Results for SURPASS-1 and SURPASS-2 trials of GIP/GLP-1 agonist tirzepatide in patients with type 2 diabetes inadequately controlled with diet and exercise alone were presented at this year’s virtual symposium. If you weren’t able to attend the symposium, you can read about the trials here.
GLP-1 agonists currently on the market have successfully provided cardioprotection, weight loss benefits, increased insulin sensitivity, and preservation of beta cell function. The ideal type 2 diabetes (T2DM) treatment would further lower HbA1Cs and improve weight loss. Building upon the foundation of the GLP-1 agonist, recent studies have assessed the novel dual GIP/GLP-1 agonist called tirzepatide. Tirzepatide is a 39 amino acid linear peptide with a mean half-life of 5 days, making it a once-weekly injectable, formulated in 5 mg, 10 mg, and 15 mg, antihyperglycemic medication. GIP agonism acts on the GIP receptor and enhances the receptor activity of GLP-1. The GIP has the potential to work on the adipose tissue, is lipogenic, acts on beta-cells as an incretin hormone, protects bone mass, and acts on the brain to promote weight loss.
SURPASS-1 is a randomized, double-blind placebo-controlled trial comparing the efficacy and safety of three tirzepatide doses versus placebo in patients with type 2 diabetes inadequately controlled with diet and exercise alone. Inclusion criteria consisted of type 2 diabetes diagnosis, HbA1C greater than or equal to 7% and less than or equal to 9.5%, BMI greater than or equal to 23 kg/m2 with stable weight, and naïve to T2DM injectable therapy. 478 patients were randomized 1:1:1:1 to the three doses of tirzepatide or the placebo for a total of 40 weeks. The tirzepatide intervention groups were titrated up to 2.5 mg every four weeks until the maintenance dose was achieved. The primary objective is to establish tirzepatide 5 mg, 10 mg, and 15 mg superiority to placebo for lowering HbA1C from baseline.
Mean baseline demographics are 54 years of age, HbA1C of 7.94%, the weight of 85.9 kg, and BMI of 31.9 kg/m2. Adverse events are similar to results seen in other GLP-1 agonist studies, which included nausea, diarrhea, and dyspepsia. A mild to moderate frequency of nausea and diarrhea are related to an increase in the dose of tirzepatide. The HbA1C change over time from baseline decreased by 1.87% to 2.07% at 40 weeks. Patients that achieved an HbA1C less than 7% ranged from 8 to 92%, HbA1C less than 6.5% is 81 to 86%, and an HbA1C less than 5.7 is 31% to 52%. 13 to 27% of patients achieved a weight loss of greater than or equal to 15%. The SURPASS-1 trial demonstrated that noteworthy HbA1C control and significant weight loss.
SURPASS-2 is a phase 3 randomized open-label trial comparing efficacy and safety of tirzepatide versus semaglutide once weekly as add-on therapy to metformin in people with type 2 diabetes. Inclusion criteria are the same in the SURPASS-1 trial except for the addition of T2DM treatment with metformin greater than 1,500 mg per day three months before screening and during the 40-week trial. The randomization step divides the 1,879 patients into four intervention arms: tirzepatide 5 mg and metformin, tirzepatide 10mg and metformin, tirzepatide 15 mg, and metformin, or semaglutide 1 mg and metformin. The primary objective is to establish tirzepatide 10 mg and 15 mg are non-inferior to semaglutide 1 mg for mean changes in HbA1C.
Mean baseline demographics include 56.6 years of age, HbA1C of 8.28%, a weight of 93.7 kg, and BMI of 34.2 kg/m2. HbA1C average change over time from base for tirzepatide 10 mg and metformin group decreased by 2.37%, and 15 mg and metformin group decreased by 2.46%. The semaglutide and metformin group demonstrated an average decrease of 1.83% in HbA1C. Twelve severe adverse events of death occurred across the tirzepatide, attributed to COVID-19 and significantly elevated cardiovascular risk factors. Everyday adverse events were nausea and vomiting, which were prevalent during the dose initiation and escalation phases. Semaglutide demonstrated a minor occurrence of decreased appetite when compared to tirzepatide. In conclusion, the SURPASS-2 study showed superior HbA1C control, significant weight loss, and 51% of patients returned to an A1C less than or equal to 5.7%.
- The novel dual GIP-GLP-1 agonist tirzepatide is a once-weekly injectable antihyperglycemic medication
- SURPASS-1 study analysis: tirzepatide demonstrated superior HbA1C control and significant weight loss, and 31% of patients returned to an HbA1C less than 5.7%.
- SURPASS-2 study analysis: tirzepatide exhibited superior HbA1C control, significant weight loss, and 51% of patients returned to an HbA1C less than 5.7%.
The Role of Tirzepatide, Dual GIP and GLP-1 Receptor Agonist, in the Management of Type 2 Diabetes: The SURPASS Clinical Trials. Thinzar Min & Stephen C. Bain, Diabetes Therapy, 12/2020.
Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes. Frias, et al. New England Journal of Medicine, 6/2021.
Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Rosenstock, Wysham, et.al., The Lancet, 6/2021.
A Study of Tirzepatide [LY3298176] Versus Semaglutide Once Weekly as Add-on Therapy to Metformin in Participants With Type 2 Diabetes – SURPASS-2. Kumbhani, Journal of the American College of Cardiology, 6/2021.
For those with ADA 21st Virtual Symposium access, the following presentations on SURPASS-1 and SURPASS-2 can be found here: American Diabetes Association Symposium. June 29, 2021
- Drucker D. Introduction of the next chapter in incretin-based therapies-tirzepatide, a novel dual GIP/GLP-1 receptor agonist.
- Wysham C. SURPASS-1—A Phase 3, Randomized, Double-Blind, Placebo-Controlled Trial Comparing the Efficacy and Safety of Three Tirzepatide Doses vs. Placebo in Patients with Type 2 Diabetes Inadequately Controlled with Diet and Exercise Alone.
- Frias JP. SURPASS-2—A Phase 3, Randomized, Open-Label Trial Comparing the Efficacy and Safety of Tirzepatide vs. Semaglutide Once Weekly as Add-On Therapy to Metformin in Patients with Type 2 Diabetes.
Jasmine Dumontier-Hiott, PharmD Candidate 2022, University of South Florida Taneja College of Pharmacy