Semaglutide
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How this letter has changedLatest: August 2026 · First graded.
Graded A on the cardiovascular composite, not on weight loss. SELECT (PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 37952131) and SUSTAIN-6 (PMID 27633186) are two independent randomized trials in different populations, both reporting a reduction in cardiovascular death, myocardial infarction or stroke. Weight reduction is the reason most readers arrive at this record and is not what earns the letter.PMID 37952131 PMID 27633186
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Semaglutide is a prescription drug best known for weight loss. Two large studies, in two different groups of patients, tested whether it prevents heart attacks, strokes and deaths from heart disease. Both found fewer of these events. Everyone in those studies already had heart disease or type 2 diabetes, so the results say nothing about healthy people taking it to live longer. In the larger study, about twice as many people stopped it because of side effects as stopped a dummy pill. Weight tends to come back after stopping, and muscle is lost along with fat.
Funding: Both randomized trials replicating this Grade A were funded by the maker of the drug they tested, Novo Nordisk. The funder's role in design and analysis is not stated here, because the full trial reports could not be read. The letter stands because each trial met the grading rules on its own; the funding is stated here so it can be weighed alongside it. Investigators: Both randomized trials replicating this Grade A were run by investigators employed by, founded by, or belonging to the organization that developed, sells or teaches the intervention (Novo Nordisk, the drug maker, whose employees are among the authors). The funder may read non-commercial; the people who ran the trials are part of the organization whose intervention they tested, which is stated here so it can be weighed alongside the letter.
A letter describes the human evidence, not the product, the manufacturer, or the intervention's worth.
Why this gradeThe reasoning, and what the grade does not cover.
Grade A by the replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away. hard-outcome route: two randomized trials in different populations, both on a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke.
WHAT THIS GRADE DOES NOT COVEReveryone enrolled already had established cardiovascular disease, or type 2 diabetes. The A says this drug prevents events in people who are already ill. It says nothing about a healthy adult taking it to live longer, and no trial has asked that question. Weight loss is the reason most people take semaglutide and is not the endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score. that earned the letter. Two things belong beside the A rather than below it: permanent discontinuation for adverse events ran roughly double placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received. in the larger trial, and retinopathy complications were more frequent on semaglutide in the diabetes trial.
Shared endpoint: Cardiovascular death, non-fatal myocardial infarction or non-fatal stroke
- SUSTAIN-6 (Marso): 26 percent fewer major cardiovascular events, type 2 diabetes. PMID 27633186 · Funding: manufacturer-funded (Novo Nordisk)
- SELECT (Lincoff): 20 percent fewer major cardiovascular events, obesity without diabetes. PMID 37952131 · Funding: manufacturer-funded (Novo Nordisk)
What the replication does not cover: Different populations and trial leadership, but the same sponsor funded both trials.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
Reduction of major adverse cardiovascular events, in two separate randomized populations. Weight loss is the reason most people take it and is not the endpoint that earns the A.
Replicated randomized human trials on a hard clinical outcome, an objectively measured function, or a validated scale scored by a clinician blinded to treatment.
The trials this grade rests on used the weekly injection; the daily tablet is a different route and dose. Every participant had type 2 diabetes or established cardiovascular disease, so the grade does not describe use in healthy adults.
Prescription only; requires physician management. Cardiovascular risk factors and lean mass.
Personal or family history of medullary thyroid carcinoma or MEN2, and pregnancy, are labeled contraindications A condition or medication that makes a treatment unsafe or unsuitable for a particular person.. Discontinuation is followed by weight regain in the reported off-treatment data. Lean mass is lost alongside fat mass.
- PMID 37952131 →Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes
- PMID 27633186 →Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes.
- PMID 33567185 →Once-Weekly Semaglutide in Adults with Overweight or Obesity.
This record grades the drug's own evidence. What the drug does to nutrient and lean-mass status is a separate question, answered on the GLP-1 receptor agonist depletion A fall in a nutrient's level caused by a medication, for example through reduced absorption or increased loss. record, which is where the lean-mass caution and the absolute-risk figures live.
Depletion record →Primary evidenceThree papers, each linked to its PubMed record.
Lincoff et al., SELECT (New England Journal of Medicine, 2023; PMID 37952131): 17,604 adults aged 45 and over with pre-existing cardiovascular disease and BMI 27 or higher, without diabetes, randomized to semaglutide 2.4 mg weekly or placebo. Pre-specified primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke: 6.5% versus 8.0%, hazard ratio How often an event happened in the treated group compared with the control group over the same period. A ratio of 0.80 means 20 percent fewer events. 0.80 (95% CI 0.72 to 0.90, p<0.001), over a mean 39.8 months. Permanent discontinuation for adverse events was 16.6% versus 8.2%. Marso et al., SUSTAIN-6 (New England Journal of Medicine, 2016; PMID 27633186): 3,297 adults with type 2 diabetes, same composite endpoint, 6.6% versus 8.9%, hazard ratio 0.74 (95% CI 0.58 to 0.95). Two independent randomized trials in different populations, both on a hard clinical outcome. Grade A is reached by a replicated hard clinical outcome, a replicated objectively measured function, or a replicated scale scored by a clinician blinded to treatment; this record takes the first route. Wilding et al., STEP-1 (New England Journal of Medicine, 2021; PMID 33567185) is cited for the weight endpoint and is not what the A rests on. Retinopathy complications were more frequent on semaglutide in SUSTAIN-6.
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