====== Dual GLP-1 / GIP Incretin Agonists ======

Dual incretin agonists activate both the:

  * GLP-1 receptor
  * GIP receptor

These agents enhance insulin secretion and metabolic regulation more broadly than traditional GLP-1 receptor agonists.

→ [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
→ [[endocrine:incretin:start|Incretin Pharmacology]]

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===== Physiology Background =====

GLP-1 (Glucagon-Like Peptide-1):

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

GIP (Glucose-Dependent Insulinotropic Polypeptide):

  * Stimulates insulin secretion
  * Modulates adipocyte metabolism
  * May enhance anabolic signaling in adipose tissue

Combined receptor activation amplifies metabolic response.

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

Dual agonists:

  * Increase insulin secretion (glucose-dependent)
  * Suppress glucagon
  * Reduce appetite
  * Promote weight loss
  * Improve insulin sensitivity indirectly via weight reduction

Hypoglycemia risk remains low unless combined with insulin or sulfonylureas.

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===== Approved Agents =====

  * [[endocrine:incretin:tirzepatide|Tirzepatide]]

Tirzepatide is the first FDA-approved dual GLP-1/GIP receptor agonist.

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===== Clinical Effects =====

Compared to traditional GLP-1 receptor agonists:

  * Greater weight reduction
  * Greater HbA1c reduction
  * Similar gastrointestinal side effect profile

Weight loss often exceeds that seen with:

  * [[endocrine:glp1:semaglutide|Semaglutide]]
  * [[endocrine:glp1:dulaglutide|Dulaglutide]]

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===== Cardiometabolic Impact =====

Dual incretin therapy improves:

  * Glycemic control
  * Body weight
  * Blood pressure
  * Lipid profile

Long-term cardiovascular outcome trials are ongoing.

→ [[cardio:intro:start|Cardiovascular Pharmacology]]

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

Common:

  * Nausea
  * Vomiting
  * Diarrhea
  * Early satiety

Rare:

  * Pancreatitis
  * Gallbladder disease

Similar boxed warning to GLP-1 agents regarding medullary thyroid carcinoma.

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===== Contraindications =====

  * Personal or family history of medullary thyroid carcinoma
  * MEN2 syndrome

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

Dual incretin agonists represent an evolution beyond traditional GLP-1 therapy.

Ongoing research is evaluating:

  * Cardiovascular outcomes
  * Renal protection
  * Obesity-specific indications
  * Triple incretin combinations

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===== Related =====

  * [[endocrine:glp1:start|GLP-1 Receptor Agonists]]
  * [[endocrine:incretin:tirzepatide|Tirzepatide]]
  * [[endocrine:glp1_gip_gra:triple_incretin_agonists|Triple Incretin Agonists]]
  * [[cardio:heart_failure:start|Heart Failure Module]]