Seventy-two week outcomes from the SURMOUNT-2 trial has revealed that tirzepatide (10mg and 15mg) achieved superior weight loss compared to placebo, meeting both co-primary objectives and all key secondary objectives for tirzepatide compared to placebo for both estimandsi. Those taking tirzepatide lost up to 15.7% (34.4lbs or 15.6kgs) of body weight for the efficacy estimandii. SURMOUNT-2 is the second global phase 3 clinical trial that evaluated the efficacy and safety of tirzepatide for chronic weight management. The trial evaluated 938 adult participants with obesity or overweight and type 2 diabetes.
"Obesity is a difficult-to-manage disease, and it's even more difficult for people living with type 2 diabetes," said Dr Jeff Emmick, senior vice president, product development, Lilly. "The degree of mean weight reduction seen in SURMOUNT-2 has not been previously achieved in phase 3 trials for obesity or overweight and type 2 diabetes."
Tirzepatide is a once-weekly GIP (glucose-dependent insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a single molecule that activates the body's receptors for GIP and GLP-1, which are natural incretin hormones. Both GIP and GLP-1 receptors are found in areas of the human brain important for appetite regulation. Tirzepatide has been shown to decrease food intake and modulate fat utilization. Tirzepatide is in phase 3 development for adults with obesity, or overweight with weight-related comorbidity. It is also being studied as a potential treatment for people with obesity and/or overweight with heart failure with preserved ejection fraction (HFpEF), obstructive sleep apnea (OSA), and non-alcoholic steatohepatitis (NASH). Studies of tirzepatide in chronic kidney disease (CKD) and in morbidity/mortality in obesity (MMO) are also ongoing.
SURMOUNT-2 was a multi-centre, randomised, double-blind, parallel, placebo-controlled trial comparing the efficacy and safety of tirzepatide 10mg and 15mg to placebo as an adjunct to a reduced-calorie diet and increased physical activity in adults with obesity or overweight and type 2 diabetes. The trial randomized 938 participants across the US, Argentina, Brazil, India, Japan, Puerto Rico, Russia and Taiwan in a 1:1:1 ratio to receive tirzepatide 10mg, 15mg or placebo. The co-primary objectives of the study were to demonstrate that tirzepatide 10mg and/or 15mg is superior in mean percentage change in body weight from baseline and percentage of participants achieving ≥5% body weight reduction at 72 weeks compared to placebo.
All participants in the tirzepatide treatment arms started the study at a dose of tirzepatide 2.5mg once-weekly and then increased the dose in a stepwise approach at four-week intervals to their final randomized maintenance dose of 10mg (via steps at 2.5mg, 5mg and 7.5mg) or 15 mg (via steps at 2.5mg, 5mg, 7.5mg, 10mg and 12.5mg).
For the efficacy estimand, participants taking tirzepatide achieved average weight reductions of 13.4% (29.8lbs or 13.5kgs) on 10mg and 15.7% (34.4lbs or 15.6kgs) on 15mg compared to placebo (3.3%, 7.0 lb. or 3.2 kg). Additionally, 81.6% (10mg) and 86.4% (15mg) of people taking tirzepatide achieved at least 5% body weight reduction, the other co-primary endpoint, compared to 30.5% of those taking placebo.
Tirzepatide also met all key secondary objectives, which included reduction in A1C and other cardiometabolic parameters. 41.4% (10mg) and 51.8% (15mg) of people taking tirzepatide achieved at least 15% body weight reduction compared to 2.6% of those taking placebo. Reduction in A1C compared to placebo was similar to the SURPASS trials in adults with type 2 diabetes. Study participants had a mean baseline body weight of 222lbs or 100.7kgs) and baseline A1C of 8.0%.
For the treatment-regimen estimandiii, results showed:
Average body weight reductions: 12.8% (10mg), 14.7% (15mg), 3.2% (placebo)
Percentage of participants achieving body weight reductions of ≥5%: 79.2% (10mg), 82.7% (15mg), 32.5% (placebo)
Percentage of participants achieving body weight reductions of ≥15%: 39.7% (10mg), 48.0% (15mg), 2.7% (placebo)
The overall safety profile of tirzepatide was similar to previously reported SURMOUNT and SURPASS trials and to incretin-based therapies approved for the treatment of obesity and overweight. The most commonly reported adverse events were gastrointestinal-related and generally mild to moderate in severity, usually occurring during the dose-escalation period. For those treated with tirzepatide (10mg and 15mg, respectively), nausea (20.2%, 21.9%), diarrhoea (19.9%, 21.5%), vomiting (10.9%, 13.2%) and constipation (8.0%, 9.0%) were more frequently reported compared to placebo (6.3% [nausea], 8.9% [diarrhoea], 3.2% [vomiting], 4.1% [constipation]).
Treatment discontinuation rates due to adverse events were 3.8% (10mg), 7.4% (15mg) and 3.8% (placebo). The overall treatment discontinuation rates were 9.3% (10mg), 13.8% (15mg) and 14.9% (placebo).
Lilly will continue to evaluate the SURMOUNT-2 results, which will be presented at the American Diabetes Association's 83rd Scientific Sessions and submitted to a peer-reviewed journal. Based on these results, Lilly plans to complete the US submission for tirzepatide in adults with obesity or overweight with weight-related comorbidities in the coming weeks.
The SURMOUNT phase 3 global clinical development program for tirzepatide in chronic weight management began in late 2019 and has enrolled more than 5,000 people with obesity or overweight across six registration studies, four of which are global studies. The primary period of SURMOUNT-1 was completed in 2022 and results from SURMOUNT-3 and -4 are anticipated later in 2023.
Tirzepatide was approved as Mounjaro (tirzepatide) by the FDA in May 2022. Mounjaro is a glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM.
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