ADA 2021: A Promising Future for Tirzepatide

American Diabetes Association (ADA) symposium presents new phase 3 clinical trials of tirzepatide, SURPASS-3 and SURPASS-5. 

Tirzepatide is a once-weekly injectable medication for patients with type 2 diabetes who may not have achieved optimal therapeutic outcomes while taking oral antihyperglycemic medications. The novel dual GIP-GLP-1 agonist tirzepatide has demonstrated remarkable findings in the SURPASS-1 and SURPASS-2 phase 3 clinical trials. The SURPASS-1 trial of tirzepatide versus placebo concluded a significant HbA1C reduction below 5.7% in 31-52% of participants in the tirzepatide groups. The SURPASS-2 trial of tirzepatide versus semaglutide as an add-on to metformin established a substantial HbA1C reduction below 5.7% was achieved by 29-51% of the tirzepatide participants. Additional phase 3 trials further investigated whether the significant improvements in glycemic control continue compared to guideline-recommended treatments.  

The SURPASS-3 is a randomized, open-label trial comparing the effect of tirzepatide versus titrated insulin degludec on glycemic control in patients with type 2 diabetes as an add-on to metformin with or without SGLT-2 inhibitors. The primary objective is to demonstrate tirzepatide 10 mg and 15 mg are non-inferior to insulin degludec for change from baseline in HbA1C. 1,444 participants were randomized to one of 4 groups, which are tirzepatide 5 mg, tirzepatide 10 mg, tirzepatide 15 mg, or insulin degludec, all with metformin and SGLT-2 inhibitor for 52 weeks. The tirzepatide intervention groups were titrated up to 2.5 mg every four weeks until the maintenance dose was achieved. The titration of insulin degludec was based on the median of 3 prebreakfast SMBG values. Mean baseline demographics for SURPASS-3 include an HbA1C greater than 8.5% in 70% of the participants, and on metformin alone 68% of the participants. 

Treatment discontinuation occurred from 11-18% in the tirzepatide groups primarily due to adverse events. Adverse events are related to an increase in the dose of tirzepatide, and include nausea, diarrhea, vomiting, and decreased appetite. Participants that achieved an HbA1C less than 7% in the tirzepatide 5 mg group was 82%, tirzepatide 10 mg group was 90%, tirzepatide 15 mg was 93%, and insulin degludec was 61%. Participants that achieved an HbA1C of less than 5.7% in the tirzepatide 5 mg group was 26%, tirzepatide 10 mg group was 39%, tirzepatide 15 mg was 48%, and insulin degludec was 5%. The mean daily dose of insulin degludec at 52 weeks was 48.8 units. Thus, tirzepatide 10 mg and 15 mg are superior to insulin degludec for change from baseline in HbA1C at 52 weeks. 

SURPASS-5 is a phase 3, randomized, double-blind trial comparing the efficacy and safety of three tirzepatide doses versus placebo as an add-on to insulin glargine with or without metformin in people with type 2 diabetes. The primary objective is to demonstrate the tirzepatide 10 mg and 15 mg, when added to titrated insulin glargine, are superior to placebo in HbA1C change from baseline to 40 weeks. Study phase randomizations groups included tirzepatide 5 mg, 10 mg, 15 mg, and placebo, all with insulin glargine with or without metformin for 40 weeks. Similar to SURPASS-3, the tirzepatide doses were titrated in the same manner. The baseline demographics for the 475 randomized participants are an HbA1C of 8.31%, 82.9% for participants on metformin, and an average of 37.6 units of glargine dose.  

Participants achieving HbA1C less than 7% is 93% for tirzepatide 5 mg, 97% for tirzepatide 10 mg, 94% for tirzepatide 15 mg, and 34% for the placebo. Participants achieving HbA1C less than 5.7% is 26% for tirzepatide 5 mg, 48% for tirzepatide 10 mg, 62% for tirzepatide 15 mg, and 3% for the placebo. Mean insulin glargine dose after 40 weeks for tirzepatide 5 mg was 37.6 units, tirzepatide 10 mg was 35.7 units, tirzepatide 15 mg was 29.4, placebo was 58.8 units. Adverse events were most common during the titration period of tirzepatide and consisted of diarrhea, nausea, vomiting, nasopharyngitis, and decreased appetite. Tirzepatide 10 mg and 15 mg, when added to titrated insulin glargine, are superior to placebo in HbA1C change from baseline to 40 weeks. 

Practice Pearls: 

• In the SURPASS-3 phase 3 trial, tirzepatide 5 mg, 10 mg and 15 mg are superior to insulin degludec for change from baseline in HbA1C at 52 weeks. 
• In the SURPASS-5 phase 3 trial, tirzepatide 5 mg, 10 mg and 15 mg, when added to titrated insulin glargine, are superior to placebo in HbA1C change from baseline to 40 weeks. 
• Both trials demonstrated significant improvements in glycemic control. 

Giorgino F. SURPASS-3—A Phase 3, randomized, open-label trial comparing the effect of Tirzepatide versus titrated insulin degludec on glycemic control in patients with type 2 diabetes as an add-on to metformin with or without SGLT-2 inhibitors. American Diabetes Association Symposium. June 29, 2021. (Requires ADA Symposium login) 

Latest Data From SURPASS Trials Demonstrate Tirzepatide Provided Meaningful Blood Sugar Reductions. ADA press release, June 29, 2021. 

Jasmine Dumontier-Hiott, PharmD Candidate 2022, University of South Florida Taneja College of Pharmacy 

See more about ADA and other coverage of the tirzepatide clinical trials.