Lilly’s Zepbound Outperforms Wegovy in Belly Fat Reduction: A Strategic Win for Obesity Therapeutics?

The obesity drug market is in a state of flux, with Eli Lilly’s Zepbound (tirzepatide) emerging as a formidable competitor to Novo Nordisk’s Wegovy (semaglutide). A landmark head-to-head trial, SURMOUNT-5, has revealed compelling evidence that Zepbound not only delivers superior weight loss but also excels in reducing abdominal fat—a critical metric for mitigating cardiovascular and metabolic risks. For investors, this data reshapes the competitive landscape, offering both opportunities and challenges for Lilly and its rivals.

Clinical Efficacy: A Dual-Mechanism Edge

The SURMOUNT-5 trial, published in The New England Journal of Medicine, compared Zepbound (10–15 mg weekly) and Wegovy (1.7–2.4 mg weekly) in 751 obese adults. Key findings underscore Zepbound’s advantage:

• Weight Loss: Zepbound achieved a 20.2% reduction in body weight (-50.3 lb), versus 13.7% (-33.1 lb) for Wegovy (P < 0.001). This translates to 47% greater relative weight loss for Zepbound.
• Belly Fat Reduction: Waist circumference fell by 7.2 inches (18.4 cm) with Zepbound versus 5.1 inches (13.0 cm) with Wegovy. This difference met statistical significance as a key secondary endpoint, though exact p-values were not disclosed for all metrics.
• Sustained Outcomes: 31.6% of Zepbound users lost ≥25% of baseline weight, nearly double Wegovy’s 16.1%.

Zepbound’s dual action on GLP-1 and GIP receptors—targeting two gut hormones regulating appetite—explains its edge over Wegovy’s single-GLP-1 mechanism. This differentiation could position Zepbound as a first-line therapy for patients prioritizing visceral fat reduction, a key predictor of metabolic syndrome.

Commercial Context: Market Share and Access Struggles

Despite its efficacy, Zepbound’s commercial trajectory faces hurdles:

• Sales Growth vs. Wegovy: Zepbound generated $4.9 billion in 2024, trailing Wegovy’s $8.8 billion. However, Novo’s sales forecast for 2025 was cut due to competition, suggesting Zepbound’s momentum.
• Formulary Barriers: CVS Health excluded Zepbound from its formulary starting July 2025, favoring Wegovy. Such exclusions could dampen uptake unless insurers reverse course or Zepbound secures better pricing.

LLY’s stock rose 15% in 2024 amid Zepbound’s trial success, while NVO fell 8% as competition intensified.

Risks and Limitations

• Trial Design: SURMOUNT-5 was open-label, raising potential bias in subjective outcomes.
• Safety Profile: Both drugs caused gastrointestinal side effects in over 75% of users, though Zepbound had lower discontinuation rates (6.1% vs. 8.0%).
• Regulatory and Competitive Threats: Novo’s pipeline includes a dual-agonist (NNC0360) targeting GIP and GLP-1, which could erode Zepbound’s lead.

Conclusion: A Strategic, but Fragile, Lead

Zepbound’s statistically significant superiority in both weight loss and belly fat reduction marks a pivotal moment for Lilly. The dual-mechanism approach addresses a critical unmet need—visceral fat reduction—while its 47% relative efficacy over Wegovy could drive market share gains. However, success hinges on overcoming formulary barriers and outpacing Novo’s countermeasures.

Investors should weigh Zepbound’s clinical profile against its commercial challenges. With obesity therapies projected to reach $14 billion in annual sales by 2030, Zepbound’s ability to carve out a leadership position in abdominal fat reduction could solidify Lilly’s standing in this high-growth market. For now, the data suggests Zepbound is a winner—but the race remains far from over.

Final Takeaway:
Lilly’s Zepbound outperforms Wegovy in reducing abdominal fat and weight, backed by statistically significant trial results. While formulary access and competition pose risks, its dual-receptor mechanism positions it as a contender in a market poised for explosive growth. Monitor stock performance and formulary updates closely.