====== Retatrutide ======

Retatrutide is an investigational triple incretin receptor agonist.

It activates:

  * GLP-1 receptor
  * GIP receptor
  * Glucagon receptor

Class:

  * [[endocrine:glp1_gip_gra:triple_incretin_agonists|Triple Incretin Agonists]]

Status:

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

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===== Mechanism of Action =====

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

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===== Clinical Data =====

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.

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===== Metabolic Rationale =====

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.

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===== Adverse Effects =====

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.

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===== Retatrutide vs Other Incretins =====

[[endocrine:glp1_gip:tirzepatide|Tirzepatide]]:

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

[[endocrine:glp1:start|GLP-1 Receptor Agonists]]:

  * GLP-1 only
  * Primarily reduce appetite

Retatrutide:

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

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===== Clinical Pearls =====

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

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===== Related =====

  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[endocrine:glp1_gip:dual_glp-1_gip_incretin_agonists|Dual GLP-1/GIP Agonists]]
  * [[endocrine:glp1_gip:tirzepatide|Tirzepatide]]
  * [[endocrine:diabetes:start|Diabetes Pharmacology]]