Retatrutide, semaglutide and tirzepatide in weight loss: what the evidence already shows and what is still a promise
Three drugs, three generations of mechanism and three levels of proof. From semaglutide and tirzepatide, approved and compared head to head, to retatrutide, still investigational, a comparison that separates the proven result from expectation.
Three mechanisms, one and the same family
From activating one receptor to three, the escalation in mechanism tracks the escalation in magnitude.
The three drugs belong to the family of incretin hormone analogs, which act on appetite, gastric emptying and insulin secretion. The difference lies in how many receptors each one activates. Semaglutide is a GLP-1 receptor agonist. Tirzepatide is a dual agonist, of GIP and GLP-1. Retatrutide is a triple agonist, of GIP, GLP-1 and the glucagon receptor, the last of these linked to energy expenditure.
The temptation is to conclude that more receptors automatically mean more result. What the evidence shows is a real trend toward greater weight loss as the mechanism broadens, but with a decisive difference in maturity: two of these drugs are already approved and one is still investigational.
This comparison ranks the three by what the proof supports today, and not by the expectation surrounding the highest number.
| Drug | Targets (receptors) | Class | Status |
|---|---|---|---|
| Semaglutide | GLP-1 | Single agonist | Approved for obesity |
| Tirzepatide | GIP and GLP-1 | Dual agonist | Approved for obesity |
| Retatrutide | GIP, GLP-1 and glucagon | Triple agonist | Investigational (not approved) |
Semaglutide: the approved standard, with an outcome beyond weight
The class reference, and the only one with cardiovascular benefit demonstrated in a trial.
Semaglutide at the 2.4 mg per week dose established the modern benchmark for the pharmacological treatment of obesity. In the STEP 1 trial, it produced a mean loss of about 15% of body weight over 68 weeks, far above placebo (Wilding et al., 2021).
Its differentiator is not weight alone. In the SELECT trial, in people with overweight or obesity and established cardiovascular disease, but without diabetes, semaglutide reduced major cardiovascular events by about 20% (Lincoff et al., 2023). This is a hard clinical outcome, the kind of proof that sits at the top of the evidence hierarchy and that, for now, only semaglutide has in this comparison.
In practice, this makes semaglutide the reference: not the greatest weight loss in the group, but the combination of proven efficacy with a documented cardiovascular benefit.
Tirzepatide: more weight loss, and superior head to head
Among the approved drugs, it leads on weight, now with a direct comparison.
Tirzepatide raised the efficacy ceiling among the approved drugs. In the SURMOUNT-1 trial, the highest dose achieved a mean loss of about 21% of body weight over 72 weeks (Jastreboff et al., 2022).
The data point that settled the comparison was the direct SURMOUNT-5 trial, which put tirzepatide and semaglutide face to face. Tirzepatide produced significantly greater weight loss, on the order of 20% versus 14% (Aronne et al., 2025). A head-to-head, randomized comparison is worth far more than the juxtaposition of separate studies, and here it favors tirzepatide on the weight outcome.
A calibration is in order: leading on weight loss is not the same as having the cardiovascular benefit already demonstrated, the evidence for which is still maturing for tirzepatide. Choosing between the two approved drugs depends on the goal, on tolerance and on comorbidities, not only on the number on the scale.
Retatrutide: the highest number, but still investigational
The highest promise in the class, and the one that demands the most caution in reading it.
Retatrutide is the name most often associated with high numbers, and there is a basis for that: in phase 2, it reduced about 24% of body weight over 48 weeks, the largest effect reported in this group up to that point (Jastreboff et al., 2023). The third receptor, the glucagon one, may add energy expenditure to the effect on appetite.
Here comes the caveat that defines an honest reading: retatrutide is NOT approved. The peer-reviewed evidence is phase 2. The phase 3 results of the TRIUMPH program were released as a preliminary announcement in 2025 and 2026, with even greater losses, but they await full peer-reviewed publication and regulatory evaluation. Announcing a result is not the same as consolidated evidence for an approved drug.
For this reason retatrutide should not be used outside a clinical trial, and the versions sold in parallel markets, without approval and without quality control, represent a real risk. A high promise does not authorize use without regulation.
What changes beyond the number on the scale
Tolerance, cardiovascular outcome, maintenance and access weigh as much as magnitude.
Mean weight loss does not tell the whole story. The three share gastrointestinal adverse effects, nausea, vomiting and diarrhea, more frequent at the start and on dose increase, which requires slow titration and follow-up. Some patients do not tolerate the higher doses.
Two points are decisive in the choice. First, the cardiovascular outcome: for now, only semaglutide has the reduction of events demonstrated in a trial (Lincoff et al., 2023), while for the others that proof is still maturing. Second, maintenance: these drugs treat, they do not cure. On stopping, much of the weight tends to return, which frames them as chronic treatment, not as a one-off intervention.
Added to this are the concern with loss of muscle mass along with fat, the need for nutritional support and physical activity, and the concrete question of cost and access. The best drug for a given person is the one that balances magnitude, tolerance, comorbidities, the desired outcome and sustainability, under prescription.
Synthesis: magnitude is not the only yardstick
Among the approved drugs, tirzepatide leads on weight and semaglutide has the cardiovascular outcome; retatrutide is a promise, not a course of action.
Bringing the three together: semaglutide is the reference with proven cardiovascular benefit (Lincoff et al., 2023); tirzepatide delivers more weight loss and won the direct comparison (Aronne et al., 2025); and retatrutide shows the highest number, but still on investigational ground (Jastreboff et al., 2023).
The yardstick cannot be only the percentage lost. An approved drug with a documented cardiovascular outcome occupies a different place from a higher number announced in a phase 3 not yet published. The clinical question is not which has the highest number, but which serves this person's goal, with what tolerance, which comorbidity in favor, what access and what maintenance plan.
These are prescription drugs, indicated and monitored by a physician, and not shortcuts. Weight returns when treatment is stopped, adverse effects exist, and retatrutide remains restricted to trials. A course of action that holds up defines the goal, individualizes, integrates diet, activity and sleep, and monitors weight, body composition, blood glucose, lipids and tolerance over time.
| Drug | Mechanism | Mean weight loss | Cardiovascular outcome | Status | Verdict |
|---|---|---|---|---|---|
| Semaglutide | GLP-1 | ~15% (STEP 1) | Proven reduction of events (SELECT) | Approved | Reference with an outcome |
| Tirzepatide | GIP/GLP-1 | ~21% (SURMOUNT-1); superior to semaglutide (SURMOUNT-5) | Maturing | Approved | Greatest loss among the approved |
| Retatrutide | GIP/GLP-1/glucagon | ~24% in phase 2; phase 3 announced | Not established | Investigational | Promise, not a course of action |
Why this matters for your care
This comparison follows the library's line: separating the proven outcome from expectation, even on a topic in high demand. These are prescription drugs, with medical indication and follow-up, and retatrutide remains investigational. To organize goals, comorbidities and history before discussing a course of action, the Functional Self-Assessment helps, and the Library gathers the other notes. Educational content; it does not replace individual medical assessment and does not constitute a prescription.
References
- Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). New England Journal of Medicine. 2021. doi:10.1056/NEJMoa2032183
- Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). New England Journal of Medicine. 2023. doi:10.1056/NEJMoa2307563
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). New England Journal of Medicine. 2022. doi:10.1056/NEJMoa2206038
- Aronne LJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). New England Journal of Medicine. 2025. doi:10.1056/NEJMoa2416394
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. New England Journal of Medicine. 2023. doi:10.1056/NEJMoa2301972
Educational and scientific content. It does not constitute diagnosis, prescription or individual clinical guidance, and does not replace a medical consultation. Management decisions must be individualized by a physician.