Tirzepatide achieves all primary and key secondary study outcomes against insulin glargine in adults with type 2 diabetes and increased cardiovascular risk in SURPASS-4 trial.- Eli Lilly.

Tirzepatide led to superior A1C and body weight reductions from baseline across all three doses in adults with type 2 diabetes who have increased cardiovascular (CV) risk compared to titrated insulin glargine in topline results from Eli Lilly and Company's SURPASS-4 clinical trial. For the efficacy estimand, the highest dose of tirzepatide led to an A1C reduction of 2.58 percent and reduced body weight by 11.7 kg (25.8 lb., 13.0 percent) compared to results for those treated with insulin glargine (A1C reduction of 1.44 percent and weight gain of 1.9 kg [4.2 lb., 2.2 percent]) at 52 weeks. The overall safety profile of tirzepatide was consistent with the glucagon-like peptide-1 (GLP-1) receptor agonist class in this patient population. Gastrointestinal side effects were the most commonly reported adverse events, usually occurring during the escalation period and then decreasing over time. 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 to be completed. The study completion was driven by the accrual of major adverse cardiovascular events (MACE) in order to meet the regulatory submission requirements for evaluating CV risk for type 2 diabetes therapies. The primary endpoint was measured at 52 weeks, and many participants continued treatment beyond 52 weeks, some up to two years. A CV safety meta-analysis was conducted across the clinical program once the predefined number of MACE events occurred. The meta-analysis consisted of 116 participants with adjudicated MACE-4, a composite endpoint of death from cardiovascular or undetermined causes, myocardial infarction, stroke and hospitalization for unstable angina. Comparing pooled tirzepatide versus pooled comparators, a hazard ratio of 0.81 (97.85% confidence interval [CI], 0.52 to 1.26) was attained. SURPASS-4 contributed the majority of the MACE-4 events for the CV safety meta-analysis, and within SURPASS-4, a hazard ratio of 0.74 (95% CI, 0.51 to 1.08) was observed. Lilly intends to submit the full registration package to regulatory authorities by the end of 2021. Tirzepatide is a novel investigational once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist that integrates the actions of the GIP and GLP-1 incretins into a single molecule, representing a new class of medicines being studied for the treatment of type 2 diabetes.. SURPASS-4 is an open-label global trial comparing the safety and efficacy of three tirzepatide doses (5 mg, 10 mg and 15 mg) to titrated insulin glargine in more than 2,000 people with type 2 diabetes who have increased CV risk and are treated with between one and three oral antihyperglycemic medicines (metformin, a sulfonylurea or an SGLT-2 inhibitor). Study participants had a mean duration of diabetes of 11.8 years, a baseline A1C of 8.52 percent and a baseline weight of 90.3 kg. More than 85 percent of participants had a history of cardiovascular events. 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 (5 mg, 10 mg and 15 mg) led to superior A1C and body weight reductions compared to insulin glargine for both estimands . At the highest dose of tirzepatide, 91 percent of participants achieved an A1C less than 7 percent – the American Diabetes Association's recommended target for people with diabetes – and 43 percent achieved an A1C less than 5.7 percent – the level seen in people without diabetes. For the treatment-regimen estimand all doses of tirzepatide led to superior A1C and body weight reductions compared to insulin glargine Specifically, results showed: i. A1C reduction: -2.11% (5 mg), -2.30% (10 mg), -2.41% (15 mg), -1.39% (insulin glargine). ii. Weight change: -6.4 kg (5 mg), -8.9 kg (10 mg), -10.6 kg (15 mg), +1.7 kg (insulin glargine) iii. Percent of participants achieving A1C <7%: 75.1% (5 mg), 82.9% (10 mg), 84.9% (15 mg), 48.8% (insulin glargine). hypoglycemia less than 54 mg dl at 52 weeks was reported in 6.7 percent (5 mg), 5.5 percent (10 mg) and 6.5 percent (15 mg) of participants in the tirzepatide arms and in 15.0 percent of participants in the insulin glargine arm. episodes of hypoglycemia were seen more often in participants who had a background therapy of a sulfonylurea. the most commonly reported adverse events in the tirzepatide arms at 52 weeks were gastrointestinal-related and generally mild to moderate in severity. for study participants treated with tirzepatide (5 mg, 10 mg and 15 mg, respectively), nausea (11.9 percent, 15.9 percent, 22.2 percent), diarrhea (12.2 percent, 19.5 percent, 20.4 percent) and vomiting (4.9 percent, 8.2 percent, 8.3 percent) were more frequently experienced compared to insulin glargine (1.6 percent [nausea], 3.2 percent [diarrhea], 1.1 percent [vomiting]). treatment discontinuation rates due to adverse events at 52 weeks were 8.2 percent (tirzepatide 5 mg), 7.3 percent (tirzepatide 10 mg) and 8.9 percent (tirzepatide 15 mg), compared to 2.9 percent (insulin glargine).>