Companion data & citations

The Third Receptor — Sources & Supporting Data

Every figure in the scrollytelling (retatrutide-third-receptor.html) is reproduced here with its source. The piece compares three obesity drugs across three separate Phase 3 trials: semaglutide (STEP-1), tirzepatide (SURMOUNT-1), and retatrutide (TRIUMPH-1).

The load-bearing caveat. No head-to-head trial exists. These three studies differ in duration (68 / 72 / 80 weeks), baseline BMI (37.9 / 38.0 / 40.0) and placebo-arm response. All cross-drug comparisons are indicative, not the result of a controlled comparison. Retatrutide is investigational as of June 2026; the full peer-reviewed TRIUMPH-1 dataset is expected at ADA Scientific Sessions, June 2026.

Efficacy figures use the efficacy estimand (on-treatment) where reported. Retatrutide values are from Eli Lilly's TRIUMPH-1 topline investor release (May 21, 2026); some deep-threshold responder rates are approximate pending full publication.

0. Scene map

Sixteen scroll scenes in nine movements; the figures below map to them.

Movement	Scenes	Data §
The Frontier	High-water mark · Seventy pounds	§1
The Caveat	Three different trials · Different starting lines	§2
The Depth	Deeper, not just higher · Off the right edge	§3
Dose economy	It scales with dose · Lowest beats the best of the old class	§4
The Cost	Less than nothing · Then you climb · Gains flatten	§5
The Signal	A new side effect · Not in the class	§6
The Mechanism	One more receptor · The engine is the question mark	§7
The Horizon	Still descending (104 weeks)	§8

1. Mean body weight loss (top maintenance dose)

Primary efficacy. Percent change and absolute pounds from baseline, efficacy estimand.

Drug (top dose)	Trial	Mean % loss	Absolute lb	Trial placebo
Semaglutide 2.4 mg	STEP-1	−14.9%	−33.7 lb	−2.4%
Tirzepatide 15 mg	SURMOUNT-1	−22.5%	−52.0 lb	—
Retatrutide 12 mg	TRIUMPH-1	−28.3%	−70.3 lb	—

Retatrutide treatment-regimen estimand (includes off-treatment): −25.0% at 12 mg. Deltas vs. semaglutide 2.4 mg: tirzepatide −7.6 pp / −18.3 lb; retatrutide −13.4 pp / −36.6 lb. Retatrutide vs. tirzepatide 15 mg: −5.8 pp / −18.3 lb.

2. Trial characteristics (the cross-trial caveat)

Parameter	STEP-1	SURMOUNT-1	TRIUMPH-1
Compound	Semaglutide	Tirzepatide	Retatrutide (LY3437943)
Sponsor	Novo Nordisk	Eli Lilly	Eli Lilly
Population	Overweight/obese, no diabetes	Overweight/obese, no diabetes	Overweight/obese, no diabetes
N randomized	1,961	2,539	2,339
Duration	68 wks	72 wks	80 wks
Baseline weight	105.3 kg	104.8 kg	112.7 kg
Baseline BMI	37.9	38.0	40.0
Doses tested	2.4 mg	5 / 10 / 15 mg	4 / 9 / 12 mg
Publication	NEJM 2021	NEJM 2022	Investor release 2026

3. Responder rates by weight-loss threshold

Percent of participants achieving ≥X% body weight loss (efficacy estimand). Top doses shown; dashes are thresholds not reported in the respective release.

Drug (top dose)	≥5%	≥10%	≥15%	≥20%	≥25%	≥30%	≥35%
Semaglutide 2.4 mg	86.4	69.1	50.5	32.0	—	—	—
Tirzepatide 15 mg	96.0	90.0	78.0	63.0	36.2	—	—
Retatrutide 12 mg	—	—	—	—	62.5	45.3	27.2

Retatrutide sub-25% thresholds were not reported in the topline release and are pending full ADA data (June 2026). At the overlapping ≥25% point, retatrutide (62.5%) sits well above tirzepatide (36.2%). Retatrutide lower doses: 4 mg reaches ≥25% 27.8%, ≥30% 15.3%, ≥35% 5.9%; 9 mg ≈ ≥25% 55%, ≥30% 36%, ≥35% 18% (approximate).

4. Dose economy

Retatrutide mean weight loss by dose, against semaglutide's maximum dose.

Dose	Trial	Mean % loss
Retatrutide 4 mg	TRIUMPH-1	−19.0%
Retatrutide 9 mg	TRIUMPH-1	−25.9%
Retatrutide 12 mg	TRIUMPH-1	−28.3%
Semaglutide 2.4 mg (max)	STEP-1	−14.9%

Retatrutide's lowest tested dose (4 mg, −19.0%) exceeds semaglutide's maximum dose (−14.9%) — subject to the cross-trial caveat in §2.

5. Treatment discontinuation due to adverse events

Per-trial discontinuation by dose; each trial's own placebo arm shown for context.

Drug · dose	Trial	AE discontinuation	Trial placebo	Δ vs. placebo
Semaglutide 2.4 mg	STEP-1	7.0%	3.1%	+3.9 pp
Tirzepatide 5 mg	SURMOUNT-1	4.3%	2.6%	+1.7 pp
Tirzepatide 10 mg	SURMOUNT-1	7.1%	2.6%	+4.5 pp
Tirzepatide 15 mg	SURMOUNT-1	6.2%	2.6%	+3.6 pp
Retatrutide 4 mg	TRIUMPH-1	4.1%	4.9%	−0.8 pp
Retatrutide 9 mg	TRIUMPH-1	6.9%	4.9%	+2.0 pp
Retatrutide 12 mg	TRIUMPH-1	11.3%	4.9%	+6.4 pp

Retatrutide 12 mg (11.3%) is the highest AE discontinuation of any dose across all three trials. The 4 mg sub-placebo finding is robust within TRIUMPH-1, but note its placebo arm (4.9%) ran higher than STEP-1 (3.1%) or SURMOUNT-1 (2.6%), so the absolute comparison across trials is imperfect.

6. Dysesthesia — a retatrutide-specific signal

Paresthesia / skin-sensation disorders (tingling, burning). A novel signal versus the GLP-1 and GLP-1/GIP comparator class.

Retatrutide dose	Dysesthesia rate	Trial placebo	Δ vs. placebo
4 mg	5.1%	0.9%	+4.2 pp
9 mg	12.3%	0.9%	+11.4 pp
12 mg	12.5%	0.9%	+11.6 pp

Mechanism unconfirmed; a leading working hypothesis is GCGR (glucagon-receptor) mediation. Resolution pending full ADA data.

7. Receptor profile & peptide chemistry

Drug	GLP-1R	GIPR	GCGR	Class
Semaglutide	Yes	No	No	GLP-1 mono-agonist
Tirzepatide	Yes	Yes	No	GLP-1 / GIP dual
Retatrutide	Yes	Yes	Yes	GLP-1 / GIP / glucagon triple

Retatrutide receptor-potency rank: GIPR > GLP-1R > GCGR (Coskun 2022). Canonical contributions:

GLP-1R (β-cells, brain, GI) — appetite suppression, slower gastric emptying, glucose-dependent insulin secretion.
GIPR (β-cells, adipose, brain) — complementary incretin signaling; may improve tolerability and metabolic efficiency vs. GLP-1 alone.
GCGR (liver, adipose, brain) — raises energy expenditure, promotes fat oxidation and hepatic lipid handling. A weight-loss pathway distinct from incretin biology — the major mechanistic departure, and the leading suspect for the dysesthesia signal.

Chemistry	Semaglutide	Tirzepatide	Retatrutide
Peptide length	31 aa	39 aa	39 aa
Backbone	GLP-1(7-37) analog	GIP-based	GIP-based
Lipidation site	Lys26	Lys20	Lys17
Fatty diacid	C18	C20	C20
Half-life (subQ)	~1 wk	~5 days	~6 days
Dosing	Weekly	Weekly	Weekly

8. TRIUMPH-1 extension — 104 weeks

Retatrutide 12 mg	% weight loss	Absolute lb
80 weeks (primary)	−28.3%	−70.3 lb
104 weeks (extension)	−30.3%	≈ −85 lb

The top-dose curve continued to descend between 80 and 104 weeks (no plateau). The time-course curve in the scrollytelling is a smooth monotonic fit anchored to the two reported readouts (80 wk, 104 wk); intermediate points are illustrative, not measured values.

9. Primary sources

STEP-1 — Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. NEJM 2021;384:989–1002.
SURMOUNT-1 — Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. NEJM 2022;387:205–216.
TRIUMPH-1 — Eli Lilly. TRIUMPH-1 Phase 3 topline results. Investor release, May 21, 2026. Primary source for retatrutide efficacy/regimen estimands, responder rates, discontinuation and dysesthesia.
Chemistry — semaglutide — Lau J, Bloch P, Schäffer L, et al. J Med Chem 2015;58:7370–7380.
Chemistry — tirzepatide — Coskun T, Sloop KW, Loghin C, et al. Mol Metab 2018;18:3–14.
Chemistry / receptor — retatrutide — Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist. Cell Metab 2022;34:1234–1247.
Pending — ADA Scientific Sessions, June 2026. Full peer-reviewed TRIUMPH-1 presentation; expected to resolve sub-25% responder thresholds and detailed safety.

10. Methodology & caveats

Cross-trial comparison. STEP-1, SURMOUNT-1 and TRIUMPH-1 are independent trials. Differences in baseline BMI, duration and placebo response mean head-to-head conclusions cannot be drawn; figures are indicative.
Estimand basis. Mean-loss figures use the efficacy (on-treatment) estimand where reported; the treatment-regimen estimand is lower. Mixing estimands across drugs would bias comparison, so efficacy-estimand values are used throughout.
Retatrutide maturity. Topline-release figures may be revised on full publication. Approximate values (some responder rates) are flagged.
Absolute pounds. Derived from mean % loss × mean baseline weight; rounding applies.

11. Disclaimers

Not medical advice. This is editorial analysis of public clinical data for general information. It is not a recommendation to use, prescribe or avoid any drug. Treatment decisions belong with a qualified clinician.

Not investment advice. Nothing here is a recommendation regarding any security or company.

Investigational status. Retatrutide is investigational and not approved for any use as of June 2026.