Purpose
The metabolic-research stack is a reference for the GLP-1 receptor axis. Unlike the recovery or GH-axis stacks, GLP-1 receptor engagement is well-characterised in large randomised human clinical trials — the SUSTAIN, STEP, and SELECT programs for semaglutide, and the SURPASS and SURMOUNT programs for tirzepatide.
Because the clinical evidence base is large, this stack profile focuses on documenting what those trials reported, and on the pharmacology that underlies the observed effects.
Component peptides
- Semaglutide — long-acting GLP-1 receptor agonist; dose-escalated from 250 mcg to 2,400 mcg weekly in the STEP obesity program.
- Tirzepatide — dual GLP-1 / GIP receptor agonist. Profile pending — will be documented on its own page. Reported here as a comparator only.
Note: semaglutide is described in the STEP clinical program as a single agent. This is a documentation stack rather than a “combination” stack.
Timing & escalation
The dose-escalation schedule used in the pivotal STEP trials is a reference pattern in the research literature:
| Week | Dose |
|---|---|
| 1–4 | 250 mcg |
| 5–8 | 500 mcg |
| 9–12 | 1,000 mcg |
| 13–16 | 1,700 mcg |
| 17+ | 2,400 mcg (maintenance) |
The escalation is designed to reduce the incidence and severity of gastrointestinal side effects, which are the most-cited dose-dependent adverse events across the semaglutide clinical program.
Weekly administration is on the same day each week to stabilise serum concentrations, given the ~1-week half-life.
Reported outcomes
- STEP-1 — 68 weeks of semaglutide 2.4 mg weekly plus lifestyle intervention: mean body-weight reduction of approximately 14.9% versus 2.4% for placebo (Wilding et al., 2021).
- SELECT — 2.4 mg weekly reduced the primary MACE composite by approximately 20% in adults with established cardiovascular disease and overweight/obesity without diabetes (Lincoff et al., 2023).
- SUSTAIN-6 — 0.5–1.0 mg weekly reduced the composite of cardiovascular death, non-fatal MI, or non-fatal stroke by 26% in adults with type 2 diabetes (Marso et al., 2016).
Cautions in the literature
- GI side effects during escalation. Nausea, vomiting, and diarrhea are the most common adverse events in the semaglutide trials; incidence peaks during the escalation phase and generally attenuates on stable maintenance dosing.
- Pancreatitis, gallbladder disease. Both are noted in the labelling for regulated semaglutide formulations.
- Rodent thyroid C-cell tumours. The regulated-drug labelling carries a boxed warning based on animal-study findings; the human relevance is uncertain and contested in the literature.
- Not for personal medical use. Research-grade material is not equivalent to the regulated pharmaceutical formulation and this profile is not a treatment guide.
References
See the Semaglutide profile for the primary clinical-trial citations. Tirzepatide references will be added with that profile.