Darwin's Our Take: Lilly’s ‘triple G’ candidate exceeds analysts’ expectations

Eli Lilly released top-line results from a Phase III trial of retatrutide, a once-weekly investigational triple hormone receptor agonist, showing the strongest weight-loss efficacy reported to date.

Participants who received the 12 mg dose and completed the full 68-week trial lost an average of 28.7% of their body weight. Within this group:

• 39.4% lost at least 30% of body weight
• 23.7% lost at least 35% of body weight

As a “triple G” drug, retatrutide activates GLP-1, GIP, and glucagon receptors, giving it greater weight-loss potential than Novo Nordisk’s Wegovy (GLP-1 only) and Lilly’s Zepbound (GLP-1/GIP).

TRIUMPH-4 Trial Overview

The TRIUMPH-4 trial evaluated retatrutide in patients with:

• BMI ≥ 27 kg/m²
• Knee osteoarthritis

Baseline averages:

• Weight: 248.5 lbs
• BMI: 40.4 kg/m²
• 84% had BMI ≥ 35

Pain Reduction Results

Retatrutide reduced knee pain by up to 4.5 points on the WOMAC pain scale (1–20 range), representing:

• ~75% pain reduction in treatment groups
• ~40% reduction with placebo

Post hoc analysis showed:

• 14.1% of patients on 9 mg
• 12% on 12 mg

were completely pain-free at 68 weeks, compared with 4.2% in the placebo group.

Safety and Discontinuation

Approximately 20% of patients on the highest dose experienced dysesthesia, a mild skin sensitivity. Discontinuation rates due to adverse events were:

• 12.2% (9 mg)
• 18.2% (12 mg)
• 4% (placebo)

Among patients with BMI ≥ 35, discontinuation dropped to:

• 8.8% (9 mg)
• 12.1% (12 mg)

Some patients discontinued due to perceived excessive weight loss.

What’s Next

Seven additional Phase III readouts are expected in the coming year, including data on a 4 mg maintenance dose. Retatrutide is also being studied in:

• Type 2 diabetes
• Obstructive sleep apnea
• Chronic low back pain
• Cardiovascular and renal outcomes
• MASLD (fatty liver disease)

Analysts called the results the strongest weight-loss efficacy ever reported for a medication.

Our Take

Lilly recently became the first pharmaceutical company to reach a $1 trillion market valuation, driven largely by tirzepatide sales (Mounjaro and Zepbound).

The company plans to submit an NDA for its oral incretin therapy, orforglipron, before year-end using its Priority Voucher to accelerate review.

Truist Securities estimates Mounjaro, Zepbound, and orforglipron could generate $101 billion in combined peak annual sales. Retatrutide “could be the cherry on top.”

While Lilly leads today, the obesity and diabetes market is large enough to support multiple major players, influenced by patient preferences, formularies, pricing models, safety profiles, and access programs.

Health Care Rounds #194: Dr. David Shulkin

Former VA Secretary Dr. David Shulkin explains why U.S. health care reform requires structural change — not just subsidies or payment tweaks. He explores misaligned incentives, lessons from the VA’s population-based model, and what real reform will require.

Watch the episode or listen wherever you get your podcasts.

What Else You Need to Know

Medline IPO

Medline filed for an IPO that could raise up to $5.37B, valuing the company at approximately $55B.

Key metrics:

• Founded: 1966
• 2024 revenue: $25.5B
• 2025 (9 months) revenue: $20.6B
• Employees: 43,000+
• Operates in 100+ countries

CVS Health Platform

CVS is launching an AI-native consumer engagement platform that integrates:

• EHR data
• Pharmacy claims
• Wearables and home health data

Users will manage appointments, claims, appeals, and receive AI-guided care suggestions.

CVS expects competitors to join as partners.

Cost Plus Drugs + Humana

Mark Cuban’s Cost Plus Drugs is exploring a direct-to-employer model with Humana’s CenterWell to bypass PBMs. Humana CEO Jim Rechtin said employer demand is key to enabling alternative drug distribution models.

Hawaii Health Merger Talks

Hawaii Pacific Health and HMSA are in early talks to integrate. The Queen’s Medical Center warned the move could reduce competition and increase costs.

Mayo Clinic + GE HealthCare

Mayo Clinic and GE launched GEMINI-RT, an initiative integrating AI, imaging, and monitoring for personalized radiation therapy. Focus areas include:

• AI automation
• Predictive oncology
• Multi-modal therapies
• Connected patient monitoring

What We’re Reading

• The Law That Saved America’s Vaccines — Health Affairs
• Real-World Evidence for Medicare Drug Price Negotiations — JAMA
• Insurance Coverage and Pricing of Weight-Loss Drugs in the U.S. — NEJM

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