Tirzepatide
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How this letter has changedLatest: October 2026 · Downgraded.
Incident type 2 diabetes rests on one trial, the SURMOUNT-1 three-year analysis (Jastreboff et al., N Engl J Med, 2025; 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. 39536238), and the cardiovascular trial is a non-inferiority comparison with dulaglutide (Nicholls et al., N Engl J Med, 2025; PMID 41406444). Under Rule 03 a single positive trial without independent replication 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. is C, the rule applied to retatrutide in October. Closes the review opened October. Applied by the written grade definitions, October 2026.PMID 39536238 PMID 41406444
SURMOUNT-1 (PMID 39536238) reports a reduction in incident type 2 diabetes over 176 weeks against placebo An inactive substitute made to look like the real treatment, so participants cannot tell which one they received., a hard clinical outcome from a single trial. SURPASS-CVOT (PMID 41406444) is a non-inferiority trial against dulaglutide, which shows tirzepatide is not worse than a drug that works rather than that it beats placebo. That combination is B, not A.PMID 39536238 PMID 41406444
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Tirzepatide is a weekly injection for weight loss and diabetes. In people with obesity and prediabetes, one large study followed them for three years. About 1 in 75 people on the drug developed diabetes, compared with about 1 in 8 on a dummy shot. The result is large, but only one study has shown it so far.
A letter describes the human evidence, not the product, the manufacturer, or the intervention's worth.
Why this gradeGrade C, small or unreplicated trials. The reasoning, and what the grade does not cover.
Grade C on onset of type 2 diabetes in obesity with prediabetes, resting on one trial: in SURMOUNT-1's three-year analysis, diabetes developed in 1.3 percent on tirzepatide against 13.3 percent on placebo (Jastreboff et al., 2025; PMID 39536238). The result is large and the outcome is clinical, but under Rule 03 a single positive trial nobody has independently repeated is C however large or well run, the rule that moved retatrutide to C in October. The cardiovascular trial, SURPASS-CVOT (Nicholls et al., 2025; PMID 41406444), compared tirzepatide with dulaglutide, an active drug, and showed it was not worse; it is not a placebo-controlled benefit.
WHAT THIS GRADE DOES NOT COVERweight loss as its own endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score., a surrogate; cardiovascular events against placebo, which no trial has tested; and healthy adults taking it for longevity, which no trial has studied. It returns to B when a second trial reports diabetes onset as a prespecified outcome.
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Grade C: human trials exist, but they are small, mixed or not yet repeated. This is not a finding that it does not work. How to read a grade →
See the full evidence record →Prevention of progression to type 2 diabetes in obesity with prediabetes, and weight reduction. Its cardiovascular trial was designed to show it is not worse than another drug, not that it beats placebo.
Preliminary randomized evidence, small trials, or mixed results.
Tirzepatide subcutaneously once weekly, dose-escalated to 5, 10 or 15 mg, for 176 weeks in SURMOUNT-1. SURPASS-CVOT compared tirzepatide against dulaglutide rather than placebo.
Prescription only; requires physician management. Weight, HbA1c A blood test that reflects average blood sugar over the previous two to three months. 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.. Weight regain after discontinuation was measured in the trial's own off-treatment period. Lean mass is lost alongside fat mass.
- PMID 39536238 →Tirzepatide for Obesity Treatment and Diabetes Prevention.
- PMID 41406444 →Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes.
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 evidenceTwo papers, each linked to its PubMed record.
Jastreboff et al., SURMOUNT-1 three-year analysis (New England Journal of Medicine, 2025; PMID 39536238): phase 3, 2,539 participants with obesity of whom 1,032 had prediabetes, 176 weeks of treatment. Onset of type 2 diabetes 1.3% on tirzepatide versus 13.3% on placebo, 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. 0.07. Mean weight change at 176 weeks was -12.3% to -19.7% by dose versus -1.3%. Nicholls et al., SURPASS-CVOT (New England Journal of Medicine, 2025; PMID 41406444): 13,299 adults with type 2 diabetes and atherosclerotic disease randomized to tirzepatide or dulaglutide, an ACTIVE comparator already shown to reduce events. The primary composite occurred in 12.2% versus 13.1%. That is a non-inferiority result against another drug, not a demonstration of benefit against placebo. Incident diabetes is a hard clinical outcome, but the SURMOUNT-1 result is a single trial, which under Rule 03 is C until a second trial repeats it.
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tirzepatide[tiab] AND (prediabetes[tiab] OR "progression to type 2 diabetes"[tiab] OR "incident type 2 diabetes"[tiab] OR "onset of type 2 diabetes"[tiab] OR normoglycemia[tiab]) AND randomized controlled trial[pt]Grades move when new trials publish. A free monthly email lists every grade EBL moved, with the reason and the trial behind it: the sign-up is on the Evidence Log →