Lilly's Tirzepatide Demonstrates Superior Glycemic Control and Weight Loss Versus Semaglutide in Head-to-Head Phase 3 SURPASS-2 Trial

On March 4, Eli Lilly announced that the top-line results of its 40-week SURPASS-2 study demonstrated that all three doses of tirzepatide were superior to semaglutide 1 mg in improving glycemic control and body weight in adults with type 2 diabetes.

The SURPASS-2 trial is the largest study to date within Eli Lilly’s large-scale Phase III SURPASS program. It enrolled 1,879 adult patients with type 2 diabetes worldwide who had inadequate glycemic control despite daily monotherapy with metformin at doses ≥1,500 mg (baseline HbA1c 8.28%; baseline body weight 93.7 kg). Participants were randomized in a 1:1:1:1 ratio to receive once-weekly tirzepatide at doses of 5 mg, 10 mg, or 15 mg, or semaglutide 1 mg, all added to metformin background therapy. The primary endpoint was to demonstrate that the reduction in HbA1c from baseline at week 40 with tirzepatide 10 mg and 15 mg was non-inferior to that with semaglutide. Key secondary endpoints included: 1) non-inferiority of glycemic lowering with tirzepatide 5 mg; 2) greater improvements from baseline in HbA1c and body weight, as well as a higher proportion of patients achieving HbA1c <7% across all three tirzepatide dose groups; and 3) a higher proportion of patients achieving HbA1c <5.7% in the tirzepatide 10 mg and 15 mg treatment groups.

Results based on efficacy assessments showed that all three tirzepatide dose groups were superior to semaglutide in reducing blood glucose and body weight, with a higher proportion of patients achieving HbA1c <7% compared to semaglutide (statistically significant differences were observed in the 10 mg and 15 mg dose groups, as well as in the 5 mg group).

Based on specific data from the treatment regimens, the HbA1c levels in the tirzepatide 5 mg, 10 mg, and 15 mg groups and the semaglutide 1 mg group decreased from baseline by 2.01%, 2.24%, 2.30%, and 1.86%, respectively; body weight decreased by 7.6 kg, 9.3 kg, 11.2 kg, and 5.7 kg, respectively; the proportions of patients with HbA1c <7% were 82.0%, 85.6%, 86.2%, and 79.0%, respectively; and the proportions of patients with HbA1c <5.7% were 27.1%, 39.8%, 45.7%, and 18.9%, respectively.

In terms of safety, the data reported in the SURPASS-2 trial were consistent with previous studies and the profile of GLP-1 receptor agonists. The most common adverse events for tirzepatide at doses of 5 mg, 10 mg, and 15 mg, as well as for semaglutide 1 mg, were gastrointestinal-related adverse events, including nausea (17.4%, 19.2%, 22.1%, and 17.9%), diarrhea (13.2%, 16.4%, 13.8%, and 11.5%), and vomiting (5.7%, 8.5%, 9.8%, and 8.3%). The proportions of patients who discontinued treatment due to adverse events were 5.1%, 7.7%, 7.9%, and 3.8%, respectively. The incidence rates of hypoglycemia (<54 mg/dL) were 0.6%, 0.2%, 1.7%, and 0.4%, respectively.

Tirzepatide is a novel once-weekly dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR), integrating the effects of two incretin hormones into a single molecule. GLP-1 (glucagon-like peptide-1) is an endogenous “incretin” secreted by the gastrointestinal mucosa in humans. It binds to receptors on pancreatic islet cells to stimulate insulin secretion, thereby lowering blood glucose levels. Additionally, it reduces food intake and delays gastric emptying, which facilitates weight control and helps preserve pancreatic β-cell function. GIP (glucose-dependent insulinotropic polypeptide) is a hormone that may complement the actions of GLP-1 receptor agonists. Preclinical studies have demonstrated that GIP can reduce body weight by decreasing food intake and increasing energy expenditure. When combined with GLP-1 receptor agonists, it may exert a greater impact on patients’ glycemic control and body weight.

Undoubtedly, tirzepatide is directly challenging Novo Nordisk’s blockbuster drug, semaglutide. Its large-scale Phase III SURPASS program comprises 10 clinical trials and plans to enroll more than 13,000 patients with type 2 diabetes. Five of these trials are global registration studies that not only mirror the design of semaglutide’s large-scale Phase III SUSTAIN program but also engage in direct “head-to-head” comparisons with semaglutide.

In December 2020, Eli Lilly announced the positive top-line results from the SURPASS-1 trial, which evaluated tirzepatide versus placebo without any background therapy; on February 17 of this year, Eli Lilly announced the positive top-line results from the SURPASS-3 trial, which assessed the addition of tirzepatide to metformin versus insulin degludec, and the SURPASS-5 trial, which assessed the addition of tirzepatide to basal insulin versus placebo.

The various trials of the SURPASS program were successively initiated in late 2018, with the full results of five global registration-enabling clinical trials expected to be released sequentially in 2021, and the marketing authorization application anticipated to be submitted in 2022.

Currently, GLP-1 drugs constitute the second-largest segment of the diabetes market, after insulin. Eight GLP-1 receptor agonists have been launched globally, with the total market size reaching $12.4 billion in 2020. However, this market is predominantly dominated by two giants, Novo Nordisk and Eli Lilly, which collectively hold a 95% market share.

Source: Data sourced from company financial reports; data below USD 50 million is not displayed.

In 2020, Novo Nordisk’s semaglutide was truly at the peak of its popularity. In terms of market performance, sales of its once-weekly subcutaneous formulation, Ozempic, nearly doubled to reach $3.45 billion, while its oral formulation, Rybelsus, gained market acceptance and rapidly increased in volume. On the clinical development front, semaglutide saw the submission of a marketing application for weight management, received Breakthrough Therapy designation for nonalcoholic steatohepatitis (NASH), and initiated large-scale Phase III clinical trials for Alzheimer’s disease, cementing its status as an industry star.

Relying solely on dulaglutide, it is clearly difficult for Eli Lilly to maintain its advantage against the aggressive competition from semaglutide. The crown of the best-selling GLP-1 diabetes medication will inevitably be handed over sooner or later. Therefore, Eli Lilly must continue to prepare backup strategies and seek new weapons to counter semaglutide, with tirzepatide becoming a key asset in which the company has heavily invested. In addition to diabetes, tirzepatide is also being developed as a potential treatment for non-alcoholic steatohepatitis (NASH).

Note: The original text has been abridged.