Retatrutide and IGF-1: The First-of-Its-Kind “GLP-4”

Retatrutide (Reta) and IGF-1: The First-of-Its-Kind “GLP-4” Explained

The next generation of incretin-based therapies is here. Following the success of semaglutide (Ozempic®, Wegovy®) and tirzepatide (Mounjaro®, Zepbound®), pharmaceutical development has moved beyond dual agonists to triple-pathway signaling.

Enter Retatrutide (Reta) - a GLP-1 / GIP / glucagon triple agonist showing unprecedented fat-loss and metabolic-rebalancing effects. Early studies also hint at downstream changes in IGF-1 (insulin-like growth factor-1) and growth-hormone axis signaling - sparking speculation that Retatrutide could function as a next-generation “GLP-4.”

This article explains how Retatrutide works, what distinguishes it mechanistically, and what IGF-1 modulation could mean for longevity, muscle preservation, and metabolic health.

From GLP-1 to “GLP-4”: A Quick Evolution

Researchers have informally coined the term “GLP-4” to describe this new class of poly-agonists - drugs that integrate multiple metabolic signals to address energy intake, expenditure, and composition simultaneously.

How Retatrutide Works

1. GLP-1 Pathway - Appetite and Glucose Regulation

• Slows gastric emptying, enhances satiety, lowers post-meal glucose.

• Improves insulin secretion and reduces appetite.

2. GIP Pathway - Insulin Sensitivity and Adipose Remodeling

• Enhances pancreatic insulin response in a glucose-dependent manner.

• Appears to reduce nausea commonly seen with GLP-1 monotherapy.

• Improves adipocyte metabolism, promoting “healthy fat” turnover.

3. Glucagon Pathway - Energy Expenditure and Fat Oxidation

• Stimulates hepatic fat oxidation and thermogenesis.

• Counters the metabolic slowdown that often follows caloric restriction.

• Elevates basal metabolic rate, supporting preservation of lean tissue.

Combined Effect

Together, these pathways reduce calorie intake while increasing energy expenditure, explaining why Retatrutide has produced the largest body-weight reductions ever recorded in metabolic-disease trials - averaging 24 %+ after 48 weeks in non-diabetic participants (NEJM, 2023).

Retatrutide and IGF-1: Why This Connection Matters

The Growth Hormone / IGF-1 Axis

IGF-1 is a hormone produced mainly in the liver in response to growth hormone (GH). It mediates GH’s anabolic and repair effects - influencing:

• Muscle growth and maintenance

• Fat distribution and energy utilization

• Cellular repair and mitochondrial biogenesis

Early Observations

Some Retatrutide participants have shown modest increases in IGF-1 and improvements in lean mass preservation compared with GLP-1 or dual-agonist therapies. While still preliminary, this suggests Retatrutide’s glucagon activity may:

• Enhance hepatic GH receptor sensitivity, slightly raising IGF-1 output.

• Support fat-to-energy conversion that indirectly promotes anabolic signaling.

• Improve mitochondrial ATP efficiency, paralleling GH/IGF-1’s metabolic roles.

Why It’s Significant

Traditional GLP-1 therapies can occasionally suppress anabolic hormones through calorie reduction and mild catabolism. Retatrutide appears to rebalance this by boosting energy turnover and lean preservation - critical for longevity and long-term metabolic health.

The “GLP-4” Concept: Integrating Anabolism and Catabolism

Retatrutide’s glucagon component gives it a dual-direction advantage:

• Catabolic for fat: Drives lipolysis and fat oxidation.

• Anabolic for muscle: May maintain IGF-1 and protein synthesis through improved hepatic signaling and energy efficiency.

This unique harmony between fat loss and muscle preservation has led some experts to label the triple-agonist category informally as “GLP-4” - representing a metabolic re-education system rather than simple appetite control.

Clinical Findings So Far

Weight and Composition

• 24 % mean body-weight reduction in 48 weeks (non-diabetic cohort).

• Up to 30 % reductions at higher doses with continued therapy.

• Imaging shows a preferential reduction in visceral fat and preservation of lean tissue - unlike most calorie-restricted regimens.

Metabolic Improvements

• Marked reductions in fasting glucose, HbA1c, triglycerides, and ALT.

• Improvements in insulin sensitivity and lipid oxidation.

• Reductions in inflammatory markers (CRP, IL-6).

Safety and Tolerability

• Main side effects: mild gastrointestinal discomfort, transient nausea.

• No significant hypoglycemia or cardiovascular adverse signals reported to date.

Comparing Retatrutide to Other Metabolic Peptides

Longevity and Healthspan Implications

1. Visceral Fat Reduction

By reducing deep visceral adipose tissue - a key driver of systemic inflammation - Retatrutide may lower long-term cardiometabolic and neurodegenerative risk.

2. Metabolic Re-education

Its multi-agonist design helps retrain the body to burn energy efficiently, a feature relevant to age-related metabolic slowdown.

3. Muscle Preservation via IGF-1 Stability

If ongoing trials confirm IGF-1 support, Retatrutide could become the first anti-obesity therapy that burns fat while preserving youthful muscle metabolism, a major leap for healthspan.

4. Potential Combination Pathways

Future research is exploring how Retatrutide might pair with peptides like MOTS-c (mitochondrial resilience) or Tesamorelin (visceral fat reduction and GH support) for even broader metabolic optimization.

What’s Next in Research

• Phase 3 Trials (2025–2026): Larger populations and long-term endpoints (cardiovascular outcomes, lean-mass preservation).

• IGF-1 Sub-studies: Clarify how triple-agonism affects GH/IGF-1 axis, mitochondrial signaling, and protein turnover.

• Combination Therapy Models: Retatrutide plus exercise-mimetics (e.g., SLU-PP-332) or mitochondrial peptides for next-gen metabolic stacking.

• Longevity Investigations: Potential role in metabolic aging prevention, not just weight management.

Clinical Considerations and Best Practices

• Candidate Profile: Adults with obesity, metabolic syndrome, insulin resistance, or fatty liver disease seeking comprehensive fat reduction and muscle preservation.

• Dosing: Weekly injection (dose-escalation over 12–16 weeks).

• Lifestyle Synergy: Optimal outcomes when paired with resistance training, high-protein diets, and consistent circadian alignment.

• Monitoring: Fasting insulin, HbA1c, lipids, IGF-1, and body composition (DEXA).

• Safety: Ongoing studies suggest excellent tolerability; monitor GI symptoms and hydration during early dosing.

The Regen Therapy Perspective

At Regen Therapy, we see Retatrutide as the prototype for “intelligent peptides” - compounds that coordinate multiple pathways rather than focusing on one outcome.

Our approach integrates Retatrutide within:

1. Precision Metabolic Frameworks: Customized stacks with mitochondrial and peptide support (MOTS-c, AOD-9604, Tesamorelin).

2. Data-Driven Tracking: Continuous glucose, HRV, and body-composition metrics to quantify metabolic re-education.

3. Longevity Lens: Focus on visceral-fat reduction, muscle retention, and inflammation control - the trifecta of metabolic youth.

We believe Retatrutide represents the first step toward what may eventually be recognized as “GLP-4 medicine” - holistic metabolic modulation that transcends appetite control to restore metabolic harmony.

Key Takeaways

• Retatrutide (Reta) is a triple-agonist targeting GLP-1, GIP, and glucagon - achieving record-setting fat loss while supporting metabolic balance.

• Emerging evidence suggests modest IGF-1 support, pointing to improved muscle preservation and anabolic balance.

• Represents the potential beginning of the “GLP-4” era - integrated metabolic therapies addressing both intake and output.

• May redefine treatment of obesity, visceral fat, and metabolic aging.

• Regen Therapy incorporates Retatrutide into precision longevity programs focused on sustainable metabolic re-education, not short-term weight loss.

FAQs

Is Retatrutide available yet?
As of 2025, Retatrutide remains in phase 3 clinical trials but is expected to move toward FDA review in 2026–2027.

How is Retatrutide different from Semaglutide or Tirzepatide?
It adds a third glucagon-receptor activation pathway, boosting energy expenditure and fat oxidation while maintaining appetite control.

Does Retatrutide increase IGF-1?
Early data suggest slight increases or stabilization of IGF-1 levels - promising for muscle maintenance - but full analyses are ongoing.

Will Retatrutide replace GLP-1 drugs?
Not immediately. It will likely complement or follow them, offering enhanced fat-loss and metabolic benefits for advanced cases.

Can Retatrutide be combined with other peptides?
Potentially yes - especially mitochondrial peptides like MOTS-c or Tesamorelin for targeted visceral-fat and energy optimization - under medical supervision.

References

1. Jastreboff AM, et al. Retatrutide, a triple GIP, GLP-1, and glucagon receptor agonist for obesity. N Engl J Med. 2023.

2. Drucker DJ. Incretin biology: from GLP-1 to multi-agonists. Cell Metab. 2024.

3. Wilding JPH, et al. Metabolic adaptations to GLP-1 and GIP co-agonism. Lancet Diabetes Endocrinol. 2023.

4. Barzilai N, et al. Visceral adiposity, IGF-1, and metabolic aging. Nat Med. 2022.