Retatrutide

Retatrutide is an investigational triple incretin receptor agonist.

It activates:

• GLP-1 receptor
• GIP receptor
• Glucagon receptor

Class:

• Triple Incretin Agonists

Status:

• Phase 3 clinical trials (not yet FDA-approved)

Retatrutide stimulates three metabolic pathways:

GLP-1 receptor activation:

• ↑ Glucose-dependent insulin secretion
• ↓ Glucagon
• ↓ Gastric emptying
• ↑ Satiety

GIP receptor activation:

• ↑ Insulin secretion
• May enhance adipocyte metabolism
• Synergistic incretin signaling

Glucagon receptor activation:

• ↑ Energy expenditure
• ↑ Lipolysis
• ↑ Fat oxidation
• Mild ↑ hepatic glucose output (balanced by GLP-1 effect)

Net effect:

• Potent weight loss
• Improved glycemic control
• Increased metabolic rate

Phase 2 obesity trials demonstrated:

• ~24% mean body weight reduction at highest doses
• Significant A1C reduction in type 2 diabetes

Weight loss magnitude approaches bariatric surgery levels.

GLP-1:

• Appetite suppression

GIP:

• Insulin potentiation

Glucagon:

• Energy expenditure increase

Unlike pure GLP-1 agents, retatrutide increases metabolic rate rather than just reducing caloric intake.

Similar to GLP-1 receptor agonists:

• Nausea
• Vomiting
• Diarrhea

Glucagon receptor activation may cause:

• Mild increase in heart rate
• Possible increase in liver enzymes (under investigation)

Long-term safety data pending.

Tirzepatide:

• Dual GLP-1/GIP agonist
• No glucagon receptor activation

GLP-1 Receptor Agonists:

• GLP-1 only
• Primarily reduce appetite

Retatrutide:

• Triple agonist
• Adds metabolic rate increase
• Greater weight loss potential

• Triple incretin agonist
• Not yet FDA approved
• Produces near–bariatric-level weight loss
• Combines appetite suppression + energy expenditure
• Represents next-generation obesity pharmacotherapy

• GLP-1 Receptor Agonists
• Dual GLP-1/GIP Agonists
• Tirzepatide
• Diabetes Pharmacology