Retatrutide vs Zepbound Side Effects: Which Has Fewer Adverse Events?

Comparing the Side Effect Profiles

Zepbound (tirzepatide) and retatrutide share the same manufacturer — Eli Lilly — and share the GIP and GLP-1 mechanism components. The difference in side effects comes from retatrutide’s additional glucagon receptor activation. Both drugs cause gastrointestinal side effects at similar rates: nausea in 30-40% for retatrutide and 30-35% for Zepbound, diarrhea in 20-25% for both, constipation in 15-20% for retatrutide and 12-17% for Zepbound. The rates are close enough that individual variation matters more than the small differences between the drugs.

The Heart Rate Difference

The one side effect that clearly differs between the two drugs is the effect on heart rate. Retatrutide causes a dose-dependent increase in resting heart rate of 2 to 5 beats per minute due to the glucagon receptor activation. Zepbound does not cause a measurable heart rate increase — the GIP and GLP-1 receptors do not have chronotropic effects. This is the most significant distinguishing factor between the two side effect profiles. Whether the heart rate increase carries clinical significance over the long term is not yet known, as the TRIUMPH trials have a maximum follow-up of two years.

Which Is Better Tolerated?

The discontinuation rate due to side effects is approximately 10% for both retatrutide and Zepbound in their respective Phase 3 trials. This suggests that overall tolerability is similar. The choice between them may come down to the weight loss difference: retatrutide produces roughly 28-30% weight loss compared to Zepbound’s 18-20%. If the higher weight loss is important enough to accept the 2-5 bpm heart rate increase and the lack of FDA approval, retatrutide is the more effective option. If the heart rate increase is a concern, Zepbound is the safer choice with similar tolerability but lower maximum efficacy.