SURPASS-4: Tirzepatide reduces HbA1c, body weight in type 2 diabetes
The GIP/GLP-1 receptor agonist tirzepatide significantly reduced HbA1c and body weight compared with insulin glargine for adults with type 2 diabetes at high cardiovascular risk, according to new data from the SURPASS trial program.
New top-line data from SURPASS-4 show treatment with tirzepatide (Eli Lilly), a novel investigational once-weekly dual GIP/GLP-1 receptor agonist, led to superior reductions in HbA1c and body weight from baseline across three doses in adults with type 2 diabetes and a history of CV events compared with titrated insulin glargine (Lantus, Sanofi), according to an industry press release. For the efficacy estimand, the highest dose of tirzepatide led to an HbA1c reduction of 2.58% and reduced body weight by -11.7 kg compared with insulin glargine (mean HbA1c reduction of 1.44% and mean weight gain of 1.9 kg) at 52 weeks.
“Tirzepatide delivered impressive results in this study, providing superior A1C reductions compared to insulin glargine — as well as the addition of significant weight loss — in people with type 2 diabetes who have increased cardiovascular risk,” John Doupis, MD, PhD, director, diabetes division and clinical research center, Iatriko Paleou Falirou Medical Center, Athens, Greece, and senior investigator for SURPASS-4, said in the release. “Type 2 diabetes is a complex condition that requires personalized approaches to treatment, and results from SURPASS-4 demonstrate the potential of tirzepatide to be an important option to help reduce HbA1c and weight for people with type 2 diabetes on one or up to three oral medicines.”
New trial data
As Healio previously reported, top-line data from the SURPASS-1 study showed adults with type 2 diabetes assigned tirzepatide for 40 weeks experienced significant reductions in HbA1c and body weight compared with those assigned placebo. 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 nondiabetes range. Participants had a mean diabetes duration of 4.7 years and a baseline HbA1c of 7.9%.
SURPASS-4 is the largest and longest trial of the program to date and is the fifth and final global registration study for tirzepatide in type 2 diabetes. The study completion was driven by the accrual of major adverse CV events to meet the regulatory submission requirements for evaluating CV risk for type 2 diabetes therapies. The primary endpoint was measured at 52 weeks; many participants continued treatment beyond 52 weeks, some up to 2 years, according to the release.
SURPASS-4 is an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) with titrated insulin glargine in more than 2,000 people with type 2 diabetes with increased CV risk who are treated with one to three oral diabetes drugs (metformin, a sulfonylurea or an SGLT-2 inhibitor).
Study participants had a mean duration of diabetes of 11.8 years, a baseline HbA1c of 8.52% and a baseline weight of 90.3 kg. More than 85% of participants had a history of CVD. In the insulin glargine arm, the insulin dose was titrated following a treat-to-target algorithm with the goal of fasting blood glucose below 100 mg/dL. The starting dose of insulin glargine was 10 units per day, and the mean dose of insulin glargine at 52 weeks was 43 units per day.
SURPASS-4 achieved each of its primary and key secondary endpoints. All three doses of tirzepatide led to superior HbA1c and body weight reductions compared with insulin glargine for both estimands. At the highest dose of tirzepatide, 91% of participants achieved an HbA1c of 7% or lower and 43% achieved an HbA1c of 5.7% or lower.
Severe hypoglycemia (less than 54 mg/dL at 52 weeks) was reported in 6.7%, 5.5% and 6.5% of participants for the 5 mg, 10 mg and 15 mg tirzepatide doses, respectively, and in 15% of participants assigned insulin glargine. Episodes of hypoglycemia were seen more often in participants who had a background therapy of a sulfonylurea.
Researchers conducted a CV safety meta-analysis with 116 participants with adjudicated major adverse CV events, a composite endpoint of CV death, myocardial infarction, stroke and hospitalization for unstable angina. The HR for pooled tirzepatide vs. pooled comparators was 0.81 (97.85% CI, 0.52-1.26). SURPASS-4 contributed most of the major adverse CV events for the CV safety meta-analysis, and within SURPASS-4, an HR 0.74 (95% CI, 0.51-1.08) was observed. Lilly intends to submit the full registration package to regulatory authorities by the end of 2021, according to the release.
The most commonly reported adverse events in the tirzepatide arms at 52 weeks were gastrointestinal related with mild to moderate severity. Treatment discontinuation rates due to adverse events at 52 weeks were 8.2%, 7.3% 8.9% for the 5 mg, 10 mg and 15 mg tirzepatide doses, respectively, compared with 2.9% for insulin glargine.
“These strong results reinforce our belief that tirzepatide has the potential to be an exciting treatment for people living with type 2 diabetes,” Mike Mason, president, Lilly Diabetes, said in the release. “We look forward to meeting our goal of bringing an important new therapy to people living with this condition, including sharing more detailed results at scientific congresses and submitting to regulatory authorities later this year.”
Additional results from SURPASS-4 will be presented at the 57th Annual Meeting of the European Association for the Study of Diabetes and published in a peer-reviewed journal, according to Eli Lilly.