Tirzepatide versus insulin glargine in higher-risk diabetes: SURPASS-4

Why this study matters

Many people with type 2 diabetes also have heart disease or a high risk of it. Before a new diabetes medicine is used widely in this group, regulators want evidence that it does not raise the risk of heart attacks and strokes. SURPASS-4 was designed with that safety question in mind. It compared tirzepatide (Zepbound, Mounjaro) with insulin glargine, a long-acting insulin. The published summary we reviewed does not report weight results.

Who was in the study

The trial screened 3045 people and randomized 2002 adults aged 18 or older. All had type 2 diabetes treated with some combination of metformin, a sulfonylurea or an SGLT2 inhibitor, with an HbA1c of 7.5 to 10.5% and a body mass index, or BMI, of 25 or more. HbA1c is a blood test that reflects average blood sugar over about three months. BMI is a number that relates weight to height. Everyone had established heart or blood vessel disease or a high risk of heart events.

It ran at 187 sites in 14 countries. Everyone was treated for at least 52 weeks, with treatment continued for up to 104 weeks to collect heart events.

What the researchers did

This was an open-label trial, meaning participants and researchers knew which medicine each person received. People were randomized, meaning assigned by chance, in a 1:1:1:3 ratio to weekly tirzepatide injections at 5 mg, 10 mg or 15 mg, or to daily insulin glargine 100 U/mL. The insulin dose was adjusted to reach a fasting blood sugar below 100 mg/dL.

The primary outcome was the change in HbA1c from the start to 52 weeks for tirzepatide 10 mg and 15 mg compared with glargine, tested for noninferiority, meaning tirzepatide was no worse than glargine by more than 0.3 percentage points. Major adverse cardiovascular events, called MACE-4, were reviewed by an independent committee. MACE-4 combined death from heart causes, heart attack, stroke and hospital admission for unstable angina.

What they found

In total, 1995 people received at least one dose: 329 on tirzepatide 5 mg, 328 on 10 mg, 338 on 15 mg and 1000 on glargine.

At 52 weeks, HbA1c fell by 2.43 percentage points with tirzepatide 10 mg and 2.58 with 15 mg, compared with 1.44 percentage points with glargine. The differences from glargine were -0.99 percentage points for 10 mg (97.5% CI -1.13 to -0.86) and -1.14 for 15 mg (97.5% CI -1.28 to -1.00). A confidence interval, or CI, is the range within which the true difference most likely sits. Both doses met the noninferiority margin.

MACE-4 events occurred in 109 participants. The hazard ratio for tirzepatide compared with glargine was 0.74, with a 95% CI of 0.51 to 1.08 (R32-C54). A hazard ratio below 1 points toward fewer events, but this interval includes 1.0, which means the trial could not rule out no difference. The authors describe this as tirzepatide not being associated with excess cardiovascular risk. It does not establish a heart benefit. In total, 60 people died during the study.

Side effects and people who stopped

Stomach and bowel side effects were more common with tirzepatide than with glargine: nausea in 12 to 23% versus 2%, diarrhea in 13 to 22% versus 4%, decreased appetite in 9 to 11% versus less than 1%, and vomiting in 5 to 9% versus 2%. Most were mild to moderate and happened while the dose was being raised. Low blood sugar was less common with tirzepatide, especially in people not taking a sulfonylurea (1 to 3% versus 16%). The published summary we reviewed does not report how many people in each group stopped treatment, or stopped because of side effects.

What this study does not tell you

• Heart events were a safety measure, not the main outcome, and the confidence interval includes no difference. This trial does not show that tirzepatide prevents heart attacks or strokes.
• The published summary does not report weight change, so this page cannot describe weight effects.
• The trial was open-label, which may affect how side effects were reported.
• Everyone had type 2 diabetes with high heart risk on specific oral medicines, and the comparator was insulin, not another injectable diabetes or weight medicine. Results may not apply to other groups.
• Results should not be lined up against other trials to rank medicines, and we reviewed the abstract only.

What it means in Canada

For Canadian readers with type 2 diabetes and heart risk, SURPASS-4 shows how tirzepatide compared with insulin glargine on blood sugar and on heart safety over about one to two years. It does not describe how the medicine is prescribed or paid for here. See tirzepatide in Canada, public drug coverage by province and compare services.

Related reading

Other studies in this library that bear on the same question.

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