Side Effects
Gastrointestinal events are the dominant adverse effect across all doses and both published Phase 2 trials. From the obesity Phase 2 trial (n=338, 48 weeks): nausea 14-60% (dose-dependent, vs. 11% placebo), vomiting 3-26% (vs. 1%), diarrhea 9-20% (vs. 11%), constipation 7-16% (vs. 3%). Events were mostly mild to moderate, occurred predominantly during dose escalation, and were partially mitigated by a lower starting dose of 2 mg. Overall GI adverse events affected up to 82% of participants, discontinuation due to GI effects occurred in 6-16% across dose arms vs. 0% placebo. One case of acute pancreatitis was reported (12 mg group). ALT > 3x ULN in approximately 1% of participants, resolving over time. Serious adverse events occurred in approximately 4% of both active and placebo groups. A glucagon-specific signal: dose-dependent heart rate increase of approximately 5-10 bpm, peaking around week 24 and declining -- larger than seen with semaglutide or tirzepatide. In Phase 3 TRIUMPH-4 (topline, n=445, 68 weeks): nausea 38.1-43.2% (vs. 10.7% placebo), vomiting approximately 20%, diarrhea 33%, and a dysesthesia (tingling/altered skin sensation) signal in 20.9% at 12 mg not prominently noted in Phase 2. Discontinuation rates due to adverse events: 12.2% (9 mg) and 18.2% (12 mg) vs. 4% placebo. Mental health monitoring (suicidal ideation, depression) is ongoing class-wide per FDA requirement, no specific retatrutide signal in published data. Thyroid C-cell preclinical concern is a class-level issue for all GLP-1 receptor agonists, no human cases reported in retatrutide trials.