Top-line data show efficacy for dual GIP/GLP-1 receptor agonist in type 2 diabetes
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Adults with type 2 diabetes assigned a novel dual GIP/GLP-1 receptor agonist for 40 weeks experienced significant reductions in HbA1c and body weight compared with those assigned placebo, according to top-line data from the SURPASS-1 study.
During the phase 3 study, 51.7% of participants assigned the highest dose of tirzepatide (Eli Lilly; 15 mg) achieved an HbA1c of 5.7%, which is considered a nondiabetic range. Participants had a mean diabetes duration of 4.7 years and a baseline HbA1c of 7.9%.
“Tirzepatide delivered impressive HbA1c and weight reductions for people with type 2 diabetes in this trial, confirming and building upon the phase 2 data that were released in 2018,” Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City and clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, and principal investigator of SURPASS-1, said in a press release. “The study took a bold approach in assessing HbA1c targets. Not only did nearly 90% of all participants taking tirzepatide meet the standard HbA1c goal of less than 7%, more than half taking the highest dose also achieved an HbA1c of less than 5.7%, the level seen in people without diabetes — an unprecedented finding and unique endpoint in trials evaluating glucose-lowering agents.”
Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist that integrates the actions of both incretins into a single novel molecule, according to Lilly. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure, resulting in weight reductions.
Using the efficacy estimand, the highest dose of tirzepatide led to an HbA1c reduction of 2.07% and reduced body weight by 9.5 kg (11%). More than half (51.7%) of participants in this arm achieved an HbA1c less than 5.7%.
The overall safety profile of tirzepatide was similar to the GLP-1 receptor agonist class, with gastrointestinal side effects being the most commonly reported adverse events. Treatment discontinuation rates due to adverse events were less than 7% in each tirzepatide treatment arm.
The primary and key secondary endpoints of SURPASS-1, the first phase 3 trial of the comprehensive SURPASS program, included superior HbA1c and mean body weight reductions compared with placebo. More than half of participants were treatment-naive at baseline.
Researchers evaluated treatment differences for two estimands — efficacy and treatment-regimen — for the three tirzepatide doses (5 mg, 10 mg and 15 mg) compared with placebo. Across both estimands, all three tirzepatide doses reached statistical significance for HbA1c and body weight reductions from baseline and in the percentage of participants who achieved an HbA1c of less than 7% or less than 5.7%.
In the treatment-regimen estimand, mean HbA1c reductions across the three doses were –1.75% (5 mg), –1.71% (10 mg) and –1.69% (15 mg), compared with 0.09% in the placebo arm.
Mean body weight reductions across the three doses were –6.3 kg (5 mg), –7 kg (10 mg) and –7.8 kg (15 mg), compared with –1 kg in the placebo arm.
The percentage of participants achieving an HbA1c of less than 7% were 81.8% (5 mg), 84.5% (10 mg), 78.3% (15 mg) and 23% (placebo). The percentage of participants achieving an HbA1c of less than 5.7% were 30.9% (5 mg), 26.8% (10 mg), 38.4% (15 mg) and 1.4% (placebo).
There were no events of severe hypoglycemia or severe hypoglycemia in the tirzepatide treatment arms. The most commonly reported adverse events were gastrointestinal-related and mild to moderate in severity, usually occurring during the dose-escalation period.
The overall treatment discontinuation rates were 9.1% (5 mg), 9.9% (10 mg), 21.5% (15 mg) and 14.8% (placebo).
“The majority of the discontinuations in the 15 mg and placebo arms were due to reasons other than adverse events, such as concerns due to the coronavirus pandemic and family or work reasons,” Lilly stated in the release.
“Tirzepatide is the first dual GIP/GLP-1 receptor agonist to complete a phase 3 trial,” Mike Mason, president of Lilly Diabetes, said in the release. “We are impressed by these initial results showing how tirzepatide performed in people with a relatively short duration of diabetes, and we look forward to seeing more results in people who are later in the course of diabetes in future studies from our robust SURPASS clinical trial program.”
Tirzepatide is in phase 3 development for blood glucose management in adults with type 2 diabetes and for chronic weight management. It is also being studied as a potential treatment for nonalcoholic steatohepatitis.
The complete SURPASS-1 study data have not yet been evaluated but will be presented at the upcoming American Diabetes Association Scientific Sessions and published in a peer-reviewed publication in 2021, according to Lilly.
Perspective
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These are outstanding first phase 3 results for a new molecular entity, tirzepatide, the first potential GLP-1/GIP co-agonist poised to be introduced for the treatment of type 2 diabetes. The robust reduction of HbA1c and body weight is impressive. Clinicians eagerly await the forthcoming results of the additional trials in the SURPASS program, with attention to the metabolic benefits, cardiovascular safety, as well as the tolerability of this exciting new medicine.
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