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.

→ GLP-1 Receptor Agonists → Incretin Pharmacology

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.

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.

• Tirzepatide

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

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:

• Semaglutide
• Dulaglutide

Dual incretin therapy improves:

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

Long-term cardiovascular outcome trials are ongoing.

→ Cardiovascular Pharmacology

Common:

• Nausea
• Vomiting
• Diarrhea
• Early satiety

Rare:

• Pancreatitis
• Gallbladder disease

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

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

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

• GLP-1 Receptor Agonists
• Tirzepatide
• Triple Incretin Agonists
• Heart Failure Module