Tirzepatide cuts A1c by up to 2.07 points in phase 3 type 2 diabetes trial

The once-weekly drug tirzepatide lowered A1c by 1.87 to 2.07 percentage points over 40 weeks in adults with type 2 diabetes whose blood sugar was not controlled by diet and exercise alone, while A1c rose 0.04 points in those taking placebo, according to a phase 3 trial reported in The Lancet ^[1].

SURPASS-1 enrolled 478 adults who were not taking injectable diabetes therapy. Their average starting A1c was 7.9%, average age was 54.1 years, 48% were women, average diabetes duration was 4.7 years, and average body mass index was 31.9 ^[1]. The trial ran at 52 medical research centers and hospitals in India, Japan, Mexico, and the United States ^[1]. Participants were assigned at random to once-weekly tirzepatide at 5, 10, or 15 mg, or to placebo: 121 people in each tirzepatide group and 115 in the placebo group ^[1]. Screening began June 3, 2019, and the last participant was randomized October 28, 2020, out of 705 people assessed for eligibility ^[1]. The study is registered as NCT03954834 ^[1][2].

At 40 weeks, the primary endpoint, mean A1c fell 1.87 points on 5 mg, 1.89 points on 10 mg, and 2.07 points on 15 mg, compared with the 0.04-point increase on placebo. Estimated differences versus placebo were 1.91, 1.93, and 2.11 points (all p<0.0001) ^[1]. More people on tirzepatide reached common treatment targets than on placebo: an A1c below 7.0% in 87% to 92% versus 20%, an A1c of 6.5% or less in 81% to 86% versus 10%, and an A1c below 5.7% in 31% to 52% versus 1% ^[1]. Body weight fell 7.0 to 9.5 kg with tirzepatide, with larger losses at higher doses ^[1].

The most frequent side effects were mild to moderate and temporary gastrointestinal events: nausea in 12% to 18% of tirzepatide participants versus 6% on placebo, diarrhea in 12% to 14% versus 8%, and vomiting in 2% to 6% versus 2% ^[1]. No clinically significant hypoglycemia (below 54 mg/dL) or severe hypoglycemia was reported with tirzepatide, and one death occurred in the placebo group ^[1]. In total, 66 participants (14%) stopped the study drug and 50 (10%) left the study early ^[1]. The authors described the safety profile as consistent with GLP-1 receptor agonists and said the results point to possible monotherapy use of tirzepatide for type 2 diabetes ^[1]. The trial was funded by Eli Lilly and Company; six authors are Lilly employees and shareholders, and several others reported consulting fees or research support from Lilly, Novo Nordisk, and other drugmakers ^[1].

SURPASS-1 was placebo-controlled. It did not test tirzepatide against any approved diabetes drug, so how it compares with semaglutide or other GLP-1 medicines has not been reported from this trial ^[1]. The study followed participants for 40 weeks; longer-term results, including effects on heart and kidney outcomes, are not in this report ^[1]. Whether the drug would be submitted for regulatory approval, and on what timeline, is not addressed in the published report ^[1].

Why it matters for patients

The people in this trial had type 2 diabetes that was not controlled by diet and exercise alone, and none were taking insulin or other injectable diabetes medicines ^[1]. That is a specific group, so the results do not describe how tirzepatide performs in people already using insulin or another GLP-1 drug.

The trial measured two things patients often ask about. One is how far A1c can drop: the average falls here were roughly two percentage points, and about a third to half of participants on the drug reached an A1c below 5.7% ^[1]. The other is that gastrointestinal side effects were common but usually mild, moderate, and temporary, and that no clinically significant or severe low blood sugar occurred with tirzepatide in this study ^[1]. Those findings come from a trial in which participants were not taking insulin or sulfonylureas, which are common causes of hypoglycemia.

Because the comparison group received placebo rather than an existing diabetes drug, patients and clinicians still lack a direct answer on whether tirzepatide works better than, the same as, or worse than medicines already on the market. That question has not been answered by this trial ^[1].

What happens next

The trial record lists NCT03954834 as the registration number ^[2]. A correction notice for the published paper appeared in The Lancet on July 17, 2021 ^[1]. No further steps, such as regulatory filings or the timing of additional comparative results, are disclosed in the report ^[1].