Gastrointestinal Side Effects (most common, typically transient):
- Nausea: ~20-30% (varies by drug and dose; e.g., liraglutide 3.0 mg q.d. = 6%, 1.8 mg q.d. = 4.7%)
- Vomiting: ~5-10%
- Diarrhea: ~5-10%
- Esophageal reflux: ~5-10%
- Rationale: Due to delayed gastric emptying and increased motility.
- Hypoglycemia (with concomitant use of insulin or sulfonylurea):
- ~5-10% (higher risk if combined with other hypoglycemic agents)
- Rationale: GLP-1 RAs enhance insulin secretion in a glucose-dependent manner.
- Pancreatitis (rare but serious):
- ~0.5-1% (higher in clinical trials vs. real-world data)
- Rationale: Possible mechanism involves GLP-1 receptor expression in pancreatic acinar cells.
- Other Notable Side Effects:
- Injection-site reactions: ~5-10%
- Fatigue: ~5-10%
- Headache: ~5-10%
- Rationale: Likely due to systemic effects of GLP-1 receptor activation.
- Dual GIP/GLP-1 RAs (e.g., tirzepatide):
- Similar GI side effects (~20-30% nausea, ~10-15% diarrhea)
- Rationale: GIP co-agonism may exacerbate GI effects.
- DPP-4 Inhibitors (for comparison):
- Very low incidence of GI side effects (~5% nausea, ~2% diarrhea)
- Rationale: Minimal impact on gastric motility.
Key References:
- AACE/ACE 2023 guidelines, FDA labels for GLP-1 RAs, LEADER/SUSTAIN trials.