Orforglipron: Side Effects
Known side effects, contraindications, and interactions
๐TL;DR
- โข5 known side effects documented
- โข5 mild, 0 moderate, 0 severe
- โข3 contraindications listed
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Side Effects Severity Chart
Most common adverse event. In ATTAIN-1, nausea occurred in 20.1% (6 mg), 31.1% (12 mg), and 36.4% (36 mg) vs 8.4% placebo. Generally mild to moderate, occurring primarily during dose escalation and improving over time.
Second most common GI adverse event. In ATTAIN-1, diarrhea occurred in 21.3% (6 mg), 24.8% (12 mg), and 27.4% (36 mg) vs 15.0% placebo. Usually mild to moderate and self-limiting.
In ATTAIN-1, vomiting occurred in 12.8% (6 mg), 20.2% (12 mg), and 23.1% (36 mg) vs 3.8% placebo. Most common during dose escalation period. Generally mild to moderate.
Reported as a common GI adverse event in clinical trials. Attributed to slowed GI transit from GLP-1 receptor activation.
Reflects the intended pharmacological effect of GLP-1 receptor activation on appetite centers in the brain.
โContraindications
- โขPersonal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2) -- GLP-1 agonist class warning
- โขPregnancy (potential fetal harm based on GLP-1 agonist class data)
- โขPrior serious hypersensitivity reaction to orforglipron or excipients
โ ๏ธDrug Interactions
- โขInsulin and sulfonylureas: Potential increased risk of hypoglycemia when combined with orforglipron (GLP-1 agonist class interaction)
- โขOral medications affected by gastric emptying: Orforglipron may delay gastric emptying, potentially affecting absorption of co-administered oral drugs
- โขDrug-drug interaction studies have not been fully published; comprehensive interaction data will be available upon regulatory submission
Community-Reported Side Effects
See which side effects community members report most frequently.
0View community protocolsSafety Overview#
Orforglipron's safety profile has been characterized through Phase 1, Phase 2, and Phase 3 clinical trials enrolling thousands of participants. The adverse event profile is consistent with the GLP-1 receptor agonist class, with gastrointestinal symptoms being the most commonly reported events. As an investigational agent, the full safety profile continues to be defined.
Gastrointestinal Adverse Events#
The most commonly reported adverse events with orforglipron are gastrointestinal, consistent with on-target GLP-1 receptor activation in the gut and central nervous system.
ATTAIN-1 GI Adverse Event Rates (72 weeks)#
| Adverse Event | 6 mg | 12 mg | 36 mg | Placebo |
|---|---|---|---|---|
| Nausea | 20.1% | 31.1% | 36.4% | 8.4% |
| Diarrhea | 21.3% | 24.8% | 27.4% | 15.0% |
| Vomiting | 12.8% | 20.2% | 23.1% | 3.8% |
ACHIEVE-1 GI Adverse Event Rates (40 weeks, T2D)#
| Adverse Event | 3 mg | 12 mg | 36 mg | Placebo |
|---|---|---|---|---|
| Diarrhea | 19% | 21% | 26% | 9% |
| Nausea | 13% | 18% | 16% | 2% |
| Vomiting | 5% | 7% | 14% | 1% |
Characteristics#
- Dose-dependent: Higher doses are associated with higher GI adverse event rates
- Timing: Most GI events occur during the dose escalation phase and tend to diminish with continued treatment
- Severity: The majority of events are classified as mild to moderate
- Comparison to injectable GLP-1 agonists: GI adverse event rates are broadly similar to those observed with injectable semaglutide (Wegovy)
Treatment Discontinuation#
Adverse events led to treatment discontinuation in a minority of patients:
- ATTAIN-1: 5.3-10.3% across orforglipron dose groups vs 2.7% placebo
- ACHIEVE-1: 6% (3 mg), 4% (12 mg), 8% (36 mg) vs 1% placebo
- Phase 2 obesity: 10-17% across dose cohorts
These discontinuation rates are generally comparable to those observed with injectable GLP-1 agonists.
GLP-1 Agonist Class Warnings#
As a GLP-1 receptor agonist, orforglipron is expected to carry the standard class warnings, although the specific label language will depend on regulatory review:
Thyroid C-Cell Tumors#
All GLP-1 receptor agonists carry a boxed warning regarding thyroid C-cell tumors based on rodent carcinogenicity studies. Whether this risk extends to humans is not established. Orforglipron is expected to carry the same warning. It should not be used in patients with a personal or family history of medullary thyroid carcinoma or MEN2.
Pancreatitis#
Acute pancreatitis has been reported with GLP-1 agonists as a class. The incidence with orforglipron in clinical trials has not been separately detailed but is expected to be low and consistent with the class.
Gallbladder Disease#
GLP-1 agonist-associated weight loss increases the risk of cholelithiasis and cholecystitis, consistent with the general association between rapid weight loss and gallstone formation.
Heart Rate Effects#
GLP-1 agonists as a class are associated with modest increases in resting heart rate (typically 2-4 bpm). Specific heart rate data for orforglipron have not been prominently reported but are expected to be consistent with the class effect.
Hepatic Effects#
Elevations in hepatic enzymes have been observed with some GLP-1 agonists. The hepatic safety profile of orforglipron will be fully characterized in the regulatory filing.
Comparison with Injectable GLP-1 Agonist Safety#
| Parameter | Orforglipron 36 mg | Semaglutide 2.4 mg (Wegovy) |
|---|---|---|
| Nausea | 36.4% | 44% |
| Vomiting | 23.1% | 24% |
| Diarrhea | 27.4% | 30% |
| Discontinuation (AE) | 5.3-10.3% | ~7% |
| Route | Oral | Subcutaneous injection |
| Food restrictions | None | N/A (injection) |
The GI adverse event rates for orforglipron appear broadly similar to or slightly lower than those for injectable semaglutide at the weight management dose.
Contraindications (Expected)#
Based on the GLP-1 agonist class:
- MTC/MEN2: Contraindicated in patients with personal or family history
- Pregnancy: Should not be used during pregnancy
- Hypersensitivity: Prior serious allergic reaction to orforglipron
Drug Interactions (Expected)#
- Insulin and sulfonylureas: Risk of hypoglycemia when combined
- Drugs affected by gastric emptying: Orforglipron delays gastric emptying and may affect the absorption of co-administered oral medications
- CYP interactions: As a small molecule (unlike peptide GLP-1 agonists), orforglipron may have CYP-mediated interactions; full DDI data await regulatory filing
Special Populations#
Full data on special populations (renal impairment, hepatic impairment, elderly, pediatric) have not been published and will be available in the prescribing information upon regulatory approval.
Related Reading#
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This website is for educational and informational purposes only. The information provided is not intended to diagnose, treat, cure, or prevent any disease. Always consult with a qualified healthcare professional before using any peptide or supplement.