S tier · elite
Semaglutide is the only compound in this set with a completed, published cardiovascular outcomes programme (SELECT, SOUL) on top of multiple approvals across diabetes, obesity, CV risk reduction and MASH, making its evidence base the deepest of any incretin.
semaglutide
Semaglutide is a long-acting acylated GLP-1 receptor agonist approved in injectable and oral formulations for type 2 diabetes, chronic weight management and cardiovascular risk reduction. Randomised trials consistently report roughly 15% mean weight reduction in non-diabetic obesity and a significant reduction in major adverse cardiovascular events, though gastrointestinal intolerance drives meaningfully higher discontinuation than placebo.
the explanation
Semaglutide is a copy of a natural gut hormone that tells your brain you are full and slows how fast your stomach empties, so people eat less. In large studies it produced about 15% body-weight loss and cut the rate of heart attacks and strokes, but nausea and other stomach problems are common.
regulatory status
FDA-approved 2017 (Ozempic); 2021 (Wegovy)
Approved for type 2 diabetes (Ozempic 2017, oral Rybelsus 2019), chronic weight management (Wegovy 2021), cardiovascular risk reduction in overweight/obesity (2024), MASH (2025) and an oral weight-management formulation (2025).
how it works · proposed mechanism
Semaglutide is a chemically stabilised mimic of endogenous GLP-1 engineered for weekly dosing.
Glucose-dependent insulin release
Binding GLP-1 receptors on pancreatic beta cells amplifies insulin secretion only when glucose is elevated, and suppresses inappropriate glucagon release from alpha cells. Because the effect is glucose-dependent, monotherapy carries low intrinsic hypoglycaemia risk.
Slowed stomach emptying
GLP-1 receptor activation delays gastric emptying, prolonging distension and blunting post-meal glucose excursions. This same effect is the main driver of the nausea, vomiting and early satiety that dominate the adverse-event profile.
Appetite signalling in the brain
Semaglutide reaches GLP-1 receptor populations in the hypothalamus and area postrema, regions with an incomplete blood-brain barrier, reducing hunger and food reward valuation. Human imaging and ad-libitum feeding studies show reduced energy intake rather than increased energy expenditure.
Weight-independent vascular effects
SELECT secondary analyses reported cardiovascular benefit emerging earlier than and only partly proportional to weight loss. Reductions in hsCRP and blood pressure suggest anti-inflammatory and haemodynamic contributions that are not fully characterised.
what’s reported
evidence shape
6 sourcesThe composition of the cited literature by study type. This describes the shape of the evidence, not its quality — and it does not by itself set the grade.
⚠ the catch
Gastrointestinal intolerance is the dominant cost: in SELECT, adverse events led to trial-drug discontinuation in 16.6% of semaglutide recipients versus 8.2% on placebo. Weight regain after withdrawal is also substantial, with the STEP 1 extension showing participants regained roughly two-thirds of lost weight within a year of stopping.
key published findings
- SELECT (n=17,604, mean 40-month follow-up) reported MACE in 6.5% on semaglutide 2.4 mg versus 8.0% on placebo (HR 0.80, 95% CI 0.72–0.90, p<0.001) in adults with overweight/obesity and established CVD but without diabetes.
- STEP 1 (n=1,961, 68 weeks) reported mean weight change of −14.9% with semaglutide 2.4 mg versus −2.4% with placebo; 50.5% versus 4.9% achieved ≥15% weight loss.
- SOUL (n=9,650, median 47.5 months) reported MACE in 12.0% on oral semaglutide 14 mg versus 13.8% on placebo (HR 0.86, 95% CI 0.77–0.96, p=0.0028) in type 2 diabetes with ASCVD and/or CKD.
- SELECT reported adverse events leading to discontinuation in 16.6% of semaglutide recipients versus 8.2% on placebo (p<0.001), predominantly gastrointestinal.
- In the head-to-head SURMOUNT-5 trial (n=751, 72 weeks), semaglutide 1.7–2.4 mg produced −13.7% weight change versus −20.2% for tirzepatide 10–15 mg (p<0.001), placing it second among approved incretins for weight efficacy.
limitations of the evidence
- SELECT enrolled a secondary-prevention population aged ≥45 with established CVD and no diabetes; extrapolation to primary prevention or younger cohorts is not directly supported.
- Long-term data beyond roughly four years are sparse, so durability of both weight loss and cardiovascular benefit past that horizon is unestablished.
- The relative contribution of weight loss versus direct vascular mechanisms to the MACE reduction remains inferred from post-hoc mediation analyses rather than tested prospectively.
identity
| full name | Semaglutide (NN9535, acylated GLP-1 receptor agonist) |
| category | Metabolic |
| modality | peptide |
| formula | C187H291N45O59 |
| molar mass | 4113.58 g/mol |
| cas | 910463-68-2 |
| half-life | ~7 days (165–184 h) |
| sequence | HAibEGTFTSDVSSYLEGQAAK(AEEA-AEEA-γGlu-C18 diacid)EFIAWLVRGRG |
laboratory handling
| storage | Lyophilised reference material is typically stored at −20 °C protected from light and moisture, with vendor stability data commonly citing up to about 3 years; reconstituted aqueous solutions are generally held at 2–8 °C for short-term laboratory use or aliquoted at −80 °C to limit freeze-thaw degradation. |
| solubility | Poorly soluble in water at neutral pH; laboratory preparations commonly use bacteriostatic or sterile water at mildly alkaline pH, or DMSO (~1.6 mg/mL) for in vitro stock solutions. |
| co-studied with | Combination with the amylin analogue cagrilintide has been formally tested as CagriSema, and semaglutide is the reference comparator in most modern obesity trial designs. |
Handling information describes laboratory practice for a research reagent. It is not a preparation guide for use in humans.
the receipts
6 citedAmerican College of Cardiology · 2023 · official
NEJM · 2023 · peer-reviewed
NEJM · 2021 · peer-reviewed
NEJM · 2025 · peer-reviewed
Nature Medicine · 2024 · peer-reviewed
Diabetes, Obesity and Metabolism · 2022 · peer-reviewed
others in Metabolic