Complete Data Show Tirzepatide, Lilly’s Dual-Action Diabetes Drug, Brings Greater A1C Reduction, Weight Loss Than Semaglutide

The once-weekly therapy is also being studied in nonalcoholic steatohepatitis and heart failure with preserved ejection fraction and obesity.

Complete data for the dual-action diabetes drug tirzepatide, a once-weekly investigational treatment, show that it dramatically reduces blood glucose and weight by combining a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with a glucose-dependent insulinotropic polypeptide (GIP). The therapy brought significantly greater reductions in glycated hemoglobin (A1C) and weight than semaglutide, a well-known GLP-1 RA sold by Novo Nordisk.

Although some data had been previously released, full results from the 40-week SURPASS-2 study were released today during the 81st Scientific Sessions of the American Diabetes Association (ADA) and published in the New England Journal of Medicine.

Tirzepatide is among the most anticipated treatments in years for type 2 diabetes and obesity. The therapy from Eli Lilly is also being studied for the treatment of nonalcoholic steatohepatitis and heart failure with preserved ejection fraction and obesity. Data from the 52-week SURPASS-3 study, which compares tirzepatide with insulin degludec (Tresiba), will be presented later in the meeting; a late-breaking poster available today shows similar superiority for tirzepatide.

"Tirzepatide delivered superior blood glucose and weight reductions compared to semaglutide and, importantly, many people on tirzepatide achieved significant A1C reductions without experiencing hypoglycemia less than 54 mg/dL," Juan Pablo Frías, MD, medical director, National Research Institute and principal investigator of SURPASS-2, said in a statement. "These findings are significant as we continue to evaluate the comprehensive efficacy and safety profile of this potential new treatment option for people with type 2 diabetes."

Diabetes is a progressive disease, and clinicians struggle to keep patients’ A1C in check with therapies other than insulin, which many patients do not want to take or cannot afford. Many patients whose A1C is above 8% never achieve glycemic control, which can lead to multiple long-term complications, including blindness or cardiovascular events.

The arrival of GLP-1 RAs offered an option that could reduce A1C and help patients lose weight, but even this powerful incretin needed a helper. Enter GIP, which further aids—and optimizes—the right amount of insulin secretion.

The open-label, phase 3 trial randomized 1879 patients to 4 groups: patients took either 5-mg, 10-mg, or 15-mg doses of tirzepatide, or 1-mg semaglutide. At baseline, mean A1C was 8.28%, mean weight was 93.7 kg, and mean age was 56.6 years. The primary end point was change in A1C.

Results published in NEJM showed:

  • Patients taking 5 mg of tirzepatide had mean A1C reductions of 2.01 percentage points
  • Patients taking 10 mg of tirzepatide had mean A1C reductions of 2.24 percentage points
  • Patients taking 15 mg of tirzepatide had mean A1C reductions of 2.30 percentage points
  • Patients taking semaglutide had mean A1C reductions of 1.86 percentage points

The estimated A1C differences between the tirzepatide and semaglutide doses were as follows:

  • The A1C difference between the 5-mg dose and semaglutide was –0.15 percentage points (95% CI, –0.28 to –0.03; P = .02)
  • The A1C difference between the 10-0mg dose and semaglutide was –0.39 percentage points (95% CI, –0.51 to –026; P < .001)
  • The A1C difference between the 15-mg dose and semaglutide was –0.45 percentage points (95% CI, –0.57 to –0.32; P < .001)

Reductions in body weight were also greater with tirzepatide and increased with the dose: 1.9 kg for 5 mg, 3.6 kg for 10 mg, and 5.5 kg for 15 (all P < .001).

The most common adverse events were gastrointestinal and were more common among patients taking tirzepatide vs semagutide; they were nausea (17% to 22% vs 18%), diarrhea, (13% to 16% vs 12%), and vomiting (6% to 10% vs 8%).

Serious adverse events were reported in 5% to 7% of patients who took tirzepatide compared with 3% of those who took semaglutide. Of interest to payers: many more patients taking tirzepatide had adverse events that caused them to stop taking the drug; 28 at the 5 mg dose, and 40 each at 10 mg and 15 mg; only 19 patients stopped taking semaglutide.

Among the limitations the study authors noted: only 4.2% of the study patients were Black, even though diabetes and obesity disproportionately affect members of this group. Another limitation was the fact that the study was not blinded.

SUPRASS-3. Results from SURPASS-3, which compare tirzepatide with insulin degludec (Tresiba), were released in a late-breaking poster session Friday morning. In this 52-week study, 1444 insulin-naïve patients with T2D were randomized to receive either one of the 3 doses of tirzepatide or once-daily insulin.

At baseline, the average age was 57.4 years, average A1C was 8.17%, average body mass index was 33.5 kg/m2, and 32% were taking a sodium glucose co-transporter 2 inhibitor. The primary end point was change in A1C.

As with SURPASS-2, the results showed tirzepatide was superior to insulin degludec on all doses; results were dose dependent and showed that among patients taking the 15 mg dose of tirzepatide, 48.4% achieved an A1C of <5.7% and 42.5% achieved a body weight loss of at least 15%.

During a press availability to lead off the meeting, Ruth Weinstock, MD, PhD, of Upstate University Hospital, ADA’s president of Medicine and Science remarked on the recent therapeutic advances. “It’s an extremely exciting time.” The new treatments are “helping us take way better care of our patients.”

Jens Juul Holst, MD, of the University of Copenhagen, noted results for SURPASS-2 show up to half the study patients—a very hard-to-treat population—can achieve an A1C of 5.7%., “The results are really stunning. … These are new times. We are seeing some completely unexpected and wonderful advances.”


Frias JP, Davies MJ, Rosenstock J, et al; for the SURPASS-2 investigators. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med. Published online June 25, 2021. doi:10.1056/NEJMoa2107519