What are the indications, dosing regimens, contraindications, adverse effects, and monitoring recommendations for semaglutide (Wegovy, Rybelsus) in adults?

Semaglutide (Wegovy, Rybelsus): Clinical Overview

Indications

Semaglutide is FDA-approved for two distinct indications: chronic weight management (Wegovy 2.4 mg) and type 2 diabetes treatment (Rybelsus oral, Ozempic injectable). 1

Weight Management (Wegovy 2.4 mg)

• Adults with BMI ≥30 kg/m² qualify without additional requirements 1, 2
• Adults with BMI ≥27 kg/m² require at least one weight-related comorbidity (hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, or obstructive sleep apnea) 1, 2
• Cardiovascular risk reduction: For patients with established cardiovascular disease and BMI ≥27 kg/m², semaglutide 2.4 mg reduces cardiovascular death, nonfatal MI, or nonfatal stroke by 20% (HR 0.80) 1

Type 2 Diabetes (Rybelsus, Ozempic)

• Indicated for glycemic control in adults with type 2 diabetes as monotherapy or combination therapy 1
• Particularly beneficial for patients requiring both glucose lowering and weight loss 1
• Preferred for patients with established cardiovascular disease due to 26% reduction in major adverse cardiovascular events (HR 0.74,95% CI 0.58-0.95) 1

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Dosing Regimens

Wegovy (Semaglutide 2.4 mg for Weight Loss)

Slow titration over 16-20 weeks is essential to minimize gastrointestinal adverse effects. 1

• Week 1-4: 0.25 mg subcutaneously once weekly 1
• Week 5-8: 0.5 mg once weekly 1
• Week 9-12: 1.0 mg once weekly 1
• Week 13-16: 1.7 mg once weekly 1
• Week 17+: 2.4 mg once weekly (maintenance dose) 1

Missed dose protocol: 1

• If ≤4 days since missed dose: administer as soon as possible
• If >4 days since missed dose: skip and resume at next scheduled dose
• If 2 consecutive doses missed: resume at same dose if previously tolerated
• If ≥3 consecutive doses missed: consider restarting titration schedule

Rybelsus (Oral Semaglutide for Type 2 Diabetes)

• Week 1-30 days: 3 mg once daily 1
• After 30 days: Increase to 7 mg once daily 1
• Optional escalation: 14 mg once daily if additional glycemic control needed 1

Critical administration requirements: 1

• Take on empty stomach with ≤4 oz water
• Wait 30 minutes before eating, drinking, or taking other medications
• Failure to follow these instructions significantly reduces absorption

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Contraindications

Absolute Contraindications

• Personal or family history of medullary thyroid carcinoma (MTC) – based on animal studies showing thyroid C-cell tumors 1, 3
• Multiple endocrine neoplasia syndrome type 2 (MEN 2) 1, 3
• Pregnancy or breastfeeding – potential fetal exposure 1
• History of severe hypersensitivity reaction to semaglutide 1

Relative Cautions

• History of pancreatitis – use with caution; causality not definitively established 1
• Symptomatic gallbladder disease – semaglutide increases risk of cholelithiasis and cholecystitis by 38% versus placebo 1
• Severe gastroparesis or significant GI motility disorders – may worsen symptoms 1
• Recent heart failure decompensation – avoid GLP-1 receptor agonists 1

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Adverse Effects

Common Gastrointestinal Effects (Most Frequent)

Nausea, vomiting, and diarrhea are dose-dependent and typically resolve within 4-8 weeks. 1, 2

• Nausea: 18-44% of patients 1
• Diarrhea: 12-32% of patients 1
• Vomiting: 8-25% of patients 1
• Constipation: 10-23% of patients 1
• Abdominal pain: Common, typically mild-to-moderate 1

Mitigation strategies: 1

• Slow titration (as outlined above)
• Reduce meal size
• Limit alcohol and carbonated beverages
• Eat slowly and stop when comfortably full

Serious Adverse Events

• Pancreatitis – rare but serious; discontinue if persistent severe abdominal pain occurs 1
• Gallbladder disease – 38% higher risk of cholelithiasis and cholecystitis versus placebo 1
• Acute kidney injury – monitor renal function, especially with dehydration from GI effects 1
• Delayed gastric emptying – creates aspiration risk during anesthesia; retained gastric contents documented in 24.2% of semaglutide users versus 5.1% of controls despite extended fasting 1

Hypoglycemia Risk

• Minimal risk as monotherapy due to glucose-dependent mechanism 1
• Increased risk when combined with insulin or sulfonylureas – requires dose reduction of these agents 1

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Monitoring Recommendations

Pre-Treatment Screening

• Screen for personal/family history of MTC or MEN 2 (absolute contraindications) 1
• Obtain baseline HbA1c and fasting glucose (for diabetes patients) 1
• Check comprehensive metabolic panel including renal function (eGFR) and liver enzymes 1
• Document history of pancreatitis or gallbladder disease 1
• Assess cardiovascular disease status 1

During Titration Phase (First 16-20 Weeks)

• Every 4 weeks: Assess gastrointestinal tolerance, weight loss progress, blood pressure, and signs of pancreatitis or gallbladder disease 1, 2
• For diabetes patients: Monitor fasting glucose and adjust concomitant medications (reduce insulin by 20%, reduce/discontinue sulfonylureas) 1

Maintenance Phase (After Reaching Target Dose)

• Every 3 months minimum: Monitor weight, blood pressure, cardiovascular risk factors, medication adherence 1, 2
• For diabetes patients: Check HbA1c every 3 months until target achieved, then every 3-6 months 1
• Renal function: Monitor periodically, especially if GI side effects cause dehydration 1

Treatment Response Evaluation

Assess efficacy at 12-16 weeks on maximum tolerated dose. 1, 2

• Continue therapy if: Weight loss ≥5% of baseline body weight 1, 2
• Consider discontinuation if: Weight loss <5% after 3 months at therapeutic dose 1, 2

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Special Populations & Considerations

Renal Impairment

• No dose adjustment required for any degree of renal impairment, including eGFR <30 mL/min/1.73 m² 1
• Monitor for dehydration secondary to GI side effects 1

Cardiovascular Disease

• Semaglutide 2.4 mg is preferred for patients with established CVD due to proven 20% reduction in cardiovascular events 1
• Monitor blood pressure closely as weight loss may necessitate antihypertensive medication adjustment 1

Perioperative Management

Discontinue semaglutide at least 3 weeks (three half-lives) before elective surgery requiring anesthesia due to delayed gastric emptying and aspiration risk 1, 2

• For diabetic patients, consult endocrinology to weigh risks/benefits of holding medication 1
• Consider gastric ultrasound pre-operatively to assess residual gastric contents 1

Concomitant Medications

• Insulin: Reduce dose by 20% when initiating semaglutide 1
• Sulfonylureas: Discontinue or reduce dose by 50% to prevent hypoglycemia 1
• DPP-4 inhibitors: Discontinue before starting semaglutide (no additional benefit) 1
• Oral contraceptives: Women should switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation (applies to tirzepatide, similar caution for semaglutide) 1

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Weight Loss Efficacy

Clinical Trial Data

• Semaglutide 2.4 mg: Mean weight loss of 14.9-16.0% at 68 weeks 1, 4, 5
• 64.9% of patients achieve ≥10% weight loss 1
• Real-world data: Mean weight loss of -14.1% to -17.6% at 12 months 4, 5
• Long-term (24 months): Mean weight loss of -20.4% with patient support program 4

Weight Regain After Discontinuation

Significant weight regain occurs after stopping semaglutide—patients regain one-half to two-thirds of lost weight within 1 year. 1

• This highlights the need for lifelong treatment to maintain weight loss 1
• Patients must be counseled that semaglutide requires long-term use in conjunction with lifestyle modifications 1

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Lifestyle Integration (Mandatory)

Pharmacotherapy must be combined with lifestyle modifications for optimal outcomes. 1, 2

• Caloric deficit: 500-kcal reduction below daily requirements 1, 2
• Physical activity: Minimum 150 minutes/week of moderate-intensity exercise 1, 2
• Resistance training: Essential to preserve lean body mass 1, 3
• Behavioral counseling: Structured lifestyle management support 1, 2

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Cost Considerations

• Semaglutide 2.4 mg (Wegovy): ~$1,557-$1,619 per 30-day supply 1, 2
• Oral semaglutide (Rybelsus): Similar cost to injectable formulations 1
• Insurance authorization may be challenging, particularly for obesity management without diabetes 1
• Long-term financial planning is essential given the need for lifelong treatment 1

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Common Pitfalls to Avoid

• Do not skip slow titration – initiating at maintenance dose markedly increases GI adverse events and discontinuation rates 1
• Do not prescribe to normal-weight patients – no safety or efficacy data exists, and risk-benefit ratio is unacceptable 3
• Do not ignore perioperative aspiration risk – discontinue 3 weeks before elective surgery 1, 2
• Do not combine with other GLP-1 receptor agonists or DPP-4 inhibitors – no additional benefit 1
• Do not forget to reduce insulin/sulfonylureas – failure to do so significantly increases hypoglycemia risk 1