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  1. Home
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  4.  / The GLP-1 Incretin Landscape: Approved and Late-Stage Therapeutics in 2026
Comparisons · 17 min read

The GLP-1 Incretin Landscape: Approved and Late-Stage Therapeutics in 2026

A structured reading list of the modern incretin class — semaglutide, tirzepatide, retatrutide, CagriSema, survodutide, and orforglipron. Receptor pharmacology, the trials that established each compound, the headline weight and metabolic effects, and what each program does and does not yet establish.

By PepMax Research TeamPublished April 30, 2026
  1. Why this class, and why now
  2. A short class timeline
  3. The class at a glance
  4. Reading the receptor combinations
  5. Where the strongest evidence sits
  6. Semaglutide (Wegovy / Ozempic)
  7. Tirzepatide (Mounjaro / Zepbound)
  8. Retatrutide (LY3437943)
  9. CagriSema (cagrilintide + semaglutide)
  10. Survodutide (BI 456906)
  11. Orforglipron (LY3502970)
  12. Patterns across the class
  13. Open questions
  14. Further reading
Key takeaways

Key takeaways

  • The modern incretin class spans five receptor-targeting strategies: mono GLP-1 agonism (semaglutide, orforglipron), dual GLP-1/GIP (tirzepatide), triple GLP-1/GIP/glucagon (retatrutide), GLP-1 plus amylin co-agonism (CagriSema), and GLP-1/glucagon dual agonism (survodutide).
  • Semaglutide 2.4 mg (Wegovy) reported a mean weight change of approximately −14.9% at 68 weeks in STEP 1 and a 20% relative reduction in major adverse cardiovascular events in the SELECT trial in adults with overweight or obesity and pre-existing cardiovascular disease.
  • Tirzepatide reported approximately −20.9% weight change at 72 weeks in SURMOUNT-1 (15 mg arm), and the SUMMIT trial in HFpEF with obesity reported improvements in KCCQ-CSS symptom score and a reduction in heart-failure events versus placebo.
  • Retatrutide reported approximately −24.2% weight change at 48 weeks in its Phase 2 obesity trial; Phase 3 (TRIUMPH) is enrolling and has not yet read out — see our dedicated retatrutide reading list for the full set of references.
  • Three compounds are reshaping the late-stage pipeline beyond the established trio: CagriSema (cagrilintide + semaglutide co-administration) reported approximately −22.7% at 68 weeks in REDEFINE-1; survodutide reported MASH histologic improvement in a Phase 2 trial; orforglipron is the first non-peptide oral small-molecule GLP-1 agonist with Phase 3 obesity and type-2-diabetes data.
  • Cross-trial weight-change percentages are not equivalent to randomised comparisons. Differences in trial populations, escalation schedules, dropout handling, and analysis sets all affect how the headline numbers compare across programs.

Five years ago, the modern incretin class was effectively a single approved peptide — semaglutide — with a thin pipeline behind it. Today, the published clinical record covers at least six distinct molecules across five mechanistic strategies, and the late-stage pipeline is the most crowded it has ever been. This article is a structured reading list across that landscape: what each compound is, the trials that established it, the headline metabolic effects, and what each program does and does not yet establish.

Nothing here is a recommendation. Most of the molecules below are either approved prescription pharmaceuticals (semaglutide, tirzepatide) outside the scope of what PepMax sells, or investigational research compounds without regulatory approval for therapeutic use. Where a compound is sold by PepMax, it is sold for laboratory research use only. Treat the published trials as the scientific record any researcher evaluating these molecules should be working from — not as off-label clinical guidance.

Why this class, and why now

The incretin hormones — glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) — were characterized as gut-derived regulators of post-prandial insulin secretion in the 1970s and 1980s. The first long-acting synthetic GLP-1 receptor agonist, exenatide, was approved for type 2 diabetes in 2005. What changed between exenatide and the present landscape is twofold: weekly-dose pharmacokinetics (achieved through fatty-acid–based albumin binding and DPP-4–resistant residue substitutions) made the class practical at scale, and the discovery that activating multiple gut-hormone receptors simultaneously produces effect sizes the single-receptor agonists could not reach.

The result, in the 2020s, has been a cascade of unbalanced multi-receptor agonists, co-administered combinations, and orally bioavailable small molecules — each testing a different hypothesis about which receptor combination produces the best ratio of weight and glycemic effect to tolerability and durability.

A short class timeline

The compounds covered in this article are the result of two decades of incremental engineering on a single therapeutic premise — that activating gut-hormone receptors with weekly-stable synthetic peptides could produce metabolic effects out of reach of any prior class. The milestones below mark the publications and approvals that defined the modern shape of the field.

Selected milestones, 2017–2025
  1. 2017Semaglutide approved for type 2 diabetes (Ozempic)
    First once-weekly GLP-1 agonist with the modern fatty-acid albumin-binding architecture, marketed by Novo Nordisk.
  2. 2021STEP 1 publishes; Wegovy approved for obesity
    Phase 3 obesity trial reports −14.9% mean weight change at 68 weeks, establishing 2.4 mg weekly as the obesity dose and the modern reference point for GLP-1 monotherapy in obesity.
  3. 2022Tirzepatide approved (Mounjaro); SURMOUNT-1 publishes
    First approved GLP-1/GIP dual agonist; SURMOUNT-1 reports −20.9% weight change at 72 weeks at the 15 mg dose, demonstrating the additive benefit of GIP-receptor activation.
  4. 2023Retatrutide Phase 2 + SELECT publish; Zepbound approved
    Retatrutide Phase 2 obesity trial reports −24.2% at 48 weeks; SELECT extends the semaglutide indication into cardiovascular outcomes; tirzepatide receives obesity approval as Zepbound.
  5. 2024Survodutide MASH Phase 2; retatrutide MASLD substudy
    Two large GLP-1/glucagon datasets land within months of each other, reframing MASH and hepatic steatosis as central endpoints for the class rather than secondary effects.
  6. 2025SUMMIT, REDEFINE-1, and ACHIEVE-1 read out
    Tirzepatide demonstrates benefit on a heart-failure (HFpEF) endpoint; CagriSema reports its Phase 3 obesity result; orforglipron reads out as the first late-stage non-peptide oral GLP-1 agonist.

The class at a glance

The table below summarizes the six compounds covered in this article. Headline weight figures are reproduced as published in the highest-dose arm of the cited trial; they are not randomised head-to-head comparisons, and trial populations differ in baseline BMI, comorbidity, escalation schedules, and analysis estimands.

Approved and late-stage incretin therapeutics, April 2026.
CompoundReceptor activityRoute / cadenceHeadline trialHighest reported phase
SemaglutideGLP-1RSubcutaneous, weekly; oral dailySTEP 1: −14.9% at 68 wkApproved (obesity, T2D, CV risk reduction)
TirzepatideGIPR + GLP-1R (dual)Subcutaneous, weeklySURMOUNT-1: −20.9% at 72 wkApproved (obesity, T2D); SUMMIT positive in HFpEF + obesity
RetatrutideGIPR + GLP-1R + GCGR (triple)Subcutaneous, weeklyPhase 2 obesity: −24.2% at 48 wkPhase 3 (TRIUMPH) enrolling
CagriSemaGLP-1R (semaglutide) + amylin/calcitonin family (cagrilintide), co-administeredSubcutaneous, weekly (single combination injection in development)REDEFINE-1: ≈ −22.7% at 68 wkPhase 3 read-outs in 2025
SurvodutideGCGR + GLP-1R (dual)Subcutaneous, weeklyPhase 2 obesity: ≈ −19% at 46 wk; Phase 2 MASH: histologic improvementPhase 3 (SYNCHRONIZE) in obesity, T2D, MASH
OrforglipronGLP-1R (non-peptide small molecule)Oral, daily, no food/water restrictionsPhase 2 obesity: ≈ −14.7% at 36 wk; ACHIEVE-1 Phase 3 T2D positivePhase 3 (ACHIEVE / ATTAIN) reading out
On comparing percentages across trials
It is tempting to read the right-hand column of the table above as a ranking. It is not. Trial duration differs (36 to 72 weeks). Baseline populations differ (with or without diabetes; different BMI ranges). Estimand frameworks differ (treatment-policy vs. efficacy estimands handle dropouts and rescue medication differently and produce different numbers from the same underlying trial). The SURMOUNT-5 trial, which directly randomised tirzepatide against semaglutide 2.4 mg in obesity, is the kind of comparison that actually sizes a between-compound effect — and even there, the result applies only to the two doses studied in the population enrolled.

Reading the receptor combinations

Five distinct receptor strategies are represented in the table above. The therapeutic rationale for each is different.

Receptor activity matrix across the incretin classSix rows of compounds against five columns: GLP-1 receptor, GIP receptor, glucagon receptor, amylin/calcitonin receptor, and oral availability. Filled and empty circles indicate the activity profile of each compound.GLP-1RGIPRGCGRAmylin/CTOralSemaglutideTirzepatideRetatrutideCagriSemaSurvodutideOrforglipronPrimary activityNo meaningful activity
Figure 1. Receptor activity profile for each compound. Filled circles indicate primary pharmacological activity; half-filled circles indicate co-administered or complementary activity; empty circles indicate no meaningful activity at that receptor. Orforglipron is shown as a non-peptide small molecule.
  • Mono GLP-1 agonism (semaglutide, orforglipron) leverages the canonical GLP-1 effects: glucose-dependent insulin secretion, glucagon suppression, delayed gastric emptying, and central appetite suppression via hindbrain and hypothalamic GLP-1 receptors.
  • GLP-1/GIP dual agonism(tirzepatide) adds GIP receptor activation. The mechanistic story for the additive weight effect is contested — it may involve GIP-mediated effects on adipose-tissue insulin sensitivity, additional central nuclei, or pharmacological synergy distinct from native GIP biology — but the empirical additive benefit on weight is reproducible.
  • GLP-1/GIP/glucagon triple agonism(retatrutide) adds glucagon-receptor activation to the dual backbone. Glucagon-receptor activation increases hepatic glucose output (which a GLP-1 component must counteract) but also increases energy expenditure and reduces hepatic lipid content — the latter is the mechanism the MASLD substudy was designed to test.
  • GLP-1 + amylin co-agonism(CagriSema) combines a GLP-1 agonist with a long-acting amylin analogue. Amylin signaling at calcitonin/amylin receptors in the area postrema produces satiety effects that appear to add to GLP-1’s appetite suppression through a mechanistically distinct circuit.
  • GLP-1/glucagon dual agonism(survodutide) tests the glucagon-receptor hypothesis without GIP — relevant both for obesity and, more directly, for metabolic-associated steatohepatitis (MASH), where hepatic-lipid effects are a central endpoint.

Semaglutide (Wegovy / Ozempic)

Semaglutide is a 31-residue analogue of native GLP-1, fatty-acid-acylated at lysine-26 to bind albumin and stabilized at position 2 with α-aminoisobutyric acid (Aib) to resist DPP-4 cleavage. It is approved by the FDA, EMA, and other major regulators for type 2 diabetes (Ozempic, Rybelsus oral), obesity (Wegovy), and — following the SELECT trial — for cardiovascular risk reduction in adults with overweight or obesity and established cardiovascular disease. It is the most extensively studied molecule in the class and the comparator against which most newer compounds are sized.

Wilding et al., 2021 — STEP 1: Phase 3 obesity trial design and headline weight result.
ParameterDetail
DesignPhase 3, 68-week, double-blind, randomised, placebo-controlled
Participants1,961 adults with BMI ≥30, or ≥27 with at least one weight-related comorbidity, without type 2 diabetes
InterventionSemaglutide 2.4 mg subcutaneous weekly + lifestyle intervention
Primary endpointPercentage change in body weight and proportion achieving ≥5% reduction at 68 weeks
Headline findingMean weight change −14.9% with semaglutide vs. −2.4% placebo; 86.4% achieved ≥5%, 69.1% achieved ≥10%, 50.5% achieved ≥15%

The STEP 1 result is the modern reference point for “what a GLP-1 agonist does for weight” in adults without diabetes[1]. It established 2.4 mg weekly as the obesity dose, separated the obesity indication from the lower diabetes dose, and provided the comparator that subsequent multi-receptor programs have been measured against. The adverse-event profile was dominated by transient gastrointestinal events (nausea, diarrhoea, vomiting, constipation) clustered during dose escalation.

The cardiovascular evidence comes from two distinct trials. SUSTAIN 6 enrolled adults with type 2 diabetes at high cardiovascular risk and reported a hazard ratio of 0.74 for the composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke versus placebo[3]. SELECT enrolled 17,604 adults with overweight or obesity and established cardiovascular disease but without diabetes and reported a 20% relative reduction in major adverse cardiovascular events (HR 0.80) over a mean follow-up of more than three years[2]. SELECT is the trial that moved the obesity indication into a cardiovascular-outcomes label and that the rest of the class is now expected to either match or improve upon.

What semaglutide’s evidence base does and does not establish
STEP 1 and SELECT establish semaglutide as a weight-reducing and cardiovascular-protective intervention in their respective populations. They do not establish that the weight effect is durable after discontinuation — STEP 4, a withdrawal substudy, reported substantial regain after switching to placebo — or that the cardiovascular benefit extends to populations not enrolled (those without prior cardiovascular disease, those with type 1 diabetes, etc.). The evidence is broad but not unbounded.

Tirzepatide (Mounjaro / Zepbound)

Tirzepatide is a 39-residue synthetic peptide that activates both the GIP and GLP-1 receptors. Like semaglutide, it carries Aib substitutions for DPP-4 resistance and a fatty-acid acylation at lysine-20 to enable weekly dosing. It is approved as Mounjaro for type 2 diabetes and as Zepbound for obesity. The defining feature of the molecule is that the addition of GIP-receptor activation to a GLP-1 backbone produced a step change in weight effect at the population level — large enough that the clinical question is no longer “does dual agonism work” but how much further multi-receptor pharmacology can extend.

Jastreboff et al., 2022 — SURMOUNT-1: Phase 3 obesity trial.
ParameterDetail
DesignPhase 3, 72-week, double-blind, randomised, placebo-controlled
Participants2,539 adults with BMI ≥30, or ≥27 with at least one weight-related comorbidity, without type 2 diabetes
Doses studied5 mg, 10 mg, 15 mg subcutaneous weekly
Primary endpointPercentage change in body weight and proportion achieving ≥5% reduction at 72 weeks
Headline findingMean weight change −15.0% (5 mg), −19.5% (10 mg), −20.9% (15 mg) vs. −3.1% placebo; 91% achieved ≥5% at the 15 mg dose

The SURMOUNT-1 result placed tirzepatide’s 15 mg dose at approximately −20.9%weight change at 72 weeks — the largest reported in any approved-pharmacotherapy obesity trial to date[4]. SURPASS-2 randomised tirzepatide directly against semaglutide 1 mg in adults with type 2 diabetes and reported greater HbA1c and weight reduction across all three tirzepatide doses[5].

Tirzepatide’s most consequential 2025 result was outside the obesity indication. SUMMIT randomised adults with heart failure with preserved ejection fraction (HFpEF) and obesity to tirzepatide vs. placebo; the trial reported clinically meaningful improvements in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and a reduction in worsening heart-failure events, alongside the expected weight effects[6]. The result is the first time an incretin-class therapy has shown benefit on a heart-failure endpoint, and it has reframed how the class is positioned within cardiometabolic medicine more broadly.

Retatrutide (LY3437943)

Retatrutide is a 39-residue synthetic peptide engineered to activate the GIP, GLP-1, and glucagon receptors. The Phase 2 obesity trial reported a least-squares mean weight change of −24.2%at 48 weeks at the 12 mg dose — the largest figure published from a blinded, placebo-controlled obesity trial of any incretin-class molecule at the time of publication[7]. The Phase 3 program (TRIUMPH-1 through TRIUMPH-5) is enrolling across obesity, type 2 diabetes, MASH, HFpEF, and cardiovascular outcomes; none of the Phase 3 trials had reported a primary endpoint at the time of this article.

Because retatrutide’s evidence base is the most rapidly evolving piece of this landscape, we have written a separate dedicated reading list covering the discovery paper, the two Phase 2 trials, the MASLD substudy, and the TRIUMPH program in detail. See What recent trials show about retatrutide.

CagriSema (cagrilintide + semaglutide)

CagriSema is the working name for the co-administration of two distinct molecules: semaglutide (the GLP-1 agonist described above) and cagrilintide, a long-acting amylin analogue. Native amylin is co-secreted with insulin from pancreatic β-cells and signals through the calcitonin/amylin receptor family in the area postrema, contributing to satiety through a circuit mechanistically distinct from GLP-1. Cagrilintide is engineered for a once-weekly half-life that matches semaglutide’s, allowing the two to be co-administered on the same dosing cadence (and ultimately in a single combination injection).

Enebo et al., 2021 — Phase 1b cagrilintide + semaglutide co-administration trial.
ParameterDetail
DesignPhase 1b, 20-week, randomised, double-blind, placebo-controlled, single-centre
Participants95 adults with overweight or obesity
InterventionCagrilintide (escalated to 0.16, 0.30, 0.60, 1.2, 2.4, or 4.5 mg weekly) co-administered with semaglutide 2.4 mg weekly, vs. placebo + semaglutide and vs. double placebo
Primary endpointSafety, tolerability, and pharmacokinetics of co-administration
Headline findingCo-administration was tolerable; the highest cagrilintide dose with semaglutide produced approximately −17.1% weight change vs. −9.8% with semaglutide alone at 20 weeks (post-hoc descriptive comparison)

The Phase 1b trial was not powered to demonstrate efficacy — the small sample size and short duration mean the percentage figures are descriptive — but it was the proof-of-concept that the two molecules could be co-administered without unexpected pharmacokinetic interactions and that the combination produced an effect on body weight beyond what semaglutide produced alone[8]. Novo Nordisk subsequently advanced the combination into the REDEFINE Phase 3 program.

REDEFINE-1, the Phase 3 trial in adults with overweight or obesity without diabetes, reported approximately −22.7% weight change at 68 weeks at the highest co-administered dose[9]. The result is incrementally larger than the SURMOUNT-1 tirzepatide figure but smaller than the Phase 2 retatrutide figure — with the same caveats about cross-trial comparison that apply throughout this article. Phase 3 trials in type 2 diabetes (REDEFINE-2) and across additional populations are part of the broader registration program[15].

Why amylin co-agonism is a distinct mechanism
Amylin signals at receptors in the area postrema (a circumventricular organ outside the blood–brain barrier), producing satiety effects through a circuit that does not overlap with GLP-1’s primary central targets. The clinical interest in amylin co-agonism is precisely that the mechanism is parallel rather than redundant — the weight effect of the combination should approach the sum of the two individual effects rather than substantially overlap them.

Survodutide (BI 456906)

Survodutide is a synthetic peptide developed by Boehringer Ingelheim and Zealand Pharma that activates both the glucagon and GLP-1 receptors. It is the closest analogue to retatrutide’s receptor strategy without the GIP component — a controlled test of what glucagon-receptor activation contributes to a GLP-1 backbone in isolation.

le Roux et al., 2024 — Survodutide Phase 2 obesity trial.
ParameterDetail
DesignPhase 2, 46-week, randomised, double-blind, placebo-controlled, dose-finding
Participants387 adults with BMI ≥27 without diabetes
Doses studied0.6, 2.4, 3.6, and 4.8 mg weekly subcutaneous, with varied escalation schedules
Primary endpointPercentage change in body weight at 46 weeks
Headline findingMean weight change of approximately −14.9% to −18.7% across the active doses vs. −2.3% placebo; dose-dependent gastrointestinal adverse events

The dose-finding trial established a coherent dose–response on body weight without identifying unexpected safety signals at the 46-week horizon[10]. More consequential, however, was the molecule’s Phase 2 trial in metabolic-dysfunction–associated steatohepatitis (MASH).

Sanyal et al., 2024 — Survodutide Phase 2 MASH trial.
ParameterDetail
DesignPhase 2, 48-week, randomised, double-blind, placebo-controlled
Participants293 adults with biopsy-confirmed MASH and F1–F3 fibrosis
InterventionSurvodutide 2.4, 4.8, or 6.0 mg weekly vs. placebo
Primary endpointHistologic improvement in MASH without worsening of fibrosis at 48 weeks
Headline findingHistologic MASH improvement in 47–62% of survodutide arms vs. 14% placebo, with concomitant reductions in liver fat and ALT

The MASH result is the survodutide program’s most distinctive contribution[11]. MRI-based liver-fat reduction is informative but biopsy-confirmed histologic improvement is the endpoint regulators ultimately weigh, and survodutide is one of the first incretin-class molecules to demonstrate it in a Phase 2 trial. The SYNCHRONIZE Phase 3 program, currently enrolling, is testing the molecule across obesity, type 2 diabetes, and MASH indications.

Orforglipron (LY3502970)

Orforglipron is the outlier of this group. Every other compound in this article is a synthetic peptide; orforglipron is a non-peptide small molecule that activates the GLP-1 receptor. It is taken as a daily oral tablet without the food and water restrictions that constrain oral semaglutide (Rybelsus). If approved, it would be the first oral small-molecule GLP-1 agonist on the market and would substantively change the access profile of the class.

Wharton et al., 2023 — Orforglipron Phase 2 obesity trial.
ParameterDetail
DesignPhase 2, 36-week, double-blind, randomised, placebo-controlled
Participants272 adults with BMI ≥30, or ≥27 with at least one weight-related comorbidity, without type 2 diabetes
Doses studied12, 24, 36, and 45 mg orally once daily
Primary endpointPercentage change in body weight at 26 weeks
Headline findingMean weight change of approximately −9.4% to −14.7% across the active doses at 36 weeks vs. −2.3% placebo

The Phase 2 obesity trial established the dose–response and a tolerability profile broadly consistent with the injectable GLP-1 agonists: predominantly gastrointestinal adverse events, dose-related, attenuating after escalation[12]. A companion Phase 2 trial in type 2 diabetes (Frías et al., 2023) reported HbA1c reductions of approximately 1.5–2.2 percentage points across active doses[13].

The ACHIEVE-1 Phase 3 trial in type 2 diabetes reported topline results in 2025 consistent with the Phase 2 dose–response, including HbA1c reductions in the range of approximately −1.3 to −1.6 percentage points and meaningful body-weight reductions without the food/water timing constraints of oral semaglutide[14]. The broader ATTAIN obesity Phase 3 program is reading out on a similar timeline.

Why the “non-peptide” detail matters
Peptide manufacture is constrained by solid-phase synthesis economics, cold-chain distribution, and (critically) injection delivery. A small-molecule oral GLP-1 agonist with comparable efficacy could be manufactured at substantially lower per-dose cost, distributed without cold chain, and absorbed without the gastrointestinal-formulation constraints that limit oral semaglutide to morning fasted dosing with a small water volume. The strategic stakes of the orforglipron program are about access and supply scale, not just incremental efficacy.

Where the strongest evidence sits

The published trials cluster around a defined set of cardiometabolic endpoints. The map below summarizes which compound currently anchors the strongest published evidence for each domain, alongside the highest evidence level reached.

Class-wide endpoint coverage, April 2026
  • Obesity (mass / % weight change)
    Tirzepatide approved (Zepbound); semaglutide approved (Wegovy)
    Approved
    Two compounds with full obesity approvals; retatrutide and CagriSema have produced larger Phase 2/3 effects but are not yet approved for obesity.
  • Type 2 diabetes (glycemic control)
    Tirzepatide and semaglutide approved; orforglipron Phase 3 (ACHIEVE-1) positive
    Approved
    Tirzepatide is the head-to-head benchmark from SURPASS-2 against semaglutide. Orforglipron extends the indication to a non-peptide oral small molecule.
  • Cardiovascular outcomes (MACE)
    SELECT (semaglutide) and SUSTAIN-6 (semaglutide in T2D)
    Approved
    Semaglutide is the only compound in the class with a primary cardiovascular-outcomes label in obesity (SELECT). Retatrutide TRIUMPH-3 is the trial designed to test whether the triple agonist can reach the same endpoint.
  • Heart failure (HFpEF)
    Tirzepatide SUMMIT (HFpEF + obesity)
    Phase 3
    First positive incretin-class trial on a heart-failure endpoint. Retatrutide TRIUMPH-4 is the equivalent triple-agonist trial currently enrolling.
  • MASH (histologic improvement)
    Survodutide Phase 2 (Sanyal 2024); retatrutide MASLD substudy
    Phase 2
    Survodutide demonstrated histologic MASH improvement in Phase 2; retatrutide showed MRI-PDFF reductions of approximately 80% in the MASLD substudy. Histologic Phase 3 confirmation (TRIUMPH-5; SYNCHRONIZE) is pending.
  • Oral delivery
    Orforglipron ACHIEVE / ATTAIN program
    Phase 3
    First non-peptide oral GLP-1 agonist to reach Phase 3 with positive read-outs; oral semaglutide (Rybelsus) is approved but constrained by fasted-dose, low-water requirements.

Patterns across the class

Read against each other, the trials covered above support several class-wide observations that are now reasonably well established.

Headline mean weight change at trial endpointHorizontal bar chart comparing reported mean weight change for six incretin compounds. Semaglutide STEP 1: −14.9% at 68 weeks. Tirzepatide SURMOUNT-1: −20.9% at 72 weeks. Retatrutide Phase 2: −24.2% at 48 weeks. CagriSema REDEFINE-1: −22.7% at 68 weeks. Survodutide Phase 2: −18.7% at 46 weeks. Orforglipron Phase 2: −14.7% at 36 weeks.−0%−5%−10%−15%−20%−25%Mean weight change at endpointSemaglutideSTEP 1, 68 wk−14.9%TirzepatideSURMOUNT-1, 72 wk−20.9%RetatrutidePhase 2, 48 wk−24.2%CagriSemaREDEFINE-1, 68 wk−22.7%SurvodutidePhase 2, 46 wk−18.7%OrforglipronPhase 2, 36 wk−14.7%
Figure 2. Headline mean weight change at the highest published dose for each compound, drawn from the trials cited in this article. Bars are not equivalent to a randomised head-to-head comparison — trial duration, baseline population, escalation schedule, and analysis estimand differ across studies. Values represent the highest-dose arm at the trial’s reporting endpoint.
  • Multi-receptor agonism extends the weight-effect curve. The progression from mono GLP-1 (semaglutide ≈ −15%) to GLP-1/GIP (tirzepatide ≈ −21%) to triple agonism (retatrutide Phase 2 ≈ −24%) is consistent with the hypothesis that adding receptor targets broadens the addressable pharmacology rather than producing a redundant signal.
  • The cardiometabolic envelope is broadening.SELECT moved semaglutide into a cardiovascular-outcomes indication; SUMMIT moved tirzepatide into HFpEF; the MASH endpoint is now actively pursued (survodutide Phase 2; retatrutide TRIUMPH-5). The class is no longer a weight-loss class with secondary metabolic effects — it is a cardiometabolic class with weight loss as one of several converging endpoints.
  • Tolerability is qualitatively similar across the class. Predominantly gastrointestinal adverse events, dose-related, concentrated during escalation. None of the published Phase 2 or Phase 3 trials covered above identified a class-wide novel safety signal at the studied horizons. This is reassuring but is not the same as long-term safety beyond the durations studied.
  • Delivery is diversifying. The dominant format remains weekly subcutaneous injection, but oral small-molecule GLP-1 agonism (orforglipron) and combination single-injection co-formulations (CagriSema in development) are reading out on similar timelines.

Open questions

The published evidence is broad and growing rapidly, but several questions remain consequential for how this class is interpreted.

  • Comparative effectiveness.Cross-trial weight-change percentages are not randomised comparisons. The handful of head-to-head trials that exist (SURPASS-2 in T2D; SURMOUNT-5 directly comparing tirzepatide to semaglutide 2.4 mg in obesity) cover only a small fraction of the possible compound×dose×population combinations. Most class-comparative claims in the broader literature are inferences from cross-trial data, not measurements.
  • Durability after discontinuation. Withdrawal substudies (STEP 4 for semaglutide, SURMOUNT-4 for tirzepatide) consistently show substantial weight regain after the molecule is stopped. The clinical question of whether and how the class can be cycled, paused, or transitioned without rebound is not fully answered.
  • Long-term safety.Phase 3 obesity trials run 68–72 weeks. Some cardiovascular-outcomes trials extend to several years of follow-up. Beyond that, the class is in the early years of population-scale exposure. Specific long-horizon questions — pancreatic, biliary, gastrointestinal motility, lean-mass preservation, mental-health signals — will require pharmacovigilance over a longer interval than the published trials cover.
  • Population breadth.The published Phase 3 datasets are predominantly adults aged 18–75 in middle- and high-income settings. Generalization beyond those populations — older adults, paediatric populations, populations with significant medical comorbidity outside the studied indications — awaits dedicated trials.
  • The hepatic-fat hypothesis. The retatrutide MRI-PDFF result and the survodutide histologic-MASH result both support the hypothesis that glucagon-receptor activation contributes meaningfully to hepatic-fat reduction. Whether the histologic benefit translates into long-term cirrhosis prevention and hepatic-outcome reduction requires the longer follow-up that TRIUMPH-5 and the SYNCHRONIZE MASH program are designed to provide.

Further reading

Each of the citations below links to the source paper or registry record. For the deep retatrutide reading list referenced throughout this article, see What recent trials show about retatrutide. For methods context on what an HPLC purity number actually means for any peptide in this class, see what ≥99% purity actually means and how we verify peptide purity.

Available from PepMax

PM-3RT

PM-3RT (retatrutide / LY3437943) is the only compound on the PepMax catalog covered in this article. It is supplied for laboratory research use only. Each lot ships with the lot-specific COA — HPLC chromatogram and ESI-Q-TOF identity confirmation — referenced on the product page. The trials summarized above are independent published clinical research and are not endorsements of any product use.

Purity ≥99%5mgLot-specific COA included
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References

  1. [1]Wilding, J. P. H., Batterham, R. L., Calanna, S., Davies, M., Van Gaal, L. F., Lingvay, I., McGowan, B. M., et al. (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). New England Journal of Medicine doi:10.1056/NEJMoa2032183
  2. [2]Lincoff, A. M., Brown-Frandsen, K., Colhoun, H. M., Deanfield, J., Emerson, S. S., Esbjerg, S., Hardt-Lindberg, S., et al. (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). New England Journal of Medicine doi:10.1056/NEJMoa2307563
  3. [3]Marso, S. P., Bain, S. C., Consoli, A., Eliaschewitz, F. G., Jódar, E., Leiter, L. A., Lingvay, I., et al. (2016). Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN 6). New England Journal of Medicine doi:10.1056/NEJMoa1607141
  4. [4]Jastreboff, A. M., Aronne, L. J., Ahmad, N. N., Wharton, S., Connery, L., Alves, B., Kiyosue, A., et al. (2022). Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). New England Journal of Medicine doi:10.1056/NEJMoa2206038
  5. [5]Frías, J. P., Davies, M. J., Rosenstock, J., Pérez Manghi, F. C., Fernández Landó, L., Bergman, B. K., Liu, B., et al. (2021). Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes (SURPASS-2). New England Journal of Medicine doi:10.1056/NEJMoa2107519
  6. [6]Packer, M., Zile, M. R., Kramer, C. M., Baum, S. J., Litwin, S. E., Menon, V., Ge, J., et al. (2025). Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity (SUMMIT). New England Journal of Medicine doi:10.1056/NEJMoa2410027
  7. [7]Jastreboff, A. M., Kaplan, L. M., Frías, J. P., Wu, Q., Du, Y., Gurbuz, S., Coskun, T., et al. (2023). Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine doi:10.1056/NEJMoa2301972
  8. [8]Enebo, L. B., Berthelsen, K. K., Kankam, M., Lund, M. T., Rubino, D. M., Satylganova, A., Lau, D. C. W. (2021). Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. The Lancet doi:10.1016/S0140-6736(21)01751-7
  9. [9]Garvey, W. T., Blüher, M., Osorto, C. K., Ryan, D. H., Sattar, N., Valensi, P., Wadden, T. A., et al. (2025). Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity (REDEFINE 1). New England Journal of Medicine doi:10.1056/NEJMoa2502081
  10. [10]le Roux, C. W., Steen, O., Lucas, K. J., Startseva, E., Unseld, A., Hennige, A. M. (2024). Glucagon and GLP-1 receptor dual agonist survodutide for obesity: a randomised, double-blind, placebo-controlled, dose-finding phase 2 trial. The Lancet Diabetes & Endocrinology doi:10.1016/S2213-8587(24)00139-3
  11. [11]Sanyal, A. J., Bedossa, P., Fraessdorf, M., Neff, G. W., Lawitz, E., Bugianesi, E., Anstee, Q. M., et al. (2024). A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis. New England Journal of Medicine doi:10.1056/NEJMoa2401755
  12. [12]Wharton, S., Blevins, T., Connery, L., Rosenstock, J., Raha, S., Liu, R., Ma, X., et al. (2023). Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. New England Journal of Medicine doi:10.1056/NEJMoa2302392
  13. [13]Frías, J. P., Hsia, S., Eyde, S., Liu, R., Ma, X., Konig, M., Kazda, C., et al. (2023). Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. The Lancet doi:10.1016/S0140-6736(23)01302-8
  14. [14]Eli Lilly and Company (2025). ACHIEVE-1: A Study of Daily Oral Orforglipron Compared with Placebo in Adult Participants with Type 2 Diabetes Mellitus. ClinicalTrials.gov registry Source
  15. [15]Novo Nordisk A/S (2025). REDEFINE Phase 3 program for cagrilintide–semaglutide (CagriSema) — registry overview. ClinicalTrials.gov Source
Author
PepMax Research Team · Editorial

PepMax Research Library articles are written and edited in-house against the primary literature cited in each piece. We document our analytical methods openly so readers can verify the underlying chemistry against the references provided rather than relying on author authority. Where a topic exceeds our internal expertise, we either commission external review or do not publish on it.

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FOR RESEARCH USE ONLY

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