Can retatrutide (dual GLP-1 (Glucagon-Like Peptide-1) and glucagon receptor agonist) decrease visceral adiposity?

Retatrutide's Effect on Visceral Adiposity

Retatrutide, a novel triple agonist targeting GLP-1, GIP, and glucagon receptors, significantly reduces visceral adiposity as part of its substantial weight loss effects, with clinical trials showing up to 24.2% total body weight reduction at 48 weeks. 1

Mechanism of Action and Effects on Visceral Fat

Retatrutide works through multiple mechanisms that specifically target visceral fat:

1. Triple receptor activation: By simultaneously activating GLP-1, GIP, and glucagon receptors, retatrutide creates a synergistic effect that enhances weight loss beyond what single-target GLP-1 agonists achieve 1

2. Visceral fat targeting: While most weight loss medications reduce overall body weight, GLP-1-based therapies like retatrutide have demonstrated specific effects on visceral adiposity 2

   • Visceral fat is particularly resistant to mild weight loss, but the substantial weight reduction seen with retatrutide (17-24% at higher doses) is sufficient to impact these fat deposits
   • This is clinically significant as visceral fat is strongly associated with metabolic syndrome, insulin resistance, and cardiovascular disease

3. Body composition changes: Retatrutide reduces waist circumference by a mean difference of 10.51 cm, indicating significant reductions in central adiposity where visceral fat accumulates 3

Clinical Evidence

The strongest evidence for retatrutide's effect on visceral adiposity comes from recent clinical trials:

• In a phase 2 trial published in NEJM, retatrutide demonstrated dose-dependent weight loss at 48 weeks 1:

  • 8.7% reduction at 1 mg dose
  • 17.1% reduction at 4 mg dose
  • 22.8% reduction at 8 mg dose
  • 24.2% reduction at 12 mg dose

• A systematic review and meta-analysis found that retatrutide significantly reduced 3:

  • Body weight (mean difference: -14.33%)
  • BMI (mean difference: -5.38)
  • Waist circumference (mean difference: -10.51 cm)

• In patients with type 2 diabetes, retatrutide demonstrated dose-dependent weight loss at 36 weeks 4:

  • 3.19% reduction at 0.5 mg dose
  • 7.92-10.37% reduction at 4 mg doses
  • 16.34-16.94% reduction at 8-12 mg doses

Comparison to Other Therapies

Retatrutide appears to have superior weight loss effects compared to many existing therapies:

• Retatrutide's maximum weight loss of 24.2% exceeds that of most existing GLP-1 receptor agonists 1
• For context, pharmaceutical GLP-1 receptor agonists typically reduce weight by 8-16% compared to 2.4-5.7% with placebo 5
• The American Heart Association notes that retatrutide produces substantial weight loss exceeding most existing GLP-1 receptor agonists 5

Clinical Implications for Visceral Fat Reduction

The reduction in visceral adiposity with retatrutide has several important clinical implications:

1. Cardiovascular benefits: Visceral fat reduction may contribute to improved cardiovascular outcomes, as visceral adiposity is strongly linked to cardiovascular disease 2

2. Metabolic improvements: Retatrutide significantly reduces fasting plasma glucose (-23.51 mg/dL), HbA1c (-0.91%), and blood pressure (systolic: -9.88 mmHg, diastolic: -3.88 mmHg) 3

3. Potential benefits for NAFLD/NASH: GLP-1 based therapies reduce hepatic fat and steatosis, which are commonly linked with diastolic dysfunction and heart failure with preserved ejection fraction (HFpEF) 2

Safety Considerations

While effective, retatrutide has important safety considerations:

• Most common adverse events are gastrointestinal (nausea, diarrhea, vomiting) 1
• Dose-dependent increases in heart rate (up to 6.7 beats/min) were observed, which may partially offset some benefits of weight loss 6
• Starting with lower doses and titrating gradually can minimize gastrointestinal side effects 5

Conclusion

Retatrutide represents a promising advancement in treating visceral adiposity through its triple-receptor agonist mechanism. The substantial weight loss and specific reduction in waist circumference strongly suggest significant effects on visceral fat deposits, which may translate to improved metabolic and cardiovascular outcomes.