Tirzepatide significantly reduced A1C and body weight in type 2 diabetes in two phase III trials from the SURPASS program.- Eli Lilly

Tirzepatide led to significant A1C and body weight reductions from baseline in adults with type 2 diabetes in Eli Lilly and Company's SURPASS-3 and SURPASS-5 phase III clinical trials after 52 weeks and 40 weeks, respectively . In topline results, the primary and all key secondary endpoints were met for both estimands in SURPASS-3, which compared tirzepatide to titrated insulin degludec, and in SURPASS-5, which compared tirzepatide to placebo, both as an add-on to titrated insulin glargine. Using the efficacy estimand the highest dose of tirzepatide (15 mg) reduced A1C by 2.37 percent and body weight by 12.9 kg (13.9 percent) in SURPASS-3, and reduced A1C by 2.59 percent and body weight by 10.9 kg (11.6 percent) in SURPASS-5. At the highest dose, 62.4 percent of SURPASS-5 participants – who had a mean duration of diabetes of 13.3 years – achieved an A1C of less than 5.7 percent, the level seen in people without diabetes. In both studies, the overall safety profile of tirzepatide was similar to that of the well-established glucagon-like peptide-1 (GLP-1) receptor agonist class, with gastrointestinal side effects being the most commonly reported adverse events and decreasing with continued dosing. SURPASS-3 :SURPASS-3 was a 52-week randomized, open-label trial comparing the efficacy and safety of three doses of tirzepatide (5 mg, 10 mg and 15 mg) to titrated insulin degludec in adults with type 2 diabetes who have inadequate glycemic control on stable doses of metformin with or without an SGLT-2 inhibitor. Study participants were insulin-naïve and had a mean duration of diabetes of 8.4 years, a baseline A1C of 8.17 percent and a baseline weight of 94.3 kg. The study met its primary and key secondary endpoints across both the efficacy and treatment-regimen estimands. All three tirzepatide doses (5 mg, 10 mg and 15 mg) led to superior A1C and body weight reductions compared to titrated insulin degludec (mean dose at 52 weeks was 48.8 units per day). Across the three doses, up to 92.6 percent of participants on tirzepatide achieved an A1C of less than 7 percent (the American Diabetes Association's recommended target for people with diabetes). Further, in an additional secondary endpoint, up to 48.4 percent of participants treated with tirzepatide achieved an A1C of less than 5.7 percent. In the treatment-regimen estimand, each of the tirzepatide doses led to statistically significant A1C and body weight reductions versus titrated insulin degludec ;: i. A1C reduction: -1.85% (5 mg), -2.01% (10 mg), -2.14% (15 mg), -1.25% (insulin degludec).ii. Weight change: -7.0 kg (5 mg), -9.6 kg (10 mg), -11.3 kg (15 mg), +1.9 kg (insulin degludec). iii. Percent of participants achieving A1C <7%: 79.2 5 mg 81.5 10 mg 83.5 15 mg 58.0 insulin degludec iv. hypoglycemia less than 54 mg dl level two was reported in 1.4 percent 5 mg 1.1 percent 10 mg and 2.2 percent 15 mg of participants in the tirzepatide arms and in 7.3 percent of participants in the insulin degludec arm. the most commonly reported adverse events in the tirzepatide arms were gastrointestinal-related and generally mild to moderate in severity usually occurring during the dose escalation period and decreasing with continued dosing. for study participants treated with tirzepatide 5 mg 10 mg and 15 mg respectively nausea 11.5 percent 22.5 percent 23.7 percent diarrhea 15.4 percent 16.7 percent 15.6 percent and vomiting 5.9 percent 9.4 percent 10.0 percent were more frequently experienced compared to titrated insulin degludec 1.7 percent nausea 3.9 percent diarrhea 1.1 percent vomiting. treatment discontinuation rates due to adverse events were 7.2 percent tirzepatide 5 mg 9.7 percent tirzepatide 10 mg and 10.9 percent tirzepatide 15 mg compared to 1.4 percent insulin degludec.. surpass-5 : surpass-5 was a 40-week randomized double-blind trial comparing the efficacy and safety of three doses of tirzepatide 5 mg 10 mg and 15 mg compared to placebo both as an add-on to titrated insulin glargine with or without metformin in adults with type 2 diabetes. study participants had a mean duration of diabetes of 13.3 years a baseline a1c of 8.31 percent a baseline weight of 95.2 kg and a baseline insulin glargine dose of 37.6 units per day. the study met its primary and key secondary endpoints across both the efficacy and treatment-regimen estimands. all three doses of tirzepatide demonstrated superior a1c reductions and weight reductions from baseline compared to placebo. across the three doses up to 97.4 percent of participants on tirzepatide achieved an a1c of less than 7 percent. further 62.4 percent of participants treated with the highest dose of tirzepatide achieved an a1c of less than 5.7 percent. the mean insulin glargine dose at 40 weeks was lower in all of the tirzepatide arms than in placebo and was 37.6 units per day 5 mg 35.7 units per day 10 mg 29.4 units per day 15 mg and 58.8 units per day placebo. in the treatment-regimen estimand each of the tirzepatide doses led to statistically significant a1c and body weight reductions versus placebo : i. a1c reduction: -2.11 5 mg -2.40 10 mg -2.34 15 mg -0.86 placebo. ii. weight reduction: -5.4 kg 5 mg -7.5 kg 10 mg -8.8 kg 15 mg 1.6 kg placebo. iii. percent of participants achieving a1c><7%: 87.3 5 mg 89.6 10 mg 84.7 15 mg 34.5 placebo. iv. hypoglycemia less than 54 mg dl was reported in 15.5 percent 5 mg 19.3 percent 10 mg and 14.2 percent 15 mg of participants in the tirzepatide arms and in 12.5 percent of participants in the placebo arm. the most commonly reported adverse events in the tirzepatide arms were :gastrointestinal-related and generally mild to moderate in severity usually occurring during the dose escalation period and decreasing with continued dosing. for study participants treated with tirzepatide 5 mg 10 mg and 15 mg respectively nausea 12.9 percent 17.6 percent 18.3 percent diarrhea 12.1 percent 12.6 percent 20.8 percent vomiting 6.9 percent 7.6 percent 12.5 percent and constipation 6.0 percent 6.7 percent 6.7 percent were more frequently experienced compared to placebo 2.5 percent nausea 10.0 percent diarrhea 2.5 percent vomiting 1.7 percent constipation. treatment discontinuation rates due to adverse events were 6.0 percent tirzepatide 5 mg 8.4 percent tirzepatide 10 mg and 10.8 percent tirzepatide 15 mg compared to 2.5 percent placebo..>