# Research timeline and gaps: Semaglutide Microdosing and Clinical Outcomes

Selected publication milestones, not an exhaustive history or discovery priority claim.

**2016 — Early weekly dose-finding establishes short exposure-response evidence and selects higher doses for phase 3; it is not long microdose maintenance.** [Original PMID26358288](https://pubmed.ncbi.nlm.nih.gov/26358288/).

**2017 — SUSTAIN 1 provides placebo-controlled 0.5/1 mg diabetes results at 30 weeks.** [Original PMID28110911](https://pubmed.ncbi.nlm.nih.gov/28110911/).

**2017 — A small 1 mg weekly crossover study directly measures reduced intake and appetite.** [Original PMID28266779](https://pubmed.ncbi.nlm.nih.gov/28266779/).

**2018 — Daily obesity dose-ranging demonstrates weight effects under a distinct injection schedule.** [Original PMID30122305](https://pubmed.ncbi.nlm.nih.gov/30122305/).

**2020 — SUSTAIN 8 DXA highlights absolute lean loss versus higher lean proportion without function testing.** [Original PMID31897524](https://pubmed.ncbi.nlm.nih.gov/31897524/).

**2021 — STEP 1 establishes 2.4 mg efficacy in BMI-defined non-diabetic adults at 68 weeks.** [Original PMID33567185](https://pubmed.ncbi.nlm.nih.gov/33567185/).

**2021 — STEP 4 demonstrates standard-dose continuation sensitivity after a tolerability run-in.** [Original PMID33755728](https://pubmed.ncbi.nlm.nih.gov/33755728/).

**2022 — Pooled STEP analyses separate gastrointestinal events from most observed weight loss without direct mediator manipulation.** [Original PMID34514682](https://pubmed.ncbi.nlm.nih.gov/34514682/).

**2023 — STEP 5 adds longer-term craving/eating-control measures, with early-only hunger/fullness contrasts.** [Original PMID36655300](https://pubmed.ncbi.nlm.nih.gov/36655300/).

**2023 — SELECT demonstrates hard cardiovascular benefit at the tested standard exposure.** [Original PMID37952131](https://pubmed.ncbi.nlm.nih.gov/37952131/).

**2025 — An older-diabetes retrospective cohort raises a context-specific functional concern requiring causal follow-up.** [Original PMID40631351](https://pubmed.ncbi.nlm.nih.gov/40631351/).

**2026 — SEMALEAN reports improved grip despite early lean loss in an uncontrolled standard-dose cohort.** [Original PMID41068996](https://pubmed.ncbi.nlm.nih.gov/41068996/).

**2026 — FLEX-SEMA documents response-selected flexible dosing; original-body threshold bins require correction of the indexed summary.** [Original PMID41725422](https://pubmed.ncbi.nlm.nih.gov/41725422/).

**2026 — A selected reduced-frequency case series suggests a distinct de-escalation question rather than microdose initiation.** [Original PMID41732031](https://pubmed.ncbi.nlm.nih.gov/41732031/).

**2026 — INFORM introduces semaglutide-specific FNQ recall data but cannot establish necessary mediation.** [Original PMID42217114](https://pubmed.ncbi.nlm.nih.gov/42217114/).

**2026 — A 60-week randomized study separates persistent objective intake/weight effects from waning subjective appetite contrasts.** [Original PMID42323166](https://pubmed.ncbi.nlm.nih.gov/42323166/).

## Research gaps

Direct randomized below-0.5 mg weekly maintenance at 24-68 weeks in the registered baseline BMI population.

Separate low-dose initiation from de-escalation after successful higher-dose loss; retain response/tolerance selection explicitly.

Matched noninferiority and simultaneous benefit-harm comparison against 2.4 mg, rather than final-dose observational nulls.

Prospective validated food-noise measurement and necessary-mediator testing distinct from appetite, cravings, nausea and one-meal intake.

Integrated absolute muscle mass, muscle quality, objective strength/function and nutrition across baseline age/diabetes strata.

Arm-specific low-dose phase 2 data and independent checking of complete bodies/supplements; three selected partial-body checks do not constitute a full-paper audit.

## Boundary experiment

A blinded randomized study in baseline-defined adults meeting the registered BMI criteria, stratified by diabetes, assigns a specified weekly injectable maintenance exposure below 0.5 mg, matched placebo and 2.4 mg with identical behavioral support. Prespecify 52-week weight change and at least 5% responder status, estimands, missingness, adverse events and objective strength/function. A separately randomized de-escalation arm can test maintenance after standard-dose loss without redefining the initial-treatment claim.