Lilly's Dual GIP/GLP-1 Receptor Agonist Tirzepatide Demonstrates Superior Glycemic Control and Weight Reduction Compared to Semaglutide in Phase 3 SURPASS-2 Trial
Jun 28, 2021 00:26
CST Updated
00:26
Eli Lilly
Global Pharmaceutical R&D and Production Company
June 27, 2021 /BioonBIOON/ --Eli Lilly(Eli Lilly) recently announced the evaluation of the dual GIP/GLP-1 receptor agonist tirzepatide for the treatment of type 2DiabetesHead-to-Head Phase 3 SURPASS-2Clinical TrialThe 40-week results showed: in type 2Diabetes mellitusIn adult patients,Compared with Novo Nordisk’s injectable semaglutide (1 mg, subcutaneous injection once weekly), all three doses of tirzepatide (subcutaneous injection once weekly) demonstrated superiority in reducing A1C and body weight.These results were simultaneously published in*The New England Journal of Medicine* (NEJM), and held in the United States from June 25 to 29Diabetes mellitusAssociation (ADA) 81st ScientificConferencepublished on.
In addition, the study also evaluated a pre-specifiedExploratory composite endpoint (proportion of patients with A1C level ≤6.5%, weight loss ≥10%, and no blood glucose <54 mg/dL or severe hypoglycemia). Among the three tirzepatide doses, there were respectively32% (5 mg group), 51% (10 mg group), and 60% (15 mg group) of patients achieved this composite endpoint, compared with 22% in the 1 mg semaglutide treatment group.. In this study, the overall safety profile of tirzepatide was similar to that of established glucagon-like peptide-1 (GLP-1) receptor agonists. Across all treatment groups, the most common adverse reactions were gastrointestinal-related.Adverse Reactions。
Tirzepatide is developed byEli LillyA once-weekly dual agonist of the glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor and the glucagon-like peptide-1 (GLP-1) receptor, developed. GIP and GLP-1 are both hormones secreted by the intestine that promote insulin secretion.Tirzepatide integrates two insulinotropic effects into a single molecule, representing the treatment of type 2Diabetes mellitusa novel class of drugs.Semaglutide is a GLP-1 receptor agonist developed by Novo Nordisk, 1 mg isFDAApproved the maximum dose of semaglutide for injection for the treatment of type 2 diabetes.
SUPERSESS-2 is the second of five global registration studies evaluating tirzepatide for the treatment of type 2 diabetes, all of which have been completed.Eli LillyPlans to submit the complete registration dossier to the regulatory authorities by the end of 2021.
Juan Pablo Frias, Principal Investigator of the SURPASS-2 trial and Medical Director at the National Research Institute, stated: “Compared with semaglutide, tirzepatide demonstrated superior efficacy in lowering blood glucose and reducing body weight. Importantly, among patients treated with tirzepatide, many achieved significant reductions in A1C without experiencing hypoglycemia (<54 mg/dL). These findings are significant, and we continue to evaluate the overall efficacy and safety of this potential new treatment option for patients with type 2 diabetes.”
Mike Mason, President of Eli Lilly Diabetes, stated: “In this study, tirzepatide demonstrated superior efficacy in glycemic control and weight loss, both of which are important indicators for assessing the health status of patients with type 2 diabetes. As a leader in diabetes care,Eli LillyCommitted to providing innovative solutions for patients with type 2 diabetes, including this dual GIP and GLP-1 receptor agonist, which leverages the effects of two incretins.”
tirzepatide (LY3298176, image sourced from reference PMID: 31686879)
SUPERSESS-2 was a 40-week, randomized, open-label trial conducted in adult patients with type 2 diabetes, evaluating the efficacy and safety of tirzepatide versus semaglutide as add-on therapy to metformin. This study enrolled a total of 1,879 patients, with a mean diabetes duration of 8.6 years, a baseline A1C of 8.28%, and a baseline body weight of 93.7 kg.
In this study, two estimand strategies (Efficacy estimand [Efficacy estimand] and Treatment-regimen estimand [Treatment-regimen estimand]) were used to compare treatment differences. The Efficacy estimand refers to the efficacy prior to discontinuation of the study drug or initiation of rescue therapy for persistent severe hyperglycemia. The Treatment-regimen estimand refers to the efficacy regardless of adherence to the study drug or the use of rescue therapy for persistent severe hyperglycemia.
The results showed that,Using two analytical approaches, the study met both the primary endpoint and key secondary endpoints: all three doses of tirzepatide (5 mg, 10 mg, and 15 mg) demonstrated superior efficacy in lowering blood glucose (A1C) and reducing body weight compared with semaglutide.Among patients receiving the maximum dose of tirzepatide (15 mg), 92% achieved an A1C <7% (the treatment target for patients with diabetes recommended by the American Diabetes Association [ADA]), compared with 81% of patients treated with semaglutide.
Blood glucose-lowering effect (Image sourced from literature PMID: 34170647; click image to view larger version)
——Efficacy Assessment:All three doses of tirzepatide were superior to semaglutide in reducing A1C and body weight. The specific results were as follows: (1) A1C reduction: -2.09% (5 mg), -2.37% (10 mg), -2.46% (15 mg), -1.86% (semaglutide); (2) weight loss: -7.8 kg (-8.5%, 5 mg), -10.3 kg (-11.0%, 10 mg), -12.4 kg (-13.1%, 15 mg), -6.2 kg (-6.7%, semaglutide); (3) proportion of patients with A1C <7%: 85% (5 mg), 89% (10 mg), 92% (15 mg), 81% (semaglutide); (4) proportion of patients with A1C <5.7%: 29% (5 mg), 45% (10 mg), 51% (15 mg), 20% (semaglutide).
—— Treatment Plan Assessment:All three doses of tirzepatide demonstrated superior efficacy compared to semaglutide in reducing A1C and body weight, with a higher proportion of patients achieving the A1C <7% target. The differences were statistically significant for the 10 mg and 15 mg doses, whereas the 5 mg dose did not reach statistical significance. The specific results were as follows: (1) A1C reduction: -2.01% (5 mg), -2.24% (10 mg), -2.30% (15 mg), and -1.86% (semaglutide); (2) Weight loss: -7.6 kg (5 mg), -9.3 kg (10 mg), -11.2 kg (15 mg), and -5.7 kg (semaglutide); (3) Proportion of patients achieving A1C <7%: 82.0% (5 mg), 86% (10 mg), 86% (15 mg), and 79% (semaglutide); (4) Proportion of patients achieving A1C <5.7%: 27% (5 mg), 40% (10 mg), 46% (15 mg), and 19% (semaglutide); (5) Incidence of Level 2 hypoglycemia (<54 mg/dL): 0.6% (5 mg), 0.2% (10 mg), 1.7% (15 mg), and 0.4% (semaglutide).
Body Weight and Lipid-Lowering Effects (Image sourced from PMID: 34170647. Click image to view full size.)
At another exploratory endpoint, all three doses of tirzepatide resulted in favorable changes in fasting lipids from baseline. Specifically, at the highest dose of tirzepatide (15 mg): triglycerides decreased by 24.8%, very-low-density lipoprotein (VLDL) cholesterol decreased by 23.7%, and high-density lipoprotein (HDL) cholesterol increased by 7.1%.
In this study, the most common across all treatment groupsAdverse ReactionsAll were gastrointestinal-related, including nausea (17.4% [5 mg], 19.2% [10 mg], 22.1% [15 mg], 17.9% [semaglutide]), diarrhea (13.2% [5 mg], 16.4% [10 mg], 13.8% [15 mg], 11.5% [semaglutide]), and vomiting (5.7% [5 mg], 8.5% [10 mg], 9.8% [15 mg], 8.3% [semaglutide]). Discontinuation rates due to adverse events were 5.1% (5 mg), 7.7% (10 mg), 7.9% (15 mg), and 3.8% (semaglutide), respectively. (Bioon.com)