Role of Glucagon in Metabolic Disease Management
GLP-1 receptor agonists are the most effective glucagon-related therapy for managing type 2 diabetes, providing benefits in glycemic control, weight reduction, and cardiovascular outcomes. 1
Glucagon Physiology and Its Role in Metabolic Disease
- Glucagon is a hormone produced by alpha cells in the pancreatic islets that increases blood glucose by activating hepatic glucagon receptors, stimulating glycogen breakdown and glucose release from the liver 2
- In type 2 diabetes, there is a dysregulation characterized by both impaired insulin secretion and exaggerated glucagon secretion, contributing to hyperglycemia 3, 4
- Native glucagon has a short half-life of approximately 2 minutes in circulation due to rapid degradation by dipeptidyl peptidase-4 (DPP-4) 3
Glucagon-Based Therapeutic Approaches
GLP-1 Receptor Agonists
- GLP-1 receptor agonists have emerged as a primary glucagon-related therapy for type 2 diabetes management 1
- These agents work by:
- GLP-1 receptor agonists have been modified to resist DPP-4 degradation, allowing for various administration schedules (twice-daily, once-daily, or once-weekly) 1
- They significantly reduce HbA1c (by approximately 0.8-1.6%) and body weight (by approximately 1-3 kg) 6
Cardiovascular and Renal Benefits
- For patients with established atherosclerotic cardiovascular disease (ASCVD), GLP-1 receptor agonists have demonstrated significant reduction in major adverse cardiovascular events (MACE) 1
- The 2019 ADA/EASD consensus update recommends GLP-1 receptor agonists for patients with type 2 diabetes and established ASCVD where MACE is the gravest threat 1
- GLP-1 receptor agonists can also be considered in patients without established CVD but with high-risk indicators (age ≥55 years, coronary/carotid/lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73m², or albuminuria) 1
Dual Agonists: Emerging Therapies
- Novel dual GLP-1/glucagon receptor co-agonists are being developed to leverage the beneficial metabolic effects of both hormones 7
- These co-agonists have demonstrated significant weight loss, reductions in hepatic fat content, improved lipid profiles, and enhanced insulin sensitivity 7
- The balance between GLP-1 and glucagon agonism is critical to avoid potential hyperglycemic effects of glucagon while maximizing metabolic benefits 7
Clinical Application in Type 2 Diabetes Management
- GLP-1 receptor agonists are positioned as add-ons to metformin alone or in combination with oral agents in the clinical treatment paradigm 1
- They are also effective when combined with insulin, and fixed-dose combinations with long-acting insulin have been developed 3
- The decision to treat high-risk individuals with a GLP-1 receptor agonist should be considered independently of baseline HbA1c or individualized HbA1c target 1
- GLP-1 receptor agonists have a low risk of hypoglycemia, with gastrointestinal effects being the most common adverse reactions 6
Special Considerations for Glucagon Use in Metabolic Disease
- Native glucagon is primarily used for emergency treatment of severe hypoglycemia rather than chronic management of type 2 diabetes 2
- Caution is needed when using glucagon in patients with:
Conclusion for Clinical Practice
- When managing type 2 diabetes, target the dual hormonal imbalance (insufficient insulin and excessive glucagon) by using GLP-1 receptor agonists 4
- For patients with established ASCVD, heart failure, or chronic kidney disease, incorporate GLP-1 receptor agonists or SGLT2 inhibitors based on specific risk profiles 1
- Monitor for gastrointestinal side effects when initiating GLP-1 receptor agonist therapy, as these are the most common adverse effects 6