Study Notes: GLP-1 Agonists

 I. Overview

• GLP-1 = Glucagon-Like Peptide-1, a natural incretin hormone.

• Agonists = drugs that mimic/activate GLP-1’s effects.

• Indications:

  • Type 2 Diabetes Mellitus (T2DM) (not Type 1)

  • Weight loss (popular in recent years)

• Formulation: Primarily subcutaneous injections; one oral option (Rybelsus).

• Naming rule: Most end in -glutide or -tide.

II. Mechanism of Action

When food is ingested → GLP-1 & GIP incretins released → multiple effects:

1. Delayed gastric emptying → prolonged satiety.

2. ↑ Insulin secretion (via pancreatic β-cells).

3. ↓ Glucagon secretion (from pancreas → less hepatic glucose output).

GLP-1 Agonists mimic this pathway exogenously:

• Direct injection increases GLP-1 activity without requiring food intake.

• Net effect = ↓ Blood glucose and ↓ appetite/weight loss.

III. Clinical Uses

• T2DM → 2nd or 3rd line (after metformin).

• Weight loss → slows gastric emptying → reduced caloric intake.

IV. Common Agents & Dosing

• Semaglutide (Ozempic, Wegovy, Rybelsus [oral])

  • Weekly SQ: start 0.25 mg, ↑ gradually → up to 2 mg weekly.

  • Rybelsus: only oral GLP-1 agonist.

• Exenatide (Byetta, Bydureon)

  • Byetta: 5 mcg BID → 10 mcg BID.

  • Bydureon: 2 mg weekly.

  • Avoid if GFR < 30.

• Liraglutide (Victoza, Saxenda)

  • Daily SQ: start 0.6 mg → titrate to 1.8 mg daily.

• Tirzepatide (Mounjaro, Zepbound)

  • Dual GLP-1 & GIP agonist.

  • Weekly SQ: start 2.5 mg → titrate up to 15 mg weekly.

V. Key Considerations

• GI effects common → nausea, vomiting, delayed gastric emptying.

• Renal dosing: Only exenatide contraindicated in renal impairment (GFR < 30).

• Dosing schedule varies: daily vs weekly injections; adherence influenced by frequency.

VI. Adverse Effects

• Very common: Nausea, GI upset (improves with time).

• Weight loss (beneficial or unwanted, depending on indication).

• Hypoglycemia (esp. when combined with insulin/sulfonylureas).

• Rare: Pancreatitis.

VII. Drug Interactions

• Avoid combination with DPP-4 inhibitors (e.g., sitagliptin).

  • Both increase GLP-1 → excessive activity → ↑ side effects, no added benefit.

VIII. Summary

• GLP-1 agonists ↓ blood glucose & promote weight loss by:

  1. Delaying gastric emptying

  2. ↑ Insulin release

  3. ↓ Glucagon secretion

• Indicated for T2DM & weight management.

• Common side effect = nausea.

• Oral option = Rybelsus (semaglutide).

• Do not combine with DPP-4 inhibitors.

IX. Quick Quiz

1. What are the two main indications for GLP-1 agonists?

2. Which incretins are mimicked/increased by semaglutide?

3. What is the most common side effect?

4. Which drug class should not be combined with GLP-1 agonists?