Semaglutide is a once-weekly GLP-1 receptor agonist with phase 3 obesity data (STEP 1) and a completed cardiovascular-outcome trial (SELECT). Retatrutide is a triple GIP/GLP-1/glucagon receptor agonist with published phase 2 obesity and type 2 diabetes trials. They share GLP-1-receptor activity and almost nothing else at the receptor map.
There is no published head-to-head RCT of semaglutide versus retatrutide. Treat every percentage below as the result of the trial that produced it, not as a league table.
This page is informational and research-use framed. It is not medical advice and not a dosing protocol.
Research notice: Research-grade peptides discussed here are not approved for human consumption, medical treatment, or diagnosis. FDA-approved semaglutide products are prescription medicines, separate from laboratory vials.
| Parameter | Semaglutide | Retatrutide |
|---|---|---|
| Receptor targets | GLP-1 receptor | GIP, GLP-1, and glucagon receptors |
| Chemistry (published discovery) | Acylated GLP-1 analogue designed for once-weekly exposure | Fatty-acid-acylated peptide on a GIP backbone with GCGR, GIPR, and GLP-1R activity |
| Sponsor | Novo Nordisk | Eli Lilly |
| US FDA status | Approved products include Ozempic (initial US approval 2017) and Wegovy (June 4, 2021) | Not approved |
| Obesity evidence cited here | STEP 1, phase 3, 1961 adults, 68 weeks | Phase 2, 338 adults, 48 weeks |
| Published mean weight change (separate trials) | -14.9% vs -2.4% placebo at 68 weeks (2.4 mg) | -24.2% vs -2.1% placebo at 48 weeks (12 mg) |
| Cardiovascular outcomes | SELECT: HR 0.80 for death from CV causes, nonfatal MI, or nonfatal stroke | No published CVOT in the sources below |
| Direct human head-to-head | None versus retatrutide | None versus semaglutide |
Semaglutide is a GLP-1 analogue. Lau et al. described the medicinal chemistry that produced a once-weekly GLP-1 analogue; Knudsen and Lau reviewed that discovery path. Clinically it is used as a selective GLP-1 receptor agonist. It does not agonize GIP or glucagon receptors.
Retatrutide (LY3437943) agonizes GCGR, GIPR, and GLP-1R. Coskun et al. reported balanced GCGR and GLP-1R activity in vitro, higher GIPR activity, greater weight loss than tirzepatide in obese mice, and GCGR-mediated increases in energy expenditure added to reduced calorie intake. Human single-dose pharmacokinetics supported weekly administration.
If someone collapses this comparison to "both are GLP-1s," they are wrong. Semaglutide is GLP-1 only. Retatrutide is three receptors, one of which (glucagon) is absent from semaglutide's target list.
Semaglutide is an approved US drug substance in multiple labeled products:
Retatrutide is not FDA-approved. Published human papers cited here are phase 1 (Coskun 2022) and phase 2 (Jastreboff 2023 obesity; Rosenstock 2023 type 2 diabetes). Rosenstock et al. stated that the diabetes phase 2 data informed phase 3 dose selection. That is not an approval.
Research vials labeled semaglutide or retatrutide are not Ozempic, Wegovy, or a licensed investigational drug supply.
Wilding et al. enrolled 1961 adults with BMI of 30 or greater, or 27 or greater with a weight-related condition, without diabetes. Assignment was 2:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 68 weeks, plus lifestyle intervention. Mean body-weight change was -14.9% with semaglutide versus -2.4% with placebo (estimated treatment difference -12.4 percentage points; 95% CI -13.4 to -11.5; P less than 0.001). Nausea and diarrhea were the most common adverse events; gastrointestinal events led to discontinuation in 4.5% versus 0.8%.
Lincoff et al. enrolled 17,604 patients aged 45 or older with preexisting cardiovascular disease and BMI of 27 or greater, without diabetes. Assignment was once-weekly subcutaneous semaglutide 2.4 mg or placebo. A primary composite event (CV death, nonfatal MI, or nonfatal stroke) occurred in 569/8803 (6.5%) on semaglutide and 701/8801 (8.0%) on placebo (hazard ratio 0.80; 95% CI 0.72 to 0.90; P less than 0.001). Mean follow-up was 39.8 months. Permanent discontinuation for adverse events was 16.6% versus 8.2%.
SUSTAIN-6 (Marso et al.) previously reported cardiovascular outcomes for semaglutide in type 2 diabetes. SELECT is the obesity-without-diabetes outcome trial.
Jastreboff, Kaplan, Frias et al. enrolled 338 adults for 48 weeks of once-weekly retatrutide or placebo. At 48 weeks, least-squares mean weight change at 12 mg was -24.2% versus -2.1% placebo. Gastrointestinal adverse events were dose-related and mostly mild to moderate. Heart-rate increases were dose-dependent, peaked at 24 weeks, and then declined.
Rosenstock et al. (n=281 safety population) compared retatrutide with placebo and dulaglutide 1.5 mg. At 24 weeks, HbA1c change at retatrutide 12 mg was -2.02% versus -0.01% placebo and -1.41% dulaglutide. At 36 weeks, weight change at 12 mg was -16.94% versus -3.00% placebo. No severe hypoglycemia and no deaths were reported in that trial.
STEP 1 is 68 weeks, phase 3, n=1961, people without diabetes. The retatrutide obesity study is 48 weeks, phase 2, n=338. SELECT has no retatrutide counterpart in the papers below. Cross-trial subtraction ("24% minus 15%") is not a result.
For a completed dual-agonist versus GLP-1 obesity head-to-head, see Semaglutide vs Tirzepatide (SURMOUNT-5). For dual versus triple, see Tirzepatide vs Retatrutide.
| Question | Semaglutide | Retatrutide |
|---|---|---|
| Receptor count | One (GLP-1) | Three (GIP, GLP-1, glucagon) |
| Phase 3 obesity RCT cited here | Yes (STEP 1) | No (phase 2 only) |
| CV outcome RCT | Yes (SELECT; also SUSTAIN-6 in T2D) | Not in the cited sources |
| FDA-approved products | Yes | No |
| Glucagon-receptor energy-expenditure data | Not a semaglutide mechanism in these papers | Reported in obese mice (Coskun 2022) |
| Heart-rate finding called out in the obesity abstract | Not the STEP 1 abstract's main safety line | Dose-dependent increase, peak week 24 |
Semaglutide is the compound with licensed products and a published MACE result in obesity without diabetes. Retatrutide is the compound with triple-receptor pharmacology and larger phase 2 point estimates over a shorter, smaller study. Those are different claims. Do not fuse them.
Related: Semaglutide research guide, Semaglutide vs Tirzepatide, Tirzepatide vs Retatrutide.
No. STEP 1 and SELECT tested semaglutide against placebo. Retatrutide obesity and diabetes papers are phase 2 versus placebo (and dulaglutide in the diabetes trial). Cross-trial percentage weight loss is not a ranking.
No. Semaglutide has FDA-approved products, including Ozempic (initial US approval 2017) and Wegovy (June 4, 2021). Retatrutide is investigational.
Semaglutide is a selective GLP-1 receptor agonist. Retatrutide is a triple agonist at GIP, GLP-1, and glucagon receptors. Shared GLP-1 activity does not make them pharmacologic equivalents.
Semaglutide. SELECT (n=17,604) reported a primary MACE hazard ratio of 0.80 versus placebo in people with preexisting cardiovascular disease and overweight or obesity without diabetes. Retatrutide has no equivalent published outcome trial in the sources cited here.
No. It summarizes published research and regulatory status. It is not medical advice. Research-grade vials are not the same as Ozempic or Wegovy.
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