Semaglutide
A once-weekly GLP-1 receptor agonist licensed for type 2 diabetes and obesity — the drug that defined the current weight-loss era. Large, well-evidenced weight loss with a gastrointestinal side-effect profile as the main limit.
01 Overview
Semaglutide agonises the GLP-1 receptor, slowing gastric emptying and reducing appetite centrally. Its trial evidence base is among the strongest of any compound on this site.
Tirzepatide edges it on raw weight loss in head-to-head data, but semaglutide has the longer safety record and cardiovascular-outcome data.
02 Mechanism
A GLP-1 analogue resistant to enzymatic degradation. Enhances glucose-dependent insulin secretion, slows gastric emptying, and reduces appetite via central pathways.
03 Dosing
| Tier | Dose | Route | Notes |
|---|---|---|---|
| Starting | 0.25 mg/wk | SubQ | Four-week initiation dose to build tolerance. |
| Maintenance | 1–2.4 mg/wk | SubQ | Titrated up in monthly steps; 2.4 mg is the obesity dose. |
04 Effects
| Effect | Magnitude | Evidence | |
|---|---|---|---|
| Weight lossSTEP-1 trial at 2.4 mg | ~15% at 68 weeks | Clinical | |
| Glycaemic controlEstablished in type 2 diabetes | HbA1c −1.5 to −1.8% | Clinical | |
| Reduced cardiovascular eventsSELECT trial in overweight patients without diabetes | Significant | Clinical |
05 Side effects
| Effect | Severity | Frequency | Evidence | Countermeasures |
|---|---|---|---|---|
| Gastrointestinal effectsNausea, vomiting, diarrhoea and constipation — the dose-limiting effect and main reason for discontinuation. | Moderate | Very common | Clinical | |
| Lean mass lossA meaningful fraction of rapid weight loss is lean tissue. | Moderate | Common | Clinical |
06 Commonly used with
What semaglutide is combined with, and why. This is about intent rather than safety — the interactions table below covers what is dangerous. Nothing here is listed without what it costs.
| Compound | Frequency | Purpose & trade-off |
|---|---|---|
| Stacked compounds | ||
| Tirzepatideswitch/overlap, not co-administration | Some users transition from semaglutide to tirzepatide (or briefly overlap during a switch) chasing greater weight loss from the added GIP activity.Trade-off: Running two incretin agonists together stacks GI side effects and hypoglycaemia risk (especially with insulin/sulfonylureas) for little proven extra benefit over simply switching. | |
| Support & ancillaries | ||
| Metformininsulin-sensitiser | Frequently paired in type-2 diabetes and off-label weight use because metformin improves insulin sensitivity through a different mechanism, giving additive glycaemic and modest weight benefit.Trade-off: Both are GI-heavy, so combined nausea, diarrhoea and appetite loss can be pronounced, and the added anorexia makes it easier to under-eat protein and lose muscle. | |
| Resistance training + high-protein dietmuscle preservation | Run alongside a semaglutide cut because the large calorie deficit it produces otherwise strips a substantial fraction of weight as lean mass.Trade-off: Semaglutide's appetite suppression makes hitting protein targets genuinely hard, so the very tool driving fat loss also undermines the intake needed to keep muscle. | |
| B12 / electrolyte and hydration supportadjunct | Used to offset dehydration, constipation and reduced micronutrient intake that follow from the sharply lowered food and fluid consumption.Trade-off: It is a minor patch that does nothing for the core risks (pancreatitis signal, gallbladder issues, muscle loss) and can breed complacency about inadequate overall nutrition. | |