The era of 15% weight loss is over. We are now entering the 30% era. Eli Lilly’s retatrutide has delivered 28.7% weight loss in its first Phase 3 trial, while Novo Nordisk’s CagriSema achieved 22.7% in REDEFINE 1—both representing a generational leap beyond current GLP-1 therapies. But the data tell a more nuanced story than headlines suggest, and the implications for the obesity market—and the two companies competing for dominance—are profound.

This analysis examines the Phase 3 showdown between these next-generation obesity drugs, dissects their divergent side effect profiles, and assesses what the data mean for the Lilly-Novo rivalry that will define the obesity market through the end of the decade.

The Data: Phase 3 Showdown

Retatrutide (Eli Lilly): The Triple-G Breakthrough

In December 2025, Eli Lilly announced positive topline results from TRIUMPH-4, the first Phase 3 trial for retatrutide. Participants with obesity and knee osteoarthritis taking the 12 mg dose lost an average of 28.7% of their body weight at 68 weeks—approximately 71 pounds from a baseline of 248 pounds. The 9 mg dose achieved 26.4% weight loss.

Key TRIUMPH-4 Results: 28.7% weight loss at 12 mg dose; 26.6% placebo-adjusted; 58.6% of participants achieved ≥25% weight reduction; 75.8% reduction in knee pain scores.

What makes retatrutide different is its mechanism: it is a GIP/GLP-1/glucagon triple receptor agonist—the first of its kind in late-stage development. While tirzepatide (Mounjaro/Zepbound) targets two receptors (GIP and GLP-1), retatrutide adds glucagon receptor agonism, which fundamentally changes the drug’s metabolic profile.

The Glucagon Advantage

Glucagon receptor activation does something that GLP-1 alone cannot: it increases energy expenditure. While GLP-1 agonists primarily reduce appetite and slow gastric emptying (decreasing energy intake), glucagon agonism actively promotes calorie burning through multiple pathways:

• Hepatic lipid mobilization: Glucagon signals the liver to break down stored fat for energy
• Brown fat thermogenesis: Preclinical data suggests glucagon activation promotes heat generation in brown adipose tissue
• Increased fatty acid oxidation: The body shifts toward using fat stores as fuel, even at rest

In essence, retatrutide attacks obesity from both sides: reducing what goes in (appetite suppression via GLP-1 and GIP) while increasing what goes out (energy expenditure via glucagon). This dual mechanism may explain why retatrutide achieves weight loss that approaches bariatric surgery outcomes without the plateau that characterizes GLP-1-only therapies.

CagriSema (Novo Nordisk): The Amylin Play

Novo Nordisk took a different approach with CagriSema, combining semaglutide (the active ingredient in Wegovy) with cagrilintide, an amylin analogue. The REDEFINE 1 trial, published in the New England Journal of Medicine in June 2025, showed that CagriSema achieved 22.7% mean weight reduction at 68 weeks in adults with obesity—significantly outperforming semaglutide alone (14.9%) and placebo (3%).

The “Underwhelming” CagriSema Story

While 22.7% weight loss is clinically meaningful—and better than any currently approved therapy—CagriSema missed Novo Nordisk’s own expectations. Company leadership had publicly suggested the drug would achieve at least 25% weight loss, and when results fell short, Novo’s stock dropped sharply. The disappointment wasn’t about the absolute numbers; it was about the competitive positioning against Lilly.

REDEFINE 2, which tested CagriSema in patients with type 2 diabetes, showed more modest results: 15.7% weight loss at 68 weeks (with treatment adherence), compared to 3.1% with placebo. This is consistent with the general finding that weight loss is harder to achieve in diabetic populations, but it underscored that CagriSema’s efficacy gap versus retatrutide may persist across indications.

The “Puke Factor”: Side Effect Analysis

Both retatrutide and CagriSema cause gastrointestinal side effects—the class effect of incretin-based therapies. But the discontinuation rates tell an important story about real-world tolerability.

Retatrutide Discontinuation Rates

In TRIUMPH-4, discontinuation rates due to adverse events were 12.2% for the 9 mg dose and 18.2% for the 12 mg dose, compared to 4% in the placebo arm. The most common side effects were nausea (43%), diarrhea (33%), vomiting (21%), and constipation—consistent with the GLP-1 class.

However, a new safety signal emerged: dysesthesia (an abnormal sensation on the skin) occurred in 8.8% of patients on the 9 mg dose and 20.9% on the 12 mg dose, compared to just 0.7% on placebo. Lilly stated these events were generally mild and rarely led to discontinuation, but analysts are watching for this signal in upcoming trials.

Importantly, discontinuation rates were highly correlated with baseline BMI. Patients with higher BMIs tolerated the drug better, suggesting retatrutide may be particularly suitable for the most severely obese patients—precisely the population where bariatric surgery alternatives are most needed.

CagriSema Discontinuation Rates

CagriSema’s discontinuation rates were lower in absolute terms but higher relative to the weight loss achieved. In REDEFINE 1, 5.9% of CagriSema patients discontinued due to adverse events versus 3.5% for placebo. In REDEFINE 2 (diabetic population), the rate was higher: 8.4% versus 3% for placebo.

GI side effects were prominent: 79.6% of CagriSema patients experienced gastrointestinal adverse events (versus 39.9% for placebo), including nausea (55%), constipation (30.7%), and vomiting (26.1%). While Novo emphasized these were “mostly transient and mild-to-moderate,” the higher nausea rate than typical semaglutide trials (~40-45%) suggests the amylin component adds GI burden.

The Tolerability Paradox

Here’s what’s counterintuitive: retatrutide has higher discontinuation rates than CagriSema, yet its efficacy-to-tolerability ratio may actually be better. At 18.2% discontinuation for 28.7% weight loss, retatrutide delivers approximately 1.6% weight loss per percentage point of discontinuation risk. CagriSema’s 5.9% discontinuation for 22.7% weight loss yields about 3.8% weight loss per point of discontinuation risk.

But this math misses the clinical reality: for patients with severe obesity, the magnitude of weight loss matters more than marginal tolerability differences. A patient who achieves 28% weight loss and resolves their diabetes, sleep apnea, and joint pain is likely to tolerate transient nausea. The patients who discontinue are self-selecting out, leaving a treated population that achieves remarkable outcomes.

Investment Thesis: Lilly vs. Novo

Is Novo Losing Its Edge?

The numbers are stark. Eli Lilly has captured 57% of the GLP-1 market as of mid-2025, up from parity just 18 months earlier. Novo Nordisk’s stock has fallen approximately 50% from its highs, while Lilly briefly touched a $1 trillion market capitalization. The competitive dynamics have shifted decisively.

Novo’s challenges extend beyond CagriSema’s modest miss:

• Supply constraints: Persistent Wegovy shortages allowed compounders and Lilly to capture share
• Tirzepatide superiority: Real-world data confirms Zepbound delivers more weight loss than Wegovy
• Pipeline perception: CagriSema’s 22.7% result, while strong, doesn’t clearly leapfrog tirzepatide’s 22.5%
• Medicare exposure: Semaglutide faces Medicare price negotiation in 2027; tirzepatide likely won’t until the end of the decade

Why the “Triple-G” Mechanism Is Harder to Copy

Retatrutide represents a genuine innovation moat. Creating a single molecule that optimally activates three receptors—with the right ratio of GIP to GLP-1 to glucagon activity—is extraordinarily difficult. The engineering challenge is not just binding affinity but achieving the precise balance that maximizes efficacy while managing the hyperglycemic liability of glucagon (which GIP and GLP-1 agonism must offset).

Novo Nordisk does not have a triple agonist in late-stage development. Its pipeline includes amycretin (a GLP-1/amylin combination) as an injectable and oral, but nothing that matches retatrutide’s mechanism. Other pharma companies—Pfizer (which just acquired Metsera for $4.9 billion), Roche, and AstraZeneca—are pursuing various GLP-1 combinations, but none have a triple agonist near Phase 3.

This creates a potential “winner-take-most” dynamic in the severe obesity market. If retatrutide delivers 25-30% weight loss across its remaining Phase 3 trials (with seven readouts expected in 2026), Lilly will have a differentiated product for patients who need more than what semaglutide or tirzepatide can deliver.

The Bull Case for Novo

Novo is not without advantages. The company has filed CagriSema for FDA approval (submitted December 2025) and will likely reach the market before retatrutide, which still needs to complete its Phase 3 program. Novo’s oral Wegovy launched in January 2026 at $149/month for starting doses—a competitive price point that could expand the market. And the company’s cardiovascular outcomes data for semaglutide (SELECT trial) provides label advantages that Lilly cannot yet match.

For income-oriented investors, Novo’s 2.4% dividend yield versus Lilly’s 0.8% is meaningful, particularly with Novo trading at 16x forward earnings compared to Lilly’s 26x.

The Bottom Line

2026 will likely cement Eli Lilly’s position as the obesity market leader. Retatrutide’s mechanism—attacking obesity through both reduced intake and increased expenditure—represents a genuine therapeutic advance. If the remaining TRIUMPH trials confirm the TRIUMPH-4 results, Lilly will have a differentiated product that CagriSema cannot match on efficacy.

But the obesity market is projected to reach $100 billion by 2030. There is room for multiple winners, and Novo’s first-mover advantage in oral formulations, superior cardiovascular data, and lower valuation make it far from a lost cause. The question is not whether Novo survives—it will—but whether it can reclaim the innovation leadership it held when Wegovy launched.

For investors, the retatrutide readouts throughout 2026 are the key catalysts. Seven Phase 3 trials will report, covering obesity, type 2 diabetes, sleep apnea, chronic low back pain, liver disease, and cardiovascular outcomes. If the data hold, Lilly’s obesity franchise—already generating $10 billion quarterly—will have its most powerful weapon yet.

Related BioMed Nexus Coverage

Obesity Market Analysis

• The Obesity Wars: 2026–2030 Landscape — GLP-1 competition and market evolution
• Corxel Raises $287M for Oral GLP-1 — The “Obesity 2.0” oral small molecule race
• JPM 2026 Day 3: Clinical Reality and the Procedure Signal — Lilly direct-to-consumer strategy

Regulatory and Clinical

• FDA MRD Guidance Reshapes Myeloma Development — Regulatory trends in drug development
• Celcuity Priority Review Sets July PDUFA Clock — Oncology regulatory pathway

Capital Markets

• Post-JPM 2026: $2.5B Capital Clearing — Biotech financing environment
• BMS Commits $850M to Tumor-Activated T-Cell Engagers — Big Pharma BD trends

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Frequently Asked Questions: Retatrutide vs. CagriSema

What is the difference between retatrutide and CagriSema?

Retatrutide is a GIP/GLP-1/glucagon triple receptor agonist from Eli Lilly. CagriSema is a combination of semaglutide (GLP-1 agonist) and cagrilintide (amylin analogue) from Novo Nordisk. Retatrutide’s glucagon component increases energy expenditure, while CagriSema relies primarily on appetite suppression.

How much weight loss did retatrutide achieve in Phase 3?

In TRIUMPH-4, retatrutide achieved 28.7% weight loss at the 12 mg dose and 26.4% at the 9 mg dose over 68 weeks. Approximately 50% of participants achieved at least 25% weight reduction.

Why did CagriSema disappoint investors?

CagriSema achieved 22.7% weight loss in REDEFINE 1—clinically meaningful but below Novo Nordisk’s publicly stated target of at least 25%. The miss raised questions about CagriSema’s ability to differentiate from Lilly’s tirzepatide (22.5% weight loss) and retatrutide.

What is dysesthesia and should investors be concerned?

Dysesthesia is an abnormal skin sensation that occurred in up to 20.9% of retatrutide patients at the highest dose. Lilly stated these events were generally mild and rarely led to discontinuation, but analysts are monitoring for this signal in upcoming trials.

When will retatrutide be approved?

Retatrutide is still completing its Phase 3 program, with seven additional trial readouts expected in 2026. Regulatory submission will likely follow completion of the TRIUMPH program, with potential approval in 2027 or later.

Which stock is better: Lilly or Novo Nordisk?

Lilly trades at a premium valuation (26x forward earnings vs. Novo’s 16x) but has superior growth prospects and pipeline momentum. Novo offers a higher dividend yield (2.4% vs. 0.8%) and potential recovery upside from depressed levels. Investment choice depends on risk tolerance and time horizon.

What other Phase 3 trials are expected for retatrutide in 2026?

Seven TRIUMPH trials will report in 2026, covering obesity without comorbidities, type 2 diabetes, obstructive sleep apnea, chronic low back pain, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular outcomes.

BioMed Nexus provides daily intelligence for leaders in biotech, medtech, and pharma. This editorial deep dive is intended for context, not investment recommendation.