suicidal ideation emerge

Medication Adjustments

Semaglutide often necessitates adjustments to other medications, particularly for diabetes management.

Insulin Dose Reduction

When adding semaglutide to insulin therapy:

• Reduce basal insulin dose by 20% when starting semaglutide
• Monitor glucose closely and adjust further based on response
• Some people can discontinue insulin entirely as semaglutide dose increases
• Bolus insulin doses may need reduction as appetite decreases and carbohydrate intake declines
• Continuous glucose monitoring is particularly valuable during this transition

Sulfonylurea Dose Reduction

When adding semaglutide to sulfonylurea therapy:

• Reduce sulfonylurea dose by 50% when starting semaglutide
• Monitor for hypoglycemia closely
• Many people can discontinue sulfonylureas as semaglutide dose increases
• Consider switching to medications with lower hypoglycemia risk (metformin, SGLT2 inhibitors, DPP-4 inhibitors)

Blood Pressure Medication Adjustments

Semaglutide's blood pressure-lowering effects may necessitate antihypertensive dose reductions:

• Monitor blood pressure regularly, especially during dose escalation
• If blood pressure drops below target or symptoms of hypotension develop, reduce antihypertensive doses
• Some people can discontinue one or more antihypertensive medications
• Maintain blood pressure monitoring even after medication adjustments

Other Medication Considerations

• Oral contraceptives: Consider additional contraceptive methods due to potential absorption effects
• Levothyroxine: May need dose adjustment; monitor TSH
• Warfarin: Monitor INR more frequently as weight loss can affect warfarin metabolism
• Diuretics: May need dose reduction if dehydration occurs from gastrointestinal side effects

Lifestyle Modifications

Semaglutide is most effective when combined with appropriate lifestyle modifications. These are not optional add-ons but essential components of safe, effective treatment.

Dietary Recommendations

• Reduced-calorie diet: Aim for 500-1000 calorie deficit from baseline
• Adequate protein: At least 1.2-1.6 g/kg body weight daily to preserve muscle mass
• Balanced macronutrients: Include adequate healthy fats and complex carbohydrates
• Smaller, more frequent meals: Helps manage early satiety and nausea
• Avoid high-fat meals: Can exacerbate nausea and delayed gastric emptying
• Adequate hydration: Especially important given gastrointestinal side effects
• Micronutrient supplementation: Multivitamin recommended, especially with significant calorie restriction

Physical Activity

• Aerobic exercise: At least 150 minutes moderate-intensity weekly
• Resistance training: At least 2-3 sessions weekly to preserve muscle mass
• Gradual progression: Start slowly and increase intensity/duration gradually
• Consistency: Regular activity is more important than intensity
• Variety: Mix different types of activity to maintain engagement

Behavioral Strategies

• Self-monitoring: Track weight, food intake, physical activity, and glucose (if applicable)
• Goal setting: Establish realistic, specific, measurable goals
• Problem-solving: Identify barriers and develop strategies to overcome them
• Social support: Engage family, friends, or support groups
• Stress management: Address emotional eating and develop healthy coping strategies
• Sleep hygiene: Aim for 7-9 hours nightly; poor sleep undermines weight loss efforts

Emergency Situations

Certain symptoms require immediate medical attention. Patients should be educated about these warning signs.

Seek Emergency Care Immediately For:

• Severe persistent abdominal pain, especially if radiating to the back (possible pancreatitis)
• Severe right upper quadrant pain with fever (possible cholecystitis)
• Signs of severe allergic reaction (difficulty breathing, swelling of face/lips/tongue/throat, severe rash)
• Severe hypoglycemia with confusion, loss of consciousness, or seizures
• Chest pain or pressure (possible cardiac event)
• Severe dehydration (inability to keep down fluids, decreased urination, severe dizziness)
• Signs of bowel obstruction (severe abdominal pain, inability to pass gas or stool, severe bloating)
• Suicidal ideation or intent

Contact Healthcare Provider Promptly For:

• Persistent nausea or vomiting lasting more than 3 days
• Severe diarrhea (more than 6 loose stools daily for more than 3 days)
• Signs of dehydration (dark urine, dizziness, rapid heartbeat)
• Unexplained weight loss exceeding 2-3 pounds per week
• New or worsening vision changes
• Symptoms of hypoglycemia occurring frequently
• Persistent headache or neurological symptoms
• Mood changes or worsening depression
• Thyroid nodule or neck swelling
• Pregnancy or suspected pregnancy

Long-Term Safety Considerations

As semaglutide is increasingly used for chronic treatment, long-term safety considerations become important.

Duration of Treatment

Clinical trials have followed participants for up to 4 years, demonstrating sustained benefits and acceptable safety profiles. However, many people may use semaglutide for longer periods. Questions remain about very long-term safety (decades of use), particularly regarding thyroid cancer risk, bone health, and muscle mass preservation. Ongoing post-marketing surveillance and long-term extension studies will provide additional data.

Bone Health

Rapid weight loss can negatively affect bone health, increasing fracture risk. While semaglutide trials have not shown increased fracture rates, this remains a theoretical concern, particularly for older adults and postmenopausal women. Strategies to protect bone health include ensuring adequate calcium and vitamin D intake, weight-bearing exercise, and bone density monitoring in high-risk individuals.

Muscle Mass Preservation

Loss of lean muscle mass with semaglutide-induced weight loss is a concern, particularly for older adults at risk of sarcopenia. Long-term strategies to preserve muscle include adequate protein intake, regular resistance exercise, and potentially slower rates of weight loss. Some experts recommend periodic DEXA scans to monitor body composition, particularly in older adults.

Nutritional Status

Prolonged appetite suppression and reduced food intake raise concerns about nutritional adequacy. Micronutrient deficiencies can develop, particularly with very low calorie intakes. Regular nutritional assessment, multivitamin supplementation, and consultation with a registered dietitian can help prevent deficiencies.

Weight Maintenance After Discontinuation

Most people regain substantial weight after discontinuing semaglutide. Strategies for maintaining weight loss include intensive lifestyle modification, consideration of alternative weight loss medications, and possibly intermittent or reduced-dose semaglutide treatment. More research is needed on optimal strategies for long-term weight maintenance after semaglutide discontinuation.

Special Populations

Older Adults

Older adults may derive substantial benefit from semaglutide but also face unique risks:

• Higher risk of dehydration from gastrointestinal side effects
• Greater concern about muscle loss and sarcopenia
• Increased fall and fracture risk with rapid weight loss
• More likely to be taking multiple medications with interaction potential
• May have reduced renal function requiring closer monitoring

Consider slower dose escalation, more frequent monitoring, emphasis on protein intake and resistance exercise, and careful assessment of whether weight loss benefits outweigh risks in frail older adults.

Adolescents

Semaglutide is approved for type 2 diabetes in adolescents aged 10 and older but not for weight management in this age group. Use in adolescents requires special considerations:

• Long-term effects on growth and development unknown
• Psychological impacts of weight loss medication in developing individuals
• Importance of family involvement and lifestyle modification
• Need for pediatric endocrinology expertise
• Careful monitoring of growth, puberty, and bone health

Racial and Ethnic Minorities

Clinical trials enrolled predominantly white populations, with limited representation of certain racial and ethnic groups. Some evidence suggests response to GLP-1 agonists may vary by race/ethnicity, though more research is needed. Healthcare providers should be aware of potential differences in response and side effect profiles across diverse populations.

Quality Assurance: Brand vs. Compounded

The shortage of brand-name semaglutide has led to widespread use of compounded versions, which raise important safety considerations.

FDA-Approved Formulations

Brand-name semaglutide (Ozempic, Wegovy, Rybelsus) undergoes rigorous FDA review ensuring:

• Consistent purity and potency
• Sterility and absence of contaminants
• Proper storage and stability
• Accurate dosing
• Post-marketing surveillance for adverse events

Compounded Semaglutide

Compounded semaglutide is not FDA-approved and may vary in:

• Purity (may contain impurities or degradation products)
• Potency (may be under- or over-dosed)
• Sterility (risk of contamination)
• Stability (may degrade more rapidly)
• Formulation (may use different salt forms or excipients)

If using compounded semaglutide, ensure the compounding pharmacy:

• Is licensed and follows USP standards
• Provides certificates of analysis from independent laboratories
• Uses pharmaceutical-grade ingredients
• Follows proper sterile compounding procedures
• Provides clear labeling and storage instructions

Even with these precautions, compounded products carry inherent risks not present with FDA-approved formulations. Reports of adverse events from compounded semaglutide underscore these concerns.