Can tirzepatide (Zepbound) be approved for a middle‑aged adult with moderate obstructive sleep apnea and morbid obesity (BMI 48.3 kg/m²) who has been adherent to CPAP for four years without improvement in apnea severity or weight loss?

Appeal Letter Support for Tirzepatide (Zepbound) in Moderate OSA with Morbid Obesity

Tirzepatide (Zepbound) is strongly indicated for this patient with moderate OSA and BMI 48.3 who has failed to achieve weight loss or OSA improvement despite 4 years of CPAP adherence, as it represents the most effective FDA-approved pharmacologic intervention for obesity-related OSA. 1

Clinical Justification for Tirzepatide

FDA-Approved Indication Met

• This patient meets FDA criteria for tirzepatide: BMI ≥30 kg/m² (patient has BMI 48.3) with weight-related comorbidity (moderate OSA qualifies as a weight-related comorbidity). 1, 2
• Tirzepatide received FDA approval in 2025 specifically for moderate-to-severe OSA in adults with obesity, making this an on-label use. 3

Failure of Standard First-Line Therapy

• The patient has demonstrated 4 years of CPAP adherence without improvement in OSA severity or weight loss, establishing failure of the primary recommended therapy. 4
• After CPAP failure or inadequate response, the American Thoracic Society recommends evaluating for anti-obesity pharmacotherapy when comprehensive lifestyle interventions have not produced adequate weight loss. 1
• The American College of Cardiology recommends tirzepatide as first-line pharmacologic intervention for overweight and obese patients with OSA who have not achieved sufficient weight loss through lifestyle modifications alone. 1

Superior Efficacy Data Supporting Tirzepatide

Weight Loss Outcomes

• Tirzepatide produces mean weight loss of 20.9% at 72 weeks (15 mg dose), 19.5% (10 mg dose), and 15.0% (5 mg dose) versus 3.1% for placebo. 4
• This represents superior weight reduction compared to all other FDA-approved anti-obesity medications, including semaglutide (mean difference of 5.1% greater weight loss) and liraglutide (mean difference of 13.0% greater weight loss). 4

Direct OSA Improvement

• The SURMOUNT-OSA trials demonstrated that tirzepatide significantly reduced apnea-hypopnea index (AHI), hypoxic burden, and body weight in adults with moderate-to-severe OSA and obesity. 5, 6
• Tirzepatide produces substantial weight reduction with proportionate AHI improvement, with treatment effects becoming significant as early as Week 4 for peripheral AHI. 1, 3
• Beyond weight loss, tirzepatide improves OSA through modulation of fat distribution, inflammatory status, and autonomic nervous system function. 7

Cardiovascular Risk Reduction

• Tirzepatide treatment results in hypoxic burden values associated with lower cardiovascular mortality rates, potentially attenuating the negative cardiovascular impact of OSA-related hypoxia. 5
• The medication improves oxygen desaturation, blood pressure, and cardiovascular disease-related risk factors in OSA patients. 7

Clinical Algorithm Supporting This Decision

Step 1: CPAP Trial Completed (✓ Patient has completed)

• Patient has used CPAP for 4 years with documented adherence but without clinical improvement. 4

Step 2: Lifestyle Modification Assessment

• After CPAP failure, comprehensive lifestyle intervention should be attempted or documented as insufficient. 1
• If lifestyle modifications have been attempted without adequate weight loss over 4 years of CPAP use, proceed to Step 3.

Step 3: Pharmacotherapy Selection

• Tirzepatide is the first-line medication choice based on superior efficacy for both weight loss and direct OSA improvement. 1
• Alternative second-line option would be liraglutide 3.0 mg (produces AHI reduction of -6.1 events/hour versus placebo). 1
• Third-line option would be phentermine/topiramate ER (produces mean weight loss of -6.5 kg and AHI improvement of -14.9 events/hour), but this is contraindicated if the patient has cardiovascular disease. 1

Expected Clinical Outcomes

Weight and OSA Metrics

• For every 1% body weight lost, approximately 0.45 events/hour reduction in AHI can be achieved. 1
• At BMI 48.3, even a 15% weight loss (lowest effective tirzepatide dose) would represent approximately 7.2 BMI points reduction, translating to clinically meaningful AHI improvement.

Timeline for Response

• Significant improvements in peripheral AHI occur as early as Week 4, with treatment differences versus placebo becoming significant by Week 20. 3
• Full assessment of efficacy should occur at 52 weeks based on SURMOUNT-OSA trial design. 6, 3

Monitoring Plan

• Weight and BMI assessment at each follow-up visit (typically every 4-12 weeks during titration). 1
• Follow-up sleep study at 6-12 months to evaluate improvements in AHI and oxygen saturation. 1
• Blood pressure monitoring given expected improvements in cardiovascular parameters. 7
• Assessment of gastrointestinal adverse events during dose titration. 4

Critical Safety Considerations

• Tirzepatide requires ongoing use; discontinuation leads to weight regain, emphasizing the importance of combining pharmacotherapy with lifestyle modifications. 1
• Common adverse events include gastrointestinal symptoms (nausea, vomiting, diarrhea), which typically improve with dose titration. 4
• The medication should not be abruptly discontinued if switching to alternative therapy. 1

Cost-Effectiveness Argument

• Untreated or inadequately treated OSA with morbid obesity carries substantial long-term costs including cardiovascular events (myocardial infarction, stroke, heart failure), metabolic complications (type 2 diabetes, hypertension), and increased mortality risk. 4, 5
• Tirzepatide addresses both the underlying obesity and directly improves OSA severity, potentially reducing need for escalated OSA interventions (surgical options, alternative devices). 1, 7
• The cardiovascular risk reduction associated with hypoxic burden improvement may prevent costly cardiovascular events. 5

Conclusion Statement for Appeal

This patient with moderate OSA (BMI 48.3) who has demonstrated 4 years of CPAP adherence without improvement represents a clear indication for tirzepatide therapy. The medication is FDA-approved for this specific indication, recommended as first-line pharmacotherapy by the American College of Cardiology, and supported by robust Phase 3 trial data demonstrating superior efficacy for both weight loss and OSA improvement compared to all alternative pharmacologic options. Denial of this therapy would leave the patient without evidence-based treatment options and at continued risk for obesity-related and OSA-related cardiovascular morbidity and mortality.