A detailed side-by-side comparison of the investigational triple agonist and the world's best-known GLP-1 drug — Ozempic and Wegovy.
Semaglutide works entirely through one pathway: GLP-1 receptor agonism. This suppresses appetite, slows gastric emptying, and improves blood sugar control. It was a breakthrough when it launched, and the weight loss results were genuinely impressive for a once-weekly injection.
Retatrutide adds two additional mechanisms on top of GLP-1. The GIP component is believed to improve tolerability and amplify the metabolic response. More significantly, the glucagon receptor component increases energy expenditure — essentially causing the body to burn more calories at rest. This is a fundamentally different approach from appetite suppression alone, and the Phase 2 weight loss data suggests it matters.
The numbers: In their respective pivotal trials, semaglutide produced approximately 15% mean weight loss. Retatrutide Phase 2 data showed 24% at the highest dose — though these are different trials with different designs, so direct comparison requires caution.
Both drugs share the core GLP-1 side effect profile: nausea, vomiting, diarrhea, and constipation are the most common complaints, particularly during dose escalation. These are generally mild to moderate and decrease over time.
Retatrutide appears to produce a slightly higher rate of GI side effects at the highest doses compared to standard semaglutide dosing — though the comparison is imperfect because retatrutide doses in Phase 2 were being pushed to the edges of tolerability to establish the efficacy ceiling. The commercial dose, if approved, may be calibrated differently.
One notable difference is the modest heart rate increase seen with retatrutide, which is consistent with glucagon receptor activation. Semaglutide produces similar but generally smaller increases in heart rate.
Semaglutide has significant advantages that retatrutide simply cannot match right now: it is FDA approved, widely available, has years of real-world safety data, and has proven cardiovascular benefits established in the SELECT trial. For anyone who needs treatment today, semaglutide (and tirzepatide) are the clear choices.
Semaglutide also comes in an oral tablet form (Rybelsus) for type 2 diabetes — an option that does not yet exist for retatrutide.
If Phase 3 data confirms the Phase 2 results, retatrutide could be particularly valuable for patients who need substantial weight loss — those with severe obesity, obesity-related liver disease, or who have had inadequate response to existing GLP-1 therapies. The glucagon-mediated increase in energy expenditure and liver fat reduction could also make it a preferred option for patients with MASH/NAFLD.
Approved, available, proven cardiovascular benefit, years of real-world data. The right choice for anyone seeking treatment now. Available as Ozempic (diabetes) or Wegovy (obesity).
Greater weight loss in Phase 2, novel glucagon mechanism, potential liver disease benefits. Could redefine the standard of care — if Phase 3 data delivers.