What are some of the best proven peptides other than Glucagon-like peptide-1 (GLP-1)s?

Best Proven Peptides Beyond GLP-1 Receptor Agonists

Dual and triple agonist peptides that combine GLP-1 with other hormones (GIP and/or glucagon) show the most promising results for weight loss and metabolic improvements beyond traditional GLP-1 receptor agonists. 1, 2

Emerging Multi-Agonist Peptides

Dual Agonists

• GLP-1/GIP dual agonists

  • Tirzepatide (GLP-1/GIP) has shown significant reduction in both liver and visceral fat in patients with T2DM 1
  • Demonstrates weight loss comparable to bariatric surgery 1
  • Promising results for steatohepatitis resolution in phase II studies 1

• GLP-1/Glucagon dual agonists

  • Examples: cotadutide, survodutide, efinopegdutide 1
  • Improve liver steatosis, liver enzymes, and fibrosis indexes in MASLD 1
  • Survodutide has shown promising weight loss effects and preliminary positive histology data 1

Triple Agonists

• GLP-1/GIP/Glucagon triple agonists
  • Example: retatrutide 1
  • May induce weight loss comparable to bariatric surgery 1
  • Combines anorexigenic effects with increased lipolysis, lipid oxidation, and energy expenditure 1

Mechanism of Action Advantages

The multi-agonist peptides offer several advantages over single GLP-1 receptor agonists:

• Enhanced weight loss effects through complementary mechanisms:

  • Central appetite suppression
  • Delayed gastric emptying
  • Increased energy expenditure (particularly with glucagon component)
  • Enhanced satiety 2, 3

• Improved metabolic effects through:

  • Potentiation of insulin secretion
  • Inhibition of glucagon secretion (except for dual/triple agonists with glucagon component, which have balanced effects)
  • Improved lipid metabolism 2

Clinical Evidence and Applications

While GLP-1 receptor agonists are well-established for diabetes and obesity management, the newer multi-agonist peptides are showing promising results:

• For metabolic dysfunction-associated steatotic liver disease (MASLD):

  • Dual and triple agonists may provide additional benefits beyond GLP-1 RAs alone 1
  • Combining with lipogenesis inhibitors may further enhance benefits 1

• For obesity management:

  • When GLP-1 RAs alone don't deliver sufficient efficacy, dual/triple agonists may provide enhanced weight loss 2
  • May overcome the dose-dependent GI side effects that limit GLP-1 RA monotherapy 2

Important Considerations and Limitations

• Most dual and triple agonists are still in clinical development phases
• Limited long-term safety and efficacy data compared to established GLP-1 RAs
• Current evidence suggests they may provide superior weight loss and metabolic benefits compared to GLP-1 RAs alone 1, 2
• When these agents are not available, bariatric surgery remains the most effective treatment for significant obesity 4

Alternative Peptides with Different Mechanisms

• Oxyntomodulin - naturally occurring peptide with dual GLP-1/glucagon activity 2
• Peptide YY (PYY) - gut hormone with complementary effects on appetite regulation 2

The field of therapeutic peptides is rapidly evolving, with dual and triple agonists representing the most promising next generation beyond traditional GLP-1 receptor agonists for treating obesity and metabolic disorders.