Tirzepatide—a novel, once-weekly, dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist—showed superiority compared to semaglutide or basal insulin as an add-on to metformin or insulin, and as monotherapy for type 2 diabetes across four phase 3 clinical trials, according to a summary of the trials presented at the Scientific Sessions.

Tirzepatide showed superior results in A1C reduction, fasting glucose, and weight loss across the four SURPASS clinical trials: SURPASS-1, SURPASS-2, SURPASS-3, and SURPASS-5.

New, detailed results of the four trials were presented in multiple abstracts at the meeting, and researchers provided a global perspective of the trials on Tuesday, June 29, during a dedicated symposium, Next Chapter in Incretin-Based Therapies—Tirzepatide, a Novel Dual GIP/GLP-1 Receptor Agonist—Results from the First Phase 3 SURPASS Clinical Trials. The session can be viewed by registered meeting attendees at ADA2021.org through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Results from the four trials are summarized below.

SURPASS-1

This 40-week international trial randomized 478 individuals with type 2 diabetes inadequately controlled with diet and exercise to placebo or one of three weekly doses of  tirzepatide: 5 mg, 10 mg, and 15 mg. The cohort had a mean age of 54 years, had been diagnosed with type 2 diabetes for a mean of 5.38 years, were overweight with a mean weight of 85.9 kg, and 48.3% were female. Mean A1C for the group was 7.95 at baseline and fasting serum glucose was 153.6 mg/dL.

After 40 weeks, patients taking 5 mg weekly tirzepatide had an A1C of 6.08, patients taking 10 mg weekly tirzepatide had an A1C of 6.06, and patients taking 15 mg weekly tirzepatide had an A1C of 5.88. Patients on placebo had worsened to 7.99 A1C.

Only 20% of the placebo group reached an A1C less than 7 versus a range of 87% to 92% of the study participants receiving the tirzepatide dosages. And just 10% of the placebo group had an A1C ≤6.5 versus 81% to 86% on tirzepatide, and only 1% of placebo patients had an A1C <5.75 versus 31% to 52% of the tirzepatide patients.

The results for fasting serum glucose were similar: An increase from 154.0 mg/dL at baseline to 166.9 mg/dL in the placebo group and reductions to 110.5 mg/dL, 108.1 mg/dL, and 104.8 mg/dL for tirzepatide 5 mg, 10 mg, and 15 mg, respectively.

“Not only do you see a reduction in fasting glucose with all three tirzepatide doses, there is a significant reduction in peak postprandial glucose and, most notable, in glucose excursions with each meal throughout the day,” said Carol H. Wysham, MD, Clinical Associate Professor of Medicine, University of Washington School of Medicine, and Section Head of Diabetes and Endocrinology, Rockwood Clinic.

Body weight changes followed a similar pattern—no change in the placebo and weight loss of 7.9%, 9.3%, and 11.0% for tirzepatide 5 mg, 10 mg, and 15 mg, respectively. None of the placebo patients experienced weight loss of at least 15%, while 13%, 17%, and 27% of patients achieved 15% weight loss on the three tirzepatide doses.

Adverse events were balanced across the four groups, Dr. Wysham reported, and were largely gastrointestinal (GI). There was no severe or clinically significant hypoglycemia in any of the groups.

SURPASS-2

This open-label trial compared tirzepatide to semaglutide as add-on therapy to metformin. A total of 1,879 individuals were randomized to the same three weekly tirzepatide doses (5 mg, 10 mg, and 15 mg) or 1 mg semaglutide weekly for 40 weeks. And while the trial was open label, the three tirzepatide doses were double-blinded, noted Juan Pablo Frias, MD, Medical Director and Principal Investigator, National Research Institute.

The study cohort had a mean age of 56.6 years, had a mean duration of type 2 diabetes of 8.6 years, were obese with a mean weight of 93.7 kg, and 53% were female. The mean A1C at baseline was 8.38 and mean fasting serum glucose was 172.9 mg/dL.

After 40 weeks, the semaglutide group had an A1C of 6.42 versus 6.19, 5.91, and 5.82 for tirzepatide 5 mg, 10 mg, and 15 mg, respectively. An impressive 81% of the semaglutide group had an A1C less than 7, but that was eclipsed by the tirzepatide groups at 85%, 89%, and 92%, respectively. The results were similar for A1C ≤6.5: 66% for semaglutide versus 74%, 82%, and 87% at the three tirzepatide doses. Differences were more notable for A1C <5.7: 20% for semaglutide versus 29%, 45%, and 51% at the three tirzepatide doses.

Fasting serum glucose dropped from 172.0 mg/dL at baseline to 124.4 mg/dL in the semaglutide group, and was reduced to 117 mg/dL, 111.3 mg/dL, and 109.6 mg/dL at the three tirzepatide doses. Reductions in all glucose measures began around week 4 of the trial.

Body weight dropped in all four groups, as expected, falling to a mean of 87.8 kg in the semaglutide cohort and means of 86.2 kg, 83.7 kg, and 81.6 kg at the three tirzepatide doses. A total of 58% of the semaglutide patients lost at least 5% of their body weight versus 69%, 82%, and 86% of patients in the tirzepatide groups. Just 9% of the semaglutide group lost at least 15% of their body weight versus 15%, 28%, and 40% of patients at the three tirzepatide doses.

“It appeared that body weight had not plateaued at week 40,” Dr. Frias noted.

SURPASS-3

SURPASS-3 compared tirzepatide to insulin degludec in 1,444 individuals with type 2 diabetes taking a stable dose of metformin with or without a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Patients in this 52-week trial had a mean age of 57.4 years, were obese with a mean weight of 94.3 kg, and 44.2% were female. The mean duration of type 2 diabetes was 8.4 years, mean A1C was 8.18, and the mean fasting serum glucose was 169.4 mg/dL.

Insulin degludec was titrated to pre-breakfast, self-measured blood glucose of 71 mg/dL to 90 mg/dL. The mean daily dose of insulin increased from 9.9 units at baseline to 48.8 units at week 52 of the trial.

The increased insulin dosing reduced A1C to 6.85 at week 52, reported Francesco Giorgino, MD, PhD, Professor and Chief of Endocrinology, University of Bari Aldo Moro, Bari, Italy, but the tirzepatide groups had even lower A1C of 6.25, 5.99, and 5.81 at the 5 mg, 10 mg, and 15 mg doses, respectively. Only 5% of insulin patients had an A1C ≤5.7 versus 26%, 39%, and 48% of the tirzepatide patients at the three trial doses.

“Nearly half of patients taking 15 mg tirzepatide had an A1C of 5.7 or less at the end of the trial and there was a very important reduction in body weight—up to a 13.9% loss with tirzepatide,” Dr. Giorgino said. “As expected, there was weight gain in the insulin degludec group, from 94.5 kg to 97.1 kg.”

The decline in fasting serum glucose was similar in all four arms of the study, from 169.3 mg/dL at baseline to 121.6 mg/dL in the insulin group and 114.9 mg/dL, 114.1 mg/dL, and 110.5 mg/dL at the three tirzepatide doses. As in the other SURPASS studies, the most common adverse events were GI-related. Nausea, diarrhea, and other GI reactions were mild to moderate and decreased over time.

“Tirzepatide emerges as a highly valuable therapeutic solution when patients need to intensify their treatment with an injectable solution,” said Dr. Giorgino, summarizing SURPASS-3 findings.

SURPASS-5

The final SURPASS trial presented at the Scientific Sessions compared tirzepatide versus placebo as an add-on to insulin glargine in 475 individuals with insulin-dependent type 2 diabetes and uncontrolled blood glucose. The baseline characteristics were similar to the other SURPASS cohorts: median age of 60.6 years, a mean duration of 13.3 years with type 2 diabetes, and 44% were female. The mean A1C was 8.31, the mean fasting serum glucose was 162.4 mg/dL, and patients were obese with a mean weight of 95.2 kg.

After 40 weeks of study, the placebo-plus-glargine group had an A1C of 7.39 while the tirzepatide-plus-glargine groups had dropped to 6.09, 5.44, and 5.73 at the 5 mg, 10 mg, and 15 mg weekly doses. Just 3% of the placebo-plus-glargine group achieved an A1C ≤5.7 compared to 26%, 48%, and 62% of the tirzepatide-plus-glargine groups.

Fasting serum glucose fell from 162.5 mg/dL at baseline to 123.9 mg/dL in the placebo group and 101.5 mg/dL, 95.1 mg/dL, and 94.9 mg/dL in the three tirzepatide groups.

“At the end of 40 weeks, we saw improvement in postprandial glucose in the tirzepatide groups,” said Michelle Welch, MD, FACE, Founder and President, Diabetes and Metabolism Specialists.

Not surprisingly, she added, the placebo group gained weight, ending the study at 97.4 kg, up from 95.3 kg at baseline. The three tirzepatide groups lost 4.6%, 8.9%, and 11.6% of body weight during the 40-week study. Adverse events were balanced across all four arms, with GI complaints most commonly reported.

“These are consistent findings of robust glucose lowering and also a consistent reduction in body weight with tirzepatide,” said Alice Y.Y. Cheng, MD, FRCPC, Associate Professor of Medicine, University of Toronto, Canada. “The road ahead for the treatment of type 2 diabetes is fresh. The future, in terms of what we will be able to offer our patients to help them meet their metabolic goals, appears to be very positive.”