How do I initiate tirzepatide (Mounjaro) for weight loss in an adult patient with BMI ≥ 30 kg/m² (or ≥ 27 kg/m² with a weight‑related comorbidity) after confirming no contraindications and obtaining baseline labs?

How to Initiate Tirzepatide (Mounjaro) for Weight Loss

Start tirzepatide at 5 mg subcutaneously once weekly, then escalate by 5 mg every 4 weeks (5 mg → 10 mg → 15 mg) based on gastrointestinal tolerance, while combining treatment with a 500-kcal daily caloric deficit and at least 150 minutes of weekly moderate-intensity exercise. 1

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Patient Eligibility Criteria

Confirm the patient meets BMI thresholds:

• BMI ≥ 30 kg/m² qualifies without additional requirements 1
• BMI ≥ 27 kg/m² requires at least one weight-related comorbidity (hypertension, dyslipidemia, type 2 diabetes, obstructive sleep apnea, or cardiovascular disease) 1

Screen for absolute contraindications before prescribing:

• Personal or family history of medullary thyroid carcinoma 1
• Multiple endocrine neoplasia syndrome type 2 (MEN2) 1
• History of severe hypersensitivity to tirzepatide 2

Use with caution if:

• History of pancreatitis (causality not definitively established, but monitor closely) 1
• Symptomatic gallbladder disease (tirzepatide increases cholelithiasis/cholecystitis risk) 2
• Severe gastroparesis or clinically meaningful GI motility disorders 2

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Pre-Treatment Assessment

Obtain baseline measurements:

• Body weight and BMI 1
• Blood pressure (tirzepatide lowers BP; antihypertensive adjustments may be needed) 1
• Lipid panel (total cholesterol, LDL, HDL, triglycerides) to assess cardiovascular risk 2
• Fasting glucose and HbA1c if diabetes is suspected 2
• Comprehensive metabolic panel including liver enzymes (mild ALT elevation is common in obesity/MASLD) 2

Review concomitant medications:

• If on insulin: reduce basal insulin by 20% immediately to prevent hypoglycemia 2
• If on sulfonylureas: discontinue or reduce dose by 50% before starting tirzepatide 2
• If on DPP-4 inhibitors: stop entirely (no additional benefit when combined with tirzepatide) 2
• Women on oral contraceptives: switch to non-oral methods or add barrier contraception for 4 weeks after initiation and each dose escalation 2

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Dosing and Titration Schedule

Week 0–4: Start at 5 mg subcutaneously once weekly 1

• This is the FDA-approved starting dose designed to minimize gastrointestinal adverse events 2
• Administer on the same day each week (timing of day is flexible) 2
• Inject subcutaneously in abdomen, thigh, or upper arm 2

Week 5–8: Increase to 10 mg once weekly 1

• Advance dose only if the 5 mg dose is tolerated (no severe nausea, vomiting, or diarrhea) 1
• The 4-week interval between dose changes minimizes GI side effects 1

Week 9–12: Increase to 15 mg once weekly (maximum dose) 1

• This is the highest approved weekly dose for weight loss 3
• At 15 mg, expect mean weight loss of 20.9% at 72 weeks 3

If a dose is missed:

• ≤ 4 days late: administer as soon as possible, then resume regular schedule 2

• 4 days late: skip the missed dose and give the next dose on the originally scheduled day 2

• ≥ 3 consecutive doses missed: consider restarting the titration schedule 2

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Mandatory Lifestyle Interventions

Dietary modification:

• Prescribe a 500-kcal daily caloric deficit below maintenance requirements 1
• Reduce meal size to manage early satiety and nausea 2
• Limit alcohol and carbonated beverages (worsens GI symptoms) 2

Physical activity:

• Minimum 150 minutes per week of moderate-intensity exercise 1
• Include resistance training 2–3 times per week to preserve lean body mass during weight loss 1

Behavioral counseling:

• Structured lifestyle management programs and behavioral therapy are essential for long-term weight maintenance 1

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Monitoring Schedule

Weeks 0–12 (titration phase):

• Assess monthly for gastrointestinal tolerance, weight loss progress, and blood pressure 1
• Monitor for signs of pancreatitis (persistent severe abdominal pain) 1
• Monitor for gallbladder symptoms (right upper quadrant pain, fever) 1

Week 12–16 (efficacy assessment):

• Discontinue tirzepatide if weight loss is < 5% after 12 weeks at maintenance dose (predicts poor long-term response) 1
• If ≥ 5% weight loss achieved, continue treatment 1

After Week 16 (maintenance phase):

• Monitor every 3 months for weight stability, blood pressure, cardiovascular risk factors, and medication adherence 1
• Re-assess lipid panel and fasting glucose at 6 months 2

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Expected Outcomes

Weight loss:

• 15 mg dose: mean 20.9% weight loss at 72 weeks 3
• 10 mg dose: mean 19.5% weight loss at 72 weeks 3
• 5 mg dose: mean 15.0% weight loss at 72 weeks 3
• 50–57% of patients on 10–15 mg achieve ≥ 20% weight reduction 1

Cardiometabolic benefits:

• Blood pressure reduction (systolic and diastolic) 1
• Superior triglyceride reduction compared to semaglutide 1
• Improved lipid profiles and insulin sensitivity 2
• Reduction in hepatic steatosis and visceral adipose tissue 2

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Managing Adverse Effects

Gastrointestinal symptoms (nausea, diarrhea, vomiting):

• Occur in 17–22% (nausea), 13–16% (diarrhea), 6–10% (vomiting) 1
• Typically mild-to-moderate and resolve within 4–8 weeks after reaching a new dose 1
• Mitigation strategies: slow titration, smaller meals, avoid high-fat foods, limit alcohol 1

Serious adverse events (rare but important):

• Pancreatitis: discontinue immediately if persistent severe abdominal pain develops 1
• Gallbladder disease: monitor for right upper quadrant pain, fever, jaundice 1
• Hypoglycemia: only if combined with insulin or sulfonylureas (reduce doses of these agents) 2

Treatment discontinuation rates:

• 4.3% (5 mg), 7.1% (10 mg), 6.2% (15 mg) discontinued due to adverse events 3

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Special Populations

Type 2 diabetes with obesity:

• Prioritize tirzepatide for dual benefits of glycemic control (HbA1c reduction 1.87–2.59%) and superior weight loss 1
• Reduce insulin by 20% and sulfonylureas by 50% before starting 2

Chronic kidney disease:

• No dose adjustment required for any level of renal impairment, including eGFR < 30 mL/min/1.73 m² 1
• Tirzepatide reduces albuminuria and slows eGFR decline 2

Established cardiovascular disease:

• Consider semaglutide 2.4 mg instead of tirzepatide if proven cardiovascular benefit is a priority (semaglutide reduces MACE by 20%) 2
• Tirzepatide shows cardiovascular safety but does not yet have proven superiority for MACE reduction 2

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Common Pitfalls to Avoid

• Do not start at 10 mg or 15 mg: This markedly increases nausea/vomiting and discontinuation rates 1
• Do not declare treatment failure before 12 weeks at maintenance dose: Early non-responders (< 5% weight loss at 12 weeks) may still achieve meaningful weight loss by 72 weeks (90% of late responders achieve ≥ 5% weight loss) 4
• Do not forget to reduce insulin/sulfonylureas: Combining tirzepatide with these agents without dose reduction causes hypoglycemia 2
• Do not prescribe if personal/family history of medullary thyroid cancer or MEN2: This is an absolute contraindication 1
• Do not stop treatment after achieving weight loss goals: Discontinuation leads to regain of 50–67% of lost weight within 1 year 5

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When to Consider Bariatric Surgery

Refer for bariatric surgery if:

• BMI > 40 kg/m² and insufficient weight loss with tirzepatide after 12–16 weeks 6
• BMI ≥ 35 kg/m² with severe obesity-related complications requiring more aggressive intervention 2
• Surgery is regarded as the definitive treatment for severe obesity 6