What the new indication says
Section 1 of the US label lists two uses. The first is the long-standing one: improving blood sugar control, alongside diet and exercise, in adults with type 2 diabetes and in children with it from age 10. The second is reducing the risk of major adverse cardiovascular events, defined as cardiovascular death, non-fatal myocardial infarction (heart attack) or non-fatal stroke, in adults with type 2 diabetes who are at high risk for these events [1].
The Recent Major Changes box at the top of the label dates the cardiovascular indication 08/2026 and the pediatric wording 12/2025. Two warnings were also updated: severe gastrointestinal reactions in 12/2025 and diabetic retinopathy complications in people with a history of retinopathy in 08/2026 [1].
The indication does not extend to people without type 2 diabetes. The Zepbound® label, which contains tirzepatide for weight management and obstructive sleep apnea, carries no cardiovascular indication [4].
How the US, European and Canadian documents compare
Regulators reviewed the same trial but word the outcome differently. The table summarises what each document checked on 20 October 2026 says, with the section where it says it.
| Document | Cardiovascular wording | Where |
|---|---|---|
| Mounjaro®, US prescribing information, revised 08/2026 [1] | Separate indication to reduce major cardiovascular events in adults with type 2 diabetes at high risk | Section 1; trial in 14.6 |
| Mounjaro®, EU product information [2] | No separate indication; section 4.1 points to section 5.1, which says the result demonstrated a cardiovascular risk-reduction benefit | Sections 4.1 and 5.1 |
| Mounjaro®, Canadian product monograph, authorized 2026-06-23 [3] | Blood sugar control only; no cardiovascular indication | Section 1 |
| Zepbound®, US prescribing information, revised 08/2026 [4] | Weight management and sleep apnea; no cardiovascular indication | Section 1 |
Who was in SURPASS-CVOT
- Adults aged 40 or older with type 2 diabetes and established cardiovascular disease, an HbA1c between 7.0% and 10.5%, and a BMI of 25 kg/m² or higher [1].
- Average age 64, with diabetes for about 15 years; average HbA1c 8.4% and BMI 33 kg/m². About 71% were men, and 23% had an eGFR below 60, a marker of reduced kidney function [1].
- Heart and vessel history was common: 65% had coronary artery disease, 47% a previous heart attack, 25% peripheral artery disease, 19% a previous stroke and 20% previous heart failure [1].
- Most were already on heart-protective treatment, with 86% taking a statin and 83% an antiplatelet medicine. Almost half (49%) used insulin at the start. Among those on tirzepatide, half were 65 or older and 11% were 75 or older [1].
An active comparator, not placebo
Instead of placebo, the comparison group received dulaglutide 1.5 mg once a week. Dulaglutide is the active ingredient of Trulicity®, which has its own indication to reduce major cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or several risk factors [1][5]. In the trial, tirzepatide was started at 2.5 mg weekly and raised every 4 weeks up to 15 mg, or the highest dose a person tolerated [1].
Investigators were expected to adjust blood sugar, cholesterol and blood pressure treatment to local standards of care throughout. Both groups therefore received active care, and the question was how tirzepatide compared with a medicine already known to lower risk [1]. The trial publication set the non-inferiority margin at 1.05 for the upper limit of the confidence interval, and required an upper limit below 1.00 to call tirzepatide superior [10].
How GLP-1 heart trials were designed
Each US label below describes the trial behind its cardiovascular indication. The hazard ratios cannot be compared with one another directly: the populations, comparators and lengths differ, and a ratio against an active medicine answers a different question from a ratio against placebo.
| Label and section | Trial and population | Compared with | Hazard ratio for a first major event (95% CI) |
|---|---|---|---|
| Mounjaro®, 14.6 [1] | SURPASS-CVOT; 13,299 adults with type 2 diabetes and established cardiovascular disease | Dulaglutide | 0.92 (0.83 to 1.01); non-inferior, superiority not established |
| Trulicity®, 14.5 [5] | REWIND; 9,901 adults with type 2 diabetes and established disease or several risk factors | Placebo | 0.88 (0.79 to 0.99) |
| Ozempic®, 14.2 [6] | SUSTAIN 6; 3,297 adults with type 2 diabetes and atherosclerotic cardiovascular disease | Placebo | 0.74 (0.58 to 0.95) |
| Rybelsus® and Ozempic® tablets, 14.4 [7] | Trial 7; 9,650 adults with type 2 diabetes and cardiovascular or chronic kidney disease | Placebo | 0.86 (0.77 to 0.96) |
| Victoza®, 14.3 [8] | LEADER; 9,340 adults with type 2 diabetes and atherosclerotic disease | Placebo | 0.87 (0.78 to 0.97) |
| Wegovy®, 14.1 [9] | SELECT; 17,604 adults with cardiovascular disease and obesity or overweight, no diabetes | Placebo | 0.80 (0.72 to 0.90) |
The main result
Over a median follow-up of 210.1 weeks, the combined event (cardiovascular death, heart attack or stroke) occurred in 803 of 6,647 people on tirzepatide (12.1%) and 863 of 6,647 on dulaglutide (13.0%). The hazard ratio was 0.92, with a confidence interval from 0.83 to 1.01 [1].
Non-inferior means the trial ruled out tirzepatide being meaningfully worse than dulaglutide. Because the upper end of the interval reaches past 1.00, it did not show tirzepatide to be better at preventing these events [1].
The trial publication gives slightly different counts, 801 (12.2%) and 862 (13.1%), because it analysed 6,586 and 6,579 people after excluding 134 who did not meet the entry criteria; the hazard ratio is the same [10]. The label counts everyone randomized and treated [1].
The individual outcomes
| Outcome | Dulaglutide | Mounjaro® | Hazard ratio (95% CI) |
|---|---|---|---|
| Combined event (primary) [1] | 13.0% | 12.1% | 0.92 (0.83 to 1.01) |
| Cardiovascular death | 6.2% | 5.5% | 0.89 (0.77 to 1.02) |
| Non-fatal heart attack | 4.7% | 4.4% | 0.93 (0.80 to 1.09) |
| Non-fatal stroke | 3.3% | 3.2% | 0.97 (0.80 to 1.16) |
| Fatal or non-fatal heart attack | 5.4% | 4.7% | 0.87 (0.74 to 1.01) |
| Fatal or non-fatal stroke | 3.7% | 3.4% | 0.91 (0.76 to 1.09) |
| Death from any cause | 10.1% | 8.5% | 0.84 (0.75 to 0.94) |
Reading the secondary numbers and later analyses
Death from any cause was lower on tirzepatide, with an interval of 0.75 to 0.94. The label nonetheless marks this and each component as not controlled for the family-wise type I error rate [1]. Put simply, the trial was not set up to confirm these results, so they describe what was observed rather than a proven benefit. Both groups saw lower HbA1c and body weight at month 36; the label does not give the size of those changes in this section [1].
The European product information adds a kidney observation: among participants at high or very high risk of chronic kidney disease, eGFR fell less on tirzepatide than on dulaglutide by month 36, which the document calls clinically meaningful [2]. The US label does not include this finding.
- Indirect “imputed placebo” analysis, 2026: the investigators multiplied the SURPASS-CVOT result by the dulaglutide-versus-placebo result from REWIND and estimated a hazard ratio of 0.72 for tirzepatide against a placebo that was never actually given. The authors call it prespecified but exploratory; borrowing a comparison from another trial cannot replace a randomized placebo group [11].
- Heart failure with preserved ejection fraction (SUMMIT): in 731 adults with obesity and this type of heart failure, tirzepatide lowered the combined risk of cardiovascular death or worsening heart failure against placebo (9.9% versus 15.3%) [12]. The EU product information reports this trial in section 5.1 [2]; neither the US Mounjaro® nor the Zepbound® label lists heart failure as an indication [1][4].
Side effects and warnings in this population
The label says adverse reactions in SURPASS-CVOT were similar to those in the earlier diabetes trials, with some higher figures: decreased appetite in 17%, constipation in 13%, vomiting in 12%, fatigue and abdominal pain each in 10%, and dysesthesia (altered skin sensation) in 0.7%. Average pancreatic amylase rose 29% and lipase 28% from baseline [1]. The label found no overall differences in safety or effectiveness between people 65 and older and younger adults [1].
Two warnings matter more for people in this group. Section 5.3 says that using Mounjaro® with insulin or a sulfonylurea can raise the risk of low blood sugar, including severe episodes, and that a lower dose of those medicines may be needed; that decision belongs to your prescriber [1]. Section 5.7, updated in 08/2026, says rapid improvement in blood sugar has been linked with temporary worsening of diabetic retinopathy, and asks for people with a history of it to be monitored [1]. The boxed thyroid C-cell tumor warning is unchanged by the new indication.
Mounjaro®, Zepbound® and Trulicity® are registered trademarks of Eli Lilly and Company. Ozempic®, Rybelsus®, Victoza® and Wegovy® are registered trademarks of Novo Nordisk A/S. PepLabo is not affiliated with or endorsed by Eli Lilly and Company or Novo Nordisk.
When to get help
| Sign | Who to contact | How fast | Source |
|---|---|---|---|
| Chest pressure, squeezing or pain lasting more than a few minutes, or sudden shortness of breath | Emergency services (911 or your local number), even if unsure | Emergency | MedlinePlus [13] |
| Sudden weakness or numbness on one side, trouble speaking, sudden vision loss or a sudden severe headache | Emergency services (911 or your local number) | Emergency | MedlinePlus [14] |
| Repeated low blood sugar while also using insulin or a sulfonylurea | Your prescriber | Today | US label, sections 5.3 and 17 [1] |
| Changes in vision if you have a history of diabetic retinopathy | Your prescriber or eye specialist | Today | US label, sections 5.7 and 17 [1] |
| Questions about whether the heart indication applies to you | Your prescriber or cardiologist | At your next appointment | US label, section 1 [1] |
