SURPASS-2 puts tirzepatide head-to-head against semaglutide 1 mg

Results from SURPASS-2, a head-to-head phase 3 trial, show that once-weekly tirzepatide beat once-weekly semaglutide 1 mg on blood sugar control and weight loss in adults with type 2 diabetes who were already taking metformin ^[1][2]. The trial randomly assigned 1,879 patients in a 1:1:1:1 ratio to tirzepatide 5 mg, 10 mg, or 15 mg, or to semaglutide 1 mg, and followed them for 40 weeks ^[1].

At the start, participants had a mean HbA1c of 8.28%, a mean age of 56.6 years, and a mean weight of 93.7 kg (about 207 pounds) ^[1]. The primary endpoint was the change in HbA1c — a blood test that reflects average blood sugar over roughly three months — from baseline to week 40 ^[1].

What the numbers showed

Estimated mean HbA1c dropped 2.01 percentage points with tirzepatide 5 mg, 2.24 points with 10 mg, and 2.30 points with 15 mg, compared with 1.86 points with semaglutide 1 mg ^[1]. The differences versus semaglutide were −0.15 points (95% CI, −0.28 to −0.03; P=0.02) for 5 mg, −0.39 points (95% CI, −0.51 to −0.26; P<0.001) for 10 mg, and −0.45 points (95% CI, −0.57 to −0.32; P<0.001) for 15 mg ^[1]. All three tirzepatide doses met the bar for both noninferiority and superiority ^[1].

Weight loss also favored tirzepatide at every dose. The estimated treatment differences versus semaglutide were −1.9 kg, −3.6 kg, and −5.5 kg for the 5 mg, 10 mg, and 15 mg groups respectively — roughly 4 to 12 pounds of extra weight loss — with P<0.001 for all comparisons ^[1]. The published abstract reports these differences but not the total weight change in each group, so the absolute pounds lost per arm is not available from this source ^[1].

Side effects were mostly digestive and mostly mild to moderate in both drugs ^[1]. Nausea was reported in 17% to 22% of tirzepatide patients versus 18% with semaglutide; diarrhea in 13% to 16% versus 12%; and vomiting in 6% to 10% versus 8% ^[1]. Low blood sugar under 54 mg/dL was uncommon: 0.6% (tirzepatide 5 mg), 0.2% (10 mg), 1.7% (15 mg), and 0.4% with semaglutide ^[1]. Serious adverse events occurred in 5% to 7% of tirzepatide patients and 3% of semaglutide patients ^[1]. The trial was open-label, meaning patients and clinicians knew which drug was given, and it was funded by Eli Lilly, which makes tirzepatide ^[1].

Why it matters for patients

This is one of the few direct, randomized comparisons between two incretin drugs rather than a comparison against placebo, so it carries more weight than cross-trial guesswork. It suggests that for people with type 2 diabetes on metformin, tirzepatide's dual action on the GIP and GLP-1 receptors produced somewhat larger average HbA1c and weight reductions than semaglutide's GLP-1-only action ^[1].

The comparator dose matters, and it is often blurred in secondary coverage. SURPASS-2 used semaglutide 1 mg — the once-weekly diabetes dose studied here — not a higher dose ^[1][2]. What would happen against a larger semaglutide dose is not answered by this trial and is not known from these sources.

Two other limits are worth keeping in mind. The averages hide wide individual variation, and group averages do not predict what any one person will experience. And the trial reports blood sugar and weight over 40 weeks, not longer-term outcomes like heart attacks, kidney disease, or death ^[1]. Serious adverse events were numerically higher with tirzepatide (5–7% versus 3%), though the abstract does not break down what those events were ^[1].

What happens next

The results were published June 25, 2021, alongside a New England Journal of Medicine editorial titled "Breaking New Ground with Incretin Therapy in Diabetes" ^[1]. At the time of publication, tirzepatide was described as still under development for type 2 diabetes ^[1]. SURPASS-2 is registered as NCT03987919 ^[1][2].