Tirzepatide lowers A1c and weight more than semaglutide 1 mg in head-to-head trial

In a 40-week head-to-head trial, three once-weekly doses of tirzepatide lowered A1c more than semaglutide 1 mg in adults with type 2 diabetes, and the tirzepatide groups also lost more weight on average ^[1]. The study was funded by Eli Lilly, which makes tirzepatide, and was published in the New England Journal of Medicine ^[1].

The trial, called SURPASS-2, randomly assigned 1,879 adults with type 2 diabetes to four groups of equal size ^[1]. All were taking metformin, and the drugs were added to that treatment ^[2]. Participants received tirzepatide 5 mg, 10 mg, or 15 mg once a week, or semaglutide 1 mg once a week ^[1]. The trial was open-label, meaning participants and researchers knew which drug each person was receiving, and it ran 40 weeks ^[1]. At the start, the average A1c was 8.28%, the average age was 56.6 years, and the average weight was 93.7 kg ^[1]. The main goal was the change in A1c from the start of the trial to week 40 ^[1].

Tirzepatide is a dual GIP and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist ^[1]. The report described tirzepatide as under development for type 2 diabetes at the time of publication ^[1].

The numbers

A1c fell by an estimated 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 estimated differences between each tirzepatide dose and semaglutide were 0.15 points (95% confidence interval, -0.28 to -0.03; P = 0.02) at 5 mg, 0.39 points (95% CI, -0.51 to -0.26; P<0.001) at 10 mg, and 0.45 points (95% CI, -0.57 to -0.32; P<0.001) at 15 mg ^[1]. The trial reported tirzepatide as noninferior and superior to semaglutide at all three doses ^[1].

Weight fell more with tirzepatide at every dose. The estimated differences compared with semaglutide were 1.9 kg, 3.6 kg, and 5.5 kg for the 5 mg, 10 mg, and 15 mg groups, with P<0.001 for all three comparisons ^[1].

Gastrointestinal side effects were the most common in both groups and were mostly mild to moderate in severity ^[1]. Nausea was reported by 17% to 22% of people taking tirzepatide and 18% of those taking semaglutide; diarrhea by 13% to 16% and 12%; and vomiting by 6% to 10% and 8% ^[1]. Blood sugar below 54 mg per deciliter was reported in 0.6% of the 5 mg group, 0.2% of the 10 mg group, and 1.7% of the 15 mg group, compared with 0.4% of the semaglutide group ^[1]. Serious adverse events were reported in 5% to 7% of people taking tirzepatide and 3% of those taking semaglutide ^[1]. Which serious adverse events occurred has not been reported in the summary of the trial results.

Why it matters for patients

The comparison was against semaglutide 1 mg, the dose used in this trial. No other semaglutide dose was tested ^[1]. The results therefore describe how tirzepatide compared with that one dose, and how tirzepatide compares with other doses of semaglutide has not been reported in this trial.

The A1c advantage for tirzepatide was smallest at the lowest dose: 0.15 percentage points, a gap the trial reported as statistically significant but modest in size ^[1]. The differences were larger at 10 mg and 15 mg.

The weight differences, 1.9 kg to 5.5 kg on average, come from a trial of people with type 2 diabetes whose average starting weight was 93.7 kg ^[1]. The study was not designed as a weight-loss trial, so its weight findings are secondary to its main A1c goal.

Side effects were common in both groups, with gastrointestinal symptoms leading the list in each ^[1]. The trial lasted 40 weeks and was open-label, so longer-term safety and how the two drugs compare when people do not know which one they are receiving have not been reported in these results.

What happens next

The trial is registered on ClinicalTrials.gov as NCT03987919 ^[2]. The published report does not describe further studies or say what regulatory steps follow for tirzepatide ^[1].