Tirzepatide vs semaglutide vs retatrutide vs CagriSema: the data, side by side

TL;DR

• Only one pair here was ever tested against the other - SURMOUNT-5: tirzepatide −20.2% vs semaglutide −13.7% over 72 weeks.
• **Tirzepatide is the most potent approved option**, reaching up to −22.5% at 72 weeks in SURMOUNT-1 by adding GIP to GLP-1.
• Retatrutide posts the biggest number - about −28% at 80 weeks in TRIUMPH-1 - but it is investigational, not approved, not available.
• CagriSema reached −20.4% in REDEFINE 1, below the ~25% its maker had targeted, and is also still investigational.
• Semaglutide owns the outcomes data: SELECT showed a 20% reduction in heart attack, stroke and cardiovascular death.
• The percentages can't be ranked against each other - 68, 72 and 80-week trials, different populations, different statistical methods.

Educational content, not medical advice or a ranking to act on. Trial figures are reported as published; cross-trial comparisons are not head-to-head, which we flag explicitly. Two of the four are investigational. No doses appear as instructions.

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There are really only four compounds driving the entire weight-loss-injection conversation right now, and they line up neatly by how many hormone pathways each one hits. Semaglutide works on one (GLP-1), tirzepatide on two (GLP-1 + GIP), retatrutide on three (GLP-1 + GIP + glucagon), and CagriSema pairs a GLP-1 with a completely different lever (amylin). More pathways has so far meant more weight loss - but two of these aren't approved yet, the biggest numbers come from different trials that can't be compared directly, and "most potent" is not the same as "right for you." Here's the whole field on one page.

The comparison at a glance

Compound references for each: semaglutide · tirzepatide · cagrilintide · retatrutide - the last two remain investigational.

Reading the table honestly

Semaglutide is the established workhorse - the most studied, the most available, and the one with the strongest dedicated cardiovascular-outcomes evidence (the SELECT trial showed a 20% reduction in heart attack, stroke and cardiovascular death). It's the lowest weight-loss number of the four, but "lowest" here still means roughly 15% of body weight.

Tirzepatide is the most potent option you can actually get today. It's the only pair in this group with a genuine head-to-head: in SURMOUNT-5, tirzepatide produced −20.2% versus semaglutide's −13.7% over 72 weeks. Adding the GIP pathway to GLP-1 is what buys that extra effect.

CagriSema validates a different idea - that pairing GLP-1 with the amylin pathway (a separate brainstem satiety route) beats either alone. It reached −20.4% in REDEFINE 1, which is excellent, but it's worth saying plainly that this landed below the ~25% its maker had hoped for and sits in tirzepatide's territory rather than beyond it. It's also still investigational.

Retatrutide posts the biggest number - about 28% at the top dose over 80 weeks in its first phase 3 trial, with ~30% in a longer extension - by adding a third pathway (glucagon) that raises energy expenditure and mobilises liver fat. But it is investigational, not approved, not available, and crucially has never been compared head-to-head with tirzepatide.

The cross-trial trap

This is the single most important caveat, so it gets its own section: you cannot rank these four by lining up their headline percentages. Retatrutide's 28% came from an 80-week trial; tirzepatide's 22.5% from a 72-week trial; CagriSema's 20.4% and semaglutide's 14.9% from 68-week trials - with different patient populations, different protocols, and different statistical methods. Longer trials and different enrolment criteria inflate or deflate the comparison in ways that have nothing to do with the drug.

The only fair comparison in this entire group is tirzepatide vs semaglutide, because they were actually tested against each other (SURMOUNT-5). Everything else is "trial A's number next to trial B's number" - useful for a rough sense of the landscape, useless as a definitive ranking.

What each one is for

Potency is only one axis. In practice the choice turns on the person:

• Semaglutide - a strong, well-understood first option, and the pick when cardiovascular risk reduction is a priority given its outcomes data.
• Tirzepatide - the choice when maximum approved efficacy matters and titration is tolerated; also strong on insulin sensitivity.
• CagriSema - a second-pathway approach (once available) for added effect or to manage tolerability at lower component doses.
• Retatrutide - the horizon option: most promising on paper, but a clinician can only plan around it, not prescribe it, until it's approved.

The bottom line - and where to start

The pattern is real - more pathways has meant more weight loss, from semaglutide's one to retatrutide's three. But the honest reading is that only two of these are available, only one comparison is truly head-to-head, and the "best" molecule is the one matched to your physiology, risk profile and tolerance - not the one with the largest number lifted from the longest trial. That matching is a clinical decision, not a leaderboard.

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Frequently asked questions

Which is the strongest weight-loss injection? By headline trial number, retatrutide (~28%) > tirzepatide (~22.5%) ≈ CagriSema (~20%) > semaglutide (~15%). But those come from different trials and can't be ranked directly - and retatrutide and CagriSema are still investigational. Tirzepatide is the most potent approved option.

Is retatrutide better than tirzepatide? On separate trial numbers it produced more weight loss, but the two have never been compared head-to-head, and retatrutide isn't approved or available. "Better on paper, unproven against tirzepatide directly" is the honest answer.

How is CagriSema different from the others? It pairs a GLP-1 (semaglutide) with an amylin analogue (cagrilintide) - a separate satiety pathway - rather than stacking incretin receptors. It reached −20.4% in REDEFINE 1 but remains investigational.

Which has the best heart-health evidence? Semaglutide, via the SELECT trial (a 20% reduction in major cardiovascular events), currently has the largest dedicated cardiovascular-outcomes dataset.

Related reading

• How GLP-1 agonists actually work - the mechanism behind the table
• Cagrilintide as a GLP-1 bridge or stack - the amylin outlier, in depth
• Mounjaro vs Wegovy vs Ozempic - untangling the brand names
• Tirzepatide vs retatrutide: what's next after Mounjaro - the investigational frontier

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Educational content, not medical advice or a recommendation of any product. Retatrutide and CagriSema are investigational and not approved; cross-trial comparisons are not head-to-head. All weight-loss medications are prescription-only and physician-supervised. Trial figures describe study populations; individual results vary. Claims for the Malaysian market are subject to MAB requirements.

Primary references

• Wilding JPH, et al. STEP 1. N Engl J Med. 2021;384:989–1002. (semaglutide −14.9%)
• Jastreboff AM, et al. SURMOUNT-1. N Engl J Med. 2022;387:205–216. (tirzepatide up to −22.5%)
• Aronne LJ, et al. SURMOUNT-5 (tirzepatide vs semaglutide). N Engl J Med. 2025. (−20.2% vs −13.7%)
• Davies M, Garvey WT, et al. REDEFINE 1 (CagriSema). N Engl J Med. 2025. doi:10.1056/NEJMoa2502081. (−20.4%)
• Eli Lilly. TRIUMPH-1 topline (retatrutide), 21 May 2026. (up to ~28% at 80 weeks)
• Lincoff AM, et al. SELECT. N Engl J Med. 2023;389:2221–2232. (semaglutide, 20% MACE reduction)