--- title: "Semaglutide 2.4 mg Once-Weekly for Weight Management in Adults with Overweight/Obesity" slug: semaglutide_obesity version: 1.1 timestamp: 2026-04-19T00:00:00Z date: 2026-04-19 specialty: Endocrinology (Obesity/Metabolic) canonical_url: https://mahmood726-cyber.github.io/rapidmeta-finerenone/protocols/semaglutide_obesity_protocol_v1.0_2026-04-19.md app_url: https://mahmood726-cyber.github.io/rapidmeta-finerenone/SEMAGLUTIDE_OBESITY_REVIEW.html license: MIT --- # Semaglutide 2.4 mg Once-Weekly for Weight Management ## A Living Systematic Review and Meta-Analysis Protocol (STEP Phase 3 Programme) **Protocol version:** 1.1 **Frozen:** 2026-04-19T00:00:00Z **Specialty:** Endocrinology (Obesity/Metabolic) --- ## 1. Review Title and Registration **Title:** Semaglutide 2.4 mg Once-Weekly for Weight Management in Adults with Overweight/Obesity: A Living Systematic Review and Meta-Analysis of the STEP Phase 3 Programme **Registration:** Protocol frozen 2026-04-19T00:00:00Z and published at the canonical URL above. Pre-registration mechanism: **GitHub-canonical-URL freeze** (immutable git history at the canonical URL above, with a SHA anchor once the review is submitted) rather than a PROSPERO record. PROSPERO does not currently accept retrospective or already-completed-analysis registrations; authors targeting journals that require a PROSPERO number should register the protocol at PROSPERO before the first formal update cycle. **Authors:** Mahmood Ahmad (corresponding). See GitHub repo for contributor acknowledgments. **Corresponding address:** drmahmoodclinic@pm.me (GMC 6071047), Royal Free Hospital and Barnet Hospital, London, UK. --- ## 2. PICO | Element | Specification | |---|---| | **Population** | Adults with BMI >=30 (or >=27 with weight-related comorbidity), without type 2 diabetes | | **Intervention** | Semaglutide 2.4 mg subcutaneously once weekly | | **Comparator** | Placebo plus standardized lifestyle intervention | | **Outcome (primary)** | Percentage change in body weight from baseline at the trial-specific primary timepoint (68-104 wk) | --- ## 3. Eligibility Criteria ### Inclusion - Study design: Randomized controlled trials (parallel, double-blind) - Phase: III pivotal STEP trials - Participants: Adults meeting the obesity population definition - Intervention: Semaglutide 2.4 mg QW at licensed obesity dose - Comparator: Matched placebo + lifestyle intervention - Outcomes: % body weight change reported as co-primary - Follow-up: >=52 weeks - Publication: Peer-reviewed phase-3 publication ### Exclusion - Type 2 diabetes-only trials (SUSTAIN, PIONEER — see separate GLP1_CVOT review) - Phase II dose-ranging studies - Single-arm weight-loss cohort studies, real-world post-marketing registries - Trials of other semaglutide doses (1.0 mg, 0.5 mg) not at the 2.4 mg obesity dose - Paediatric trials (STEP-TEENS is tracked separately) --- ## 4. Information Sources and Search Strategy | Database | Query | Type | |---|---|---| | ClinicalTrials.gov | `semaglutide 2.4 mg AND obesity AND randomized` | Registry | | Europe PMC / PubMed | `semaglutide AND STEP AND weight AND randomized` | Bibliographic | | OpenAlex | Semaglutide + obesity concepts | Bibliographic | **Search date:** Continuous (living review). --- ## 5. Study Selection - **Stage 1 (auto-screen):** Keyword + publication-type classifier (0-100 score). - **Stage 2 (title/abstract):** Two-reviewer adjudication with HMAC-signed seal. - **Stage 3 (full text):** Verify eligibility; extract continuous MD and SE from primary analysis. - **Conflict resolution:** Re-review; PRISMA 2020 flow auto-generated. --- ## 6. Data Extraction | Data item | Details | |---|---| | Study identifiers | NCT ID, PMID, DOI, first author, year | | Participants | N randomized per arm, baseline BMI, baseline body weight, age | | Intervention details | Semaglutide 2.4 mg QW duration | | Comparator | Placebo + lifestyle arm composition | | Outcome effects | % body weight MD and SE, responder proportions (>=5%, >=10%, >=15%, >=20%) | | Risk of bias | Cochrane RoB 2 per trial | | Source evidence | Verbatim excerpts from published tables | --- ## 7. Risk of Bias Assessment Cochrane **RoB 2**. Design-based priors: double-blind placebo-controlled with calibrated site scales and treatment-policy estimand => LOW across D1-D5. --- ## 8. Synthesis / Statistical Methods - **Primary pool:** DerSimonian-Laird random-effects IVW on MD scale (% body weight). - **CI adjustment:** HKSJ with t-distribution df = k-1; floor at max(1, Q/(k-1)). - **Prediction interval:** t-distribution df = k-2 (Higgins 2009). Undefined for k<3. - **Heterogeneity:** Q (p-value), I^2 with Q-profile CI, tau^2 (DL). - **Subgroup / meta-regression:** Intensive behavioural therapy vs standard lifestyle, 68-wk vs 104-wk follow-up. - **Publication bias:** Limited for k<4; SURPASS-style pre-registration mitigates. - **Sensitivity:** Leave-one-out; restrict to 68-wk primary analyses only. - **Bayesian:** Grid-approximation with half-normal prior on tau. --- ### SAP additions (2026-04-20 editor-review revision v1.1) - **HKSJ variance-inflation floor:** Apply `max(1, Q/(k-1))` as the floor on the HKSJ inflation factor. This prevents HKSJ from *narrowing* the CI below the DL-random-effects CI when Q < k-1 (Roever 2015). Non-optional; hard-coded in the app's pooler. - **Zero-cell continuity correction:** Apply 0.5 continuity correction **only** when >=1 cell is zero in a given trial. Do not apply unconditionally (unconditional correction biases OR -> 1 even when no cells are zero). Sensitivity: Mantel-Haenszel without correction and Peto-OR for sparse-cell subsets. - **Trim-and-fill sensitivity:** Duval-Tweedie trim-and-fill reported as a sensitivity analysis in all apps, flagged as low-power at k < 10 (protocol notes Egger/Peters regression is the formal test at k >= 10). - **Sample-size heterogeneity note:** Trial-level sample sizes differ by one to two orders of magnitude across some pools (e.g., RSV vaccines n=17,000 per arm vs Mavacamten n ~ 250 per arm). DL random-effects inverse-variance weights handle the imbalance correctly but GRADE indirectness should note the heterogeneous population scale when the pool mixes pivotal mega-trials with smaller confirmatory trials. - **Prediction interval:** Suppressed for k < 3 (display reads "PI undefined"). Enabled with t-df = k-2 (Higgins 2009) once k >= 3. - **Browser-hosted WebR cross-validation (optional, user-triggered):** The Analysis tab exposes a "Validate pool with R" button that loads WebR (WebAssembly R) and installs `metafor` on first click (~40 MB one-time download, cached thereafter). Running the validation re-computes the DL random-effects pool via `metafor::rma(method="DL", test="knha")` independently of the app's native pool and reports an EXACT / CLOSE / DIFFER flag against the displayed pool. No automated sharing of code between the R and JS poolers — independent implementations in two languages, two numerical libraries. --- ## 9. Certainty of Evidence (GRADE) Standard GRADE domains. MCID for body-weight MD typically ~5% in obesity trials. --- ## 10. Reporting and Dissemination - **Reporting guideline:** PRISMA 2020 - **Published benchmark:** Pooled % body weight MD approximately -12% across STEP-1/-3/-5 at 2.4 mg (consistent with Singh N et al. 2024 network MA of the STEP programme). --- ## 11. Living-MA Update Cadence - **Trigger:** User-initiated CT.gov + Europe PMC re-query; new STEP-family trials auto-proposed as pending-include. --- ## 12-14 Aggregate-data only. No competing interests, no funding. --- - **Formal 3-monthly cadence:** Independent of new trial publications, a formal search + protocol-check is run every 3 months (quarterly); the result is recorded in the app's Version Timeline with a dated "no change" or "new trial added" entry. - **Change-of-estimate threshold:** If a newly-added trial shifts the pooled estimate by > the pre-specified MCID (or by > half the width of the current 95% CI, whichever is smaller), a protocol amendment bump (v1.1 -> v1.2) is issued and noted in the Changelog. ## Appendix A. AMSTAR-2 Critical-Domain Self-Assessment AMSTAR-2 has 16 items; the **8 critical domains** most load-bearing for the journal editor's confidence judgment are 2, 4, 7, 9, 11, 13, 15 (Shea 2017 BMJ). Our self-assessment below should be re-scored by the second reviewer before journal submission. | # | Domain | Self-rating | Evidence / location | |---|---|---|---| | 2 (critical) | Protocol registered before data extraction | Yes (partial) | GitHub-canonical-URL freeze at the `canonical_url` above; PROSPERO registration not attempted (see §1). Authors targeting PROSPERO-required journals should register before the first formal update cycle. | | 4 (critical) | Comprehensive search strategy | Yes | §4. CT.gov API v2 + Europe PMC + OpenAlex with CT.gov live re-query triggered from the Search tab. Search cadence documented in §11. | | 7 (critical) | List of excluded studies with reasons | Yes | App Screening tab "Excluded" filter lists each excluded trial with the Protocol-§3 exclusion reason in the audit log. | | 9 (critical) | RoB assessment | Yes | Authors have double-checked screening and data extraction against the record excerpts shown in the Extraction tab; the provisional AI-drafted RoB-2 ratings have been author-confirmed. Formal dual-assessor RoB-2 with inter-rater kappa remains a per-submission artefact (see Extraction-tab banner). | | 11 (critical) | Appropriate statistical methods for combining results | Yes | §8. DL random-effects with HKSJ t-distribution df=k-1 and variance-inflation floor `max(1, Q/(k-1))`. Fixed-effect primary substituted at k=2 per CART-MM protocol pattern. | | 13 (critical) | Account for RoB when interpreting / discussing results | Partial | GRADE-profile §9 downgrades for RoB when >=50% of weight comes from trials rated Some concerns / High. Interpretation reflects this in the app's Scientific Output tab. | | 15 (critical) | Publication bias assessment | Yes (k-appropriate) | §8. Contour-enhanced funnel plot (all k); Egger/Peters regression for k>=10; Duval-Tweedie trim-and-fill as sensitivity at k<10 noting low power. | | 1 | PICO research question | Yes | §2 PICO table. | **Non-critical domains (brief):** Item 3 (Design-for-inclusion rationale) Yes; Item 5 (Duplicate study selection) Yes via two-reviewer HMAC-signed seal; Item 6 (Duplicate data extraction) Yes same mechanism; Item 8 (Adequate description of included studies) Yes (Extraction tab); Item 10 (Funding sources of included studies) Partial (tracked for demonstrators only); Item 12 (Heterogeneity discussion) Yes §8; Item 14 (Satisfactory explanation of heterogeneity) Yes §8 subgroup/meta-regression; Item 16 (Funding/conflicts of this review) Yes §14. **Author sign-off gate:** Second reviewer to initial each critical-domain rating against the protocol text before PDF generation for journal submission. --- ## Changelog - **v1.1** (2026-04-20) -- Editor-review revision: AMSTAR-2 critical-domain appendix populated, PROSPERO reframing, HKSJ-floor + zero-cell rules promoted to SAP bullets, 3-monthly formal cadence, trim-and-fill sensitivity, timepoint harmonisation rule where applicable. Pre-registered at canonical-URL freeze. - **v1.0** (2026-04-19) — Initial protocol registration at portfolio expansion of 2026-04-19.