Lilly files cardiovascular outcomes supplements for both tirzepatide brands

Eli Lilly has filed prior approval supplements with the FDA for both of its tirzepatide medicines, seeking to add data from a completed cardiovascular outcomes trial to their prescribing information, and, for Mounjaro, to add a brand-new indication tied to heart risk ^[1][2].

For Zepbound, the supplement (S-041) is dated October 24, 2025, and was received by the FDA on October 27, 2025 ^[1][3]. For Mounjaro, two supplements were received on October 27 and November 5, 2025: S-044, which carries the cardiovascular trial data and a proposed new indication, and S-045, which addresses use of the 2.5 mg starting dose ^[2].

Both filings draw on trial I8F-MC-GPGN, known as SURPASS-CVOT, described in FDA correspondence as "The Effect of Tirzepatide versus Dulaglutide on Major Adverse Cardiovascular Events in Patients with Type 2 Diabetes" ^[1][2]. The study enrolled adults with type 2 diabetes and established cardiovascular disease ^[1]. The sources describe the trial's purpose and population but do not include specific results, such as event rates or hazard ratios, so those numbers are not yet known from the documents available.

For Mounjaro, S-044 seeks a new indication: reducing the risk of major adverse cardiovascular events — cardiovascular death, non-fatal heart attack, or non-fatal stroke — in adults with type 2 diabetes who are at high risk for those events ^[2]. Both drugs' labels would also gain updated warnings about diabetic retinopathy complications in patients with a history of retinopathy, based on findings from the same trial ^[1][2]. Mounjaro's separate S-045 supplement would update labeling to say the 2.5 mg dose can be used for ongoing glycemic control, not just as a starting dose ^[2].

Why it matters for patients

If granted, these changes would let Mounjaro's label state that the drug can lower the chance of a heart attack, stroke, or cardiovascular death in adults with type 2 diabetes and high cardiovascular risk — a claim Zepbound, which is approved for weight management rather than diabetes, would not carry under this filing ^[1][2]. That distinction matters because Zepbound's supplement adds trial data and retinopathy warning language but does not add a cardiovascular indication ^[1].

The retinopathy warning updates could be relevant for patients who already have a history of diabetic eye disease, since the labels would reflect findings from a trial specifically in people with type 2 diabetes and existing heart disease ^[1][2]. The documents do not describe what those retinopathy changes say in detail beyond noting they stem from SURPASS-CVOT.

The Mounjaro dosing update in S-045 could affect how doctors think about the lowest available dose, since it would formally support using 2.5 mg for continued blood sugar management rather than only as an introductory dose ^[2].

What happens next

FDA correspondence in these files shows the agency later approved these supplements. A letter regarding Zepbound's S-041 was signed August 26, 2026, with a correction issued September 2, 2026, after the agency found it had attached outdated versions of the Medication Guide and certain instructions for use; the corrected letter kept the same effective date ^[1][3]. A separate letter approving Mounjaro's S-044 and S-045 was signed August 27, 2026 ^[2]. Under S-044, the FDA waived pediatric study requirements for the new cardiovascular indication because the condition being studied "rarely or never occurs" in children ^[2]. Lilly must submit final product labeling and any promotional materials for FDA review to ensure they match the approved changes ^[1][2].