GLP-1 Agonists – Pharmacology & Clinical Use

• GLP-1 = glucagon-like peptide-1, a natural incretin hormone.

• Agonist = drug that mimics/activates GLP-1 effects.

• Primary uses:

  • Type 2 diabetes (↓ blood glucose).

  • Weight loss (↑ satiety).

• Administration:

  • Mostly subcutaneous injection.

  • Exception: oral semaglutide (Rybelsus®).

• Drug endings: -glutide or -tide.

  • Examples: semaglutide, exenatide, liraglutide, tirzepatide.

2. Mechanism of Action

When eating → incretins (GLP-1, GIP) rise → act on pancreas & GI tract.
GLP-1 agonists mimic this process:

• ↑ Insulin secretion (from pancreatic β-cells).

• ↓ Glucagon secretion (from pancreatic α-cells).

• Delay gastric emptying → prolonged satiety, ↓ appetite.

• Net effect: ↓ blood glucose + weight loss.

3. Indications

• Type 2 diabetes:

  • Second-line/third-line therapy after metformin.

  • Not for type 1 diabetes.

• Weight loss:

  • Popular use (e.g., semaglutide, tirzepatide).

4. Major Agents & Dosing

• Semaglutide (Ozempic®, Wegovy®, Rybelsus® – oral):

  • 0.25 mg weekly ×4 wks → 0.5 mg → titrate up to 2 mg weekly.

• Exenatide (Byetta®, Bydureon®):

  • 5 mcg BID, up to 10 mcg BID.

  • Extended-release: 2 mg weekly.

  • ⚠ Contraindicated if eGFR <30.

• Liraglutide (Victoza®, Saxenda®):

  • Start 0.6 mg daily ×1 wk → 1.2 mg daily → up to 1.8 mg.

• Tirzepatide (Mounjaro®, Zepbound®):

  • Dual GLP-1 & GIP agonist.

  • 2.5 mg weekly ×4 wks → titrate to max 15 mg weekly.

5. Adverse Effects

• Very common:

  • Nausea, vomiting, GI upset (due to delayed gastric emptying).

  • Usually improves with time.

• Other:

  • Weight loss (benefit or side effect depending on indication).

  • Hypoglycemia (especially if combined with insulin or sulfonylureas).

  • Rare: pancreatitis.

6. Drug Interactions

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

  • Excessive GLP-1 activity → ↑ side effects.

7. Key Clinical Pearls

• Weekly vs daily dosing varies → important for adherence.

• Most agents safe in renal impairment → except exenatide.

• Counsel patients: GI upset is expected initially but improves.

8. Quick Quiz

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

2. Which incretins are mimicked by these drugs?

3. What is the most common side effect?

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

5. Which GLP-1 agonist is oral?

6. Which agent is contraindicated in renal impairment (eGFR <30)?