====== Triple Incretin Agonists (GLP-1 / GIP / Glucagon) ======

Triple incretin agonists activate three metabolic hormone receptors:

  * GLP-1 receptor
  * GIP receptor
  * Glucagon receptor

These agents are investigational and represent the next evolution in incretin-based metabolic therapy.

→ [[endocrine:glp1_gip:dual_glp-1_gip_incretin_agonists|Dual GLP-1/GIP Incretin Agonists]]
→ [[endocrine:glp1:start|GLP-1 Receptor Agonists]]

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===== Physiologic Rationale =====

Each receptor contributes unique metabolic effects.

GLP-1 receptor activation:

  * Increases glucose-dependent insulin secretion
  * Decreases glucagon
  * Slows gastric emptying
  * Promotes satiety

GIP receptor activation:

  * Enhances insulin secretion
  * Modulates adipocyte signaling
  * May amplify anabolic and metabolic effects

Glucagon receptor activation:

  * Increases energy expenditure
  * Promotes lipolysis
  * Raises metabolic rate

The combination aims to:

  * Maximize weight reduction
  * Improve glycemic control
  * Enhance metabolic flexibility

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

Triple agonists:

  * Increase insulin (glucose-dependent)
  * Suppress inappropriate glucagon secretion
  * Increase energy expenditure
  * Reduce appetite
  * Promote significant fat mass reduction

Hypoglycemia risk remains low due to glucose-dependent insulin release.

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===== Investigational Agents =====

  * [[endocrine:endocrine:glp1_gip_gra:triple_incretin_agonists:Retatrutide]]

Retatrutide is the most advanced triple incretin agonist in clinical development.

Early trials show:

  * Very significant weight reduction
  * Substantial HbA1c lowering
  * Improvements in cardiometabolic risk markers

Not yet FDA approved.

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===== Clinical Potential =====

Compared to:

  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[endocrine:glp1_gip:dual_glp-1_gip_incretin_agonists|Dual Incretin Agonists]]

Triple agonists may produce:

  * Greater weight loss
  * Greater metabolic improvement
  * Broader energy expenditure effects

Long-term cardiovascular outcome data are pending.

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===== Safety Considerations =====

Similar expected adverse effects to GLP-1 agents:

  * Nausea
  * Vomiting
  * Diarrhea

Potential concerns:

  * Pancreatitis
  * Gallbladder disease
  * Class warning regarding medullary thyroid carcinoma

Long-term safety is still under investigation.

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===== Future Directions =====

Triple incretin therapy may redefine obesity and diabetes management.

Ongoing studies are evaluating:

  * Cardiovascular outcomes
  * Renal protection
  * Obesity-specific indications
  * Combination therapy strategies

These agents represent a shift toward multi-hormonal metabolic modulation.

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===== Related =====

  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[endocrine:glp1_gip:dual_glp-1_gip_incretin_agonists|Dual Incretin Agonists]]
  * [[endocrine:incretin:tirzepatide|Tirzepatide]]
  * [[cardio:intro:start|Cardiovascular Pharmacology]]