Triple G-Agonists (Retatrutide and Beyond): A Continued Home Run for Obesity in 2025

By Dr Frank Yap, MD -

Introduction

The buzz around hormone-based obesity therapies, ignited at the 2023 American Diabetes Association (ADA) Scientific Sessions, has only intensified by 2025. Retatrutide, Eli Lilly's triple-hormone-receptor agonist, led the charge with phase 2 results showing 24% mean weight loss over 48 weeks in non-diabetic adults with obesity (aestheticsadvisor.com). Now in phase 3 (TRIUMPH program), with topline data expected Q4 2025 and potential FDA approval by 2027, retatrutide exemplifies the triple G-agonist class's promise. Meanwhile, competitors like Novo's UBT251 (15.4% loss in 12 weeks phase 1b) and oral candidates from Protagonist Therapeutics signal a transformative era, potentially outpacing dual agonists like tirzepatide. 

Hormonal Responses and Background

Nutrient sensing triggers a symphony of hormones—insulin, GLP-1, GIP, PYY, amylin—that curb appetite, boost insulin, and ramp up metabolism. GLP-1 agonists revolutionized T2D and obesity care; dual GLP-1/GIP (tirzepatide) amplified this with ~22% loss. Triples add glucagon (GCG) agonism for catabolic punch: lipolysis, thermogenesis, and reduced intake, balanced against incretin glycemic safeguards. Preclinical models confirmed triples' edge in weight reduction and NAFLD reversal.

What Are Triple G-Agonists?

These single-molecule therapies hit three receptors: GLP-1 (satiety, insulin ↑), GIP (fat metabolism, insulin secretion), and GCG (energy burn, liver fat ↓). Retatrutide pioneered this; 2024-2025 saw surges in development, including Boehringer Ingelheim's BI 3034701 (phase 1 initiated July 2024) and Novo's $2B acquisition of UBT251 in March 2025, yielding 15.4% loss in early data. Oral triples (e.g., Protagonist's PN-477, nominated June 2025) address injection fatigue, a barrier for 30-50% of users.

Clinical Trial Updates

Retatrutide Phase 2 Recap (2023) — In 338 obese adults (no T2D), weekly doses (1-12 mg SC) yielded 24% loss at max dose (vs. 2% placebo); 26% hit ≥30% loss. Cardiometabolic wins: BP ↓5-10 mmHg, HbA1c ↓0.5-1%, lipids improved. In T2D (n=282), 17% loss and 2% HbA1c drop at 36 weeks; NAFLD subset (n=98): 90% normalized liver fat.
2024-2025 Progress — A February 2025 meta-analysis affirmed phase 2 safety/efficacy, with no new signals. Phase 3 TRIUMPH trials (ongoing, e.g., NCT05931367 for obesity; NCT06383390 for CV outcomes) test vs. placebo/tirzepatide in obesity/T2D/NAFLD, tracking events in high-risk groups (BMI ≥27 + ASCVD/CKD). Topline data due Q4 2025–Q1 2026; full readout 2026. Projections: 25-30% loss, durable to 104 weeks if muscle-sparing protocols (e.g., resistance training) are integrated.
Broader Pipeline — Novo's UBT251 (acquired March 2025) hit 15.4% loss in phase 1b (12 weeks), targeting 2027 approval. BI 3034701's phase 1 (NCT06352437) focuses on long-acting peptides; early tolerability mirrors retatrutide; completion expected H2 2025.

Comparative Overview of Current Obesity Treatments

  • GLP-1 receptor agonists (monotherapy)
    Examples: Semaglutide (Wegovy, Ozempic), liraglutide (Saxenda)
    Mechanism: GLP-1 receptor only
    Mean weight loss at peak: 15–20 % (typically at 68 weeks)
    Key benefits: Strong glycemic control, proven 20 % cardiovascular risk reduction (SELECT trial), well-established long-term safety
    Main risks: GI side effects, muscle loss (~30–40 % of total weight lost)
    Status 2025: Widely approved and used; generic liraglutide entering market
  • Dual GLP-1/GIP receptor agonists
    Example: Tirzepatide (Zepbound, Mounjaro)
    Mechanism: GLP-1 + GIP receptors
    Mean weight loss at peak: 20–25 % (72 weeks, SURMOUNT-1/2)
    Key benefits: Superior satiety, ~2 % HbA1c reduction, excellent liver-fat reduction
    Main risks: Nausea/vomiting in 40–50 %, gallbladder events, muscle loss
    Status 2025: Fully approved for obesity and type 2 diabetes; dominant market share
  • Triple G-agonists (GLP-1 + GIP + Glucagon) – Leading candidate
    Example: Retatrutide (Eli Lilly)
    Mechanism: GLP-1 + GIP + glucagon receptors
    Mean weight loss: 24.2 % at 48 weeks (phase 2); 25–30 % projected in phase 3
    Key benefits: Highest energy expenditure increase seen so far, ~90 % resolution of liver fat in NAFLD sub-study, strong cardiometabolic improvements
    Main risks: GI side effects 45–60 %, transient heart-rate increase 5–10 bpm, muscle loss (mitigable with resistance training)
    Status 2025: Phase 3 TRIUMPH program ongoing; topline results expected Q4 2025–Q1 2026, potential approval 2027
  • Triple G-agonists – Emerging pipeline candidates
    Examples: UBT251 (Novo Nordisk, acquired 2025), BI 3034701 (Boehringer Ingelheim), PN-477 (Protagonist Therapeutics – oral & injectable)
    Mechanism: GLP-1 + GIP + glucagon (various molecular designs)
    Mean weight loss so far: 15–18 % in very early data (12–24 weeks)
    Key benefits: Potential for oral dosing (Protagonist), rapid onset
    Main risks: Still early; tolerability data limited
    Status 2025: Phase 1 / early phase 2
  • Bariatric surgery (reference standard)
    Examples: Roux-en-Y gastric bypass, sleeve gastrectomy
    Mechanism: Mechanical restriction + hormonal changes
    Mean weight loss: 30–40 % sustained at 5+ years
    Key benefits: Highest and most durable weight loss, 60–80 % diabetes remission at 5 years, proven mortality reduction
    Main risks: Invasive procedure, nutritional deficiencies, surgical complications
    Status 2025: Gold standard for BMI ≥40 or ≥35 with comorbidities

Side Effects and Safety (Including Cancer Risk)

Consistent with 2023: Dose-escalation GI events (nausea/vomiting 45-60%, transient); 16% dropout at high doses. 2025 analyses report no excess CV/oncologic risks, but monitor HR ↑ and gallbladder events (2-5%). Lean mass preservation strategies are emphasized in phase 3.
Cancer Risk with Incretin-Based Therapies (GLP-1, Dual, and Triple Agonists): Early concerns stemmed from rodent studies showing thyroid C-cell tumors with high-dose GLP-1 exposure, leading to black-box warnings for medullary thyroid cancer (MTC risk in patients with personal/family history of MTC or MEN2 syndrome. However, humans have far fewer thyroid C-cells expressing GLP-1 receptors, and >15 years of post-marketing data plus multiple 2024–2025 meta-analyses and large cohort studies show no increased risk of thyroid cancer (including MTC or overall) with GLP-1RAs or dual agonists compared to other antidiabetics.
For pancreatic cancer, early signals from adverse-event databases have not been confirmed; recent RCTs, meta-analyses, and real-world cohorts (including >1 million patients) show either neutral or modestly reduced risk, likely due to weight loss and anti-inflammatory effects.Emerging 2025 evidence on overall cancer risk is reassuring and even positive: multiple large studies report 7–17% lower incidence of obesity-related cancers (colorectal, endometrial, ovarian, kidney, etc.) with GLP-1RA use vs. non-users or other therapies, attributable to sustained weight reduction.
Specific to triple agonists: No cases of medullary thyroid cancer, C-cell hyperplasia, or pancreatic cancer were reported in retatrutide phase 2 trials (n>600). Preclinical data for retatrutide showed no C-cell pathology at clinically relevant exposures, and ongoing phase 3 trials include calcitonin monitoring. Cancer endpoints are not primary but will be tracked long-term.
In summary, current evidence (high-quality RCTs + real-world data) indicates that the oncologic safety profile of GLP-1–based therapies, including emerging triples, is favorable, with potential benefits from obesity-driven cancers outweigh theoretical risks for appropriate patients.

Extensions to Other Conditions

Beyond obesity: Phase 3 arms target T2D (HbA1c primary) and NAFLD (fat fraction endpoint). CV trial (5 years) could mirror GLP-1's 20% MACE reduction. Emerging: Chronic low back pain in obese (NCT07035093, enrolling through 2027).

Conclusions and Future Outlook

By 2025, triple G-agonists are no longer hypothetical—they're the next frontier, with retatrutide poised for 2026-2027 launch amid a pipeline boom. They offer ~25%+ loss, rivaling surgery for accessibility, but demand long-term data on regain (50-70% post-GLP-1 cessation) and combos (e.g., with metformin). Challenges: Supply chains (lessons from 2024 shortages), costs ($800-1,200/month projected), and equity—subsidies needed for low-SES groups (obesity 2x higher). Ultimately, triples could halve obesity's $200B U.S. burden, but only if integrated with lifestyle and policy reforms.

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