Module 5 — Phenotype-Guided Decision Tree Protocol

Purpose and how to use this protocol
Phenotype axes overview — the ten dimensions clinicians weigh
Obesity-type phenotype (BMI categories, pediatric, Class III)
T2D status phenotype (T2D + obesity / T2D alone / prediabetes / no diabetes)
Cardiovascular history phenotype (ASCVD / HFpEF / HFrEF / no CV history / high CV risk)
Kidney status phenotype (CKD 3-4 / proteinuric / normal / kidney transplant)
Hepatic status phenotype (MASH F2/F3 / MASH F4 / fatty liver without fibrosis / normal hepatic)
Pre-conception planning phenotype (TTC ≤12 mo / 1-3 yr / no planning)
Age-stage phenotype (10-12y / 12-17y / 18-65y / ≥65y / ≥75y)
Route preference + cost-access phenotype (oral-only / weekly-SC / daily-SC / injection-averse; insurance / cash / generic-supply-dependent)
Body-composition phenotype (lean-mass-preservation / visceral-fat / general weight reduction / post-weight-loss skin)
Cross-phenotype combination decision logic
Pattern Z patient-counseling beat library — one per phenotype-axis
Module-master clinical decision tree (one-page integrative reference)

Appendices

A. Phenotype-to-compound master table (matrix view)
B. Pattern discipline summary — Anchor 4 multi-dimensional + Pattern V trial-anchored + Pattern AA regulatory state
C. Cross-protocol wikilink index + commit log

Cross-references

Per-canonical protocols (Wave 1 + 2): [[Semaglutide Protocol]], [[Tirzepatide Protocol]], [[Retatrutide Protocol]], [[Survodutide Protocol]], [[Liraglutide Protocol]], [[Cagrilintide Protocol]], [[CagriSema Protocol]], [[IcoSema Protocol]], [[Orforglipron Protocol]]
Adjunct protocols (Wave 3 #1-3): Visceral-fat adjunct (M5.5 Tesamorelin + AOD-9604); Lean-mass adjunct (M5.6 CJC-1295/Ipamorelin + MOTS-c); Post-weight-loss-skin adjunct (M5.7 GHK-Cu) — sourced from /Peptide Projects/Pepteon Academy/m5-content/
Template: /obsidian-peptides/Methodology/Protocol Template.md (v1.0)
Pattern Z anchor: /Internal/Module-5-Pipeline/pattern-z-calibration-anchor.md
Editorial framework: /obsidian-peptides/Methodology/Synergy Editorial Framework.md (v1.2)
System observations: /obsidian-peptides/Methodology/AC2-26 - System Observations.md (Pattern R, R.1, R.2, V, W, X, Y, Z, AA, AA.marketing-claims, AB, AB.4, Z.injection-framing, Z.research-precision)
Voice profile: /obsidian-peptides/Methodology/Voice Profile - Dr. Jeff Gross MD.md

1. Purpose and how to use this protocol

1.1 What this protocol is

This is a meta-protocol for Module 5 — a phenotype-guided decision-tree framework that synthesizes the nine per-canonical compound protocols (Wave 1 + Wave 2) plus the three adjunct-class protocols (Wave 3 #1-3) into a single clinician-facing reference. The deliverable is not a compound-specific protocol; it is a phenotype-to-compound mapping structured so that a clinician evaluating a patient with phenotype X can identify which compounds from the Module 5 portfolio are most appropriate, in what order, with what alternatives, and with what handoff or escalation or transition logic.

Where the per-compound protocols answer the question “how do I use semaglutide / tirzepatide / retatrutide / etc. correctly?”, this meta-protocol answers the question “given this patient’s phenotype, which of the nine Module 5 compounds (or which combination, or which adjunct overlay) is the appropriate starting point, and what are the alternatives along each dimension that matter?”. It is the decision-axis layer that sits above the nine per-canonical protocols and routes the clinician to the appropriate per-canonical protocol once the compound selection is made.

The protocol is structurally distinct from the per-compound protocols. The per-compound protocols follow the 12-section template at /obsidian-peptides/Methodology/Protocol Template.md — §1 Indication scope through §12 Clinical decision tree, anchored to one named compound. This meta-protocol departs from that 12-section structure and operates as a phenotype-organized decision framework: each section §3 through §11 covers one phenotype-axis with its candidate compounds, alternatives, and decision logic. §12 handles the cross-phenotype combinations that arise when a patient sits on multiple axes simultaneously (T2D + ASCVD + CKD + obesity is more common than T2D in isolation). §13 collects the Pattern Z counseling beats. §14 is the one-page integrative master decision tree usable as a clinician quick-reference.

1.2 How to use this protocol

The intended use pattern is:

Identify the patient’s phenotype along the ten axes catalogued in §2. A typical Module 5 patient sits on 3–6 of the ten axes simultaneously; rare patients sit on only one. The axes are not mutually exclusive — they are independent decision dimensions that the clinician weighs jointly.
Read §3–§11 for each axis the patient is positioned on. Each axis section presents the first-line candidate compound(s) with trial-anchored rationale, the alternative compounds with multi-dimensional comparator framing, any applicable adjunct overlay (lean-mass / visceral / skin), and the sequencing or transition logic for that axis.
Reconcile cross-axis conflicts using §12. When a patient is positioned on multiple axes that point to different first-line compounds — for example, T2D-with-obesity-and-ASCVD points toward semaglutide (FLOW, SELECT, SOUL) while T2D-with-obesity-Class-III points toward tirzepatide or retatrutide (SURMOUNT magnitude advantage) — §12 walks through the cross-phenotype combination logic.
Apply §13 patient-counseling beats verbatim or adapted-verbatim per the Pattern Z calibration anchor at /Internal/Module-5-Pipeline/pattern-z-calibration-anchor.md. Every phenotype-axis recommendation has a counseling beat in §13 that opens with affirmation, presents the multi-dimensional facts, and closes with shared-decision-making invitation.
Route to the relevant per-compound protocol ([[Semaglutide Protocol]], [[Tirzepatide Protocol]], etc.) once compound selection is made; the per-compound protocol carries the operational §1–§12 detail (indication scope, selection criteria, pre-treatment workup, initiation, maintenance, AE management, plateau/non-response, discontinuation, combination rules, counseling beats, source citations, decision tree at the per-compound level).
Use §14 as a one-page quick-reference in the clinical encounter when the patient is on multiple axes and the full §3–§12 read is not operationally feasible at point of care.

1.3 What this protocol does not do

This protocol does not re-derive the evidence base. Every effect-size claim, dose threshold, contraindication, AE-management algorithm, and trial-population qualifier traces to the per-canonical protocols and to the underlying canonicals at /obsidian-peptides/Peptides/. Where a phenotype recommendation cites a specific trial (e.g., FLOW for CKD-in-T2D; ESSENCE for MASH F2/F3; SURMOUNT-5 for direct head-to-head tirzepatide vs semaglutide), the trial NCT identifier and primary-endpoint effect size are presented with trial-enrollment qualification per Pattern V; the full Bibliography lives in the per-canonical Process folder (e.g., /Process/Semaglutide/Semaglutide - Bibliography.md).

This protocol does not assert “best” or “first-choice” without trial-anchored qualification. Where the trial program produced an unambiguous head-to-head superiority result (SURMOUNT-5 tirzepatide –20.2% vs semaglutide –13.7% at max-tolerated doses for chronic weight management — PMID 40353578), this protocol presents that result with primary-source anchoring; the patient-counseling beat (Anchor 4) acknowledges the superior compound on the dimension on which superiority was demonstrated, then presents the other dimensions across which the compounds differ. The protocol does not steer toward or away from any compound on the basis of cost, branding, sponsor, or supply-chain considerations except where those considerations are themselves a phenotype-axis dimension (§10 route / cost / access).

This protocol does not displace clinician judgment. It is a decision-support framework, not a decision-execution framework. The licensed prescriber remains responsible for the prescribing decision, the clinical encounter, the informed-consent discussion, the monitoring plan, and any deviation from or adherence to this framework based on the patient’s clinical situation and the prescriber’s professional judgment.

1.4 Versioning and Pattern AA precision

Module 5 pharmacotherapy is a moving regulatory landscape. As of 2026-05-13, the regulatory state of the nine compounds is:

Semaglutide: six FDA-approved indications (T2D 2017 SC / 2019 oral; CWM 2021 / 2025 oral 25 mg / 2026 HD 7.2 mg; adolescent CWM 2022; CV risk reduction 2020 SC for T2D + ASCVD / 2024 SC for BMI ≥27 + ASCVD without diabetes / 2025 oral for T2D + ASCVD/CKD; MASH F2/F3 2025; CKD in T2D 2025) plus one investigational extension (HFpEF, label expansion pending) — see [[Semaglutide Protocol]] §1.
Tirzepatide: four FDA-approved indications (T2D 2022; CWM 2023; OSA-with-obesity 2024; HFpEF-with-obesity 2025) plus active investigational programs (CKD, MASH, CV outcomes in CWM) — see [[Tirzepatide Protocol]] §1.
Retatrutide: investigational; Phase 3 program ongoing (TRIUMPH for obesity, separate T2D programs) — not FDA-approved for any indication as of 2026-05-13. Pattern AA: state “investigational; Phase 3 pending” — do not state “FDA-approved.” See [[Retatrutide Protocol]] §1.
Survodutide: investigational; Phase 3 SYNCHRONIZE program for obesity ongoing; LIVE-1 MASH F2/F3 Phase 2 results readout (76% histologic resolution; PMID 38863223) supports continued development; not FDA-approved as of 2026-05-13. See [[Survodutide Protocol]] §1.
Liraglutide: FDA-approved for T2D (Victoza 2010) and CWM (Saxenda 2014) plus pediatric CWM (≥12y, 2020) — daily SC; off-patent in EU markets 2023, generic competition emerging in US. See [[Liraglutide Protocol]] §1.
Cagrilintide: investigational as monotherapy (Phase 2 weight-loss data; not FDA-approved as monotherapy as of 2026-05-13) — see [[Cagrilintide Protocol]] §1.
CagriSema (cagrilintide + semaglutide fixed-ratio combination): investigational; REDEFINE Phase 3 program ongoing; Novo Nordisk has filed for FDA approval; not approved as of 2026-05-13. See [[CagriSema Protocol]] §1.
IcoSema (icotrokinra + semaglutide fixed-ratio combination): investigational; Phase 3 program ongoing; not FDA-approved as of 2026-05-13. See [[IcoSema Protocol]] §1.
Orforglipron: investigational small-molecule oral GLP-1 RA; ATTAIN-1 Phase 3 obesity readout (DOI 10.1056/NEJMoa2511774); Eli Lilly filed for FDA approval Q4 2025 for obesity and Q1 2026 for T2D; not approved as of 2026-05-13 but the regulatory decision window is near-term. See [[Orforglipron Protocol]] §1.

This regulatory state is the snapshot as of 2026-05-13. Every recommendation in §3–§12 carries a Pattern AA qualifier — “FDA-approved for marketing claims for X; investigational pending Y for Z” — so the regulatory state is explicit at the point of recommendation, not buried in a footnote. When the regulatory state changes (a Retatrutide or CagriSema approval; a Tirzepatide MASH expansion; an Orforglipron approval), the protocol is updated; the last-updated date in the frontmatter is the operative date of regulatory-state precision.

1.5 Adjunct overlays — when and how

The three adjunct classes are not standalone Module 5 compounds; they are overlays that combine with the nine per-canonical compounds for specific phenotype-axis dimensions:

Visceral-fat adjunct (M5.5 — Tesamorelin + AOD-9604). Tesamorelin is FDA-approved for HIV-associated lipodystrophy (Egrifta SV / Egrifta WR; BLA022505); off-label use for visceral adiposity in non-HIV populations is supported by mechanism rationale (GHRH-receptor agonism driving visceral-adipose-tissue-selective lipolysis) plus the Falutz Phase 3 HIV program (NEJM 2007, PMID 18057338) plus the Stanley 2014 JAMA hepatic-fat RCT (PMID 25038357). AOD-9604 is development-discontinued (sponsor Metabolic Pharmaceuticals discontinued Phase 2b obesity development in 2007; not FDA-approved for any indication as of 2026-05-13); Pattern AA precision: “development-discontinued” is more accurate than “emerging” or “pre-approval.” Overlay scenario: a patient on a per-canonical compound (typically semaglutide or tirzepatide) with persistent visceral adiposity disproportionate to total-weight response — §11 covers this phenotype.
Lean-mass adjunct (M5.6 — CJC-1295 + Ipamorelin + MOTS-c). CJC-1295 (GHRH analog) plus Ipamorelin (GH secretagogue) is a clinician-judgment off-label stack for lean-mass preservation during GLP-1-driven weight loss; not FDA-approved for lean-mass preservation in CWM context (Pattern AA: “off-label-within-informed-consent-and-primary-source-supported-clinical-reasoning”). MOTS-c is a mitochondrially-encoded peptide with limited human Phase 1/2 data and is investigational; do not state “approved.” Overlay scenario: an older-adult or athletic-population patient on a per-canonical compound with DEXA-documented lean-mass loss >25–30% of total mass lost — §11 covers this phenotype.
Post-weight-loss-skin adjunct (M5.7 — GHK-Cu). GHK-Cu (glycyl-histidyl-lysine copper tripeptide) is used topically and as an injectable for skin elasticity and post-weight-loss skin tone; trial-program data are limited for the post-weight-loss-skin indication specifically; not FDA-approved as a drug for skin laxity. Pattern V direction-of-effect: clinical-effect magnitude is patient-anchored-expectation-driven; mechanism rationale (copper-binding for matrix-metalloproteinase modulation; collagen / elastin signaling) is preclinical-and-mechanism-supported, not Phase 3 RCT-supported for the indication. Overlay scenario: a patient who has completed 12+ months of significant weight loss (≥15% body weight, BMI reduction ≥5 points) with documented post-weight-loss skin laxity disproportionate to age — §11 covers this phenotype.

The adjunct overlays are not appropriate for every Module 5 patient. They are phenotype-targeted overlays for the specific phenotype dimensions on which they are mechanism-aligned. §11 walks through the body-composition phenotype dimensions where each adjunct applies.

1.6 The structural and methodological lineage

This protocol inherits methodology from:

/Methodology/Synergy Editorial Framework.md v1.2 — voice, framing discipline, length expectations, citation authority vs discovery methodology, §1.2.1 FDA-approved-for-marketing-claims nuance
/Methodology/AC2-26 - System Observations.md — Pattern R / R.1 / R.2 framing discipline; Pattern V direction-of-effect verification; Pattern W cross-section consistency; Pattern X framework execution depth; Pattern Z calibration anchors (Anchor 4 dominant for this meta-protocol); Pattern AA regulatory-claim precision; Pattern AA.marketing-claims FDA-approved-for-marketing-claims convention; Pattern AB / AB.4 identifier-integrity standing scans; Pattern N.1 small-molecule path (relevant for orforglipron); Pattern Z.injection-framing (self-injection is a routine clinical skill, not a daunting barrier); Pattern Z.research-precision (bias-vocabulary like “highly experimental” / “fringe” / “unproven” are Pattern Z violations)
/Internal/Module-5-Pipeline/pattern-z-calibration-anchor.md — Anchor 1 (compounded formulations as real-world clinical option), Anchor 2 (compounded patient-counseling beat), Anchor 3 (pregnancy section structure leading with research-state data), Anchor 4 (multi-dimensional comparator framing — dominant calibration for this meta-protocol), Anchor 5 (off-label / extrapolation transparency)
/Methodology/Voice Profile - Dr. Jeff Gross MD.md — clinician-voice calibration; the patient-counseling beats in §13 are voice-calibrated to the Dr. Gross profile

The protocol’s content (trial-enrollment-anchored effect sizes; phenotype-to-compound mapping; combination logic) comes from primary sources verified through the four-step gate documented in the per-canonical Process folders. This meta-protocol does not introduce new primary-source claims; it routes existing primary-source-anchored claims across the nine per-canonical protocols into a phenotype-organized decision framework.

2. Phenotype axes overview — the ten dimensions clinicians weigh

2.1 Purpose of the axes framework

The Module 5 patient is rarely characterized by one clinical dimension. The typical Module 5 patient sits on 3–6 of the ten axes catalogued below; the polycondition phenotype (T2D + obesity Class II + ASCVD + CKD stage 3a) is more common than the monocondition phenotype (non-diabetic Class I obesity without comorbidity). The ten-axis framework is therefore a multi-dimensional grid against which the patient is positioned, not a linear decision tree along a single axis.

Pattern Z Anchor 4 enforcement at this section: the axes framework presents the dimensions across which compounds differ; it does not pre-select a “best” compound. Each axis section (§3–§11) presents the candidate compounds for that axis with multi-dimensional comparator framing per Anchor 4. The clinician-patient dyad selects across the axes the patient is positioned on, using the §12 cross-phenotype combination logic when axes point to different first-line compounds.

Pattern V cross-section consistency: every effect-size claim or relative-effect framing in §3–§11 must be reconciled with the trial-enrollment phenotype that produced it. A SURMOUNT-5 head-to-head result (tirzepatide –20.2% vs semaglutide –13.7%) applies to the SURMOUNT-5 enrollment phenotype (BMI ≥30, or ≥27 with comorbidity, max-tolerated dose, 72 weeks); extrapolation to phenotypes outside the SURMOUNT-5 enrollment (BMI ≥40 Class III, BMI <27, paediatric, BMI ≥27 with the specific comorbidity-class not enrolled) is Pattern V flagged.

Pattern AA precision at this section: every regulatory-state claim per axis-recommendation is precise. “FDA-approved for marketing claims for X” applies where the indication is on-label; “off-label use of an FDA-approved drug for Y” applies where the compound has a different indication on-label but is used off-label for the phenotype-axis dimension; “investigational pending [trial/readout]” applies where the compound has not received any FDA approval as of 2026-05-13.

2.2 The ten axes

The ten phenotype-axes are independent decision dimensions. The axes are presented in approximate order of operational priority — obesity-type and T2D-status are the dominant dimensions for most Module 5 decisions; cardiovascular history, kidney status, and hepatic status are the comorbidity-overlay dimensions that frequently determine which of the candidate compounds carries the most relevant outcomes evidence; pre-conception planning is a time-sequenced dimension that can override an otherwise-appropriate compound selection; age-stage is a regulatory-and-trial-enrollment dimension that limits which compounds are even candidates; route preference and cost-access are patient-preference-and-feasibility dimensions; body-composition is the adjunct-overlay dimension.

Axis 1 — Obesity type (§3). BMI ≥30 without comorbidities / BMI ≥27 with one weight-related comorbidity / BMI ≥40 Class III obesity / pediatric ≥12y / pediatric <12y. This axis determines which CWM-approved compounds are even on-label candidates and which trial-enrolled effect sizes are most directly applicable.

Axis 2 — T2D status (§4). T2D + obesity / T2D without obesity / prediabetes / no diabetes. This axis interacts with Axis 1 — a T2D + obesity patient has different first-line compound options than a non-diabetic obesity patient, and the trial-program evidence base differs across SUSTAIN/PIONEER (T2D), STEP (CWM), SURPASS (T2D), SURMOUNT (CWM), with the polycondition (T2D + CWM) overlap most heavily populated in STEP-2 (semaglutide), SURMOUNT-2 (tirzepatide), and the comparator-landscape literature.

Axis 3 — Cardiovascular history (§5). ASCVD / heart failure HFpEF / heart failure HFrEF / no CV history / high CV risk. This axis determines which compounds carry the most relevant outcomes evidence: SELECT (semaglutide; BMI ≥27 + ASCVD without diabetes) and SUSTAIN-6 (semaglutide; T2D + ASCVD) and SOUL (oral semaglutide; T2D + ASCVD/CKD) anchor the ASCVD position; STEP-HFpEF and STEP-HFpEF-DM (semaglutide; HFpEF + obesity) and SUMMIT (tirzepatide; HFpEF + obesity) anchor the HFpEF position; HFrEF is under-represented across the Module 5 program (Pattern V flag — direction-of-effect in HFrEF is research-state-incomplete).

Axis 4 — Kidney status (§6). CKD stage 3-4 / proteinuric kidney disease / normal kidney / kidney transplant. This axis interacts with Axis 2 — the kidney-outcomes evidence base is anchored to FLOW (semaglutide; T2D + CKD eGFR 25–75; UACR 100–5000) and the emerging tirzepatide kidney program; kidney transplant phenotype is excluded from Phase 3 enrollment across the Module 5 program (Pattern V flag).

Axis 5 — Hepatic status (§7). MASH F2/F3 / MASH F4 cirrhosis / fatty liver without fibrosis / normal hepatic. This axis is anchored to ESSENCE (semaglutide; FDA-approved 2025 for MASH F2/F3) and to the survodutide LIVE-1 Phase 2 readout (Sanyal 2024 NEJM, PMID 38863223; 76% histologic resolution at F2/F3 in survodutide arm — but survodutide is investigational, not FDA-approved). MASH F4 cirrhosis is excluded from the ESSENCE label and is Pattern V flagged: Loomba 2023 Phase 2 in F4 (PMID 36934740) reported fibrosis improvement 11% semaglutide vs 29% placebo (NS but directionally toward placebo advantage).

Axis 6 — Pre-conception planning (§8). Actively trying-to-conceive within 12 months / within 1-3 years / no planning. This axis can override an otherwise-appropriate compound selection — the GLP-1 RA class has labeled contraindications in pregnancy for CWM indications, and the discontinuation half-life arithmetic (semaglutide ~7-day half-life; ~5 half-lives = ~35 days for substantial clearance; planned pregnancies typically require ~2-month washout) determines the operational window for compound continuation vs discontinuation in reproductive-age females. Parker 2025 (PMID 40329607) pooled human pregnancy-exposure data shows reassuring early signal — this is research-state-leading per Pattern Z Anchor 3, not steering away from the compound class.

Axis 7 — Age-stage (§9). 10-12y / 12-17y / 18-65y / ≥65y / ≥75y. This axis is regulatory-and-trial-enrollment-driven. Adolescent CWM (≥12y) is FDA-approved on-label for semaglutide (STEP TEENS 2022), liraglutide (Saxenda 2020), tirzepatide (pediatric Phase 3 ongoing; not yet approved as of 2026-05-13), and orforglipron (pediatric program ongoing). Pediatric <12y is investigational across the program; only specific monogenic-obesity contexts have published evidence (e.g., MC4R deficiency setmelanotide is outside the Module 5 portfolio but referenced for comparator framing). Older-adult ≥65y is enrolled across the program but lean-mass concern (§11 body-composition overlay) becomes increasingly load-bearing; ≥75y is under-represented in registration trials (Pattern V flag).

Axis 8 — Route preference (§10 first sub-axis). Oral-only / weekly-SC-acceptable / daily-SC-acceptable / injection-averse. This axis determines which compounds are even candidates. Oral options: Rybelsus (oral semaglutide 14 mg for T2D; oral Wegovy 25 mg for CWM 2025); oral orforglipron (FDA decision pending). Weekly-SC: semaglutide (Ozempic, Wegovy, Wegovy HD), tirzepatide (Mounjaro, Zepbound), cagrilintide (investigational), CagriSema (investigational), retatrutide (investigational). Daily-SC: liraglutide (Victoza, Saxenda). Injection-averse patients are routed to oral options or to the patient-counseling beat that frames self-injection as a routine clinical skill per Pattern Z.injection-framing.

Axis 9 — Cost / access (§10 second sub-axis). Insurance-covered / cash-pay / generic-supply-dependent. This axis is shaped by the regulatory and commercial landscape: liraglutide is off-patent in EU markets 2023 (generic competition emerging in US); compounded semaglutide and tirzepatide are real-world clinical options used by substantial patient populations under 503A and 503B pathways (Pattern Z Anchor 1 + 2). Insurance coverage varies dramatically by indication (T2D coverage typically more robust than CWM coverage), by formulation (oral Wegovy vs injectable Wegovy), and by employer / payer policy.

Axis 10 — Body-composition concern (§11). Lean-mass-preservation priority / visceral-fat priority / general weight reduction / post-weight-loss skin laxity. This axis triggers the adjunct overlays — lean-mass adjunct (CJC-Ipamorelin / MOTS-c) for the lean-mass-preservation phenotype; visceral-fat adjunct (Tesamorelin / AOD-9604) for the visceral-fat phenotype; post-weight-loss-skin adjunct (GHK-Cu) for the post-weight-loss-skin phenotype. General weight reduction without specific body-composition concern is the default; the per-canonical compound carries the primary phenotype response and no adjunct overlay is required.

2.3 How the axes interact

The axes are not strictly hierarchical. A clinician encounter typically proceeds by positioning the patient on the axes simultaneously and then identifying which axes carry the strongest constraint on compound selection.

The most common axis-interaction patterns:

Obesity + T2D (Axes 1 + 2). The polycondition phenotype most heavily populated across the Module 5 trial program. STEP-2 (semaglutide, T2D + obesity), SURMOUNT-2 (tirzepatide, T2D + obesity), SURPASS-2 (tirzepatide vs semaglutide T2D head-to-head), the orforglipron T2D/CWM dual-readout, and the comparator-landscape literature all populate this overlap. Effect-size note (Pattern V trial-enrollment qualified): weight-loss magnitude in T2D phenotype is consistently lower than in non-diabetic CWM phenotype across the program — STEP-1 semaglutide –14.9% (non-diabetic) vs STEP-2 –9.6% (T2D + obesity); SURMOUNT-1 tirzepatide –22.5% (non-diabetic, 15 mg) vs SURMOUNT-2 –13.4–15.7% (T2D + obesity).
Obesity + ASCVD (Axes 1 + 3). The SELECT enrollment phenotype (BMI ≥27 + established CVD without diabetes; Lincoff 2023 NEJM, PMID 37952131; n=17,604; HR 0.80 for three-point MACE). This combination heavily favors semaglutide on the outcomes-evidence dimension; tirzepatide CVOT (SURMOUNT-MMO) is in progress with readout pending.
Obesity + ASCVD + T2D (Axes 1 + 2 + 3). SUSTAIN-6 (semaglutide; PMID 27633186; HR 0.74) plus SELECT plus FLOW plus SOUL collectively anchor semaglutide as the most outcomes-evidence-rich compound for this triple overlap. Tirzepatide and retatrutide outcomes-evidence is at earlier-stage readout.
Obesity + T2D + CKD (Axes 1 + 2 + 4). FLOW (semaglutide; Perkovic 2024 NEJM, PMID 38785209; HR 0.76 for kidney composite + CV death) is the load-bearing trial. The polycondition T2D + CKD phenotype is heavily populated in FLOW (n=3,533; eGFR 25–75; UACR 100–5000).
Obesity + MASH F2/F3 (Axes 1 + 5). ESSENCE (semaglutide; PMID 40305708; FDA-approved 2025 for MASH F2/F3 — both co-primary endpoints met) is the load-bearing trial. Survodutide LIVE-1 Phase 2 (Sanyal 2024, PMID 38863223; 76% histologic resolution in survodutide arm) is investigational-supportive but survodutide is not FDA-approved as of 2026-05-13. Tirzepatide MASH Phase 3 is in progress.
Pre-conception planning + any other axis (Axis 6 dominant). Pre-conception planning within ~35 days for short-half-life GLP-1 RAs and within ~2-month washout for long-half-life GLP-1 RAs is the discontinuation-triggering axis. The Axis 6 timing dominates whatever combination of Axes 1–5 the patient is on; a patient positioned on Axes 1 + 2 + 3 + 5 (obesity + T2D + ASCVD + MASH) who is also positioned on Axis 6 within 1 year transitions out of the GLP-1 RA portfolio per the §8 discontinuation arithmetic, regardless of the otherwise-optimal compound selection.
Body-composition + any other axis (Axis 10 overlay). Body-composition concern does not displace the primary compound selection; it triggers the adjunct overlay. A patient on tirzepatide for Axes 1 + 2 with documented lean-mass loss >25–30% of total mass lost (typically older-adult or athletic-population phenotype) adds the CJC-Ipamorelin / MOTS-c overlay per §11 — the tirzepatide continues; the adjunct is added on top.

2.4 The Module 5 portfolio in one paragraph

Before diving into the axis-by-axis decisions, a Module 5 portfolio overview (Pattern Z Anchor 4 multi-dimensional framing):

The nine per-canonical compounds span three pharmacologic classes (GLP-1 mono-agonists: semaglutide, liraglutide, orforglipron; dual GIP/GLP-1: tirzepatide; triple GIP/GLP-1/glucagon: retatrutide; dual GLP-1/glucagon: survodutide; amylin agonist: cagrilintide; fixed-ratio combinations: CagriSema = cagrilintide + semaglutide, IcoSema = icotrokinra + semaglutide) and four operational platforms (weekly-SC injectable: semaglutide, tirzepatide, retatrutide, survodutide, cagrilintide, CagriSema, IcoSema; daily-SC injectable: liraglutide; daily-oral small-molecule: orforglipron; daily-oral peptide: Rybelsus and oral Wegovy semaglutide). They differ on weight-loss magnitude (SURMOUNT-5 anchored; retatrutide TRIUMPH Phase 2 –24.2% at 11 mg at 48 weeks suggests further magnitude advantage pending Phase 3), on outcomes-evidence base (semaglutide leads across CV, MASH, CKD outcomes; tirzepatide leads on OSA, HFpEF), on regulatory state (semaglutide six on-label / tirzepatide four on-label; retatrutide, survodutide, cagrilintide, CagriSema, IcoSema investigational; liraglutide on-label for T2D and CWM and adolescent; orforglipron filed-pending), on safety / class-differentiation findings (NAION signal: documented for semaglutide, absent for tirzepatide per PMID 40383360), and on access (cost, insurance coverage, supply-chain). The three adjunct overlays (Tesamorelin/AOD-9604, CJC-Ipamorelin/MOTS-c, GHK-Cu) handle body-composition-specific dimensions that the nine per-canonical compounds do not directly target.

The §3–§14 sections walk axis-by-axis through how this portfolio maps onto patient phenotypes.

3. Obesity-type phenotype

3.1 Purpose and sub-phenotype taxonomy

Axis 1 — obesity type — is one of two dominant decision axes (the other is Axis 2, T2D status). It determines which CWM-approved compounds are even on-label candidates and which trial-enrolled effect-size data are most directly applicable to the patient’s expected response trajectory.

Five sub-phenotypes:

3.A — BMI ≥30 without weight-related comorbidity. Non-diabetic obesity meeting the CWM-indication-label BMI threshold without comorbid hypertension, dyslipidemia, T2D, OSA, or ASCVD.
3.B — BMI ≥27 with one weight-related comorbidity. The CWM-indication-label-permitted sub-population with hypertension, dyslipidemia, T2D, OSA, or ASCVD; the SELECT (BMI ≥27 + ASCVD without diabetes) and STEP-2 (BMI ≥27 + T2D) trial-enrolled phenotypes overlap heavily.
3.C — BMI ≥40 (Class III obesity). The severe-obesity phenotype where weight-loss magnitude and durability are particularly load-bearing; the SURMOUNT and STEP and TRIUMPH program enrollments included Class III obesity sub-populations.
3.D — Pediatric ≥12 years. Adolescent obesity at the 95th-percentile-or-greater BMI threshold; STEP TEENS (semaglutide), Saxenda pediatric (liraglutide), and emerging pediatric programs.
3.E — Pediatric <12 years. Childhood obesity below the adolescent label threshold; investigational across the Module 5 portfolio (Pattern V flag — direction-of-effect in this sub-population is research-state-incomplete except for specific monogenic-obesity contexts).

Phenotype definition. Adult (≥18 years, or ≥12 for adolescent extension — see §9) with BMI ≥30 kg/m² and no documented comorbidity from the FDA CWM-indication list (hypertension, dyslipidemia, T2D, OSA, ASCVD). The patient is positioned at the threshold of the CWM-indication label but does not carry the comorbidity-driven outcomes-indication overlap.

First-line compound — trial-anchored options.

Three first-line candidates with primary-source anchoring (Pattern V trial-enrollment qualified; Pattern AA regulatory-state precise):

Tirzepatide (Zepbound). FDA-approved for marketing claims for CWM in adults with BMI ≥30 or BMI ≥27 with comorbidity (2023). Trial anchor: SURMOUNT-1 (Jastreboff 2022 NEJM, PMID 35658024; n=2,539 non-diabetic obesity BMI ≥30, or ≥27 with comorbidity): –22.5% body weight at 15 mg / 72 weeks vs –2.4% placebo. Head-to-head vs semaglutide: SURMOUNT-5 (Aronne 2025 NEJM, PMID 40353578; n=751 max-tolerated-dose comparison at 72 weeks): tirzepatide –20.2% vs semaglutide –13.7% (~6.5 percentage-point difference favoring tirzepatide). Pattern V trial-enrollment note: SURMOUNT-5 max-tolerated-dose comparison is the direct head-to-head; the cross-trial SURMOUNT-1 vs STEP-1 comparison (which favored tirzepatide by similar magnitude) was not the head-to-head. Routes to [[Tirzepatide Protocol]].
Semaglutide (Wegovy 2.4 mg / Wegovy HD 7.2 mg / oral Wegovy 25 mg). FDA-approved for marketing claims for CWM in adults with BMI ≥30 or BMI ≥27 with comorbidity (2.4 mg 2021; oral 25 mg 2025; HD 7.2 mg 2026). Trial anchor: STEP-1 (Wilding 2021 NEJM, PMID 33567185; n=1,961 non-diabetic obesity BMI ≥30): –14.9% body weight at 68 weeks vs –2.4% placebo. Higher-dose data: STEP UP / Wegovy HD (Wharton 2025 Lancet Diabetes Endocrinol, PMID 40961952; semaglutide 7.2 mg): –18.7% body weight; 31.2% achieving ≥25% loss at 72 weeks. Oral data: OASIS 4 (Wharton 2025 NEJM, PMID 40934115; oral 25 mg for obesity): –13.6% treatment-policy / –16.6% adherent. Routes to [[Semaglutide Protocol]].
Retatrutide (investigational; Phase 3 pending). Not FDA-approved as of 2026-05-13. Trial anchor: TRIUMPH Phase 2 (Jastreboff 2023 NEJM, PMID 37356046; n=338 obesity without diabetes; 48 weeks): –24.2% body weight at 12 mg vs –2.1% placebo. Pattern AA precision: state “investigational; Phase 3 TRIUMPH program ongoing” — do not state “approved.” Pattern V trial-enrollment note: Phase 2 effect sizes are not Phase 3 effect sizes; the TRIUMPH Phase 3 readout is the load-bearing future evidence. Routes to [[Retatrutide Protocol]] for the investigational positioning.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The first-line candidates differ on multiple dimensions; none is unambiguously “best” across all dimensions:

Weight-loss magnitude: Retatrutide (TRIUMPH Phase 2) > Tirzepatide (SURMOUNT-1, SURMOUNT-5 head-to-head) > Semaglutide HD 7.2 mg (STEP UP) > Semaglutide 2.4 mg (STEP-1) ≈ Semaglutide oral 25 mg (OASIS 4)
Regulatory state: Tirzepatide and Semaglutide both FDA-approved for the BMI ≥30 phenotype; Retatrutide investigational
Trial-program maturity: Semaglutide has six FDA-approved indications with deepest outcomes-evidence base; Tirzepatide has four with growing outcomes evidence; Retatrutide is Phase 3
Class-differentiation safety findings: NAION signal documented for semaglutide (Hathaway 2024 JAMA Ophthalmology); signal absent for tirzepatide per PMID 40383360. NAION is a post-marketing signal under active evaluation, not a labeled warning — Pattern AA precision applies
GI tolerability profile: all three are GI-AE-driven during titration; semaglutide and tirzepatide have established large-cohort tolerability data; retatrutide tolerability is Phase 2 stage
Route / platform: all three are weekly-SC; semaglutide additionally available oral (Rybelsus 14 mg for T2D, oral Wegovy 25 mg for CWM); see Axis 8 for route-preference layer
Cost / insurance: weekly-SC tirzepatide and semaglutide insurance coverage varies; compounded options exist under 503A / 503B for both; retatrutide not commercially available

Adjunct overlay (none required by default for 3.A). General weight reduction without specific body-composition concern is the default phenotype for 3.A. No adjunct overlay is triggered. If body-composition concern emerges during therapy (DEXA-documented lean-mass loss >25–30% of total mass lost) — typically older-adult or athletic-population — see §11.

Sequencing / transition logic.

The CWM-naive 3.A patient is initiated on the selected first-line compound per the per-canonical protocol (e.g., [[Tirzepatide Protocol]] §4 for tirzepatide initiation; [[Semaglutide Protocol]] §4 for semaglutide initiation). If the patient does not achieve ≥5% weight loss at week 16–20 on the target dose (the typical Module 5 plateau / non-response threshold per the per-canonical §7), the per-canonical plateau / non-response algorithm applies — typically a within-class switch (semaglutide → tirzepatide is the most common pattern), an adjunct overlay if body-composition is a concern, or an off-label dose escalation if available evidence supports it.

When tirzepatide and semaglutide are both reasonable first-line and the patient is on neither, the SURMOUNT-5 head-to-head result anchors the magnitude conversation. When semaglutide is already in use and the response is sub-optimal, the within-class switch to tirzepatide is supported by SURMOUNT-5 plus cross-trial magnitude data. When tirzepatide is already in use and the patient is intolerant, the switch to semaglutide reduces magnitude expectations and is supported by the SURMOUNT-5 comparison.

Pattern Z patient-counseling beat for 3.A (Anchor 4 verbatim-compliant).

“Both tirzepatide and semaglutide are FDA-approved evidence-based weight-management options for your situation — BMI ≥30 without specific weight-related comorbidities. The SURMOUNT-5 head-to-head trial directly compared the two at maximum-tolerated doses over 72 weeks and showed tirzepatide produced about 6.5 percentage points more weight loss — tirzepatide ~20.2%, semaglutide ~13.7%. The higher-dose Wegovy HD 7.2 mg was approved March 2026 and showed ~18.7% weight loss with 31% of patients achieving ≥25% loss. Beyond magnitude, the compounds differ on a few dimensions: semaglutide has a deeper outcomes-evidence base across cardiovascular, kidney, and MASH endpoints; tirzepatide has an obstructive-sleep-apnea-with-obesity approval and a HFpEF-with-obesity approval; semaglutide carries an emerging NAION ophthalmologic signal that tirzepatide does not appear to carry per published pharmacovigilance; both compounds have GI side effects during titration; insurance coverage and cost vary. Retatrutide is in Phase 3 with even higher magnitude in the Phase 2 data, but it’s not FDA-approved yet and we’d be waiting on the TRIUMPH Phase 3 readout. Here are the facts on each dimension — let’s discuss which factors matter most for your situation, your tolerance for side effects, your access and coverage, and what you’re hoping to achieve.”

Phenotype definition. Adult with BMI ≥27 to 29.9 kg/m² (the lower-BMI label-permitted threshold) plus at least one of: hypertension, dyslipidemia, T2D, OSA, ASCVD, or other recognized weight-related comorbidity. The 3.B phenotype is the typical SELECT enrollment phenotype, the typical STEP-2 enrollment phenotype, and the typical STEP-8 head-to-head enrollment phenotype.

First-line compound — trial-anchored options.

The comorbidity that the patient carries materially shapes the first-line compound selection — this is the axis-interaction with Axes 3 (CV), 4 (kidney), 5 (hepatic). For 3.B without a specific comorbidity-driven outcomes-indication overlap (e.g., BMI ≥27 + dyslipidemia without ASCVD), the first-line candidates are:

Tirzepatide (Zepbound). Same SURMOUNT-1 anchor as 3.A; enrolled BMI ≥27 with comorbidity sub-population in addition to BMI ≥30 sub-population.
Semaglutide (Wegovy 2.4 / 7.2 mg; oral Wegovy 25 mg). Same STEP-1 / STEP UP / OASIS 4 anchors; STEP-1 enrollment included BMI ≥27 with comorbidity. STEP-3 with intensive behavioral therapy (Wadden 2021 JAMA, PMID 33625476) showed –16.0% with IBT plus semaglutide vs –5.7% with IBT plus placebo at 68 weeks — IBT is effect-additive.
Retatrutide (investigational). Same TRIUMPH Phase 2 anchor; Phase 3 enrollment includes BMI ≥27 with comorbidity.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 3.B sub-phenotype’s distinguishing feature is the comorbidity. The Anchor 4 framing for 3.B routes through the comorbidity dimension into the relevant axis (§5 for CV history; §6 for kidney; §7 for hepatic). For 3.B without a comorbidity-driven outcomes-indication overlap, the magnitude / safety / regulatory / access dimensions from 3.A apply with the additional consideration that the BMI ≥27 phenotype has a more modest absolute weight to lose (a 20% reduction from BMI 28 is approximately 5.6 BMI points; a 20% reduction from BMI 38 is approximately 7.6 BMI points). Trial-enrollment effect sizes from the broader BMI ≥27 sub-population are typically slightly lower than the BMI ≥30 sub-population — STEP-2 (T2D + obesity) –9.6% vs STEP-1 (non-diabetic obesity) –14.9%.

Adjunct overlay (none required by default for 3.B without specific body-composition concern).

Pattern Z patient-counseling beat for 3.B (Anchor 4 verbatim-compliant).

“You’re at BMI ≥27 with [comorbidity name] — that puts you in the FDA-approved chronic weight management indication for both tirzepatide and semaglutide. Both compounds were trialed in your phenotype. The SURMOUNT-5 head-to-head magnitude difference (~6.5 percentage points favoring tirzepatide at max-tolerated doses) applies. The specific consideration for your situation is the [comorbidity] — the outcomes-evidence base for [comorbidity] differs across the compounds. [If CV: semaglutide has SELECT data in your phenotype — BMI ≥27 plus established CVD without diabetes — showing ~20% reduction in major cardiac events; tirzepatide’s CV outcomes trial SURMOUNT-MMO is in progress. If T2D: both have T2D outcome trials — SUSTAIN, SURPASS — with SURPASS-2 head-to-head favoring tirzepatide on HbA1c reduction.] Let’s walk through which evidence base matters most for your specific situation, plus magnitude, side effects, access, and route preference.”

3.4 Sub-phenotype 3.C — BMI ≥40 (Class III obesity)

Phenotype definition. Adult with BMI ≥40 kg/m² (Class III obesity per NIH classification) or BMI ≥35 with severe weight-related comorbidity (the bariatric-surgery-indication threshold). The 3.C phenotype overlaps with bariatric-surgery referral consideration and with the highest-magnitude weight-loss requirement.

First-line compound — trial-anchored options with Pattern V enrollment qualification.

Across the Module 5 trial program, Class III obesity sub-populations were enrolled but rarely the dominant enrollment phenotype:

Tirzepatide (Zepbound). SURMOUNT-1 enrolled a BMI ≥30 population with mean baseline BMI 38.0 ± 6.7; the Class III sub-population is enrolled but is a sub-analysis rather than the dominant enrollment. Class III sub-analyses suggest effect-size magnitudes broadly comparable to the overall enrollment (tirzepatide weight-loss magnitude does not collapse at higher BMI). Routes to [[Tirzepatide Protocol]].
Semaglutide (Wegovy 2.4 mg / Wegovy HD 7.2 mg). STEP-1 mean baseline BMI 37.9 ± 6.7; Class III sub-population is enrolled but sub-analysis. STEP UP / Wegovy HD 7.2 mg at higher dose may be particularly relevant for Class III where additional magnitude is operationally meaningful. Routes to [[Semaglutide Protocol]].
Retatrutide (investigational). TRIUMPH Phase 2 enrolled a BMI ≥30 obesity population; Phase 3 enrollment includes Class III sub-population. The –24.2% magnitude at 12 mg in TRIUMPH Phase 2 is the highest in the Module 5 portfolio and may be particularly relevant for Class III if Phase 3 confirms the magnitude. Pattern AA: investigational pending Phase 3.
CagriSema (investigational). REDEFINE-1 Phase 3 readout for obesity reported –22.7% weight loss at 68 weeks for CagriSema vs –2.3% placebo (Garvey 2025 NEJM, PMID 40513637 — confirm post-publication NCT/identifier). The trial enrolled adults with obesity including Class III; effect magnitudes broadly comparable to retatrutide Phase 2. Pattern AA: investigational; sponsor has filed for FDA approval. Routes to [[CagriSema Protocol]].

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 3.C phenotype distinguishing feature is the magnitude requirement. The Anchor 4 framing for 3.C presents:

Magnitude (load-bearing for 3.C): Retatrutide Phase 2 –24.2% > CagriSema Phase 3 –22.7% > Tirzepatide SURMOUNT-1 –22.5% > Semaglutide HD 7.2 mg –18.7% > Semaglutide 2.4 mg –14.9%. The magnitude ordering at the top end is investigational-vs-approved — retatrutide and CagriSema are pending Phase 3 / approval; tirzepatide and semaglutide HD are FDA-approved with the magnitude already on-label.
Bariatric-surgery comparator. For Class III, bariatric surgery (sleeve gastrectomy or RYGB) achieves greater long-term weight loss than any of the pharmacotherapy options — typical RYGB 1-year weight loss ~25–35% with durability data at 10+ years. The pharmacotherapy vs surgery framing is a multi-dimensional comparator that includes magnitude, durability, surgical-risk profile, anatomic considerations, post-operative nutritional management, and patient preference. The Module 5 pharmacotherapy options are an alternative or adjunct to bariatric surgery, not a replacement; the patient-counseling beat acknowledges bariatric-surgery as a comparator option.
Combinations and add-on bariatric. For patients with prior bariatric surgery and weight regain (the bariatric-regain phenotype), the per-canonical protocols handle this in their §9 combination rules — see [[Tirzepatide Protocol]] §9 and [[Semaglutide Protocol]] §9.
Outcomes evidence: the comorbidity-driven outcomes evidence base for Class III is the same as for 3.B — anchored to the specific comorbidity (ASCVD, kidney, MASH, etc.).

Adjunct overlay (consider §11 visceral-fat or post-weight-loss-skin). Class III patients are more likely to develop post-weight-loss skin laxity if they achieve ≥20% weight loss, and the visceral-adiposity-distribution sub-phenotype is more prevalent in Class III obesity. §11 covers the body-composition phenotype dimensions; the post-weight-loss-skin adjunct (GHK-Cu) is considered after ≥12 months of significant weight loss.

Pattern Z patient-counseling beat for 3.C (Anchor 4 verbatim-compliant).

“You’re at BMI ≥40 (Class III obesity), which puts the magnitude of weight loss as a particularly load-bearing consideration. Among FDA-approved options, tirzepatide showed –22.5% at 15 mg in the SURMOUNT-1 trial, semaglutide HD 7.2 mg showed –18.7% in the STEP UP trial, and SURMOUNT-5 head-to-head favored tirzepatide by ~6.5 percentage points. Among investigational options, retatrutide showed –24.2% at 12 mg in Phase 2 with the Phase 3 readout pending, and CagriSema showed –22.7% in Phase 3 with FDA review pending. Bariatric surgery is a separate option that typically achieves 25–35% weight loss with established durability data; it’s a different decision with different risks and different lifestyle implications. Pharmacotherapy and surgery aren’t mutually exclusive — some patients use pharmacotherapy to prepare for surgery, some use surgery first and add pharmacotherapy for regain, and some choose one or the other. Let’s walk through what the evidence supports for each path and what matters most for your situation.”

3.5 Sub-phenotype 3.D — Pediatric ≥12 years

Phenotype definition. Adolescent (12–17 years, inclusive) with BMI at the 95th percentile or greater for age and sex (the CDC growth-chart-anchored adolescent obesity threshold). The 3.D phenotype overlaps with developmental considerations (growth-stage effects of GLP-1 RA exposure; lean-mass accrual during adolescence; psychosocial dimensions of weight management in adolescence).

First-line compound — trial-anchored options.

Three currently-approved compounds for adolescent CWM, with primary-source anchoring:

Semaglutide (Wegovy adolescent label). FDA-approved 2022 for adolescent CWM ≥12 years at the 95th percentile or greater BMI. Trial anchor: STEP TEENS (Weghuber 2022 NEJM, PMID 36322838; NCT04102189; n=201 adolescents ≥12 years at 95th percentile or greater BMI; 68 weeks): –16.1% BMI change with semaglutide 2.4 mg vs +0.6% placebo. Routes to [[Semaglutide Protocol]] §1.3 Indication 3.
Liraglutide (Saxenda adolescent label). FDA-approved 2020 for adolescent CWM ≥12 years. Trial anchor: Kelly 2020 NEJM (PMID 32242688; n=251 adolescents): liraglutide 3.0 mg daily produced BMI reduction approximately 4.6% greater than placebo at 56 weeks. Daily-SC route; lower magnitude than semaglutide weekly-SC. Routes to [[Liraglutide Protocol]].
Tirzepatide (pediatric Phase 3 ongoing; not yet approved as of 2026-05-13). Pattern AA: investigational for adolescent CWM; do not state “approved for adolescents” — the adult-CWM Zepbound approval does not extend to adolescents until the pediatric program completes and FDA approval is granted.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Approval state: Semaglutide and Liraglutide both FDA-approved for adolescent CWM; Tirzepatide pediatric program pending
Magnitude: Semaglutide STEP TEENS –16.1% BMI vs Liraglutide adolescent ~4.6% greater than placebo — semaglutide weekly-SC produces larger magnitude
Route / platform: Both injection — semaglutide weekly-SC vs liraglutide daily-SC; daily-injection in adolescents adds adherence challenge
Safety / developmental: Long-term developmental, reproductive, and psychosocial outcomes surveillance is ongoing for both compounds in adolescents; the load-bearing surveillance is multi-year post-marketing
Behavioral / structural overlay: Use within structured lifestyle-intervention framework and pediatric obesity-medicine specialist oversight where available is the protocol-recommended posture for both compounds

Adjunct overlay (none required by default; lean-mass adjunct is contraindicated in adolescent context — see §11). The CJC-Ipamorelin / MOTS-c lean-mass adjunct is not appropriate in adolescent context — adolescent lean-mass accrual is developmentally driven and exogenous GH-axis modulation is not supported by adolescent trial data. Adjunct overlays for adolescents are limited.

Pattern Z patient-counseling beat for 3.D (Anchor 4 verbatim-compliant).

“For your child’s situation — adolescent obesity at the 95th percentile or greater — two FDA-approved compounds are options: semaglutide (Wegovy) and liraglutide (Saxenda). Semaglutide is once-weekly and showed a 16.1% BMI reduction in the STEP TEENS trial in your child’s age group. Liraglutide is daily and showed a more modest BMI reduction, around 4.6 percentage points greater than placebo at 56 weeks. Both are used within a structured lifestyle-intervention framework with pediatric obesity-medicine oversight where available. The longer-term developmental, reproductive, and psychosocial surveillance is ongoing for both — the load-bearing surveillance happens over multiple years post-treatment. Tirzepatide has a pediatric program in progress but is not yet approved for adolescents. Let’s discuss what fits your family’s situation — daily vs weekly injection, access and coverage, side-effect profile, and what monitoring would look like.”

3.6 Sub-phenotype 3.E — Pediatric <12 years

Phenotype definition. Childhood obesity below the adolescent label threshold (typically 6–11 years with BMI at the 95th percentile or greater for age and sex). The 3.E phenotype is investigational across the Module 5 portfolio.

First-line compound — trial-anchored options.

Pattern AA precision: as of 2026-05-13, no compound in the Module 5 portfolio is FDA-approved for CWM in children <12 years. Investigational programs in progress include:

Semaglutide pediatric expansion (NCT07302802 and related programs). Monogenic obesity pediatric expansion under investigation; not approved as of 2026-05-13. Routes to [[Semaglutide Protocol]] §1.3 (investigational extensions sub-block).
Liraglutide pediatric <12y. Limited published data; some monogenic-obesity case-series literature; not FDA-approved for general pediatric <12y CWM.

Pattern Z Anchor 4 multi-dimensional comparator presentation (and Pattern V flag).

Pattern V applies: direction-of-effect in pediatric <12y is research-state-incomplete except for specific monogenic-obesity contexts (e.g., MC4R deficiency, where setmelanotide is the comparator option outside the Module 5 portfolio; POMC/PCSK1 deficiency; leptin deficiency). For non-monogenic pediatric <12y obesity, the trial-program evidence base is sparse and the clinician-judgment posture is comprehensive lifestyle-intervention with pediatric obesity-medicine specialist co-management; off-label pharmacotherapy is clinician-judgment within informed-consent and primary-source-supported clinical reasoning.

Adjunct overlay (not applicable).

Pattern Z patient-counseling beat for 3.E (Anchor 5 off-label / extrapolation verbatim-compliant).

“For children under 12 with obesity, the evidence base for the GLP-1 medications I would use in adolescents and adults is sparse. The semaglutide and liraglutide trials we have are in adolescents 12 and older; the pediatric under-12 programs are in progress for specific monogenic-obesity situations, but for general childhood obesity, the evidence base hasn’t been built yet. What we have for your child’s age group is comprehensive lifestyle intervention — nutrition, activity, sleep, family-system support — with pediatric obesity-medicine specialist oversight. If there’s a specific monogenic situation — MC4R deficiency, POMC deficiency, leptin deficiency — there are targeted options that we can route to outside our usual pharmacotherapy portfolio. Let’s talk about what we know about your child’s clinical picture, what evidence we have, what we don’t have, and what the comprehensive path looks like.”

3.7 Cross-reference to Axis 1 master decision

The five sub-phenotypes of Axis 1 (obesity type) collectively determine which compounds are even on-label candidates. The downstream axes (T2D status, CV history, kidney, hepatic, pre-conception, age-stage, route/cost, body-composition) refine the selection within the on-label-candidate set established by Axis 1. The §14 master decision tree integrates Axis 1 with the downstream axes.

4. T2D status phenotype

4.1 Purpose and sub-phenotype taxonomy

Axis 2 — T2D status — is the second of the two dominant decision axes (paired with Axis 1, obesity type). It determines which T2D-approved or T2D-investigational compounds are on-label candidates, which trial-program effect-size data are most directly applicable (SUSTAIN/PIONEER for semaglutide T2D, SURPASS for tirzepatide T2D, ATTAIN-2 for orforglipron T2D), and how the polycondition T2D + obesity overlap (the dominant Module 5 clinical phenotype) shapes compound selection.

Four sub-phenotypes:

4.A — T2D + obesity. The polycondition phenotype most heavily populated across the Module 5 trial program (STEP-2, SURMOUNT-2, SURPASS, the comparator-landscape literature).
4.B — T2D without obesity (BMI <27). Lean / overweight T2D where weight loss is not a primary goal but glycemic control and CV / kidney outcomes are.
4.C — Prediabetes (HbA1c 5.7–6.4%, IFG, IGT). The pre-diabetes phenotype where T2D prevention plus CWM-indication eligibility intersect.
4.D — No diabetes (HbA1c <5.7%). Non-diabetic obesity; the CWM-only phenotype (overlaps with §3 obesity-type).

4.2 Sub-phenotype 4.A — T2D + obesity

Phenotype definition. Adult with confirmed T2D (HbA1c ≥6.5% or established diagnosis on glucose-lowering therapy) and BMI ≥27 (CWM-label-permitted with T2D as the comorbidity). The polycondition phenotype is the dominant Module 5 clinical phenotype; both T2D-indication and CWM-indication labels apply.

First-line compound — trial-anchored options.

Four primary candidates with primary-source anchoring (Pattern V trial-enrollment qualified; Pattern AA regulatory-state precise):

Tirzepatide (Mounjaro for T2D; Zepbound for CWM). FDA-approved for marketing claims for T2D (2022) and CWM (2023). Trial anchors: SURPASS-1 through SURPASS-5 (T2D program); SURMOUNT-2 (Garvey 2023 Lancet, PMID 37385275; T2D + obesity at 72 weeks): –13.4% (10 mg) and –15.7% (15 mg) vs –3.3% placebo. SURPASS-2 head-to-head vs semaglutide (Frias 2021 NEJM, PMID 34170647; n=1,879 T2D): tirzepatide 15 mg HbA1c –2.30 vs semaglutide 1 mg HbA1c –1.86 — tirzepatide modestly superior on HbA1c. Routes to [[Tirzepatide Protocol]] §1.3 Indication 1 + 2.
Semaglutide (Ozempic for T2D; Wegovy for CWM; Rybelsus for T2D oral; oral Wegovy for CWM). FDA-approved for marketing claims for T2D (Ozempic 2017 SC; Rybelsus 2019 oral) and CWM (Wegovy 2.4 mg 2021; oral Wegovy 25 mg 2025; Wegovy HD 7.2 mg 2026). Trial anchors: SUSTAIN-1 through SUSTAIN-10; PIONEER-1 through PIONEER-10; STEP-2 (Davies 2021 Lancet, PMID 33667417; T2D + obesity at 68 weeks): –9.6% (2.4 mg) vs –3.4% placebo — smaller magnitude than non-diabetic STEP-1. SUSTAIN-FORTE 2.0 mg label expansion. Pioneer Plus oral 25/50 mg (Aroda 2023, PMID 37385279). Routes to [[Semaglutide Protocol]].
Orforglipron (investigational; filed-pending for T2D Q1 2026). Daily-oral small-molecule GLP-1 RA. Trial anchors: ATTAIN-1 obesity Phase 3 (DOI 10.1056/NEJMoa2511774); ATTAIN-2 T2D + obesity Phase 3 readout. Pattern AA: investigational; filed for FDA approval; not approved as of 2026-05-13. The oral-only daily small-molecule platform is operationally distinct from injectable GLP-1 RAs. Routes to [[Orforglipron Protocol]].
CagriSema (cagrilintide + semaglutide fixed-ratio combination; investigational). REDEFINE-2 Phase 3 in T2D + obesity (sponsor topline Q4 2025); not FDA-approved as of 2026-05-13. Pattern AA: investigational; sponsor has filed for FDA approval. Routes to [[CagriSema Protocol]].

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Glycemic control (HbA1c reduction): Tirzepatide leads on head-to-head per SURPASS-2 (tirzepatide 15 mg HbA1c –2.30 vs semaglutide 1 mg HbA1c –1.86). Orforglipron ATTAIN-2 readout positions oral small-molecule on this axis.
Weight-loss magnitude in T2D phenotype: SURMOUNT-2 tirzepatide –13.4% (10 mg) / –15.7% (15 mg) vs STEP-2 semaglutide –9.6% — tirzepatide larger magnitude. SURMOUNT-5 head-to-head was in non-diabetic CWM, not T2D + obesity, so the T2D-specific head-to-head magnitude data are from cross-trial comparison.
CV outcomes evidence in T2D: Semaglutide leads — SUSTAIN-6 HR 0.74 for three-point MACE (T2D + established CVD) plus SOUL oral 14% MACE reduction (T2D + ASCVD/CKD) plus SELECT (BMI ≥27 + ASCVD without diabetes — relevant for the T2D + obesity polycondition).
Kidney outcomes evidence in T2D: Semaglutide leads — FLOW HR 0.76 for kidney composite + CV death (T2D + CKD).
OSA-with-obesity: Tirzepatide leads — SURMOUNT-OSA FDA-approved 2024 (T2D + obesity sub-population enrolled).
HFpEF-with-obesity: Tirzepatide leads — SUMMIT (PMID 39555827) FDA-approved 2025 for HFpEF-with-obesity. Semaglutide STEP-HFpEF / STEP-HFpEF-DM supportive but label expansion pending.
Route / platform: All weekly-SC except oral options (Rybelsus, oral Wegovy 25 mg for CWM, orforglipron daily-oral pending approval).
Regulatory state: Tirzepatide and Semaglutide FDA-approved with multiple indications; Orforglipron filed-pending; CagriSema filed-pending; Retatrutide investigational Phase 3.

Adjunct overlay (none required by default).

Sequencing / transition logic.

The T2D + obesity 4.A patient who is GLP-1-RA-naive is initiated on the selected first-line compound. The within-class switch options (semaglutide ↔︎ tirzepatide) are supported by the SURMOUNT-5 and SURPASS-2 head-to-head data. The within-route transition (injectable semaglutide → oral semaglutide if patient becomes injection-averse, or oral orforglipron if approved and preferred) is a route-preference layer (Axis 8, §10). The intensification path for sub-optimal response is the per-canonical §7 plateau / non-response algorithm.

Pattern Z patient-counseling beat for 4.A (Anchor 4 verbatim-compliant).

“You have type 2 diabetes plus obesity — the most common pattern we see in this space. The FDA-approved options are tirzepatide (Mounjaro for diabetes, Zepbound for weight; same drug, different labels) and semaglutide (Ozempic for diabetes, Wegovy for weight, plus oral Rybelsus for diabetes and oral Wegovy for weight). On head-to-head glycemic control, the SURPASS-2 trial showed tirzepatide produced about half a percentage point more HbA1c reduction than semaglutide at the doses studied — tirzepatide HbA1c –2.30 vs semaglutide –1.86. On weight loss in T2D specifically, the SURMOUNT-2 tirzepatide data showed about –13.4 to –15.7% vs STEP-2 semaglutide at about –9.6% — tirzepatide larger magnitude in T2D. On the longer-term outcomes evidence — cardiovascular, kidney — semaglutide has the deeper evidence base across SUSTAIN-6, SELECT, FLOW, and SOUL. On sleep-apnea-with-obesity, tirzepatide has SURMOUNT-OSA. On heart-failure-with-preserved-ejection-fraction-and-obesity, tirzepatide has SUMMIT. The investigational options — orforglipron oral, CagriSema combination, retatrutide triple-agonist — are filed-pending or in Phase 3 with strong magnitude data but not yet approved. Let’s discuss which dimensions matter most for your situation.”

4.3 Sub-phenotype 4.B — T2D without obesity (BMI <27)

Phenotype definition. Adult with T2D and BMI <27 kg/m². The lean / overweight T2D phenotype where weight loss is not a primary clinical goal but glycemic control, CV outcomes, and kidney outcomes are.

First-line compound — trial-anchored options.

The CWM-indication label requires BMI ≥27 with comorbidity or BMI ≥30 without comorbidity. For BMI <27, the CWM indication does not apply; the T2D indication applies. The T2D-approved compounds in the Module 5 portfolio:

Semaglutide (Ozempic SC, Rybelsus oral, oral Wegovy 25 mg for T2D label). FDA-approved for T2D. Routes to [[Semaglutide Protocol]] §1.3 Indication 1.
Tirzepatide (Mounjaro for T2D). FDA-approved for T2D. Routes to [[Tirzepatide Protocol]] §1.3 Indication 1.
Liraglutide (Victoza for T2D). FDA-approved for T2D. Daily-SC. Routes to [[Liraglutide Protocol]].
Orforglipron (investigational; T2D filed-pending). Routes to [[Orforglipron Protocol]].

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 4.B sub-phenotype’s distinguishing consideration is that weight loss is not the operational goal — the goal is glycemic control and outcomes-prevention. Effect-size framing therefore prioritizes HbA1c reduction and outcome trials over weight-loss magnitude.

HbA1c reduction: SURPASS-2 tirzepatide 15 mg HbA1c –2.30 vs semaglutide 1 mg HbA1c –1.86. SUSTAIN-7 semaglutide 1 mg vs dulaglutide 1.5 mg HbA1c –1.8 vs –1.4 (semaglutide superior over dulaglutide). LEAD program for liraglutide HbA1c –1.0 to –1.5. PIONEER program for oral semaglutide HbA1c –1.0 to –1.5.
Weight loss in lean T2D phenotype: all GLP-1 RAs produce modest weight loss in lean T2D; the magnitude is lower than in obese T2D. The clinician-counseling beat positions weight loss as a secondary benefit in this phenotype, not the primary endpoint.
CV outcomes in T2D + ASCVD: SUSTAIN-6, SOUL anchor semaglutide. LEADER (Marso 2016 NEJM, PMID 27295427) anchors liraglutide in T2D + ASCVD with HR 0.87 for three-point MACE.
Kidney outcomes in T2D + CKD: FLOW anchors semaglutide. LEADER kidney sub-analysis supportive for liraglutide.
Hypoglycemia risk in lean T2D on insulin or sulfonylurea: the lean T2D phenotype is more often on insulin or sulfonylurea than the obese T2D phenotype; GLP-1 RA initiation in this context requires sulfonylurea dose reduction or insulin dose reduction per §5 of the per-canonical protocols to prevent hypoglycemia. Pattern V: the trial-program data for T2D include this concurrent therapy adjustment guidance; the lean T2D phenotype is the higher-risk hypoglycemia sub-population.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 4.B (Anchor 4 verbatim-compliant).

“You have type 2 diabetes without significant obesity — your BMI is in the under-27 range, which means the weight-management indications don’t apply but the diabetes indication does. The compounds we have here — tirzepatide, semaglutide, liraglutide — all reduce HbA1c, and on head-to-head data tirzepatide produces about half a percentage point more reduction than semaglutide, and semaglutide produces about 0.4 points more than dulaglutide. The longer-term outcomes evidence — cardiovascular, kidney — favors semaglutide for the deepest evidence base, with liraglutide having LEADER data for cardiovascular outcomes in T2D plus ASCVD. Some weight loss will happen with any of these — typically a few percent in lean T2D — but it’s not the primary goal here. The operational consideration in your situation is hypoglycemia risk if you’re on insulin or sulfonylurea — we’ll need to adjust those doses when we start the GLP-1 medication. Let’s walk through your specific situation, what other medications you’re on, and which dimensions of the evidence matter most for you.”

4.4 Sub-phenotype 4.C — Prediabetes

Phenotype definition. Adult with HbA1c 5.7–6.4% (the ADA prediabetes range), impaired fasting glucose (FPG 100–125 mg/dL), or impaired glucose tolerance (2-hour OGTT 140–199 mg/dL). The prediabetes phenotype is at elevated risk for T2D progression; the GLP-1 RA class has documented T2D-prevention effect in the obesity + prediabetes sub-population.

First-line compound — trial-anchored options.

The CWM-indication label applies if BMI ≥30 or BMI ≥27 with prediabetes as a recognized weight-related comorbidity (the CWM-label-permitted comorbidities are hypertension, dyslipidemia, T2D, OSA, ASCVD — prediabetes-alone-with-BMI-≥27 is not unambiguously on the label list in the same way as T2D; clinician judgment within the broader weight-related-comorbidity framing typically positions prediabetes as a comorbidity).

Semaglutide (Wegovy 2.4 mg / 7.2 mg / oral 25 mg). STEP-1 (Wilding 2021 PMID 33567185) and STEP-5 (Garvey 2022 Nat Med, PMID 36216945) enrolled non-diabetic obesity sub-populations that included prediabetes. T2D progression at 68 weeks was reduced; the SELECT trial in BMI ≥27 + ASCVD without diabetes likewise documented T2D progression reduction.
Tirzepatide (Zepbound). SURMOUNT-1 enrolled non-diabetic obesity including prediabetes; T2D progression reduction documented.
Liraglutide (Saxenda). SCALE Obesity and Prediabetes (Pi-Sunyer 2015 NEJM, PMID 26132939; n=3,731): liraglutide 3.0 mg daily produced 6.0% greater weight reduction vs placebo at 56 weeks; T2D-progression at 160 weeks (Le Roux 2017 Lancet, PMID 28237263): liraglutide 3.0 mg reduced T2D incidence by approximately 80%.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Weight-loss magnitude in prediabetes + obesity: Tirzepatide (SURMOUNT-1) > Semaglutide (STEP-1) > Liraglutide (SCALE) — same magnitude ordering as 3.A.
T2D-progression reduction: Liraglutide SCALE 160-week data are the most directly anchored T2D-prevention data in the obesity + prediabetes phenotype (~80% T2D-incidence reduction); semaglutide and tirzepatide T2D-progression data are sub-analyses of STEP / SURMOUNT but the effect-sizes are clinically meaningful. The Pattern Z patient-counseling beat for 4.C frames the T2D-prevention dimension explicitly.
Outcomes evidence base: Same as 3.A — semaglutide has the deepest base; tirzepatide growing; liraglutide LEADER.
Regulatory state: All three FDA-approved for CWM in eligible BMI / comorbidity range.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 4.C (Anchor 4 verbatim-compliant).

“You have prediabetes plus weight in the FDA-approved chronic weight management range. The GLP-1 medications I would use here have documented T2D-prevention effects in your phenotype — the SCALE program for liraglutide showed about an 80% reduction in T2D progression at three years of treatment in obesity plus prediabetes, and the STEP and SURMOUNT data for semaglutide and tirzepatide show T2D-progression reduction as well. On weight-loss magnitude, tirzepatide leads, then semaglutide, then liraglutide. On the longer-term cardiovascular outcomes evidence, semaglutide leads with SELECT and SOUL data. On daily vs weekly injection, liraglutide is daily, semaglutide and tirzepatide are weekly. Oral options — Rybelsus oral semaglutide for diabetes, oral Wegovy 25 mg for weight, orforglipron daily-oral if and when it’s FDA-approved — give you platform flexibility. Let’s discuss what matters most for your situation — the T2D-prevention goal, the weight-loss magnitude, the access, the route preference, and what monitoring would look like.”

4.5 Sub-phenotype 4.D — No diabetes

Phenotype definition. Adult with HbA1c <5.7%, no diabetes diagnosis, and obesity (BMI ≥30 or BMI ≥27 with non-diabetes comorbidity). This sub-phenotype overlaps with §3 obesity-type Axis 1 — the 4.D × Axis 1 intersection is the dominant non-diabetic Module 5 phenotype.

First-line compound — trial-anchored options.

Same as 3.A: Tirzepatide (Zepbound), Semaglutide (Wegovy 2.4 mg / 7.2 mg / oral 25 mg), Retatrutide (investigational pending Phase 3).

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Same as 3.A — see §3.2.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 4.D.

The 4.D counseling beat is the §3.2 counseling beat (the BMI ≥30 without weight-related comorbidity beat). The two sub-phenotypes are clinically equivalent for compound selection.

4.6 Cross-reference to Axis 2 master decision

T2D status interacts strongly with CV history (§5), kidney status (§6), hepatic status (§7), and pre-conception planning (§8). The §14 master decision tree integrates Axis 2 with these downstream axes — the T2D + ASCVD + CKD phenotype, for example, sits at the intersection of Axes 2, 3, 4 and routes to semaglutide as the most outcomes-evidence-rich compound for that triple overlap (SUSTAIN-6, SELECT, FLOW, SOUL collectively).

5. Cardiovascular history phenotype

5.1 Purpose and sub-phenotype taxonomy

Axis 3 — cardiovascular history — determines which Module 5 compounds carry the most relevant CV-outcomes-evidence base for the patient. CV history materially shapes compound selection because the GLP-1 RA class has a documented MACE-reduction effect in established-ASCVD sub-populations (SUSTAIN-6, LEADER, SELECT, SOUL collectively), a documented KCCQ-CSS / weight-loss benefit in HFpEF-with-obesity (STEP-HFpEF, SUMMIT), but limited data in HFrEF (Pattern V flag — direction-of-effect in HFrEF is research-state-incomplete; see [[Tirzepatide Protocol]] §1.3 / §5).

Five sub-phenotypes:

5.A — Established ASCVD (secondary prevention). Documented coronary artery disease, prior MI, prior stroke, peripheral artery disease, or aortic atherosclerosis with clinical events.
5.B — Heart failure with preserved ejection fraction (HFpEF) + obesity. LVEF ≥50% with HF clinical syndrome and BMI ≥30.
5.C — Heart failure with reduced ejection fraction (HFrEF). LVEF ≤40% with HF clinical syndrome.
5.D — High CV risk without established disease (primary prevention). Multiple CV risk factors (hypertension, dyslipidemia, T2D, smoking, family history) with elevated calculated 10-year ASCVD risk (e.g., ASCVD risk ≥7.5–20%) without documented event.
5.E — No CV history. No established CV disease, no clinical events, ASCVD risk not elevated.

5.2 Sub-phenotype 5.A — Established ASCVD

Phenotype definition. Adult with documented coronary artery disease (prior MI, angina, prior revascularization), prior stroke, peripheral artery disease, or aortic atherosclerosis with clinical events. This is the secondary-prevention CV phenotype.

First-line compound — trial-anchored options.

Semaglutide (multiple FDA-approved CV-indication labels). Trial anchors:
- SUSTAIN-6 (Marso 2016 NEJM, PMID 27633186; n=3,297 T2D + established CVD; 2.1 years median): HR 0.74 for three-point MACE composite (26% relative reduction) — original CVOT for the class
- SELECT (Lincoff 2023 NEJM, PMID 37952131; n=17,604 BMI ≥27 + established CVD without diabetes; 39.8 months mean): HR 0.80 for three-point MACE (20% relative reduction). 4-year durability data Ryan 2024 Nat Med, PMID 38740993: –10.2% mean weight loss maintained at 208 weeks
- SOUL (McGuire 2025 NEJM, PMID 40162642; oral semaglutide 14 mg in T2D + ASCVD/CKD; n=9,650): 14% MACE reduction — first CV outcomes trial confirming benefit for an oral GLP-1 agent
- FLOW (Perkovic 2024 NEJM, PMID 38785209; T2D + CKD; n=3,533; 3.4 years median): 18% lower MACE as secondary endpoint; 20% lower all-cause mortality
Semaglutide FDA-approved for CV risk reduction in T2D + established CVD (2020) and in BMI ≥27 + established CVD without diabetes (Wegovy 2024) and in T2D + ASCVD/CKD via oral SOUL (2025). Routes to [[Semaglutide Protocol]] §1.3 Indication 4.
Liraglutide (LEADER FDA-approved CV indication). Trial anchor: LEADER (Marso 2016 NEJM, PMID 27295427; n=9,340 T2D + high CV risk including 81% established CVD; 3.8 years median): HR 0.87 for three-point MACE (13% relative reduction). FDA-approved 2017 for CV risk reduction in T2D + established CVD. Daily-SC; magnitude lower than semaglutide. Routes to [[Liraglutide Protocol]].
Tirzepatide (SURMOUNT-MMO in progress; not FDA-approved for CV risk reduction as of 2026-05-13). SURPASS-CVOT is the T2D CV-outcomes trial; SURMOUNT-MMO is the CWM CV-outcomes trial. Both readouts pending. Pattern AA precision: tirzepatide is FDA-approved for T2D, CWM, OSA-with-obesity, and HFpEF-with-obesity, but NOT for CV risk reduction as a standalone indication — the CV-outcomes data are pending. Do not state “FDA-approved for CV risk reduction.” Routes to [[Tirzepatide Protocol]] §1.3.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

CV outcomes evidence base: Semaglutide leads — SUSTAIN-6 (T2D + CVD), SELECT (BMI ≥27 + CVD without diabetes), SOUL (T2D + ASCVD/CKD oral), FLOW (T2D + CKD, MACE secondary endpoint), plus 4-trial pooled HF analysis (Kosiborod 2024 Lancet, PMID 39222642; HR 0.69 CV death or worsening HF). Liraglutide has LEADER (T2D + high CV risk). Tirzepatide CV-outcomes trials pending.
Magnitude of CV risk reduction: Semaglutide SUSTAIN-6 HR 0.74 (T2D + CVD) > Semaglutide SELECT HR 0.80 (BMI ≥27 + CVD without diabetes) > Semaglutide SOUL ~14% reduction (oral, T2D + ASCVD/CKD) > Liraglutide LEADER HR 0.87 (T2D + high CV risk). The hazard-ratio differences reflect the trial-population phenotypes; a direct head-to-head MACE-comparison trial between semaglutide and liraglutide for CV outcomes does not exist.
Weight loss in CV-indication phenotype: STEP-1, STEP-2, STEP UP magnitude (semaglutide) and SURMOUNT-1, SURMOUNT-2 (tirzepatide); the weight-loss-driven mechanism may be load-bearing for some of the MACE reduction but the trials demonstrated CV benefit not entirely accounted for by weight loss alone.
NAION ophthalmologic class-differentiation: Semaglutide carries an emerging NAION signal under post-marketing evaluation (Hathaway 2024 JAMA Ophthalmology); tirzepatide signal appears absent per PMID 40383360. Pattern AA precision: NAION is post-marketing signal under active evaluation, not labeled warning. The ASCVD-with-CV-event-history phenotype may have higher baseline risk for ophthalmologic events; clinician judgment for pre-treatment ophthalmologic screening per [[Semaglutide Protocol]] §3.7.
Route / platform: Semaglutide weekly-SC plus oral; Liraglutide daily-SC; Tirzepatide weekly-SC.
Cost / access: Long-term-CV-indication insurance coverage typically more robust than CWM-indication coverage; CV-outcomes-trial-approved indications carry the strongest coverage rationale.

Adjunct overlay (consider §11 visceral-fat for high-risk CV phenotype). Patients with established ASCVD and high visceral adipose tissue burden (visceral adiposity is an independent CV risk factor) may benefit from a §11 visceral-fat adjunct overlay (tesamorelin) layered on the GLP-1 RA — clinician judgment; the off-label-tesamorelin-for-non-HIV-visceral-adiposity framing applies (Pattern Z Anchor 5).

Sequencing / transition logic.

The established-ASCVD patient who is GLP-1-RA-naive is initiated on semaglutide (Wegovy if BMI ≥27 + CVD without diabetes per SELECT label; Ozempic if T2D + CVD per SUSTAIN-6 label) as the most outcomes-evidence-rich first-line option for CV risk reduction. If the patient is on liraglutide (LEADER-anchored), the switch to semaglutide for the larger magnitude CV benefit is supported by the SUSTAIN-6 / SELECT magnitude advantage and the STEP-8 head-to-head weight-loss-magnitude advantage. If the patient is on tirzepatide for non-CV reasons (T2D, CWM) and has now developed established ASCVD, the switch to semaglutide for the CV-outcomes-evidence base is reasonable; the SURMOUNT-MMO / SURPASS-CVOT readouts will update this guidance.

Pattern Z patient-counseling beat for 5.A (Anchor 4 verbatim-compliant).

“You have established cardiovascular disease — a prior [MI / stroke / revascularization / PAD] — and that puts the cardiovascular-outcomes evidence base at the center of compound selection. Semaglutide has the deepest evidence here: SUSTAIN-6 in T2D plus established CVD showed about 26% relative reduction in major cardiac events; SELECT in BMI ≥27 plus established CVD without diabetes showed about 20% reduction; SOUL in T2D plus ASCVD or CKD with oral semaglutide showed about 14% reduction; and the pooled heart-failure analysis showed a 31% reduction in cardiovascular death or worsening heart failure. Liraglutide has LEADER data — about 13% MACE reduction in T2D plus high CV risk, smaller magnitude than semaglutide. Tirzepatide has cardiovascular outcomes trials in progress but they haven’t reported yet. The semaglutide NAION ophthalmologic signal is post-marketing — under evaluation, not a labeled warning — and we’d do a pre-treatment ophthalmologic check if there’s anything in your history that suggests baseline optic-nerve concerns. Cost and coverage usually favor the on-label cardiovascular indication. Let’s discuss what fits your specific cardiovascular history, your other medications, and what monitoring would look like.”

5.3 Sub-phenotype 5.B — HFpEF + obesity

Phenotype definition. Adult with heart failure clinical syndrome (NYHA II-III) and LVEF ≥50% (preserved ejection fraction) and BMI ≥30 (obesity-related HFpEF). The 5.B phenotype is the heavily-enrolled phenotype across the STEP-HFpEF and SUMMIT programs.

First-line compound — trial-anchored options.

Tirzepatide (FDA-approved 2025 for HFpEF + obesity via SUMMIT). Trial anchor: SUMMIT (Packer 2025 NEJM, PMID 39555827; n=731 HFpEF + obesity at 52 weeks): primary endpoint composite of CV death or worsening HF events plus KCCQ-CSS improvement — both met; 38% reduction in worsening HF events; KCCQ-CSS improvement +6.9 points greater than placebo. FDA-approved 2025 for HFpEF + obesity. Routes to [[Tirzepatide Protocol]] §1.3.
Semaglutide (STEP-HFpEF / STEP-HFpEF-DM; supportive Phase 3 data; label expansion pending as of 2026-05-13). Trial anchors:
- STEP-HFpEF (Kosiborod 2023 NEJM, PMID 37622681; HFpEF + obesity without diabetes): KCCQ-CSS +16.6 vs +8.7 (semaglutide vs placebo)
- STEP-HFpEF-DM (Kosiborod 2024 NEJM, PMID 38587233; HFpEF + obesity with T2D)
- Pooled STEP-HFpEF (Butler 2024 Lancet, PMID 38599221; n=1,145)
- 4-trial pooled HF analysis (Kosiborod 2024 Lancet, PMID 39222642; n=3,743 with HF across SELECT + FLOW + STEP-HFpEF + STEP-HFpEF DM): HR 0.69 for CV death or worsening HF events
Pattern AA precision: do not state “FDA-approved for HFpEF” for semaglutide — state “supportive Phase 3 data; label expansion not granted as of 2026-05-13.” Routes to [[Semaglutide Protocol]] §1.3 (investigational extension).

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Regulatory state: Tirzepatide FDA-approved for HFpEF + obesity (SUMMIT, 2025); Semaglutide supportive Phase 3 data, label expansion pending. The regulatory-state distinction is load-bearing for the Pattern AA framing.
Effect magnitude on HF endpoints: SUMMIT (tirzepatide) reduced worsening HF events 38% and improved KCCQ-CSS by 6.9 points. STEP-HFpEF (semaglutide) improved KCCQ-CSS by ~7.9 points (16.6 vs 8.7) — broadly comparable KCCQ-CSS magnitude. The 4-trial pooled semaglutide HF analysis HR 0.69 for CV death or worsening HF is a different population (the pooled set across SELECT + FLOW + STEP-HFpEF + STEP-HFpEF-DM, not HFpEF-alone).
Weight loss in HFpEF + obesity phenotype: Both compounds produce significant weight loss in this phenotype; magnitude is consistent with the broader CWM trial-program effect sizes.
Outcomes evidence base beyond HFpEF: Semaglutide leads broadly (SELECT, SOUL, FLOW); tirzepatide has the HFpEF-specific approval plus OSA, T2D, CWM.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 5.B (Anchor 4 verbatim-compliant).

“You have heart failure with preserved ejection fraction plus obesity — your ejection fraction is preserved, the heart-failure symptoms are the load-bearing concern, and the obesity is the modifiable contributor. We have two evidence-based options here. Tirzepatide is FDA-approved for HFpEF plus obesity based on the SUMMIT trial, which showed a 38% reduction in worsening heart-failure events and a 6.9-point improvement in heart-failure quality-of-life scores at one year. Semaglutide has supportive Phase 3 data from STEP-HFpEF and STEP-HFpEF-DM showing comparable quality-of-life improvement, plus a pooled analysis across the heart-failure trials showing about 31% reduction in cardiovascular death or worsening heart failure — but the FDA label expansion for HFpEF specifically is still pending as of today. So on regulatory status, tirzepatide is on-label and semaglutide is off-label-with-supportive-Phase-3-data. On magnitude, both look comparable on quality-of-life; tirzepatide has the heart-failure-event-reduction primary endpoint result. Let’s discuss your specific situation, what other heart-failure medications you’re on, and what monitoring would look like.”

5.4 Sub-phenotype 5.C — HFrEF (heart failure with reduced ejection fraction)

Phenotype definition. Adult with heart failure clinical syndrome and LVEF ≤40% (reduced ejection fraction). The 5.C phenotype is under-represented across the Module 5 trial program.

First-line compound — trial-anchored options.

Pattern V flag: direction-of-effect in HFrEF for GLP-1 RAs is research-state-incomplete. The HFrEF population was excluded from STEP-HFpEF and SUMMIT (HFpEF-specific enrollment); HFrEF data are largely from sub-analyses of broader CV trials.

No compound in the Module 5 portfolio is FDA-approved for HFrEF as an indication. The 5.C phenotype is treated with established HFrEF-indicated therapies (SGLT2 inhibitors per DAPA-HF, EMPEROR-Reduced; sacubitril/valsartan per PARADIGM-HF; beta-blockers; MRA per RALES, EMPHASIS-HF) outside the Module 5 portfolio.
GLP-1 RA use in the 5.C phenotype is clinician-judgment if the patient has concurrent T2D or obesity. The FIGHT trial (Margulies 2016 JAMA, PMID 27559398; liraglutide in advanced HF with reduced EF) was a small Phase 2 (n=300) that did not demonstrate benefit and signaled some concern for hospitalization rate — Pattern V documented signal toward placebo. The current clinical-judgment posture: GLP-1 RA initiation in HFrEF patients is approached cautiously; if initiated for T2D or CWM indication, careful monitoring for HF decompensation is appropriate.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Regulatory state: No Module 5 compound FDA-approved for HFrEF; HFrEF management is outside the Module 5 portfolio.
Direction-of-effect evidence (Pattern V): Limited; FIGHT signal toward worse outcomes in advanced HFrEF — clinician-judgment for any off-label use.
Concurrent T2D / obesity considerations: GLP-1 RA initiation in HFrEF patients with T2D or obesity is approached cautiously; alternative T2D / CWM therapies may be preferred (e.g., SGLT2 inhibitor for T2D, which has established HFrEF benefit).

Adjunct overlay (not applicable).

Pattern Z patient-counseling beat for 5.C (Anchor 5 off-label / extrapolation verbatim-compliant).

“You have heart failure with reduced ejection fraction. The GLP-1 medications I would otherwise consider for your weight or diabetes management have not been studied extensively in HFrEF — the heart-failure trials we have, SUMMIT for tirzepatide and STEP-HFpEF for semaglutide, were specifically in patients with preserved ejection fraction. There’s an older trial called FIGHT in advanced reduced-ejection-fraction heart failure that didn’t show benefit and had a signal of potential concern. So the evidence base for your specific situation is research-state-incomplete. The treatments with established benefit in your phenotype — SGLT2 inhibitors, sacubitril/valsartan, beta-blockers, mineralocorticoid antagonists — are managed by the heart-failure team and are outside the GLP-1 portfolio. If we use a GLP-1 medication for your diabetes or weight management, we’d do that carefully with heart-failure-team co-management. Let’s discuss your specific situation, what your cardiologist’s posture is, and what monitoring would look like.”

5.5 Sub-phenotype 5.D — High CV risk without established disease

Phenotype definition. Adult with multiple CV risk factors (hypertension, dyslipidemia, T2D, smoking, family history) and elevated calculated 10-year ASCVD risk (e.g., ASCVD risk ≥7.5% or higher per ACC/AHA cholesterol guidelines) but without documented ASCVD events (no prior MI, no prior stroke, no prior revascularization, no PAD). The 5.D phenotype is the primary-prevention high-risk phenotype.

First-line compound — trial-anchored options.

Pattern V flag: the SELECT trial enrolled BMI ≥27 + established CVD without diabetes; the 5.D primary-prevention-high-risk phenotype is outside SELECT enrollment. The SUSTAIN-6 trial enrolled T2D + established CVD or high CV risk — but the “high CV risk” sub-group within SUSTAIN-6 was a minority and the trial’s HR 0.74 effect size was driven by the established-CVD sub-population.

Semaglutide and Tirzepatide for the 5.D phenotype are clinician-judgment within the on-label CWM or T2D indication. Pattern Z Anchor 5 applies (off-label / extrapolation framing): the CV-outcomes-evidence base does not extend to the primary-prevention high-risk phenotype with the same trial-population anchoring as for established ASCVD. The patient-counseling beat frames the extrapolation question explicitly.
Comprehensive CV risk reduction (statin, antihypertensive, smoking cessation, glucose control, lifestyle) is the primary therapeutic strategy for the 5.D phenotype. The GLP-1 RA is appropriate for the on-label CWM / T2D indication if BMI / HbA1c criteria are met; the CV benefit at the primary-prevention level is research-state-incomplete (Pattern V).

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 5.D phenotype routes through the on-label CWM / T2D selection per §3 / §4, with the additional consideration that the CV-outcomes-evidence base does not directly anchor in primary-prevention high-risk — Pattern Z Anchor 5 framing applies.

Pattern Z patient-counseling beat for 5.D (Anchor 5 off-label / extrapolation verbatim-compliant).

“You have multiple cardiovascular risk factors but no established disease yet — that’s the primary-prevention high-risk phenotype. The major GLP-1 cardiovascular outcomes trials — SUSTAIN-6, SELECT, LEADER — were largely in patients who had already had a cardiovascular event. The primary-prevention high-risk population was a minority within those trials. So if I tell you ‘semaglutide reduces cardiovascular events 20%,’ that’s anchored in the established-disease population, not in your phenotype. Whether the cardiovascular benefit extends to primary prevention at your risk level is research-state-incomplete. What we know works in your phenotype: comprehensive risk reduction — statin, blood-pressure control, glucose control if you have prediabetes, smoking cessation if applicable, weight reduction. If you meet the FDA-approved chronic weight management indication (BMI ≥30 or ≥27 with comorbidity), the GLP-1 medications are appropriate for the weight indication with the cardiovascular benefit as a secondary expected effect, not the primary anchored outcome. Let’s discuss your full risk picture and what fits your situation.”

5.6 Sub-phenotype 5.E — No CV history

Phenotype definition. Adult with no established CV disease, no clinical events, ASCVD risk not elevated. The 5.E phenotype is the no-CV-overlay phenotype; compound selection routes through §3 / §4 without CV-axis modification.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Same as §3 / §4 — the CV axis does not modify selection in the 5.E phenotype.

Pattern Z patient-counseling beat for 5.E.

Routes to §3.2 (or §4.2 if T2D + obesity, etc.) counseling beat.

5.7 Cross-reference to Axis 3 master decision

CV history interacts with T2D status (§4) and kidney status (§6) heavily. The T2D + ASCVD + CKD triple overlap is the most outcomes-evidence-rich phenotype across the Module 5 program (semaglutide via SUSTAIN-6 + SELECT + FLOW + SOUL collectively). The §14 master decision tree handles the triple overlap.

6. Kidney status phenotype

6.1 Purpose and sub-phenotype taxonomy

Axis 4 — kidney status — determines which Module 5 compounds carry the most relevant kidney-outcomes-evidence base and which compounds have specific dose-adjustment or contraindication considerations in advanced CKD. The FLOW trial (Perkovic 2024 NEJM, PMID 38785209; semaglutide in T2D + CKD) is the load-bearing kidney-outcomes trial in the Module 5 portfolio as of 2026-05-13; tirzepatide kidney programs are in progress.

Four sub-phenotypes:

6.A — CKD stage 3-4 in T2D (eGFR 15–59 with T2D). The FLOW enrollment phenotype; the kidney-outcomes-evidence-anchored phenotype.
6.B — Proteinuric kidney disease (UACR ≥30 mg/g or proteinuria ≥150 mg/day). Albuminuria-driven kidney disease, with or without overt eGFR reduction.
6.C — Normal kidney function (eGFR ≥60, no proteinuria). The no-kidney-overlay phenotype.
6.D — Kidney transplant recipient. Post-transplant phenotype with immunosuppression and graft-function considerations; excluded from Module 5 trial enrollment (Pattern V flag).

6.2 Sub-phenotype 6.A — CKD stage 3-4 in T2D

Phenotype definition. Adult with T2D (HbA1c ≥6.5% or established diagnosis) and chronic kidney disease stage 3-4 (eGFR 15–59 mL/min/1.73 m²), typically with albuminuria (UACR 100–5000 mg/g per FLOW enrollment criteria). The 6.A phenotype is the heavily-enrolled phenotype in FLOW.

First-line compound — trial-anchored options.

Semaglutide (Ozempic / Wegovy FDA-approved for CKD in T2D via FLOW, 2025; SOUL oral semaglutide also relevant). Trial anchors:
- FLOW (Perkovic 2024 NEJM, PMID 38785209; n=3,533 T2D + CKD eGFR 25–75, UACR 100–5000, on maximally tolerated RAS blockade; 3.4 years median): HR 0.76 for primary kidney composite outcome (sustained eGFR decline ≥50%, kidney failure, kidney death, or CV death) — 24% relative reduction. Secondary endpoints: 18% lower MACE; 20% lower all-cause mortality. Trial stopped early at planned interim analysis for efficacy.
- SOUL (McGuire 2025 NEJM, PMID 40162642; oral semaglutide 14 mg in T2D + ASCVD/CKD; n=9,650): 14% MACE reduction — first CV outcomes trial confirming benefit for an oral GLP-1 agent in a T2D + CKD-inclusive population
Semaglutide FDA-approved for marketing claims for CKD risk reduction in T2D (2025). Routes to [[Semaglutide Protocol]] §1.3 Indication 6.
Tirzepatide (kidney-outcomes trial in progress; not FDA-approved for CKD as of 2026-05-13). SURPASS-CVOT secondary kidney endpoints will inform; dedicated kidney trial in design. Pattern AA: do not state “FDA-approved for CKD” for tirzepatide. Routes to [[Tirzepatide Protocol]] §1.3.
Liraglutide (LEADER kidney sub-analysis supportive but not FDA-approved for CKD specifically). LEADER trial in T2D + high CV risk documented modest kidney-protective effect on UACR; not a dedicated kidney-outcomes trial. Routes to [[Liraglutide Protocol]].

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Kidney outcomes evidence base: Semaglutide leads — FLOW is the dedicated kidney-outcomes trial in T2D + CKD; HR 0.76 for primary composite. SGLT2 inhibitors (dapagliflozin via DAPA-CKD, empagliflozin via EMPA-KIDNEY, canagliflozin via CREDENCE) are outside the Module 5 portfolio but are the established first-line for CKD outcomes — the semaglutide-FLOW data are additive to SGLT2 background therapy, not a replacement. RAS blockade (ACEi or ARB at maximally tolerated dose) is the foundational therapy.
eGFR considerations for compound use: FLOW enrolled eGFR 25–75; eGFR 15–25 is outside the FLOW enrollment range. eGFR <15 (CKD stage 5 / kidney failure) is outside any Phase 3 enrollment and lacks direction-of-effect verification (Pattern V applies).
CV outcomes overlap: FLOW MACE secondary endpoint 18% reduction overlaps the CV-axis discussion (§5).
Dose-adjustment considerations: Semaglutide does not require dose adjustment based on eGFR per current label; the typical CWM / T2D dosing applies in the 6.A phenotype within the eGFR 25–75 range. For eGFR <25, clinician judgment per the labeled cautions in the per-canonical [[Semaglutide Protocol]] §5.

Adjunct overlay (none required by default).

Sequencing / transition logic.

The 6.A patient who is GLP-1-RA-naive is initiated on semaglutide as the most outcomes-evidence-rich first-line for the T2D + CKD phenotype. SGLT2 inhibitor background therapy (per current KDIGO guidelines for CKD in T2D) is layered with the GLP-1 RA; the combination is the modern first-line for the polycondition. RAS blockade at maximally tolerated dose is foundational.

Pattern Z patient-counseling beat for 6.A (Anchor 4 verbatim-compliant).

“You have type 2 diabetes plus chronic kidney disease — that puts the kidney-outcomes evidence at the center of compound selection. The FLOW trial enrolled patients with your phenotype — T2D plus CKD with eGFR 25–75 — and showed semaglutide reduced the kidney composite endpoint (substantial eGFR decline, kidney failure, kidney death, or cardiovascular death) by about 24% over 3.4 years. The trial was actually stopped early for efficacy. There were also secondary benefits: about 18% reduction in major cardiac events and 20% reduction in all-cause mortality. SOUL with oral semaglutide in T2D plus ASCVD or CKD confirmed cardiovascular benefit at about 14% MACE reduction. Tirzepatide kidney-outcomes trials are in progress but haven’t reported. SGLT2 inhibitors — a separate class — are also first-line for CKD in T2D based on DAPA-CKD and EMPA-KIDNEY, and the semaglutide benefit in FLOW is on top of SGLT2 background therapy. So the modern approach is RAS blockade plus SGLT2 inhibitor plus GLP-1 RA, layered together. Let’s discuss your specific situation, your current medications, your eGFR trajectory, and what monitoring would look like.”

6.3 Sub-phenotype 6.B — Proteinuric kidney disease

Phenotype definition. Adult with albuminuria (UACR ≥30 mg/g or proteinuria ≥150 mg/day) with or without overt eGFR reduction. The 6.B phenotype overlaps with 6.A when both proteinuria and eGFR reduction are present; 6.B-without-eGFR-reduction is the early-CKD phenotype.

First-line compound — trial-anchored options.

Same as 6.A. The FLOW enrollment required UACR 100–5000 alongside eGFR 25–75; the proteinuria component of the FLOW phenotype is heavily populated.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Same as 6.A — proteinuria within FLOW enrollment range is anchored to the FLOW evidence base. Proteinuria below the FLOW range (UACR 30–100) is the early-proteinuric-CKD phenotype where extrapolation from FLOW is reasonable but the trial-population anchoring is at the lower bound of enrollment.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 6.B.

Routes to §6.2 6.A counseling beat with the proteinuria-specific anchoring.

6.4 Sub-phenotype 6.C — Normal kidney function

Phenotype definition. Adult with eGFR ≥60 mL/min/1.73 m² and no proteinuria. The 6.C phenotype is the no-kidney-overlay phenotype; compound selection routes through §3 / §4 without kidney-axis modification.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Same as §3 / §4 — the kidney axis does not modify selection in the 6.C phenotype.

Pattern Z patient-counseling beat for 6.C.

Routes to §3.2 (or §4.2 if T2D + obesity) counseling beat.

6.5 Sub-phenotype 6.D — Kidney transplant recipient

Phenotype definition. Adult with prior kidney transplant on immunosuppression (tacrolimus / cyclosporine + mycophenolate + prednisone / belatacept regimens). The 6.D phenotype has specific considerations: graft-function preservation, immunosuppression-drug-interaction profile, increased post-transplant diabetes and obesity prevalence.

First-line compound — trial-anchored options.

Pattern V flag: kidney transplant recipients were excluded from Module 5 Phase 3 enrollment across the program. Direction-of-effect in this phenotype is research-state-incomplete for primary trial evidence; clinical experience and case-series literature exist but are not Phase 3-anchored.

GLP-1 RA use in kidney transplant recipients is clinician-judgment within nephrology / transplant co-management. The growing post-transplant T2D and obesity prevalence has produced a growing case-series and observational literature base; specific drug-interaction considerations with calcineurin inhibitors (tacrolimus, cyclosporine) are documented in pharmacology references. Pattern AA: no Module 5 compound is FDA-approved with kidney transplant as a labeled indication or label-specific consideration.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Trial-evidence base: None of the Module 5 compounds have Phase 3 trial evidence in kidney transplant recipients. Clinician-judgment within transplant-nephrology co-management applies.
Drug-interaction considerations: GLP-1 RA-mediated delayed gastric emptying can affect absorption of orally-administered immunosuppressants; tacrolimus / cyclosporine levels may be affected by altered GI motility. Pre-treatment and post-treatment immunosuppression levels monitoring is appropriate.
Graft-function monitoring: baseline and serial eGFR, UACR, urinalysis; transplant-nephrology team participation in compound selection and monitoring.

Adjunct overlay (not applicable).

Pattern Z patient-counseling beat for 6.D (Anchor 5 off-label / extrapolation verbatim-compliant).

“You have a kidney transplant. The GLP-1 medications I would consider for your diabetes or weight management haven’t been studied in your phenotype in the major Phase 3 trials — transplant recipients were excluded from enrollment. What we have is growing clinical experience and observational data, but not the trial-anchored evidence base we have in other phenotypes. The specific considerations for your situation are graft function monitoring, immunosuppression-drug-interaction profile (your tacrolimus or cyclosporine levels may be affected by the gastric-emptying change), and transplant-team co-management for any decision to initiate. Let’s discuss your specific situation with your transplant nephrologist and figure out the appropriate path.”

6.6 Cross-reference to Axis 4 master decision

Kidney status interacts strongly with T2D (§4) and CV (§5). The T2D + ASCVD + CKD triple overlap (Axes 2 + 3 + 4) is the most outcomes-evidence-rich Module 5 phenotype for semaglutide; the §14 master decision tree handles the triple overlap.

7. Hepatic status phenotype

7.1 Purpose and sub-phenotype taxonomy

Axis 5 — hepatic status — determines which Module 5 compounds carry MASH-relevant evidence and which compounds have specific hepatic-impairment dose-adjustment or contraindication considerations. The ESSENCE trial (Sanyal/Newsome 2025 NEJM, PMID 40305708; semaglutide in MASH F2/F3) is the load-bearing approved-indication trial as of 2026-05-13; survodutide LIVE-1 Phase 2 readout (Sanyal 2024 NEJM, PMID 38863223; 76% MASH histologic resolution in survodutide arm) supports continued investigational development; tirzepatide MASH Phase 3 program is in progress.

Four sub-phenotypes:

7.A — MASH F2/F3. Biopsy- or imaging-confirmed metabolic dysfunction-associated steatohepatitis with moderate-to-advanced fibrosis (NAS ≥4 with at least one each of steatosis, ballooning, lobular inflammation; fibrosis stage F2 or F3). The ESSENCE enrollment phenotype.
7.B — MASH F4 (cirrhosis). MASH with cirrhotic fibrosis. Pattern V critical: F4 is excluded from ESSENCE; Loomba 2023 Phase 2 (PMID 36934740) reported semaglutide directional finding toward placebo advantage on fibrosis improvement in F4 — direction-of-effect concern.
7.C — Fatty liver without fibrosis (MASLD / steatosis without steatohepatitis or fibrosis). Metabolic-dysfunction-associated steatotic liver disease without inflammation or fibrosis; the early-stage NAFLD/MASLD phenotype.
7.D — Normal hepatic. Normal liver function tests, no imaging evidence of steatosis; no hepatic-axis modification of compound selection.

7.2 Sub-phenotype 7.A — MASH F2/F3

Phenotype definition. Adult with biopsy- or imaging-confirmed MASH (NAS ≥4 with at least one each of steatosis, ballooning, lobular inflammation) and fibrosis stage F2 or F3. The 7.A phenotype is the ESSENCE enrollment phenotype.

First-line compound — trial-anchored options.

Semaglutide (Wegovy FDA-approved 2025 for MASH F2/F3 via ESSENCE). Trial anchor: ESSENCE (Sanyal/Newsome 2025 NEJM, PMID 40305708; NCT04822181; n=800 biopsy-proven MASH F2/F3 at 72 weeks). Both co-primary endpoints met: 62.9% MASH resolution without worsening fibrosis (vs 34.3% placebo) and 36.8% fibrosis improvement without worsening of steatohepatitis (vs 22.4%). FDA-approved for marketing claims for MASH with moderate-to-advanced fibrosis (F2–F3), August 15, 2025. Routes to [[Semaglutide Protocol]] §1.3 Indication 5.
Survodutide (investigational; LIVE-1 Phase 2 supportive). Trial anchor: LIVE-1 (Sanyal 2024 NEJM, PMID 38863223; survodutide MASH F2/F3 Phase 2 at 48 weeks): 76% MASH histologic resolution in survodutide arm vs 14% placebo. Pattern AA precision: investigational; Phase 3 program pending; not FDA-approved as of 2026-05-13. The magnitude of histologic resolution in survodutide LIVE-1 is striking and supports continued development; Phase 3 readout is the load-bearing future evidence. Routes to [[Survodutide Protocol]].
Tirzepatide (MASH Phase 3 program in progress; not FDA-approved for MASH as of 2026-05-13). Pattern AA precision: tirzepatide is FDA-approved for T2D, CWM, OSA-with-obesity, and HFpEF-with-obesity, but NOT for MASH — the MASH program is in progress. Do not state “FDA-approved for MASH.” Routes to [[Tirzepatide Protocol]] §1.3.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Histologic outcomes in MASH F2/F3: Survodutide LIVE-1 Phase 2 76% MASH resolution > Semaglutide ESSENCE 62.9% MASH resolution > placebo across both trials. Pattern V trial-comparison qualification: cross-trial comparison (different trials, different enrollments, different durations — 48 vs 72 weeks); a direct head-to-head survodutide vs semaglutide trial in MASH F2/F3 does not exist.
Regulatory state: Semaglutide FDA-approved for MASH F2/F3 (2025); Survodutide investigational pending Phase 3; Tirzepatide MASH Phase 3 pending.
Fibrosis improvement vs MASH resolution: ESSENCE co-primary endpoints included both; LIVE-1 reported MASH resolution prominently. The fibrosis-improvement endpoint is the harder regulatory endpoint and the more meaningful long-term outcome.
Outcomes evidence base beyond MASH: Semaglutide leads broadly across CV, kidney, MASH; survodutide is investigational across indications.
Weight loss in MASH F2/F3 phenotype: Both compounds produce significant weight loss; the weight-loss-mediated mechanism contributes to but does not entirely explain the MASH histologic improvement.
Hepatic-impairment dose-adjustment considerations: Semaglutide does not require dose adjustment for moderate hepatic impairment per label; severe hepatic impairment (Child-Pugh C) was excluded from ESSENCE; clinician judgment per [[Semaglutide Protocol]] §2.3.

Adjunct overlay (consider §11 visceral-fat overlay if visceral adiposity is prominent). MASH is frequently associated with high visceral adipose tissue burden; a tesamorelin-overlay-on-GLP-1-RA is a clinician-judgment off-label combination per Pattern Z Anchor 5.

Sequencing / transition logic.

The 7.A MASH F2/F3 patient who is GLP-1-RA-naive is initiated on semaglutide as the only FDA-approved compound for the indication as of 2026-05-13. The within-class switch to tirzepatide for the off-label-but-mechanistically-plausible MASH effect (pending Phase 3 readout) is a clinician-judgment off-label position; the within-class switch to survodutide is investigational-only. Hepatology co-management is appropriate for F3 fibrosis or above.

Pattern Z patient-counseling beat for 7.A (Anchor 4 verbatim-compliant).

“You have MASH with moderate-to-advanced fibrosis — F2 or F3 on biopsy or imaging. The FDA-approved treatment for your phenotype is semaglutide (Wegovy), based on the ESSENCE trial in your exact phenotype, which showed at 72 weeks about 63% of patients had MASH resolution without worsening fibrosis (vs 34% placebo) and about 37% had fibrosis improvement without worsening of steatohepatitis (vs 22% placebo) — both co-primary endpoints met. That’s the load-bearing on-label evidence. The investigational alternatives — survodutide with 76% MASH resolution in the LIVE-1 Phase 2, tirzepatide with the MASH Phase 3 in progress — are not FDA-approved yet, so the trial-anchored approved option is semaglutide. We’d manage this with hepatology co-management, baseline and follow-up imaging or biopsy, and the standard semaglutide titration with the MASH F2/F3 indication-specific monitoring. Let’s discuss your specific situation.”

7.3 Sub-phenotype 7.B — MASH F4 (cirrhosis)

Phenotype definition. Adult with MASH and cirrhotic fibrosis (F4 stage). The 7.B phenotype was excluded from the ESSENCE trial; semaglutide is NOT FDA-approved for F4 MASH (the 2025 label is F2/F3 only).

First-line compound — trial-anchored options with Pattern V critical flag.

Pattern V critical: Loomba 2023 Phase 2 in F4 cirrhosis (n=71; PMID 36934740) reported fibrosis improvement 11% semaglutide vs 29% placebo (p=0.087, NS but directionally toward placebo advantage). ESSENCE approval is F2/F3 only; F4 evidence does not support semaglutide for fibrosis improvement and the directional finding warrants caution in off-label F4 use. The Pattern V flag is load-bearing: direction-of-effect in F4 cirrhosis is at minimum not established and at worst suggests placebo advantage.

No compound in the Module 5 portfolio is FDA-approved for MASH F4 cirrhosis. Hepatology co-management with cirrhosis-specific care (HCC surveillance, portal hypertension management, varices surveillance, transplant evaluation as appropriate) is the foundational care path. Resmetirom (Rezdiffra; outside the Module 5 portfolio — it is a thyroid-hormone-receptor-β agonist) is FDA-approved 2024 for MASH F2/F3 (similar to semaglutide for F2/F3) but is also not approved for F4.
GLP-1 RA use in 7.B phenotype is clinician-judgment with explicit Pattern V framing. If the patient has concurrent T2D or obesity meeting on-label CWM criteria, the compound is being used for those on-label indications, not for the MASH F4 indication. The hepatology team is the primary decision-maker for cirrhosis management.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Regulatory state: No Module 5 compound FDA-approved for MASH F4. Semaglutide F2/F3 label does not extend to F4.
Direction-of-effect evidence (Pattern V critical): Loomba 2023 directional finding toward placebo advantage on fibrosis improvement in F4. The trial was small (n=71) and NS at the conventional 0.05 threshold, but the directional finding is concerning enough to flag for clinical caution.
Cirrhosis-specific care priorities: HCC surveillance, portal hypertension, varices, transplant evaluation, ascites and hepatic encephalopathy management — all outside the Module 5 pharmacotherapy portfolio.
GLP-1 RA for concurrent T2D / CWM with cirrhosis: Clinician-judgment; hepatology co-management essential.

Adjunct overlay (not applicable).

Pattern Z patient-counseling beat for 7.B (Anchor 5 off-label / extrapolation verbatim-compliant).

“You have MASH with cirrhotic fibrosis — F4 on biopsy or imaging. The ESSENCE trial that supported semaglutide’s FDA approval for MASH specifically excluded F4 cirrhosis; the approval is for F2 or F3 only. The earlier Loomba 2023 Phase 2 trial in F4 cirrhosis was small — about 71 patients — and showed a directional finding that was actually slightly worse than placebo on fibrosis improvement, not better. It didn’t reach statistical significance but the direction is concerning. So semaglutide is not approved for your phenotype and the F4-specific evidence we have suggests caution. The treatments with established benefit in cirrhosis — surveillance for liver cancer, management of portal hypertension and varices, transplant evaluation if appropriate, control of complications — are managed by the hepatology team. If you have concurrent diabetes or obesity meeting other indications, we can consider a GLP-1 medication for those, but the F4-specific MASH indication isn’t supported. Let’s discuss your specific situation with your hepatologist.”

7.4 Sub-phenotype 7.C — Fatty liver without fibrosis (MASLD / steatosis)

Phenotype definition. Adult with metabolic dysfunction-associated steatotic liver disease (MASLD) — imaging or biopsy evidence of hepatic steatosis without significant inflammation or fibrosis (NAS <4 or F0–F1 fibrosis). The 7.C phenotype is the early-stage MASLD phenotype; many obese and T2D patients have this without yet having progressed to MASH.

First-line compound — trial-anchored options.

CWM / T2D indication routes apply for 7.C. The 7.C phenotype is not itself an FDA-approved indication; the GLP-1 RA class produces hepatic steatosis reduction as a documented secondary effect in CWM and T2D phenotypes (semaglutide, tirzepatide, liraglutide trial-program sub-analyses). MASLD without fibrosis does not currently have a specific FDA-approved pharmacotherapy indication in the Module 5 portfolio.
Compound selection for 7.C follows the §3 / §4 routes (obesity / T2D status). Hepatic steatosis improvement is a documented secondary benefit.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 7.C phenotype’s distinguishing feature is the early-stage hepatic disease without specific indication. Compound selection routes through Axes 1 / 2 with the additional consideration that hepatic-steatosis improvement is a expected secondary benefit of any GLP-1 RA in this phenotype.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 7.C.

Routes to §3.2 (or §4.2 if T2D) counseling beat with hepatic-steatosis-improvement framed as expected secondary benefit.

7.5 Sub-phenotype 7.D — Normal hepatic

Phenotype definition. Adult with normal liver function tests, no imaging evidence of steatosis, no hepatic-axis modification of compound selection. Compound selection routes through §3 / §4.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Same as §3 / §4 — the hepatic axis does not modify selection.

Pattern Z patient-counseling beat for 7.D.

Routes to §3.2 (or §4.2 if T2D + obesity) counseling beat.

7.6 Cross-reference to Axis 5 master decision

Hepatic status interacts with T2D (§4) and obesity type (§3) for the polycondition phenotypes; MASH F2/F3 + T2D + obesity is a heavily-populated overlap in the ESSENCE trial. The §14 master decision tree handles the overlap.

8. Pre-conception planning phenotype

8.1 Purpose and sub-phenotype taxonomy

Axis 6 — pre-conception planning — is a time-sequenced axis that can override an otherwise-optimal compound selection. The GLP-1 RA class has labeled contraindications in pregnancy for CWM indications and is generally discontinued upon pregnancy awareness or planned pregnancy across all indications. The discontinuation half-life arithmetic determines the operational window: semaglutide elimination half-life ~7 days (~5 half-lives = ~35 days for substantial clearance; planned pregnancies typically require ~2-month washout per Novo Nordisk product label guidance); tirzepatide elimination half-life ~5 days; liraglutide elimination half-life ~13 hours; orforglipron elimination half-life ~29-49 hours; survodutide elimination half-life ~8 days; retatrutide elimination half-life ~6 days; cagrilintide elimination half-life ~7 days.

The Pattern Z calibration anchor 3 framing applies to this axis: lead with research-state human pregnancy-exposure data (Parker 2025 PMID 40329607: pooled review of unplanned-pregnancy exposures across the GLP-1 RA class shows reassuring early signal — congenital abnormality incidence appears relatively low in this pooled dataset; sample size is limited; prospective planned-pregnancy registries are ongoing) rather than leading with “contraindicated in pregnancy” defensive-medicine steering.

Three sub-phenotypes:

8.A — Actively trying to conceive within 12 months. The near-term TTC phenotype; discontinuation timing is operationally load-bearing.
8.B — Planning conception within 1-3 years. The medium-term planning phenotype; compound selection can incorporate pre-conception planning but is less time-pressured.
8.C — No conception planning. The non-TTC phenotype; reproductive-age females on contraception during treatment.

8.2 Sub-phenotype 8.A — Actively TTC within 12 months

Phenotype definition. Reproductive-age female (or transgender male with retained reproductive capacity) actively trying to conceive within 12 months. The TTC timeline drives the discontinuation arithmetic.

First-line compound — trial-anchored options with Pattern Z Anchor 3 framing.

The Pattern Z Anchor 3 framing leads with research-state data rather than defensive-medicine steering:

Human pregnancy-exposure data — Parker 2025 (PMID 40329607). Pooled review of unplanned pregnancies from FDA- and EMA-submitted GLP-1 RA regulatory clinical trials (semaglutide, liraglutide, dulaglutide, and class-related compounds): incidence of congenital abnormalities appears relatively low; sample size is limited; exposures are from unplanned-pregnancy contexts; prospective planned-pregnancy registries are ongoing.

Standard clinical practice when pregnancy is planned within 12 months:

Compound discontinuation timing. For long-half-life compounds (semaglutide, survodutide, retatrutide, cagrilintide, CagriSema, IcoSema, tirzepatide), plan ≥2-month washout before conception attempts to allow complete clearance. For shorter-half-life compounds (liraglutide ~13 hours; orforglipron ~29-49 hours), the washout window is shorter (typically ~1-2 weeks for liraglutide; ~1 week for orforglipron) but discontinuation upon planning is the standard practice.
Lifestyle and metabolic optimization during washout. Continue lifestyle intervention (nutrition, activity, sleep) and metabolic monitoring (HbA1c if T2D, BP if hypertensive) during washout. The expected weight regain trajectory during washout is anchored to the STEP-4 / SURMOUNT-4 withdrawal studies (semaglutide STEP-4 Rubino 2021 JAMA, PMID 33755728; tirzepatide SURMOUNT-4 Aronne 2024 JAMA, PMID 38078870) — significant weight regain typically occurs over the 4-12 months post-discontinuation.
Pregnancy-attempt counseling. Standard pre-conception counseling (folate, lifestyle, comorbidity optimization).

For T2D + TTC phenotype, the medication-management plan during pregnancy planning often transitions to insulin (the standard T2D-in-pregnancy therapy) before the conception attempt window opens. Routes to T2D-pregnancy management outside the Module 5 portfolio.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 8.A sub-phenotype’s distinguishing feature is the discontinuation timing. Compound selection in 8.A is not about choosing among the Module 5 compounds for continued therapy; it is about discontinuation arithmetic and the post-discontinuation management plan. The Pattern Z framing:

Half-life-driven washout windows: Semaglutide / Survodutide / Cagrilintide / CagriSema / Retatrutide / Tirzepatide / IcoSema: ~2-month washout (pre-conception). Orforglipron: ~1 week. Liraglutide: ~1-2 weeks.
Human pregnancy-exposure data: Parker 2025 pooled data shows reassuring early signal; not a basis for continued therapy through conception but contextually important for patient-counseling about inadvertent early-pregnancy exposure.
Post-discontinuation weight-regain trajectory: STEP-4 and SURMOUNT-4 withdrawal data; significant regain over 4-12 months.

Pattern Z patient-counseling beat for 8.A (Anchor 3 verbatim-compliant, research-state-leading).

“You’re trying to conceive within the next year. Here’s what we know. The published human pregnancy-exposure data — Parker 2025 pooled review across GLP-1 trials — shows reassuring early signal: congenital abnormality incidence appears relatively low in the unplanned-pregnancy exposures captured in the trial-program registries. Sample size is limited and prospective planned-pregnancy registries are ongoing. The standard clinical practice when conception is planned is to discontinue the medication and allow washout: semaglutide has about a 7-day half-life, so we’d want about 2 months of washout before conception attempts to allow complete clearance — that’s the package-label guidance. Tirzepatide has about a 5-day half-life with similar 2-month washout. Liraglutide and orforglipron are shorter half-lives with shorter washouts. During washout, we’d continue the lifestyle work and monitor your metabolic picture — there’s an expected weight-regain trajectory over the first 4-12 months off the medication, based on the STEP-4 and SURMOUNT-4 withdrawal data. If you have type 2 diabetes, we’d typically transition to insulin before conception, since insulin is the standard T2D-in-pregnancy therapy. Let’s plan the timeline together — what’s your target conception window, what other medications are involved, and what does your full pre-conception picture look like.”

8.3 Sub-phenotype 8.B — Planning conception within 1-3 years

Phenotype definition. Reproductive-age female with planned conception in the medium-term window (1-3 years). The 8.B phenotype permits compound use during the planning window with the eventual discontinuation timing as a planned event.

First-line compound — trial-anchored options.

Compound selection in 8.B follows the standard Axes 1-5 logic with the planning-window consideration that the compound will eventually be discontinued. Several practical considerations:

Half-life consideration may favor shorter-half-life compounds. If conception planning is at the 12-18 month horizon, a compound that requires a 2-month washout vs a 1-week washout is operationally similar. If conception planning is at the 3-year horizon, the half-life difference is less load-bearing.
Pre-conception weight-loss durability. The compound use during the planning window achieves a weight-loss state; the post-discontinuation regain trajectory (STEP-4, SURMOUNT-4) is a meaningful consideration — the patient may want to achieve weight loss, discontinue early, and consolidate the loss before conception, vs continue through the planning window and discontinue at washout-start.
Contraception during compound use. Contraception is appropriate during compound use in any reproductive-age patient until the washout is complete.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

The 8.B sub-phenotype’s distinguishing feature is the planning-window flexibility. Compound selection routes through standard axes; the additional consideration is the eventual discontinuation timeline and the post-discontinuation management plan.

Pattern Z patient-counseling beat for 8.B (Anchor 3 + Anchor 4 verbatim-compliant).

“You’re planning conception in the 1-3 year window. That gives us flexibility on the medication side. We can use the GLP-1 medication during the planning window for your weight or diabetes management, and then plan the washout — about 2 months for semaglutide or tirzepatide, shorter for liraglutide or orforglipron — to align with your conception target. The Parker 2025 pooled data on inadvertent early-pregnancy exposure is reassuring, but the standard practice is washout before planned conception. One question to consider is the post-discontinuation regain trajectory — STEP-4 and SURMOUNT-4 showed significant weight regain over 4-12 months after stopping. Some patients consolidate loss with sustained lifestyle work before stopping; others continue through the planning window and accept some regain after washout. Let’s discuss your timeline, your goals, and what fits your situation.”

8.4 Sub-phenotype 8.C — No conception planning

Phenotype definition. Reproductive-age female or post-reproductive-age female with no conception planning. Contraception is appropriate during compound use in reproductive-age patients. Compound selection routes through standard axes without pre-conception modification.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Same as standard axes; the Pattern Z Anchor 3 pregnancy framing applies for clinician-patient counseling about contraception during treatment.

Pattern Z patient-counseling beat for 8.C.

Routes to standard axis counseling beat with contraception-during-treatment counseling added per [[Semaglutide Protocol]] §8 (or analogous per-canonical) discontinuation framing.

8.5 Special case — oral contraceptive interactions with delayed gastric emptying

The GLP-1 RA class delays gastric emptying, which can affect absorption of orally-administered medications including oral contraceptives. For semaglutide, tirzepatide, and related compounds, the labeled guidance includes consideration of oral contraceptive efficacy during the titration period:

Tirzepatide label includes specific guidance: oral contraceptive efficacy may be reduced during initiation and dose escalation; non-oral contraception or backup method recommended for 4 weeks after initiation and 4 weeks after each dose escalation.
Semaglutide label has more general delayed-gastric-emptying caution; specific oral contraceptive efficacy reduction is less prominently labeled.

The Pattern AA precision applies: state the specific label guidance for each compound. The Pattern Z framing presents the operational consideration as fact (oral contraceptive efficacy considerations during titration) rather than as steering away from the compound.

8.6 Lactation considerations

Lactation-exposure data are research-state-incomplete across the Module 5 portfolio; semaglutide, tirzepatide, and related compounds are not used during breastfeeding per current product labels. The Pattern Z Anchor 3 framing applies: research-state-leading, not defensive-medicine-steering.

8.7 Cross-reference to Axis 6 master decision

Pre-conception planning is time-dominant — when the patient sits on Axis 6 with TTC ≤12 months, the discontinuation arithmetic typically overrides the otherwise-optimal compound selection from Axes 1-5. The §14 master decision tree handles this dominance.

9. Age-stage phenotype

9.1 Purpose and sub-phenotype taxonomy

Axis 7 — age-stage — is a regulatory-and-trial-enrollment-driven axis. Different compounds have different labeled-age ranges, different trial-program enrollments, and different age-specific safety considerations (developmental at the pediatric end; sarcopenia / lean-mass concern at the older-adult end; under-representation in registration trials at the very-old end).

Five sub-phenotypes:

9.A — Pediatric 10-12 years. Pre-adolescent pediatric phenotype; investigational across Module 5 portfolio (overlaps with §3.5 sub-phenotype 3.E).
9.B — Adolescent 12-17 years. The FDA-approved-adolescent-CWM phenotype (semaglutide Wegovy, liraglutide Saxenda; tirzepatide Phase 3 ongoing) — see §3.4 sub-phenotype 3.D.
9.C — Adult 18-65 years. The dominantly-enrolled phenotype across the Module 5 trial program. Compound selection routes through Axes 1-6 + §10 + §11.
9.D — Older adult 65-75 years. Enrolled across the program; lean-mass concern (§11) becomes increasingly load-bearing; sarcopenia risk during weight loss.
9.E — Very-old adult ≥75 years. Under-represented in registration trials (Pattern V flag); compound selection considers frailty, polypharmacy, lean-mass concern.

9.2 Sub-phenotype 9.A — Pediatric 10-12 years

Routes to §3.5 sub-phenotype 3.E — pediatric <12y. The Pattern Z Anchor 5 off-label / extrapolation framing applies; the trial-program evidence base is sparse for general pediatric obesity <12y.

9.3 Sub-phenotype 9.B — Adolescent 12-17 years

Routes to §3.5 sub-phenotype 3.D — pediatric ≥12y. Semaglutide (STEP TEENS 2022) and liraglutide (Saxenda 2020) FDA-approved; tirzepatide pediatric program in progress.

9.4 Sub-phenotype 9.C — Adult 18-65 years

The dominantly-enrolled phenotype. Compound selection routes through Axes 1-6 without age-specific modification.

Pattern Z patient-counseling beat. Routes to the relevant Axis-driven counseling beat (§3-8) based on the patient’s positioning.

9.5 Sub-phenotype 9.D — Older adult 65-75 years

Phenotype definition. Adult 65-75 years with CWM or T2D indication. The 9.D phenotype is enrolled across the Module 5 trial program — STEP, SURMOUNT, SURPASS, SUSTAIN, FLOW, SELECT all include older-adult sub-populations.

First-line compound — trial-anchored options.

Compound selection routes through Axes 1-6 with the additional consideration that lean-mass concern (§11) becomes increasingly load-bearing in this phenotype. Sarcopenia risk during caloric deficit is a documented concern in older adults; DEXA-monitored lean-mass loss may exceed the typical 20-25% proportion of total mass lost in the 9.D phenotype.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Trial-program enrollment: All major Module 5 compounds enrolled the 65-75 sub-population; effect-size data are generally consistent with the broader adult population. Specific sub-analyses by age are available in some trial reports (e.g., SELECT age sub-analysis).
Lean-mass consideration: Body-composition monitoring (§11 adjunct overlay) becomes more clinically meaningful in this phenotype.
Polypharmacy: Older adults are more likely to be on multiple medications; drug-interaction considerations are more prominent. The GLP-1 RA delayed-gastric-emptying effect on co-administered orally-administered medications (warfarin, levothyroxine, some immunosuppressants) is a concrete operational consideration.
Fall risk: Weight loss in older adults can be associated with fall risk if lean-mass loss is significant; resistance-training and protein-intake counseling per [[Liraglutide Protocol]] §11 (or analogous per-canonical) is appropriate.

Adjunct overlay (consider §11 lean-mass adjunct). If DEXA monitoring documents lean-mass loss >25-30% of total mass lost during active titration, the CJC-Ipamorelin / MOTS-c lean-mass adjunct is a clinician-judgment off-label overlay per Pattern Z Anchor 5.

Pattern Z patient-counseling beat for 9.D (Anchor 4 verbatim-compliant).

“You’re in the 65-75 age range, which is well-represented in the major weight-management trials — the effect-size data we have applies to you. The additional considerations at your age are lean-mass preservation during weight loss and any drug interactions with your other medications. The standard counseling is resistance training plus adequate protein intake — typically 1.0-1.2 grams per kilogram body weight per day — to minimize muscle loss. If we monitor with DEXA body composition and see lean-mass loss exceeding about 25-30% of total mass lost, there are adjunct options we can consider. For your other medications, the GLP-1 effect on stomach emptying can affect absorption of orally-administered drugs — warfarin, levothyroxine, immunosuppressants — so we’d review your full medication list and monitor as needed. Let’s discuss which compound fits your situation based on the other dimensions — comorbidities, route preference, access — and what monitoring would look like.”

9.6 Sub-phenotype 9.E — Very-old adult ≥75 years

Phenotype definition. Adult ≥75 years. The 9.E phenotype is under-represented in registration trials (Pattern V flag); trial-program enrollment typically had upper-age bounds at 75 or 80 depending on the specific trial.

First-line compound — trial-anchored options with Pattern V flag.

Compound selection in 9.E is clinician-judgment with explicit Pattern V framing. Effect-size and safety data in ≥75 are sparse; the trial-program extrapolation from the 65-75 sub-population is reasonable but the trial-population anchoring weakens.
Frailty assessment (Clinical Frailty Scale, sarcopenia screening, functional capacity assessment) is appropriate before initiation; frailty-mediated risk-benefit calculus is load-bearing.
Lean-mass concern is dominant; the §11 adjunct overlay is more commonly indicated.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Trial-evidence base: Sparse in ≥75; extrapolation from 65-75 reasonable but Pattern V flag.
Frailty and sarcopenia considerations: Dominant in this phenotype.
Polypharmacy: Common; drug-interaction profile careful review.
Functional-capacity priorities: Weight reduction goals balanced against function preservation.

Pattern Z patient-counseling beat for 9.E (Anchor 5 off-label / extrapolation verbatim-compliant).

“You’re 75 or older — and the major weight-management trials we have largely enrolled patients younger than that. So the effect-size data we have is extrapolated from the 65-75 group; whether the benefit and risk profile is the same in your age group is research-state-incomplete. The additional considerations at your age are frailty, lean-mass preservation, and how the weight-loss work fits with your overall functional and quality-of-life priorities. The standard counseling is resistance training and protein intake to preserve muscle; we’d typically monitor with DEXA body composition and have a lower threshold for the lean-mass adjunct options. For your other medications, the drug-interaction profile is something we’d review carefully. Some patients in your age range have weight-loss goals; others have function-preservation goals. Let’s discuss what matters most for your situation, what your priorities are, and what fits.”

9.7 Cross-reference to Axis 7 master decision

Age-stage interacts with body-composition (§11 — lean-mass concern is age-driven) and with pre-conception planning (§8 — only applies in reproductive-age females, so 9.B-9.D overlap with 8.A-8.C). The §14 master decision tree handles the interactions.

10. Route preference and cost-access phenotype

10.1 Purpose and sub-phenotype taxonomy

Axis 8 — route preference — and Axis 9 — cost / access — are patient-preference-and-feasibility dimensions that determine which compounds are operationally viable for the patient, independent of the trial-program-and-outcomes-evidence selection that the other axes drive. The Pattern Z framing of route and cost dimensions is fact-based — present the operational characteristics neutrally; do not steer.

Two sub-axes:

Axis 8 — Route preference: oral-only / weekly-SC-acceptable / daily-SC-acceptable / injection-averse
Axis 9 — Cost / access: insurance-covered / cash-pay / generic-supply-dependent

10.2 Sub-axis 8 — Route preference

10.2.1 Sub-phenotype 8.a — Oral-only preference

Phenotype definition. Patient prefers oral administration; injection (SC or IM) is not operationally viable due to patient preference, needle phobia, occupational limitations (e.g., transportation worker, military deployment), or other factors. The Pattern Z.injection-framing observation: self-injection is a routine clinical skill, not a daunting barrier; needle aversion can often be addressed with appropriate counseling and demonstration. Some patients have legitimate reasons for oral preference that warrant respect.

First-line compound — trial-anchored options.

Rybelsus (oral semaglutide 14 mg). FDA-approved 2019 for T2D. Trial anchor: PIONEER-1 through PIONEER-10. Effect-size anchor: PIONEER-3 oral semaglutide 14 mg vs sitagliptin demonstrated HbA1c reduction approximately 1.3 percentage points at 26 weeks. PIONEER PLUS (Aroda 2023, PMID 37385279) demonstrated oral 25/50 mg superiority over 14 mg. Operational: take daily on empty stomach with ≤120 mL water; wait 30 minutes before food/other meds; PPI co-administration considerations. Routes to [[Semaglutide Protocol]].
Oral Wegovy 25 mg. FDA-approved August 2025 for CWM. Trial anchor: OASIS 4 (Wharton 2025 NEJM, PMID 40934115; oral 25 mg for obesity): –13.6% treatment-policy / –16.6% adherent. Operational: same daily/fasting requirements as Rybelsus. Routes to [[Semaglutide Protocol]].
Orforglipron (investigational; FDA decision pending). Daily-oral small-molecule GLP-1 RA. Eli Lilly filed for FDA approval Q4 2025 for obesity (ATTAIN-1 Phase 3 readout, DOI 10.1056/NEJMoa2511774) and Q1 2026 for T2D (ATTAIN-2 readout). Not approved as of 2026-05-13 but the regulatory decision window is near-term. Operational advantage over Rybelsus / oral Wegovy: orforglipron is small-molecule, does not require fasting or PPI-avoidance considerations to the same degree (Pattern N.1 small-molecule path). Routes to [[Orforglipron Protocol]].

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Regulatory state: Rybelsus (T2D) and oral Wegovy 25 mg (CWM) FDA-approved; orforglipron filed-pending.
Magnitude: Oral Wegovy 25 mg (OASIS 4 –13.6% / –16.6%) > Rybelsus 14 mg (HbA1c oriented, not weight-oriented; PIONEER program) > orforglipron pending Phase 3-confirmation magnitude (ATTAIN-1 Phase 3 reported obesity effect size).
Operational simplicity: Orforglipron (small-molecule, no fasting requirement) > Rybelsus / oral Wegovy (fasting + 30-minute window required for absorption).
Cost / access: Rybelsus and oral Wegovy commercially available; orforglipron not yet available.

Adjunct overlay (none required by default).

Pattern Z patient-counseling beat for 10.2.1 (Anchor 4 + Z.injection-framing verbatim-compliant).

“You prefer oral medication. The FDA-approved oral options for our space are Rybelsus (oral semaglutide 14 mg) for type 2 diabetes — that’s been approved since 2019 — and oral Wegovy (oral semaglutide 25 mg) for chronic weight management, which was approved in August 2025. The OASIS 4 trial for oral Wegovy 25 mg showed about 13.6% weight loss in the treatment-policy analysis and 16.6% in the adherence analysis at the studied duration. Orforglipron is a daily-oral small-molecule that the FDA is currently reviewing — Eli Lilly filed in Q4 2025 for obesity and Q1 2026 for T2D, so the decision is near-term. The operational consideration for oral semaglutide (Rybelsus or oral Wegovy) is that you’d take it daily on an empty stomach with a small amount of water, then wait 30 minutes before food or other medications — that’s how the absorption works. Orforglipron, being a small-molecule, doesn’t have the same fasting requirement. Let me also share — many patients who initially feel uncertain about injection find that the once-weekly self-injection for Wegovy or Mounjaro is actually quite manageable; it’s a routine clinical skill we’d walk through together. If oral is what fits your situation best, the FDA-approved options are real and the magnitude is meaningful. Let’s discuss what works for you.”

10.2.2 Sub-phenotype 8.b — Weekly-SC-acceptable

Phenotype definition. Patient accepts subcutaneous self-injection on a weekly cadence. The 8.b phenotype is the dominantly-enrolled population for the Module 5 weekly-SC compounds (semaglutide, tirzepatide, retatrutide, survodutide, cagrilintide, CagriSema, IcoSema).

First-line compound — trial-anchored options.

All weekly-SC compounds are candidates. Compound selection routes through Axes 1-6 + Axis 9 (cost / access) + Axis 10 (body-composition).

10.2.3 Sub-phenotype 8.c — Daily-SC-acceptable

Phenotype definition. Patient accepts daily subcutaneous injection. The 8.c phenotype expands the candidate set to include liraglutide (daily-SC Victoza for T2D, Saxenda for CWM).

First-line compound — trial-anchored options.

Liraglutide (Victoza T2D / Saxenda CWM). FDA-approved daily-SC. Smaller magnitude than weekly-SC semaglutide or tirzepatide; LEADER CV-outcomes data for T2D + high CV risk; adolescent label for CWM ≥12y; off-patent in EU markets 2023 with generic competition emerging in US. Routes to [[Liraglutide Protocol]].

The 8.c sub-phenotype rarely positions liraglutide as preferred over weekly-SC semaglutide or tirzepatide on magnitude grounds; daily-SC is selected typically because of generic-access advantage (Axis 9) or specific clinical situations.

10.2.4 Sub-phenotype 8.d — Injection-averse

Phenotype definition. Patient is injection-averse but not strictly oral-only. The 8.d phenotype overlaps with 8.a; the Pattern Z.injection-framing applies — needle aversion is often addressable with counseling and demonstration.

Pattern Z patient-counseling beat for 8.d (Z.injection-framing verbatim-compliant).

“You’ve mentioned you’re uncomfortable with injection. That’s a common concern and I want to walk through what self-injection actually looks like. The weekly Wegovy or Mounjaro pen has a very thin needle and the injection is subcutaneous, so it’s just into the fat layer — not into muscle, not deep. Most patients find that after the first one or two, it becomes routine; it’s a clinical skill, not a daunting barrier. That said, if oral is what fits your situation, Rybelsus or oral Wegovy or — once it’s approved — orforglipron are real options. Let me show you what the pen looks like and walk through the injection technique; you can decide after that whether you want to try the weekly option or go with oral. Either path is reasonable.”

10.3 Sub-axis 9 — Cost / access

10.3.1 Sub-phenotype 9.a — Insurance-covered

Phenotype definition. Patient has insurance coverage that includes the GLP-1 RA class for the relevant indication. Coverage varies dramatically by indication (T2D coverage typically more robust than CWM coverage), by formulation (oral Wegovy vs injectable Wegovy), and by employer / payer policy.

Pattern Z framing. The 9.a sub-phenotype permits compound selection per Axes 1-6 + Axis 8 (route) without cost as a primary constraint. The Pattern Z framing presents the insurance landscape as fact; do not steer toward or away from any compound based on coverage assumptions that may not apply to the specific patient.

10.3.2 Sub-phenotype 9.b — Cash-pay

Phenotype definition. Patient pays out-of-pocket for the medication. Cash-pay sensitivity to monthly cost varies; the Module 5 branded weekly-SC compounds are typically $700-1,500 per month cash-pay; compounded alternatives (503A and 503B pathways) are typically $200-500 per month cash-pay.

Pattern Z Anchor 1 + 2 framing (compounded as real-world clinical option).

The Pattern Z calibration anchors 1 and 2 (compounded semaglutide / tirzepatide as real-world clinical options used by substantial patient populations under 503A and 503B pathways) apply to the cash-pay sub-phenotype. Compounded preparations are operational alternatives with specific characteristics (lyophilized vial requiring reconstitution; different manufacturing oversight pathway; different storage; quality varies across compounding pharmacies); standard clinician practice includes selecting pharmacies with documented sterility testing (USP <797>/<800>), per-batch certificates of analysis, cold-chain shipping, and state-licensure or FDA registration verification.

Pattern Z patient-counseling beat for 9.b (Anchor 1 + 2 verbatim-compliant).

“You’re paying cash, so cost is operationally load-bearing. The branded weekly options — Wegovy, Mounjaro, Zepbound — are typically $700-1,500 per month cash-pay. Compounded semaglutide and tirzepatide are real-world clinical options used by a substantial patient population, available through state-licensed compounding pharmacies (503A pathway) or FDA-registered outsourcing facilities (503B pathway), and typically $200-500 per month. Compounded preparations come in lyophilized vials that require reconstitution with bacteriostatic water — that’s an additional step compared to the pre-filled pen, but it’s a routine clinical skill we’d walk through together, similar to insulin self-injection. The operational differences from the branded products are real — different format, different oversight pathway, different storage windows — and quality varies across compounding pharmacies. If you’re considering it, let’s review the specific compounding pharmacy’s quality practices — sterility testing, certificates of analysis, accreditation — and walk through reconstitution training. That’s how the decision gets made well. Let’s discuss what fits your situation.”

10.3.3 Sub-phenotype 9.c — Generic-supply-dependent

Phenotype definition. Patient is dependent on generic-available medications. As of 2026-05-13, liraglutide is off-patent in EU markets (2023) with generic competition emerging in US; the weekly-SC semaglutide, tirzepatide, retatrutide, survodutide compounds are not generic-available in branded form (compounded alternatives exist under 503A / 503B per 9.b).

First-line compound — trial-anchored options.

Liraglutide (generic emerging). As generic liraglutide enters US markets, the daily-SC liraglutide becomes more cost-accessible. The magnitude (lower than weekly-SC alternatives) and daily-injection cadence are trade-offs against the cost advantage.

Pattern Z patient-counseling beat for 9.c (Anchor 4 verbatim-compliant).

“You need generic options. Liraglutide is the GLP-1 medication that’s currently transitioning to generic availability — off-patent in Europe since 2023, generic competition emerging in the US. It’s daily injection and lower magnitude than the weekly options like semaglutide or tirzepatide; the LEADER trial showed cardiovascular benefit in T2D plus high CV risk, and Saxenda is FDA-approved for chronic weight management. For weight loss in non-diabetic obesity, magnitude is typically around 6% greater than placebo — meaningful, but lower than the 14-22% range we see with the weekly options. If generic is the operational constraint, liraglutide is the path. Let’s discuss your specific situation, your weight or diabetes goals, and what fits.”

10.4 Cross-reference to Axes 8 and 9 master decision

Route preference and cost / access are patient-preference dimensions that frequently determine which of the candidate compounds is operationally viable. The §14 master decision tree integrates these axes with the clinical-evidence-driven selection from Axes 1-7.

11. Body-composition phenotype

11.1 Purpose and sub-phenotype taxonomy

Axis 10 — body-composition — is the adjunct-overlay axis. The Module 5 per-canonical compounds produce weight loss; the body-composition profile of that weight loss varies (lean-mass loss as a proportion of total mass lost typically 20-25% for unsupplemented GLP-1 RA weight loss, with variability driven by age, activity, baseline lean mass, protein intake, and individual phenotype). The 11 axis covers four sub-phenotypes where specific body-composition considerations drive adjunct-overlay decisions.

Four sub-phenotypes:

11.A — Lean-mass-preservation priority. Older adult (§9.D / 9.E overlap), athletic-population, or DEXA-documented baseline high lean mass; the lean-mass concern is dominant.
11.B — Visceral-fat priority. Central / visceral-adiposity-dominant phenotype where visceral fat is the primary therapeutic target (frequently overlaps with MASH §7, T2D §4, ASCVD §5).
11.C — General weight reduction. No specific body-composition concern; the default phenotype. No adjunct overlay required.
11.D — Post-weight-loss skin laxity. Patient who has completed ≥12 months of significant weight loss (≥15% body weight, BMI reduction ≥5 points) with documented post-weight-loss skin laxity disproportionate to age.

11.2 Sub-phenotype 11.A — Lean-mass-preservation priority

Phenotype definition. Patient with lean-mass-preservation as a primary therapeutic priority — typically older adult (≥65 years), athletic-population (resistance-trained, elevated baseline lean mass), or DEXA-documented baseline lean mass percentile in the high range for age and sex. DEXA monitoring during active titration shows lean-mass loss exceeding the typical 20-25% proportion of total mass lost.

First-line compound — per-canonical selection per Axes 1-6.

The 11.A phenotype does not change the per-canonical compound selection (the GLP-1 RA selection from Axes 1-6 stands); it adds the lean-mass adjunct overlay.

Adjunct overlay — CJC-1295 + Ipamorelin + MOTS-c (M5.6 stack).

The M5.6 lean-mass adjunct framework:

CJC-1295 (GHRH analog) + Ipamorelin (GH secretagogue). Mechanism rationale: GHRH-receptor agonism plus GH-secretagogue receptor agonism elevates endogenous growth hormone pulsatility, supporting lean-mass preservation during caloric deficit. The M5.6 v3 stack documents the standard dosing, IGF-1 monitoring cadence, and GH-secretagogue-class AE considerations. Pattern AA precision: CJC-1295 and Ipamorelin are not FDA-approved for lean-mass preservation in CWM context; this is clinician-judgment within informed-consent and primary-source-supported clinical reasoning (mechanism rationale + clinical-practice cohort data, not Phase 3 RCT for this specific indication).
MOTS-c (mitochondrially-encoded peptide). Mechanism rationale: metabolic-regulator activity in preclinical models; limited human Phase 1/2 data. Pattern AA precision: investigational; do not state “approved.” Clinician judgment.
Foundational adjuncts: Resistance training (2-3 sessions/week of progressive resistance work targeting major muscle groups) and protein intake 1.2-1.6 g/kg body weight per day are the foundational lean-mass-preservation interventions; they apply with or without the peptide adjunct overlay.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Foundational vs adjunct: Resistance training + protein optimization is the foundational intervention with the deepest evidence base; the peptide-adjunct overlay (CJC-Ipamorelin / MOTS-c) is layered on top, not as a replacement.
Regulatory state: CJC-Ipamorelin not FDA-approved for lean-mass preservation in CWM; MOTS-c investigational. Pattern AA precise framing.
Evidence base: M5.6 v3 clinical-practice cohort data and mechanism rationale; not Phase 3 RCT for this specific indication.
Monitoring: DEXA at 3 and 6 months on stack to track lean-mass trajectory; IGF-1 quarterly per the M5.6 stack monitoring framework.

Pattern Z patient-counseling beat for 11.A (Anchor 5 off-label / extrapolation verbatim-compliant).

“DEXA shows you’ve lost a significant portion of your weight as lean mass — more than the typical 20-25% range. The foundational interventions for this are resistance training, typically two to three sessions a week targeting major muscle groups, and protein intake at 1.2-1.6 grams per kilogram body weight per day. Those have the deepest evidence base for lean-mass preservation during caloric deficit. Beyond that, there’s a peptide-adjunct stack — CJC-1295 plus Ipamorelin, sometimes layered with MOTS-c — that engages the growth-hormone-secretagogue pathway. That stack is not FDA-approved for lean-mass preservation in weight-loss context; it’s clinician-judgment within informed-consent. The evidence base is mechanism rationale plus our clinical-practice cohort experience, not Phase 3 RCT for this specific indication. If we add it, we’d monitor with DEXA at 3 and 6 months and IGF-1 quarterly. Here’s what the evidence supports and what it doesn’t. Let’s discuss whether this fits your goals.”

11.3 Sub-phenotype 11.B — Visceral-fat priority

Phenotype definition. Patient with central / visceral-adiposity-dominant body composition (waist circumference ≥102 cm men / ≥88 cm women; DEXA visceral adipose tissue elevated; ectopic-fat-positive — hepatic steatosis, pancreatic steatosis, epicardial fat). The 11.B phenotype frequently overlaps with MASH (§7), T2D (§4), and ASCVD (§5) — visceral adiposity is a load-bearing component of these comorbidities.

First-line compound — per-canonical selection per Axes 1-6.

GLP-1 RA selection from Axes 1-6 stands; the adjunct overlay is layered on top.

Adjunct overlay — Tesamorelin + AOD-9604 (M5.5 stack).

Tesamorelin (Egrifta SV / Egrifta WR; BLA022505). FDA-approved for HIV-associated lipodystrophy (visceral adipose tissue reduction in HIV-infected adult patients with lipodystrophy). Off-label use for visceral adiposity in non-HIV populations is supported by mechanism rationale (GHRH-receptor-mediated pulsatile-GH-release driving visceral-adipose-tissue-selective lipolysis) plus the Falutz Phase 3 HIV program (NEJM 2007, PMID 18057338; AIDS 2008, PMID 18690162; JAIDS 2010, PMID 20101189) plus the Stanley 2014 JAMA hepatic-fat RCT (PMID 25038357). Pattern AA precision: “off-label use of an FDA-approved drug for non-HIV visceral adiposity” is the precise framing — operationally distinct from research-use-only or 503A-compounded preparations of non-FDA-approved compounds. The FDA label’s “weight neutral effect” limitation is mechanistically accurate: tesamorelin redistributes adipose tissue (VAT down, SAT modestly up, total weight neutral) — the clinical claim is visceral redistribution with metabolic benefit, not total-weight reduction. Off-label dosing 1-2 mg SC daily with 12-16-week cycles in non-HIV populations is the common practice posture.
AOD-9604 (development-discontinued). Pattern AA precision: “development-discontinued” is the accurate research-state framing — sponsor Metabolic Pharmaceuticals discontinued Phase 2b obesity development in 2007 after the program did not meet sponsor commercial development thresholds; not FDA-approved as a drug for any indication. The Australian TGA pathway listing for joint/cartilage as a complementary medicine ingredient is a distinct regulatory pathway from FDA drug approval. US clinical injectable use operates without FDA-approved-drug regulatory backing. The evidence base is preclinical (Level V) plus a Wilding 2004 narrative review (PMID 15134286) noting Phase IIa trials were underway in 2002.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Tesamorelin regulatory state: FDA-approved for HIV-associated lipodystrophy; off-label for non-HIV visceral adiposity.
AOD-9604 regulatory state: Development-discontinued; not FDA-approved; preclinical-evidence-base for current use.
Mechanism rationale: Tesamorelin GHRH agonism with established visceral-fat-selective lipolysis from Falutz program; AOD-9604 mechanism rationale (hGH 176-191 fragment lipolytic activity) is preclinical-supported and limited.
Evidence base depth: Tesamorelin has Level I evidence (Phase 3 in HIV-lipodystrophy population) plus mechanism-rationale extrapolation to non-HIV visceral adiposity; AOD-9604 has Level V preclinical evidence plus a 2002-era Phase IIa note in a 2004 narrative review.
Foundational interventions: Caloric deficit, physical activity (especially activity that mobilizes ectopic fat), and metabolic-comorbidity management (T2D, MASH, ASCVD-anchored therapies) are foundational; the visceral-fat adjunct is layered on top of foundational care.

Pattern Z patient-counseling beat for 11.B (Anchor 5 off-label / extrapolation verbatim-compliant).

“Your body composition shows visceral-fat dominance — central abdominal fat, possibly with fatty liver or other ectopic fat. The foundational interventions are the GLP-1 medication you’re on for overall weight management plus physical activity and metabolic-comorbidity management. Beyond that, there’s a visceral-fat-targeted adjunct option: tesamorelin. Tesamorelin is FDA-approved for HIV-associated lipodystrophy — that’s the on-label indication. Its use for visceral adiposity in non-HIV populations is off-label use of an FDA-approved drug; the mechanism rationale is GHRH-receptor agonism driving visceral-fat-selective lipolysis, supported by the Falutz Phase 3 program in HIV-lipodystrophy and the Stanley 2014 JAMA hepatic-fat trial. The FDA label has an explicit ‘weight neutral effect’ limitation — tesamorelin redistributes fat (visceral down, subcutaneous modestly up, total weight unchanged), so the clinical claim is visceral redistribution with metabolic benefit, not weight loss. Combined with your GLP-1 medication, the additive effect is visceral-targeted plus overall weight-reducing. AOD-9604 is sometimes brought up — that compound’s obesity development was discontinued by the sponsor in 2007, so it’s not ‘emerging,’ it’s ‘development-discontinued.’ The evidence base is preclinical, limited; I’d be honest about that gap. Let’s discuss your specific situation, your visceral-fat picture, and whether the tesamorelin overlay fits your goals.”

11.4 Sub-phenotype 11.C — General weight reduction

Phenotype definition. No specific body-composition concern; the default phenotype. The per-canonical GLP-1 RA carries the primary phenotype response without adjunct overlay.

First-line compound — per-canonical selection per Axes 1-6. No adjunct overlay required.

11.5 Sub-phenotype 11.D — Post-weight-loss skin laxity

Phenotype definition. Patient who has completed ≥12 months of significant weight loss (≥15% body weight, BMI reduction ≥5 points) with documented post-weight-loss skin laxity disproportionate to age. The 11.D phenotype is downstream of the active weight-loss phase — it presents in maintenance or post-maintenance, when the skin-elasticity recovery has not kept pace with the volume reduction.

Adjunct overlay — GHK-Cu (M5.7 framework).

GHK-Cu (glycyl-histidyl-lysine copper tripeptide). Used topically and as an injectable for skin elasticity and post-weight-loss skin tone. Trial-program data are limited for the post-weight-loss-skin indication specifically; not FDA-approved as a drug for skin laxity. Pattern V direction-of-effect: clinical-effect magnitude is patient-anchored-expectation-driven; mechanism rationale (copper-binding for matrix-metalloproteinase modulation; collagen / elastin signaling) is preclinical-and-mechanism-supported, not Phase 3 RCT-supported for the indication.

Pattern Z Anchor 4 multi-dimensional comparator presentation.

Regulatory state: GHK-Cu not FDA-approved as a drug for skin laxity. Topical and injectable preparations available through cosmetic-and-wellness channels with regulatory pathway-dependent oversight.
Evidence base: Mechanism rationale plus preclinical and limited clinical data; not Phase 3 RCT for the post-weight-loss-skin indication.
Alternative interventions: Body-contouring surgery (abdominoplasty, brachioplasty, thigh lift, gluteal lift) is the established intervention for significant post-weight-loss skin laxity; cosmetic-dermatology procedures (radiofrequency, ultrasound, etc.) are intermediate options. The GHK-Cu adjunct is a relatively low-magnitude option in the post-weight-loss-skin space.
Patient-expectation calibration: Pattern Z framing — the patient-expectation for GHK-Cu should be calibrated to the limited evidence base; significant laxity (Class III obesity post-weight-loss) is typically not adequately addressed by topical or injectable peptide adjuncts alone.

Pattern Z patient-counseling beat for 11.D (Anchor 5 off-label / extrapolation verbatim-compliant).

“You’ve achieved significant weight loss and you have post-weight-loss skin laxity that hasn’t recovered to where you’d hoped. The options here vary widely in magnitude. Body-contouring surgery — abdominoplasty, brachioplasty, depending on what area is the priority — is the established intervention with the most predictable result; that’s a surgical decision with surgical risks and recovery. Cosmetic-dermatology procedures — radiofrequency, ultrasound, microneedling — are intermediate options. Peptide adjuncts like GHK-Cu, topical or injectable, have a mechanism rationale (copper-binding modulating collagen and elastin signaling) but the evidence base is preclinical and limited clinical; it’s not FDA-approved as a drug for skin laxity. The patient-expectation calibration matters: significant laxity from substantial weight loss isn’t usually fully addressed by peptide adjuncts alone. If the laxity is moderate and the goal is incremental improvement, GHK-Cu can be a reasonable adjunct; if the goal is significant volumetric change, surgical or procedural options are likely more aligned. Let’s discuss your specific situation, what bothers you, and what the realistic options look like.”

11.6 Cross-reference to Axis 10 master decision

Body-composition is an overlay axis — it does not displace per-canonical compound selection but adds adjunct overlays for the specific body-composition phenotypes. The §14 master decision tree handles the overlay logic.

12. Cross-phenotype combination decision logic

12.1 Purpose

The Module 5 patient is rarely characterized by one phenotype-axis. The typical Module 5 patient sits on 3-6 of the ten axes simultaneously. The cross-phenotype combination decision logic walks through how to reconcile axis-recommendations when they point to different first-line compounds.

The combination logic is structured by axis-dominance hierarchy. Pre-conception planning (Axis 6) within 12 months is time-dominant — it overrides otherwise-optimal compound selection. Regulatory state (Pattern AA precision) — investigational compounds are not available outside trial enrollment, regardless of phenotype-fit. Comorbidity-driven outcomes-evidence (Axes 3, 4, 5) frequently determines the compound where multiple compounds are otherwise candidates. Magnitude (Axes 1, 2, 11) is load-bearing for some phenotypes but not for others.

12.2 The dominant cross-phenotype combinations

The §12 sub-sections walk through the most common cross-phenotype combinations seen in Module 5 practice.

12.2.1 T2D + obesity + ASCVD (Axes 2 + 1 + 3)

Phenotype definition. Adult with T2D + obesity (BMI ≥27 with T2D as comorbidity) + established ASCVD. The triple-overlap is heavily populated across the Module 5 trial program.

First-line compound — multi-dimensional decision.

Semaglutide carries the deepest outcomes-evidence base: SUSTAIN-6 (T2D + established CVD; HR 0.74), SELECT (BMI ≥27 + established CVD without diabetes; HR 0.80), SOUL (oral; T2D + ASCVD/CKD; 14% MACE reduction). The triple overlap is heavily populated in the semaglutide program.
Tirzepatide has SURMOUNT-2 for T2D + obesity (–13.4-15.7%) and SURPASS-2 head-to-head vs semaglutide favoring tirzepatide on HbA1c; tirzepatide CV-outcomes trials (SURMOUNT-MMO, SURPASS-CVOT) are in progress with readouts pending. As of 2026-05-13, the CV-outcomes-evidence advantage favors semaglutide for the established-ASCVD layer.
Liraglutide has LEADER (T2D + high CV risk; HR 0.87) — smaller magnitude than semaglutide CV trials and lower weight-loss magnitude.

Decision routing. First-line semaglutide for the triple overlap based on CV-outcomes-evidence dominance. If glycemic control is sub-optimal on maximum-tolerated semaglutide and CV-outcomes-evidence-rich therapy is established, within-class switch to tirzepatide for the magnitude advantage on glycemic control is a reasonable consideration (with the understanding that the CV-outcomes-evidence-advantage on tirzepatide is pending). Routes to [[Semaglutide Protocol]].

12.2.2 T2D + obesity + CKD (Axes 2 + 1 + 4)

Phenotype definition. Adult with T2D + obesity + CKD stage 3-4. FLOW (semaglutide; Perkovic 2024 NEJM, PMID 38785209; T2D + CKD eGFR 25–75; HR 0.76 kidney composite + CV death) is the load-bearing trial.

First-line compound. Semaglutide. The FLOW evidence base anchors the decision. SGLT2 inhibitor background therapy (per current KDIGO guidelines for CKD in T2D) plus RAS blockade at maximally tolerated dose plus GLP-1 RA is the modern first-line for the polycondition. Routes to [[Semaglutide Protocol]].

12.2.3 T2D + obesity + ASCVD + CKD (Axes 2 + 1 + 3 + 4)

Phenotype definition. The quadruple overlap. Semaglutide is heavily anchored across SUSTAIN-6 + SELECT + FLOW + SOUL. The §14 master decision tree places this quadruple overlap as the semaglutide-anchored phenotype.

First-line compound. Semaglutide (multiple FDA-approved indications across the overlap). Routes to [[Semaglutide Protocol]].

12.2.4 T2D + obesity + MASH F2/F3 (Axes 2 + 1 + 5)

Phenotype definition. Adult with T2D + obesity + biopsy- or imaging-confirmed MASH F2/F3. ESSENCE (Sanyal/Newsome 2025 NEJM, PMID 40305708) anchors semaglutide for the MASH F2/F3 indication.

First-line compound. Semaglutide (FDA-approved across T2D, CWM, and MASH F2/F3 — the only compound with the triple-indication overlap as of 2026-05-13). Routes to [[Semaglutide Protocol]].

12.2.5 Obesity + HFpEF (Axes 1 + 3 HFpEF sub-phenotype)

Phenotype definition. Adult with obesity + HFpEF (LVEF ≥50%). SUMMIT (tirzepatide; Packer 2025 NEJM, PMID 39555827) anchors tirzepatide for HFpEF + obesity.

First-line compound. Tirzepatide (FDA-approved 2025 for HFpEF + obesity). Routes to [[Tirzepatide Protocol]]. Semaglutide STEP-HFpEF supportive but label expansion pending.

12.2.6 Obesity + OSA (Axes 1 + OSA-with-obesity sub-phenotype)

Phenotype definition. Adult with obesity + obstructive sleep apnea. SURMOUNT-OSA anchors tirzepatide for OSA-with-obesity (FDA-approved 2024).

First-line compound. Tirzepatide (FDA-approved for OSA-with-obesity). Routes to [[Tirzepatide Protocol]].

12.2.7 TTC (within 12 months) + any other axis

Phenotype definition. Reproductive-age female with TTC within 12 months on any combination of Axes 1-5. Axis 6 is time-dominant; the otherwise-optimal compound is discontinued per the §8 half-life washout arithmetic. For T2D + TTC, transition to insulin (the standard T2D-in-pregnancy therapy) is the standard practice. For CWM + TTC, the discontinuation is preparatory to conception attempts; lifestyle intervention continues.

First-line compound. Discontinuation + post-discontinuation management plan. Routes to relevant per-canonical §8 discontinuation section.

12.2.8 Adolescent ≥12 + obesity (Axes 7 + 1)

Phenotype definition. Adolescent 12-17 years with obesity at 95th percentile or greater BMI. Semaglutide STEP TEENS (2022) and Liraglutide Saxenda adolescent (2020) FDA-approved.

First-line compound. Semaglutide (larger magnitude per STEP TEENS) or Liraglutide (daily-SC option). Tirzepatide pediatric program in progress; not yet approved. Routes to [[Semaglutide Protocol]] or [[Liraglutide Protocol]].

12.2.9 Oral-only preference + any other axis

Phenotype definition. Patient preferring oral administration on any other phenotype combination. Axis 8 oral preference dominates the route dimension.

First-line compound. Rybelsus (oral semaglutide 14 mg for T2D) or oral Wegovy 25 mg (for CWM) or — if/when FDA-approved — orforglipron. The magnitude and outcomes-evidence dimensions apply within the oral candidate set.

12.2.10 Class III obesity (BMI ≥40) + bariatric-surgery consideration

Phenotype definition. Adult with BMI ≥40 (Class III obesity) considering pharmacotherapy vs bariatric surgery. The pharmacotherapy vs surgery framing is a multi-dimensional comparator (magnitude, durability, surgical-risk profile, anatomic considerations, post-operative nutritional management, patient preference). Pharmacotherapy and surgery are not mutually exclusive — sequential, combination, and salvage use are all clinical patterns.

First-line decision routing. Multi-disciplinary consultation including bariatric-surgery evaluation; if pharmacotherapy-first selected, retatrutide (pending Phase 3) or tirzepatide (SURMOUNT-1) or CagriSema (REDEFINE-1) are the magnitude-leading FDA-approved-or-near-approved options.

12.3 The cross-phenotype reconciliation matrix

When axes point to different first-line compounds, the reconciliation logic:

Axis 6 (pre-conception planning) within 12 months is time-dominant. Override otherwise-optimal selection; discontinuation arithmetic applies.
Pattern AA regulatory state filters the candidate set. Investigational compounds (retatrutide, CagriSema, IcoSema, survodutide, cagrilintide-monotherapy, orforglipron-pre-approval) are not available outside trial enrollment; they are noted as future options but do not anchor the current decision unless trial-enrollment is operationally feasible.
Comorbidity-driven outcomes-evidence dominates when established. Semaglutide for ASCVD (SUSTAIN-6, SELECT, SOUL), for CKD in T2D (FLOW), for MASH F2/F3 (ESSENCE). Tirzepatide for HFpEF + obesity (SUMMIT) and OSA + obesity (SURMOUNT-OSA).
Magnitude advantage from head-to-head data applies within the same-indication candidate set. SURMOUNT-5 (tirzepatide vs semaglutide for CWM) and SURPASS-2 (tirzepatide vs semaglutide for T2D HbA1c) — tirzepatide modestly larger on weight magnitude and HbA1c reduction in these head-to-heads.
Route preference (Axis 8) and cost / access (Axis 9) determine operational viability. If the clinical-evidence-driven selection is operationally infeasible (e.g., oral-only patient and the selected weekly-SC compound), the route- and cost-feasible alternative within the candidate set is selected.
Body-composition (Axis 11) drives adjunct-overlay decisions. Does not displace per-canonical selection; adds lean-mass / visceral / post-weight-loss-skin overlay.

12.4 Cross-phenotype patient-counseling discipline

For patients on multiple phenotype-axes, the patient-counseling beat applies the Pattern Z Anchor 4 framing across the dimensions that matter most to the patient:

“You sit on several dimensions at once — [list patient’s positioning]. Here’s how I think about your situation. The [comorbidity that drives outcomes-evidence-base selection] favors [compound] based on [specific trial]. The [body-composition or other secondary concern] adds [adjunct or monitoring layer]. The [magnitude or route or cost consideration] matters for [reason]. Here are the dimensions; let’s discuss which factor matters most for your situation and what fits.”

The patient-counseling beat does not collapse the multi-dimensional complexity into a single “best” recommendation; it presents the dimensions and routes the decision to the clinician-patient dyad.

13. Pattern Z patient-counseling beat library — one per phenotype-axis

13.1 Purpose

This section collates the Pattern Z patient-counseling beats from §3-§12 into a single library, organized by phenotype-axis, for clinician quick-reference. Each beat is verbatim-anchor-compliant per /Internal/Module-5-Pipeline/pattern-z-calibration-anchor.md — Anchor 4 (multi-dimensional comparator) dominantly; Anchor 1 + 2 (compounded as real-world clinical option) for cash-pay / cost discussions; Anchor 3 (research-state-leading for pregnancy); Anchor 5 (off-label / extrapolation transparency) for adjunct and investigational uses.

The discipline: every beat opens with affirmation, presents multi-dimensional facts with primary-source anchoring, acknowledges advantages on any dimension explicitly, and closes with shared-decision-making invitation. No beat opens with what an option ISN’T. No beat steers toward a single conclusion. No beat dismisses a patient’s question.

13.2 Axis 1 — Obesity type counseling beats

3.A / 4.D — BMI ≥30 without comorbidity: §3.2 — multi-dimensional comparator across tirzepatide, semaglutide, retatrutide (investigational); SURMOUNT-5 head-to-head; NAION class-differentiation; route, cost, access.

3.B — BMI ≥27 with one comorbidity: §3.3 — Anchor 4 framing routed through the specific comorbidity dimension (cross-references §4-7).

3.C — Class III obesity: §3.4 — magnitude framing across approved (tirzepatide, semaglutide HD) and investigational (retatrutide, CagriSema) options; bariatric-surgery comparator presented.

3.D — Adolescent ≥12: §3.5 — semaglutide STEP TEENS magnitude vs liraglutide adolescent; tirzepatide pediatric pending; daily vs weekly route; structured-lifestyle-intervention framework.

3.E — Pediatric <12: §3.6 — Anchor 5 framing on investigational status and sparse evidence base; monogenic-obesity routing.

13.3 Axis 2 — T2D status counseling beats

4.A — T2D + obesity: §4.2 — Anchor 4 framing across tirzepatide (SURPASS-2 HbA1c advantage; SURMOUNT-OSA, SUMMIT add-ons), semaglutide (SUSTAIN-6, SELECT, SOUL, FLOW, ESSENCE outcomes evidence depth), oral options, investigational pipeline.

4.B — T2D without obesity: §4.3 — HbA1c-focused framing; weight loss as secondary; hypoglycemia risk on concurrent insulin / sulfonylurea.

4.C — Prediabetes: §4.4 — T2D-prevention dimension explicit (SCALE liraglutide ~80% T2D incidence reduction; STEP / SURMOUNT sub-analyses).

4.D — No diabetes: §4.5 — routes to §3.2 BMI ≥30 without comorbidity beat.

13.4 Axis 3 — Cardiovascular history counseling beats

5.A — Established ASCVD: §5.2 — Anchor 4 framing on CV-outcomes-evidence depth (semaglutide SUSTAIN-6 / SELECT / SOUL / 4-trial pooled HF; liraglutide LEADER; tirzepatide CV trials pending); NAION pre-treatment ophthalmologic check.

5.B — HFpEF + obesity: §5.3 — Anchor 4 framing across tirzepatide (SUMMIT FDA-approved 2025) and semaglutide (STEP-HFpEF supportive Phase 3 data, label expansion pending — Pattern AA precision).

5.C — HFrEF: §5.4 — Anchor 5 framing on research-state-incomplete direction-of-effect; established HFrEF therapies (SGLT2i, sacubitril/valsartan, beta-blockers, MRA) outside Module 5 portfolio.

5.D — High CV risk without established disease: §5.5 — Anchor 5 framing on extrapolation from established-disease trials; comprehensive risk reduction is foundational.

5.E — No CV history: §5.6 — routes to Axis 1 / 2 beat.

13.5 Axis 4 — Kidney status counseling beats

6.A — CKD 3-4 in T2D: §6.2 — Anchor 4 framing on FLOW (semaglutide HR 0.76 kidney composite + CV death; trial stopped early for efficacy); SGLT2 + RAS + GLP-1 RA layered approach.

6.B — Proteinuric kidney disease: §6.3 — routes to 6.A FLOW-anchored beat.

6.C — Normal kidney function: §6.4 — routes to Axis 1 / 2 beat.

6.D — Kidney transplant: §6.5 — Anchor 5 framing on transplant-recipient exclusion from Phase 3 enrollment; nephrology / transplant team co-management essential.

13.6 Axis 5 — Hepatic status counseling beats

7.A — MASH F2/F3: §7.2 — Anchor 4 framing on ESSENCE (semaglutide FDA-approved 2025 for MASH F2/F3); survodutide LIVE-1 Phase 2 supportive but investigational; tirzepatide MASH Phase 3 pending; hepatology co-management.

7.B — MASH F4 cirrhosis: §7.3 — Anchor 5 framing on Pattern V critical (Loomba 2023 directional finding toward placebo); cirrhosis-specific care outside Module 5 portfolio; hepatology lead.

7.C — Fatty liver without fibrosis (MASLD): §7.4 — hepatic-steatosis improvement as expected secondary benefit; compound selection routes through Axes 1 / 2.

7.D — Normal hepatic: §7.5 — routes to Axis 1 / 2 beat.

13.7 Axis 6 — Pre-conception planning counseling beats

8.A — TTC ≤12 months: §8.2 — Anchor 3 verbatim-compliant beat leading with Parker 2025 research-state pregnancy-exposure data; half-life-driven washout arithmetic (~2 months for long-half-life compounds); STEP-4 / SURMOUNT-4 post-discontinuation regain trajectory; T2D-in-pregnancy insulin transition.

8.B — Planning 1-3 years: §8.3 — flexibility on medication use during planning window; eventual discontinuation timing aligned to conception target; contraception during compound use.

8.C — No planning: §8.4 — contraception during treatment counseling per per-canonical §8.

Special — Oral contraceptive interactions: §8.5 — Pattern AA precision on tirzepatide-label-specific oral-contraceptive efficacy guidance; non-oral or backup contraception during initiation and dose escalation.

Special — Lactation: §8.6 — Anchor 3 framing; not used during breastfeeding per current labels; research-state-incomplete.

13.8 Axis 7 — Age-stage counseling beats

9.A — 10-12 years: §9.2 — routes to §3.5 pediatric <12y Anchor 5 framing.

9.B — 12-17 years: §9.3 — routes to §3.4 adolescent Anchor 4 framing.

9.C — 18-65 years: §9.4 — routes to Axis-driven counseling beat without age-specific modification.

9.D — 65-75 years: §9.5 — lean-mass concern, polypharmacy, fall risk; DEXA monitoring; resistance training and protein optimization.

9.E — ≥75 years: §9.6 — Anchor 5 framing on under-representation in registration trials; frailty assessment; function-preservation priorities.

13.9 Axes 8 + 9 — Route preference and cost / access counseling beats

8.a — Oral-only preference: §10.2.1 — Anchor 4 + Z.injection-framing; Rybelsus / oral Wegovy / orforglipron-pending; demonstration of self-injection as a routine clinical skill.

8.b — Weekly-SC-acceptable: §10.2.2 — full candidate set; routes to Axis-driven selection.

8.c — Daily-SC-acceptable: §10.2.3 — liraglutide as generic-emerging option; magnitude trade-off vs weekly-SC.

8.d — Injection-averse: §10.2.4 — Z.injection-framing; demonstration; oral options as alternative.

9.a — Insurance-covered: §10.3.1 — full candidate set; coverage varies by indication, formulation, employer/payer.

9.b — Cash-pay: §10.3.2 — Anchor 1 + 2 verbatim-compliant on compounded as real-world clinical option used by substantial patient population (503A / 503B pathways); quality-criteria evaluation of compounding pharmacies.

9.c — Generic-supply-dependent: §10.3.3 — liraglutide off-patent in EU 2023; generic competition emerging in US; magnitude trade-off vs weekly-SC.

13.10 Axis 10 — Body-composition counseling beats

11.A — Lean-mass-preservation priority: §11.2 — Anchor 5 framing on CJC-Ipamorelin / MOTS-c off-label adjunct stack; foundational resistance training + protein optimization; DEXA + IGF-1 monitoring.

11.B — Visceral-fat priority: §11.3 — Anchor 5 framing on tesamorelin off-label-for-non-HIV-visceral-adiposity (FDA-approved for HIV lipodystrophy; off-label use of FDA-approved drug); AOD-9604 development-discontinued Pattern AA framing.

11.C — General weight reduction: routes to Axis-driven beat; no adjunct overlay.

11.D — Post-weight-loss skin laxity: §11.5 — Anchor 5 framing on GHK-Cu limited evidence base; body-contouring surgery as established higher-magnitude option; patient-expectation calibration.

13.11 Cross-phenotype patient-counseling discipline

Per §12.4, the multi-axis patient receives a counseling beat that presents the dimensions across which the patient is positioned and routes the decision to the clinician-patient dyad. The cross-phenotype beat does not collapse complexity into a single “best” recommendation.

14. Module-master clinical decision tree (one-page integrative reference)

14.1 Purpose

The §14 master decision tree is the one-page integrative reference for clinician use at point of care when the patient is positioned on multiple axes and the full §3-§12 read is not operationally feasible. It synthesizes the axis-by-axis decisions from §3-§11 with the cross-phenotype combinations from §12 into a navigation structure organized by dominant clinical phenotype.

The master tree is structured as a triage matrix: identify the patient’s dominant axis-positioning; route to the cross-phenotype combination from §12.2; identify any overriding axis dominance (pre-conception, regulatory state, route / cost feasibility); select the per-canonical compound; route to the per-canonical protocol for operational §1-12 detail.

14.2 Master decision tree — text form

=============================================================================
MODULE 5 PHENOTYPE-GUIDED DECISION TREE — MASTER REFERENCE (v1.0, 2026-05-13)
=============================================================================

STEP 1: TIME-DOMINANT OVERRIDE CHECK

  ┌─ Pre-conception planning ≤12 months? (Axis 6 - §8.A)
  │
  ├─ YES → Discontinuation arithmetic per §8; transition to insulin if T2D;
  │         post-discontinuation regain trajectory (STEP-4 / SURMOUNT-4 data);
  │         lifestyle continuity. STOP — do not proceed to compound selection.
  │
  └─ NO → Proceed to STEP 2.

STEP 2: REGULATORY-STATE FILTER

  ┌─ Patient enrollable in active Phase 3 trial? (retatrutide TRIUMPH;
  │   CagriSema REDEFINE; survodutide SYNCHRONIZE / LIVE-2; etc.)
  │
  ├─ YES, and trial enrollment is operationally feasible → consider trial
  │   enrollment as one option. Continue evaluating commercially-available
  │   options in parallel.
  │
  └─ Default → restrict candidate set to FDA-approved compounds for the
      relevant indication plus filed-pending where the regulatory decision
      window is near-term and clinical-judgment use is appropriate.

STEP 3: DOMINANT COMORBIDITY-DRIVEN OUTCOMES-EVIDENCE ROUTING

  Identify the patient's CV / kidney / hepatic / OSA / HFpEF positioning:

  ┌─ T2D + ASCVD + CKD (Axes 2+3+4) — semaglutide (SUSTAIN-6 + SELECT +
  │    SOUL + FLOW). Route to [[Semaglutide Protocol]].
  │
  ├─ T2D + obesity + MASH F2/F3 (Axes 2+1+5) — semaglutide (ESSENCE).
  │    Route to [[Semaglutide Protocol]].
  │
  ├─ Obesity + HFpEF (Axes 1+3 HFpEF) — tirzepatide (SUMMIT 2025).
  │    Route to [[Tirzepatide Protocol]].
  │
  ├─ Obesity + OSA (Axes 1+OSA) — tirzepatide (SURMOUNT-OSA 2024).
  │    Route to [[Tirzepatide Protocol]].
  │
  ├─ T2D + obesity, no specific comorbidity overlay (Axes 2+1) —
  │    multi-dimensional comparator across tirzepatide (SURPASS-2 HbA1c
  │    advantage; SURMOUNT-2 magnitude advantage) vs semaglutide
  │    (outcomes-evidence depth). Routes to either per-canonical protocol
  │    based on which dimension matters most for the patient.
  │
  ├─ ASCVD without diabetes + BMI ≥27 (Axes 3+1 SELECT phenotype) —
  │    semaglutide (SELECT; FDA-approved 2024 for BMI ≥27 + established
  │    CVD without diabetes). Route to [[Semaglutide Protocol]].
  │
  ├─ MASH F2/F3 alone (Axis 5 without T2D / obesity overlap) — semaglutide
  │    (ESSENCE; FDA-approved 2025 for MASH F2/F3). Route to
  │    [[Semaglutide Protocol]].
  │
  ├─ MASH F4 cirrhosis (Axis 5 F4) — no Module 5 compound FDA-approved;
  │    Pattern V critical Loomba 2023 directional concern; hepatology lead;
  │    GLP-1 RA for concurrent T2D / CWM clinician-judgment with explicit
  │    Pattern V framing.
  │
  ├─ HFrEF (Axis 3 HFrEF) — no Module 5 compound FDA-approved; HFrEF
  │    management outside Module 5 portfolio; clinician-judgment for
  │    concurrent T2D / CWM with HF-team co-management.
  │
  ├─ Adolescent ≥12 + obesity (Axes 7+1 adolescent) — semaglutide STEP
  │    TEENS or liraglutide Saxenda adolescent. Route to [[Semaglutide
  │    Protocol]] or [[Liraglutide Protocol]].
  │
  ├─ Pediatric <12 — investigational across portfolio; comprehensive
  │    lifestyle intervention; pediatric obesity-medicine specialist
  │    co-management; monogenic-obesity routing if applicable.
  │
  └─ Obesity-only (Axes 1+4D/5D/6C — no significant comorbidity) —
      multi-dimensional comparator across tirzepatide (SURMOUNT-5
      magnitude advantage), semaglutide HD 7.2 mg (STEP UP), retatrutide
      (TRIUMPH Phase 2 magnitude, investigational), CagriSema (REDEFINE
      filed-pending). Decision routes through magnitude / safety /
      regulatory state / route / cost dimensions.

STEP 4: ROUTE-PREFERENCE AND COST-ACCESS LAYER

  ┌─ Oral-only preference? (Axis 8.a) — Rybelsus (T2D) / oral Wegovy 25mg
  │    (CWM) / orforglipron-pending. Magnitude trade-off acknowledged.
  │
  ├─ Cash-pay sensitivity? (Axis 9.b) — discuss compounded option (Pattern
  │    Z Anchor 1+2; 503A / 503B pathways; quality-criteria evaluation).
  │
  ├─ Generic-supply needed? (Axis 9.c) — liraglutide as generic-emerging.
  │
  └─ Default — full candidate set per STEP 3 outcomes-evidence selection.

STEP 5: BODY-COMPOSITION OVERLAY

  Per-canonical compound continues per STEP 3-4 selection. Add overlay if:

  ┌─ DEXA-documented lean-mass loss >25-30% of total mass lost OR older
  │    adult phenotype with sarcopenia concern (Axis 10.A) — consider
  │    CJC-Ipamorelin / MOTS-c lean-mass adjunct (M5.6); resistance
  │    training + protein 1.2-1.6 g/kg foundational. Pattern AA: off-label
  │    within informed-consent and primary-source-supported clinical
  │    reasoning.
  │
  ├─ Visceral-fat dominance with persistent VAT after weight loss
  │    (Axis 10.B) — consider tesamorelin (FDA-approved for HIV
  │    lipodystrophy; off-label for non-HIV visceral adiposity). Pattern
  │    AA: off-label use of FDA-approved drug. AOD-9604 is development-
  │    discontinued — Pattern AA-precise framing.
  │
  ├─ Post-weight-loss skin laxity after ≥12 months ≥15% weight loss
  │    (Axis 10.D) — GHK-Cu adjunct mechanism-rationale-supported but
  │    limited evidence base; body-contouring surgery as established
  │    higher-magnitude option for significant laxity.
  │
  └─ General weight reduction (Axis 10.C) — no adjunct overlay.

STEP 6: PER-CANONICAL PROTOCOL HANDOFF

  Route to the selected per-canonical protocol for §1-12 operational detail:

  - [[Semaglutide Protocol]]   - [[Tirzepatide Protocol]]
  - [[Retatrutide Protocol]]   - [[Survodutide Protocol]]
  - [[Liraglutide Protocol]]   - [[Cagrilintide Protocol]]
  - [[CagriSema Protocol]]     - [[IcoSema Protocol]]
  - [[Orforglipron Protocol]]

  Each per-canonical protocol carries:
  §1 Indication scope and patient phenotypes
  §2 Selection criteria (inclusion / exclusion / contraindications)
  §3 Pre-treatment workup
  §4 Initiation protocol
  §5 Maintenance protocol
  §6 Side-effect management
  §7 Plateau and non-response algorithm
  §8 Discontinuation and tapering
  §9 Combination rules
  §10 Patient counseling beats (Pattern Z verbatim-anchor-compliant)
  §11 Source citations
  §12 Clinical decision tree (compound-level)

STEP 7: PATIENT-COUNSELING BEAT

  Apply the relevant §13 beat verbatim or adapted-verbatim per the patient's
  axis-positioning. The beat opens with affirmation, presents multi-
  dimensional facts, acknowledges advantages on each dimension, and closes
  with shared-decision-making invitation.

=============================================================================
END MASTER DECISION TREE
=============================================================================

14.3 Master decision tree — phenotype-priority matrix

A complementary view organized by phenotype-priority — for the patient with multiple positionings, which axis is operationally load-bearing?

Priority	Axis	Dominant when…	First-line route
1 (time-override)	Axis 6 — pre-conception ≤12 mo	TTC within 12 months	Discontinue + washout; transition plan; STOP
2 (regulatory filter)	Pattern AA — investigational status	Compound not yet approved	Restrict to approved or filed-pending candidates
3 (outcomes-evidence)	Axis 4 — CKD 3-4 in T2D	T2D + CKD eGFR 25-75	Semaglutide (FLOW)
3 (outcomes-evidence)	Axis 3 — ASCVD	Established CVD ± T2D	Semaglutide (SUSTAIN-6, SELECT, SOUL); Liraglutide (LEADER) if generic
3 (outcomes-evidence)	Axis 5 — MASH F2/F3	Biopsy/imaging MASH F2/F3	Semaglutide (ESSENCE)
3 (outcomes-evidence)	Axis 3 — HFpEF + obesity	HFpEF + BMI ≥30	Tirzepatide (SUMMIT)
3 (outcomes-evidence)	Special — OSA + obesity	Moderate-severe OSA + BMI ≥30	Tirzepatide (SURMOUNT-OSA)
4 (head-to-head magnitude)	Axes 1+2 — obesity + T2D	No specific outcomes overlay	Tirzepatide (SURPASS-2 HbA1c; SURMOUNT-2 weight) ≈ Semaglutide
4 (head-to-head magnitude)	Axis 1 — obesity-only	No comorbidity	Tirzepatide (SURMOUNT-5 head-to-head) > Semaglutide HD > Semaglutide
5 (regulatory + age)	Axis 7 — adolescent ≥12	Age 12-17 + 95th percentile BMI	Semaglutide STEP TEENS or Liraglutide Saxenda
6 (operational viability)	Axis 8 — oral-only	Injection not viable	Rybelsus / oral Wegovy / orforglipron-pending
6 (operational viability)	Axis 9 — cash-pay	Cost-sensitive	Compounded (Pattern Z Anchor 1+2) or generic liraglutide
7 (adjunct overlay)	Axis 10.A — lean-mass	DEXA lean-mass loss >25-30%	Per-canonical + CJC-Ipamorelin / MOTS-c
7 (adjunct overlay)	Axis 10.B — visceral-fat	Central / VAT-dominant	Per-canonical + tesamorelin (off-label)
7 (adjunct overlay)	Axis 10.D — post-loss skin	≥12 mo ≥15% loss + laxity	GHK-Cu mechanism-supported; surgery for significant laxity

14.4 Master decision tree — Pattern V trial-enrollment qualification reminders

Every recommendation above carries a Pattern V trial-enrollment qualification. Key reminders for cross-phenotype application:

SURMOUNT-5 head-to-head (tirzepatide –20.2% vs semaglutide –13.7%) applies to the SURMOUNT-5 enrollment phenotype (BMI ≥30 or ≥27 with comorbidity, max-tolerated dose, 72 weeks). Extrapolation to Class III (BMI ≥40), to T2D + obesity (SURMOUNT-5 was non-diabetic), or to other comorbidity overlays uses cross-trial sub-analysis.
SUSTAIN-6 (HR 0.74) and SELECT (HR 0.80) apply to the respective enrollment phenotypes (T2D + established CVD; BMI ≥27 + established CVD without diabetes). Primary-prevention extrapolation is Pattern V flagged.
FLOW (HR 0.76 kidney composite + CV death) applies to T2D + CKD eGFR 25-75 + UACR 100-5000 + maximally tolerated RAS blockade. eGFR <25 or eGFR ≥75 or kidney disease without T2D requires extrapolation framing.
ESSENCE (62.9% MASH resolution; 36.8% fibrosis improvement) applies to MASH F2/F3 biopsy-confirmed enrollment. F1 (excluded, direction-of-effect not established) and F4 (excluded, Loomba 2023 directional concern) require explicit Pattern V framing.
SUMMIT (38% reduction in worsening HF events; KCCQ-CSS +6.9) applies to HFpEF + obesity enrollment. HFrEF extrapolation not supported by SUMMIT.
TRIUMPH Phase 2 (retatrutide –24.2% at 12 mg) is Phase 2; Phase 3 readout is the load-bearing future evidence. Pattern AA: investigational.

14.5 Master decision tree — Pattern AA regulatory-state precision reminders

Every regulatory-state claim carries Pattern AA precision. Key reminders for cross-phenotype application:

“FDA-approved for marketing claims for [X]” is the precise framing for on-label uses. Off-label uses of FDA-approved drugs remain use of FDA-approved drugs.
“Investigational; Phase 3 [trial] pending” for retatrutide (TRIUMPH), CagriSema (REDEFINE, filed-pending), IcoSema (Phase 3), survodutide (SYNCHRONIZE / LIVE-2), cagrilintide-monotherapy (Phase 2).
“Filed-pending FDA approval” for orforglipron (Eli Lilly filed Q4 2025 obesity / Q1 2026 T2D as of 2026-05-13 protocol cutoff).
“Off-label use of FDA-approved drug” for tesamorelin in non-HIV visceral adiposity (FDA-approved for HIV-lipodystrophy).
“Development-discontinued” for AOD-9604 (sponsor discontinued Phase 2b obesity development 2007).
“Mechanism-rationale-supported, evidence-base-limited” for GHK-Cu for post-weight-loss skin (not FDA-approved as drug for skin laxity), CJC-Ipamorelin / MOTS-c for lean-mass preservation (off-label, mechanism + clinical-cohort base).

Appendix A — Phenotype-to-compound master table (matrix view)

This appendix presents the §3-§11 phenotype-to-compound mapping in matrix form. The matrix is operationally complementary to the §14 master decision tree narrative; clinicians prefer either the narrative or the matrix depending on context and personal preference.

A.1 Primary phenotype × first-line compound matrix

Cells indicate first-line candidate compound(s) for the row phenotype, with regulatory state and primary-source trial anchor. Pattern V trial-enrollment qualification applies to every cell — the trial-enrolled population that anchors the recommendation may differ from the patient’s full phenotype.

Phenotype	First-line	Trial anchor	Alternative(s)	Adjunct overlay
3.A — BMI ≥30 no comorbidity	Tirzepatide (Zepbound) or Semaglutide (Wegovy / HD / oral 25 mg)	SURMOUNT-1, SURMOUNT-5; STEP-1, STEP UP, OASIS 4	Retatrutide (investigational, TRIUMPH Phase 2 / 3 pending); CagriSema (filed-pending, REDEFINE-1)	None default
3.B — BMI ≥27 + comorbidity	Routes by comorbidity (Axes 3-7)	STEP-1, SURMOUNT-1 enrollment included BMI ≥27 with comorbidity	Per comorbidity routing	Per comorbidity
3.C — BMI ≥40 (Class III)	Retatrutide (Phase 2 magnitude leader, investigational) or Tirzepatide (FDA-approved) or Semaglutide HD 7.2 mg	TRIUMPH Phase 2 / 3; SURMOUNT-1; STEP UP	CagriSema (REDEFINE-1, –22.7%); Bariatric-surgery comparator	Post-loss skin (§11.D) frequently
3.D — Adolescent ≥12	Semaglutide (STEP TEENS) or Liraglutide (Saxenda adolescent)	STEP TEENS (BMI –16.1%); Kelly 2020 NEJM	Tirzepatide pediatric Phase 3 pending	None
3.E — Pediatric <12	None FDA-approved; comprehensive lifestyle + specialist co-management	—	Monogenic-obesity routing (setmelanotide outside Module 5)	None
4.A — T2D + obesity	Tirzepatide (Mounjaro/Zepbound) or Semaglutide (Ozempic/Wegovy)	SURPASS-2, SURMOUNT-2; STEP-2, SUSTAIN	Orforglipron filed-pending; CagriSema filed-pending; Liraglutide if generic-needed	None default
4.B — T2D without obesity	Semaglutide (Ozempic/Rybelsus) or Tirzepatide (Mounjaro) or Liraglutide (Victoza)	SUSTAIN, PIONEER, SURPASS, LEAD	Orforglipron filed-pending	None default
4.C — Prediabetes + obesity	Routes through 3.A/3.B with T2D-prevention dimension	SCALE liraglutide 80% T2D incidence reduction; STEP/SURMOUNT sub-analyses	—	None
5.A — Established ASCVD	Semaglutide (Wegovy SELECT or Ozempic SUSTAIN-6 or Rybelsus SOUL)	SUSTAIN-6 HR 0.74; SELECT HR 0.80; SOUL 14% MACE	Liraglutide (LEADER HR 0.87)	None default
5.B — HFpEF + obesity	Tirzepatide (Zepbound; FDA-approved 2025 via SUMMIT)	SUMMIT 38% worsening HF reduction	Semaglutide STEP-HFpEF supportive, label expansion pending	None
5.C — HFrEF	No Module 5 compound on-label; HFrEF therapies outside portfolio	—	Clinician-judgment for concurrent T2D/CWM	None
5.D — High CV risk, no established disease	Per Axes 1/2 + comprehensive risk reduction	Primary-prevention extrapolation Pattern V flagged	—	None
6.A — CKD 3-4 in T2D	Semaglutide (Ozempic FLOW or Rybelsus SOUL)	FLOW HR 0.76 kidney composite + CV death	SGLT2 + RAS + GLP-1 RA layered approach	None
6.B — Proteinuric kidney disease	Routes to 6.A FLOW-anchored	FLOW enrollment included UACR 100-5000	—	None
6.D — Kidney transplant	No Phase 3 trial enrollment; transplant-team co-management	—	Clinician-judgment off-label	None
7.A — MASH F2/F3	Semaglutide (Wegovy FDA-approved 2025 via ESSENCE)	ESSENCE 62.9% MASH resolution; 36.8% fibrosis improvement	Survodutide LIVE-1 supportive (investigational); Tirzepatide MASH Phase 3 pending	Visceral-fat (§11.B) if VAT-dominant
7.B — MASH F4 cirrhosis	None FDA-approved; hepatology lead; Pattern V critical (Loomba 2023 directional)	—	Clinician-judgment for concurrent T2D/CWM	None
7.C — MASLD/fatty liver no fibrosis	Routes through Axes 1/2; hepatic-steatosis improvement as secondary benefit	—	—	None
8.A — TTC ≤12 mo	Time-dominant override; discontinuation + washout per §8	Parker 2025 pooled human exposure data; STEP-4 / SURMOUNT-4 regain trajectory	—	—
9.B — Adolescent 12-17	Routes to 3.D	—	—	—
9.D — Older adult 65-75	Routes through Axes 1-6 + DEXA monitoring	—	—	Consider lean-mass (§11.A) if DEXA shows lean loss >25-30%
9.E — Very-old ≥75	Routes through Axes 1-6 + frailty assessment; Pattern V flag on trial under-representation	—	—	Lean-mass (§11.A) frequently
10.a — Oral-only	Rybelsus (T2D) or oral Wegovy 25 mg (CWM) or orforglipron-pending	PIONEER; OASIS 4; ATTAIN	—	None
10.b — Cash-pay	Compounded (Pattern Z Anchor 1+2) or generic liraglutide	503A / 503B pathways; LEAD program for liraglutide	—	—
10.c — Generic	Liraglutide (off-patent EU 2023; US generic emerging)	LEAD, SCALE programs	—	—
11.A — Lean-mass	Per Axes 1-6 + CJC-Ipamorelin / MOTS-c overlay	M5.6 v3 clinical-practice cohort + mechanism rationale	Resistance training + protein 1.2-1.6 g/kg foundational	M5.6 stack
11.B — Visceral-fat	Per Axes 1-6 + tesamorelin overlay	Falutz NEJM 2007 PMID 18057338; Stanley 2014 JAMA PMID 25038357	AOD-9604 development-discontinued	Tesamorelin (off-label)
11.D — Post-loss skin	Per Axes 1-6 + GHK-Cu adjunct OR body-contouring surgery	M5.7 mechanism + limited clinical	—	GHK-Cu (limited evidence)

A.2 Compound × indication FDA-approval matrix (2026-05-13 snapshot)

Compound	T2D	CWM	Adolescent CWM	CV risk reduction	MASH	CKD in T2D	HFpEF+obesity	OSA+obesity
Semaglutide (Ozempic / Wegovy / Wegovy HD / Rybelsus / oral Wegovy)	✓ (2017 SC; 2019 oral)	✓ (2.4mg 2021; HD 7.2mg 2026; oral 25mg 2025)	✓ (2022)	✓ (T2D+CVD 2020; BMI≥27+CVD 2024; T2D+ASCVD/CKD oral 2025)	✓ (F2/F3 2025)	✓ (2025)	Phase 3 supportive; label expansion pending	—
Tirzepatide (Mounjaro / Zepbound)	✓ (2022)	✓ (2023)	Phase 3 pending	Phase 3 pending (SURMOUNT-MMO / SURPASS-CVOT)	Phase 3 pending	Phase 3 pending	✓ (2025)	✓ (2024)
Retatrutide	Phase 3 pending	Phase 3 pending (TRIUMPH)	—	Phase 3 pending	Phase 2 pending	Phase 2 pending	—	—
Survodutide	—	Phase 3 (SYNCHRONIZE)	—	—	Phase 3 (LIVE-2)	—	—	—
Liraglutide (Victoza / Saxenda)	✓ (Victoza 2010)	✓ (Saxenda 2014)	✓ (Saxenda 2020)	✓ (LEADER 2017)	—	—	—	—
Cagrilintide (monotherapy)	—	Phase 2	—	—	—	—	—	—
CagriSema	—	Filed-pending (REDEFINE)	—	—	—	—	—	—
IcoSema	—	Phase 3	—	—	—	—	—	—
Orforglipron	Filed-pending Q1 2026	Filed-pending Q4 2025	Pediatric program ongoing	Phase 3 pending	—	—	—	—

Pattern AA precision: ✓ indicates “FDA-approved for marketing claims for [the indication]”; — indicates “not currently FDA-approved and not currently in active filed-pending state.”

A.3 Compound × dimension multi-axis comparator (Pattern Z Anchor 4)

Dimension	Sema	Tirz	Reta	Surv	Lira	Cagri	CagriS	IcoS	Orfo
Weight magnitude (max-tol-dose, CWM)	–14.9 to –18.7%	–20.2 to –22.5%	–24.2% (Ph2)	Phase 3	–6% > placebo	Ph2	–22.7% (Ph3 REDEFINE-1)	Phase 3	ATTAIN-1 Ph3
HbA1c (T2D head-to-head)	–1.86 to –2.0	–2.30 (SURPASS-2)	Ph3	—	–1.0 to –1.5	—	Ph3	—	Ph3
CV outcomes evidence	SUSTAIN-6 / SELECT / SOUL deepest	SURMOUNT-MMO pending	Pending	—	LEADER HR 0.87	—	Pending	—	Pending
Kidney outcomes evidence	FLOW HR 0.76	Pending	Pending	—	LEADER sub-analysis	—	—	—	—
MASH evidence	ESSENCE ✓ F2/F3	Phase 3 pending	Phase 2 pending	LIVE-1 76% Ph2	—	—	—	—	—
HFpEF+obesity	STEP-HFpEF supportive	SUMMIT ✓	—	—	—	—	—	—	—
OSA+obesity	—	SURMOUNT-OSA ✓	—	—	—	—	—	—	—
Route	Weekly-SC + oral 14/25 mg	Weekly-SC	Weekly-SC	Weekly-SC	Daily-SC	Weekly-SC	Weekly-SC	Weekly-SC	Daily-oral
NAION signal	Documented post-marketing (under evaluation)	Absent per PMID 40383360	Phase-stage	Phase-stage	Class-shared theoretical	—	—	—	—
Regulatory state	6 FDA-approved indications	4 FDA-approved indications	Investigational	Investigational	3 FDA-approved (T2D, CWM, adolescent CWM, CV)	Investigational	Filed-pending	Investigational	Filed-pending
Generic availability	No (branded; compounded under 503A/503B)	No (branded; compounded under 503A/503B)	Investigational	Investigational	EU off-patent 2023; US generic emerging	Investigational	Investigational	Investigational	Pre-approval

The Anchor 4 framing: every dimension matters for some phenotypes; no compound is uniformly best across all dimensions; the clinician-patient dyad selects the dimensions that matter most for the specific patient.

A.4 Adjunct overlay × indication-target matrix

Adjunct	FDA-approved indication	Off-label use	Module 5 phenotype where applied	Evidence base
Tesamorelin (Egrifta SV / WR; BLA022505)	HIV-associated lipodystrophy	Non-HIV visceral adiposity	§11.B Visceral-fat priority	Level I in HIV-lipodystrophy (Falutz); mechanism extrapolation to non-HIV
AOD-9604	None (development-discontinued 2007)	All current use is off-FDA-approved	§11.B Visceral-fat priority (limited)	Level V preclinical; Wilding 2004 narrative review
CJC-1295	None (not FDA-approved)	Lean-mass preservation in CWM	§11.A Lean-mass-preservation priority	Mechanism rationale + M5.6 v3 clinical-practice cohort
Ipamorelin	None (not FDA-approved)	Lean-mass preservation in CWM	§11.A Lean-mass-preservation priority	Mechanism rationale + M5.6 v3 clinical-practice cohort
MOTS-c	None (investigational)	Mitochondrial/metabolic adjunct	§11.A Lean-mass-preservation priority	Phase 1/2 limited
GHK-Cu	None as drug	Post-weight-loss skin elasticity	§11.D Post-weight-loss skin laxity	Mechanism rationale + preclinical + limited clinical

Appendix B — Pattern discipline summary

This appendix consolidates the load-bearing Pattern discipline applied across §1-§14 for ease of auditor and clinician review.

B.1 Pattern Z Anchor 4 (multi-dimensional comparator framing) — DOMINANT CALIBRATION

Pattern Z Anchor 4 is the dominant calibration for this meta-protocol. Every phenotype recommendation in §3-§11 applies Anchor 4: multi-dimensional fact presentation; primary-source anchoring per dimension; explicit acknowledgment of any compound’s advantage on any dimension; close with shared-decision-making invitation.

The Anchor 4 calibration reference (verbatim from /Internal/Module-5-Pipeline/pattern-z-calibration-anchor.md):

“Both compounds are evidence-based weight-management options. SURMOUNT-5 head-to-head showed tirzepatide produced ~6.5 percentage points more weight loss at max-tolerated doses. Beyond that, the compounds differ on cardiovascular and other-outcome evidence bases, side-effect profiles, ophthalmologic-signal differentiation, and access. Here are the facts on each dimension; let’s discuss which factors matter most for your situation.”

Every counseling beat in §3-§13 mirrors this structural template: open with affirmation, present multi-dimensional facts with primary-source anchoring, acknowledge any compound’s advantage on any dimension explicitly, close with shared-decision-making invitation. The §13 library indexes the beats by axis for clinician quick-reference.

B.2 Pattern V (trial-enrollment-anchored effect-size disclosure)

Every effect-size claim in §3-§14 carries trial-population qualification:

SURMOUNT-5 (tirzepatide –20.2% vs semaglutide –13.7%) applies to max-tolerated-dose comparison at 72 weeks in BMI ≥30 (or ≥27 with comorbidity) non-diabetic CWM.
STEP-1 (semaglutide –14.9%) applies to non-diabetic obesity BMI ≥30 at 68 weeks.
STEP-2 (semaglutide –9.6%) applies to T2D + obesity at 68 weeks — smaller magnitude than non-diabetic STEP-1.
SUSTAIN-6 (HR 0.74) applies to T2D + established CVD at 2.1 years median.
SELECT (HR 0.80) applies to BMI ≥27 + established CVD without diabetes at 39.8 months mean.
FLOW (HR 0.76) applies to T2D + CKD eGFR 25-75 + UACR 100-5000 + maximally tolerated RAS blockade at 3.4 years median.
ESSENCE (62.9% MASH resolution, 36.8% fibrosis improvement) applies to biopsy-proven MASH F2/F3 at 72 weeks.
SUMMIT (38% worsening HF reduction) applies to HFpEF + obesity at 52 weeks.
STEP TEENS (–16.1% BMI) applies to adolescents ≥12 at 95th percentile BMI at 68 weeks.
TRIUMPH Phase 2 (retatrutide –24.2% at 12 mg) applies to Phase 2 obesity at 48 weeks — Phase 3 readout pending.
LIVE-1 Phase 2 (survodutide 76% MASH resolution) applies to MASH F2/F3 at 48 weeks — Phase 3 pending.

Pattern V flag — extrapolations beyond trial-enrolled phenotype require explicit framing:

F4 cirrhosis (Loomba 2023 directional concern toward placebo)
HFrEF (under-represented; FIGHT trial signal toward placebo)
≥75 years (registration-trial under-representation)
Pediatric <12 years (research-state-incomplete except specific monogenic-obesity contexts)
Primary-prevention high CV risk without established disease (SELECT / SUSTAIN-6 anchored in established disease)
Kidney transplant recipients (Phase 3 exclusion)
Lean / metabolically-healthy populations seeking microdose use

B.3 Pattern AA (regulatory-state precision)

Every regulatory-state claim in §3-§14 carries Pattern AA precision:

“FDA-approved for marketing claims for X” — on-label use of FDA-approved-for-marketing-claims drug for indication X
“Off-label use of FDA-approved drug for Y” — off-label use of a compound that is FDA-approved for a different indication
“Investigational; Phase 3 [trial] pending” — pre-approval state with active trial program
“Filed-pending FDA approval” — sponsor has submitted application; FDA decision pending
“Development-discontinued” — sponsor discontinued development (AOD-9604 obesity Phase 2b, 2007)
“Mechanism-rationale-supported, evidence-base-limited” — off-label or non-approved with mechanism rationale plus limited clinical evidence

The Pattern AA distinction is load-bearing: tesamorelin off-label for non-HIV visceral adiposity is operationally and regulatorily distinct from AOD-9604 (a non-FDA-approved compound used through research-use-only / 503A pathways) and from GHK-Cu (not FDA-approved as a drug for skin laxity). The Pattern AA precision is most load-bearing in the §11 adjunct-overlay axis and in the §12 cross-phenotype combination decisions involving investigational compounds.

B.4 Pattern Z.injection-framing

Self-injection is a routine clinical skill, not a daunting barrier. The §10.2.4 injection-averse counseling beat applies this framing — offering demonstration and walk-through as the first response to needle aversion, with oral alternatives as a respected secondary option.

B.5 Pattern Z.research-precision

Bias-vocabulary like “highly experimental” / “fringe” / “unproven” are Pattern Z violations. The §3-§14 use of “investigational pending Phase 3” / “research-state-incomplete” / “development-discontinued” reflects Pattern Z.research-precision discipline — accurate research-state framing without bias-vocabulary that steers clinicians away from compounds.

B.6 Pattern R / R.1 / R.2 (framing discipline)

Pattern R: regulatory status is legal context, not evidence-quality signal. Pattern R.1: structural framing (section titles, item labels, sub-block ordering) is part of Pattern R. Pattern R.2: Pattern R + R.1 must be applied at the section-architecture-design step, before content generation.

The §3-§11 phenotype-axis sections lead with what the candidate compounds do for the phenotype (the research-state content) before structural caveats (regulatory state, off-label framing, contraindications). The Pattern R.2 enforcement is at the section-architecture-design step — each axis section structure was locked before content generation.

B.7 Pattern W (cross-section enumeration consistency)

Every claim in §3-§14 must be reconciled across sections. Examples:

The §3.2 SURMOUNT-5 head-to-head magnitude framing must match the §4.2 SURPASS-2 head-to-head HbA1c framing — both head-to-heads exist, both favor tirzepatide on the respective dimension, neither extrapolates to the other dimension.
The §5.2 SELECT enrollment phenotype (BMI ≥27 + established CVD without diabetes) must match the §3.3 BMI ≥27 + comorbidity sub-phenotype framing.
The §6.2 FLOW enrollment (eGFR 25-75; UACR 100-5000; maximally tolerated RAS blockade) must match the §4.2 T2D + obesity + CKD cross-phenotype combination from §12.2.2.

B.8 Pattern AB.4 (PMID / NCT / DOI identifier integrity)

Every PMID / NCT / DOI citation in §3-§14 traces to the per-canonical protocol bibliography for verification. This meta-protocol does not introduce new primary-source citations; it routes existing citations from the per-canonical protocols. Auditor verification of the PMID / NCT / DOI integrity is performed against the per-canonical bibliographies at /obsidian-peptides/Process/{Compound}/{Compound} - Bibliography.md.

B.9 Pattern N.1 (small-molecule path)

Orforglipron is a small-molecule oral GLP-1 RA. Pattern N.1 applies — the orforglipron canonical lives at /obsidian-peptides/Small-Molecules/Orforglipron.md, not at /obsidian-peptides/Peptides/. The §10.2.1 oral-only sub-phenotype and §12.2.9 oral-only cross-phenotype routing handle the small-molecule positioning.

B.10 Self-audit checklist

This protocol’s self-audit:

Appendix C — Cross-protocol wikilink index + commit log

C.1 Per-canonical protocol wikilink index

For every compound referenced in §3-§14, the corresponding per-canonical protocol carries the §1-12 operational detail:

[[Semaglutide Protocol]] — six FDA-approved indications (T2D 2017 SC / 2019 oral; CWM 2021 / 2025 oral 25 mg / 2026 HD 7.2 mg; adolescent CWM 2022; CV risk reduction 2020 SC / 2024 SC for non-diabetic CVD / 2025 oral for T2D+ASCVD/CKD; MASH F2/F3 2025; CKD in T2D 2025); investigational extensions HFpEF
[[Tirzepatide Protocol]] — four FDA-approved indications (T2D 2022; CWM 2023; OSA-with-obesity 2024; HFpEF-with-obesity 2025); investigational pipeline (CKD, MASH, CV outcomes in CWM)
[[Retatrutide Protocol]] — investigational; TRIUMPH Phase 3 program for obesity ongoing; separate T2D programs
[[Survodutide Protocol]] — investigational; Phase 3 SYNCHRONIZE for obesity; LIVE-2 Phase 3 for MASH; LIVE-1 Phase 2 supportive (76% histologic resolution)
[[Liraglutide Protocol]] — FDA-approved for T2D (Victoza 2010), CWM (Saxenda 2014), pediatric CWM (Saxenda 2020), CV risk reduction (LEADER 2017); off-patent EU 2023; generic competition emerging in US
[[Cagrilintide Protocol]] — investigational as monotherapy (Phase 2)
[[CagriSema Protocol]] — investigational fixed-ratio combination (REDEFINE Phase 3; filed-pending)
[[IcoSema Protocol]] — investigational fixed-ratio combination (Phase 3 ongoing)
[[Orforglipron Protocol]] — investigational small-molecule oral GLP-1 RA (ATTAIN-1 obesity Phase 3 readout; filed for FDA approval Q4 2025 obesity / Q1 2026 T2D); Pattern N.1 small-molecule path

C.2 Adjunct lesson cross-references

M5.5 — Tesamorelin + AOD-9604 at /Peptide Projects/Pepteon Academy/m5-content/M5.5 v3 — visceral-fat adjunct framework
M5.6 — CJC-Ipamorelin + MOTS-c at /Peptide Projects/Pepteon Academy/m5-content/M5.6 v3 — lean-mass adjunct framework
M5.7 — GHK-Cu at /Peptide Projects/Pepteon Academy/m5-content/M5.7 v3 — post-weight-loss-skin adjunct framework

C.3 Methodology and framework cross-references

/obsidian-peptides/Methodology/Protocol Template.md (v1.0) — the 12-section per-compound template; this meta-protocol departs from the template and expands the template’s §12 (Clinical decision tree) to module level
/obsidian-peptides/Methodology/Synergy Editorial Framework.md (v1.2) — voice, framing, length, citation authority
/obsidian-peptides/Methodology/AC2-26 - System Observations.md — Pattern R / R.1 / R.2 / V / W / X / Z / AA / AB / AB.4 / N.1 / Z.injection-framing / Z.research-precision
/obsidian-peptides/Methodology/Voice Profile - Dr. Jeff Gross MD.md — clinician-voice calibration
/Internal/Module-5-Pipeline/pattern-z-calibration-anchor.md — five Pattern Z anchors; Anchor 4 dominant for this meta-protocol

C.4 Commit log

Production cycle 2026-05-13, seven commits per the orchestrator launch prompt:

C1 — Protocol: M5 Decision Tree §1-2 (Commit 1/7) — Purpose + how-to-use + Module 5 portfolio overview + ten phenotype-axes framework
C2 — Protocol: M5 Decision Tree §3-4 (Commit 2/7) — Obesity-type phenotype + T2D status phenotype
C3 — Protocol: M5 Decision Tree §5-6 (Commit 3/7) — CV history phenotype + Kidney status phenotype
C4 — Protocol: M5 Decision Tree §7-8 (Commit 4/7) — Hepatic status phenotype + Pre-conception planning phenotype
C5 — Protocol: M5 Decision Tree §9-10 (Commit 5/7) — Age-stage phenotype + Route preference + Cost/access phenotype
C6 — Protocol: M5 Decision Tree §11-14 (Commit 6/7) — Body-composition phenotype + Cross-phenotype combination logic + Counseling-beat library + Master decision tree
C7 — Protocol: M5 Decision Tree Appendices + final self-audit (Commit 7/7) — Phenotype-to-compound master table + Pattern discipline summary + Cross-protocol wikilink index

Each commit pushed to main immediately after commit per the protocol-pipeline discipline at /Users/dariapechaiko/Documents/VirtuDigital/Projects/Pepteon Academy/Synergy-Health-Academy/Internal/Module-5-Pipeline/.

C.5 Dr. Gross verification gate handoff

This protocol enters the standard Module 5 verification gate per /Internal/Module-5-Pipeline/README.md Stage 4 module-level audit. Specific verification items for this meta-protocol:

Pattern Z Anchor 4 multi-dimensional discipline verification — auditor reads §3-§11 counseling beats and §13 library; confirms each beat opens with affirmation, presents multi-dimensional facts with primary-source anchoring, acknowledges any compound’s advantage on any dimension explicitly, and closes with shared-decision-making invitation. No beat opens with what an option ISN’T.
Pattern V trial-enrollment-anchored effect-size verification — auditor confirms every effect-size claim in §3-§14 carries trial-population qualification; flags any extrapolation that lacks explicit framing.
Pattern AA regulatory-state precision verification — auditor confirms every regulatory-state claim is precise; flags any “FDA-approved” claim that should be “FDA-approved for marketing claims for X” or any “approved” claim that should be “investigational” / “filed-pending” / “off-label of FDA-approved drug.”
Cross-protocol wikilink verification — auditor confirms all 9 per-canonical protocol wikilinks resolve and that the routing logic in §3-§14 + §12 + §14 master tree is consistent with the per-canonical §1 indication scope and §12 decision tree.
§14 master decision tree usability verification — auditor confirms §14 is readable as a one-page clinician quick-reference; the text-form ASCII tree plus the phenotype-priority matrix can be exported to a single-page reference card.
Pattern W cross-section consistency verification — auditor reconciles trial-enrollment phenotypes across §3-§14; flags any inconsistency (e.g., the §3.3 BMI ≥27 + comorbidity framing must match the §5.2 SELECT enrollment phenotype for the BMI ≥27 + ASCVD overlap).
Adjunct overlay regulatory framing verification — auditor confirms tesamorelin (off-label for non-HIV visceral adiposity; FDA-approved for HIV lipodystrophy) and AOD-9604 (development-discontinued, not “emerging”) and CJC-Ipamorelin (off-label for lean-mass) and GHK-Cu (not FDA-approved as drug for skin laxity) are framed with Pattern AA precision in §11.

Dr. Gross verification items flagged for explicit clinician input:

D-M5DT-1 — Class III obesity decision routing. §3.4 presents the magnitude-leading investigational options (retatrutide TRIUMPH Phase 2 –24.2%; CagriSema REDEFINE-1 –22.7%) and the bariatric-surgery comparator. Dr. Gross input requested on whether the §3.4 decision logic appropriately weighs the bariatric-surgery comparator vs the pharmacotherapy-magnitude options for the Class III phenotype.
D-M5DT-2 — TTC discontinuation arithmetic precision. §8.2 presents the half-life-driven washout windows (~2 months for long-half-life compounds; ~1-2 weeks for liraglutide; ~1 week for orforglipron). Dr. Gross input requested on whether the protocol-recommended washout windows are consistent with current Novo Nordisk / Eli Lilly product label guidance for each specific compound.
D-M5DT-3 — Adjunct overlay clinical-judgment thresholds. §11.A specifies DEXA-documented lean-mass loss >25-30% of total mass lost as a clinical-judgment threshold for considering the M5.6 lean-mass adjunct. Dr. Gross input requested on whether 25-30% is the operative threshold or whether a different threshold (e.g., 20%, 35%) is preferred in clinical practice.
D-M5DT-4 — Pediatric <12 routing. §3.6 / §9.2 frames pediatric <12 as investigational across the Module 5 portfolio. Dr. Gross input requested on whether specific monogenic-obesity routing (setmelanotide for MC4R/POMC/PCSK1/leptin deficiencies) should be more prominently documented in this protocol or whether routing to a separate pediatric-obesity-specialist canonical is the appropriate boundary.
D-M5DT-5 — §14 master decision tree clinical workflow. §14 presents the master tree in two complementary forms (text-form ASCII + phenotype-priority matrix). Dr. Gross input requested on whether either or both forms is most useful at point of care, and whether additional decision-tree visualization (flowchart graphic) is appropriate.

End of protocol.

Module 5 – Phenotype-Guided Decision Tree Protocol

Module 5 — Phenotype-Guided Decision Tree Protocol

Table of Contents

Cross-references

1. Purpose and how to use this protocol

1.1 What this protocol is

1.2 How to use this protocol

1.3 What this protocol does not do

1.4 Versioning and Pattern AA precision

1.5 Adjunct overlays — when and how

1.6 The structural and methodological lineage

2. Phenotype axes overview — the ten dimensions clinicians weigh

2.1 Purpose of the axes framework

2.2 The ten axes

2.3 How the axes interact

2.4 The Module 5 portfolio in one paragraph

3. Obesity-type phenotype

3.1 Purpose and sub-phenotype taxonomy

3.2 Sub-phenotype 3.A — BMI ≥30 without weight-related comorbidity

3.3 Sub-phenotype 3.B — BMI ≥27 with one weight-related comorbidity

3.4 Sub-phenotype 3.C — BMI ≥40 (Class III obesity)

3.5 Sub-phenotype 3.D — Pediatric ≥12 years

3.6 Sub-phenotype 3.E — Pediatric <12 years

3.7 Cross-reference to Axis 1 master decision

4. T2D status phenotype

4.1 Purpose and sub-phenotype taxonomy

4.2 Sub-phenotype 4.A — T2D + obesity

4.3 Sub-phenotype 4.B — T2D without obesity (BMI <27)

4.4 Sub-phenotype 4.C — Prediabetes

4.5 Sub-phenotype 4.D — No diabetes

4.6 Cross-reference to Axis 2 master decision

5. Cardiovascular history phenotype

5.1 Purpose and sub-phenotype taxonomy

5.2 Sub-phenotype 5.A — Established ASCVD

5.3 Sub-phenotype 5.B — HFpEF + obesity

5.4 Sub-phenotype 5.C — HFrEF (heart failure with reduced ejection fraction)

5.5 Sub-phenotype 5.D — High CV risk without established disease

5.6 Sub-phenotype 5.E — No CV history

5.7 Cross-reference to Axis 3 master decision

6. Kidney status phenotype

6.1 Purpose and sub-phenotype taxonomy

6.2 Sub-phenotype 6.A — CKD stage 3-4 in T2D

6.3 Sub-phenotype 6.B — Proteinuric kidney disease

6.4 Sub-phenotype 6.C — Normal kidney function

6.5 Sub-phenotype 6.D — Kidney transplant recipient

6.6 Cross-reference to Axis 4 master decision

7. Hepatic status phenotype

7.1 Purpose and sub-phenotype taxonomy

7.2 Sub-phenotype 7.A — MASH F2/F3

7.3 Sub-phenotype 7.B — MASH F4 (cirrhosis)

7.4 Sub-phenotype 7.C — Fatty liver without fibrosis (MASLD / steatosis)

7.5 Sub-phenotype 7.D — Normal hepatic

7.6 Cross-reference to Axis 5 master decision

8. Pre-conception planning phenotype

8.1 Purpose and sub-phenotype taxonomy

8.2 Sub-phenotype 8.A — Actively TTC within 12 months

8.3 Sub-phenotype 8.B — Planning conception within 1-3 years

8.4 Sub-phenotype 8.C — No conception planning

8.5 Special case — oral contraceptive interactions with delayed gastric emptying

8.6 Lactation considerations

8.7 Cross-reference to Axis 6 master decision

9. Age-stage phenotype

9.1 Purpose and sub-phenotype taxonomy

9.2 Sub-phenotype 9.A — Pediatric 10-12 years

9.3 Sub-phenotype 9.B — Adolescent 12-17 years

9.4 Sub-phenotype 9.C — Adult 18-65 years

9.5 Sub-phenotype 9.D — Older adult 65-75 years

9.6 Sub-phenotype 9.E — Very-old adult ≥75 years

9.7 Cross-reference to Axis 7 master decision

10. Route preference and cost-access phenotype

10.1 Purpose and sub-phenotype taxonomy

10.2 Sub-axis 8 — Route preference

10.2.1 Sub-phenotype 8.a — Oral-only preference

10.2.2 Sub-phenotype 8.b — Weekly-SC-acceptable

10.2.3 Sub-phenotype 8.c — Daily-SC-acceptable

10.2.4 Sub-phenotype 8.d — Injection-averse

10.3 Sub-axis 9 — Cost / access

10.3.1 Sub-phenotype 9.a — Insurance-covered

10.3.2 Sub-phenotype 9.b — Cash-pay

10.3.3 Sub-phenotype 9.c — Generic-supply-dependent