Lilly's Dual GIP/GLP-1 Receptor Agonist Tirzepatide Demonstrates Superior Glycemic Control and Weight Loss Versus Insulin Degludec in Phase 3 SURPASS-3 Trial

February 18, 2021 /BioValleyBIOON/ --Eli Lilly(Eli Lilly) recently announced the evaluation of the dual GIP and GLP-1 receptor agonist tirzepatide (LY3298176) for the treatment of type 2DiabetesPositive Results from the Phase III SURPASS-3 Trial. The data showed that after 52 weeks of treatment, patients in the tirzepatide group experienced significant reductions in glycated hemoglobin (A1C) and body weight from baseline compared to those in the insulin degludec group.

Based on efficacy assessment, the highest dose of tirzepatide reduced A1C by 2.37% and body weight by 12.9 kg (13.9%); in this dose group (meanDiabetesduration of 13.3 years) more than half (62.4%) of patients had an A1C level below 5.7%, which isDiabetesnormal blood glucose levels in the population. The overall safety profile of tirzepatide is similar to that of the well-established GLP-1 receptor agonist class, with the most commonAdverse ReactionsThese are gastrointestinal side effects, which decrease with increasing dose.

Tirzepatide is manufactured byEli LillyA once-weekly dual agonist of the glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide) receptor and the glucagon-like peptide-1 (GLP-1) receptor has been developed. GIP and GLP-1 are both gut-secreted hormones that promote insulin secretion. Tirzepatide integrates the insulinotropic effects of these two hormones into a single molecule, representing a treatment for type 2Diabetesa novel class of drugs.

Notably, tirzepatide is the first dual GIP/GLP-1 receptor agonist to complete Phase 3 trials. In December 2020,Eli LillyAnnouncement that the Phase III SURPASS-1 monotherapy study met its primary and secondary endpoints: Compared with the placebo group, patients in the tirzepatide treatment group showed significant reductions from baseline in glycated hemoglobin (A1C) and body weight.

SUPERSESS-3 was a 52-week, randomized, open-label trial conducted in adult patients with type 2 diabetes who had inadequate glycemic control while receiving stable doses of metformin (with or without an SGLT-2 inhibitor). The study compared the efficacy and safety of three tirzepatide doses (5 mg, 10 mg, and 15 mg) with titrated insulin degludec. Enrolled patients were insulin-naïve, had a mean diabetes duration of 8.4 years, a baseline A1C of 8.17%, and a baseline body weight of 94.3 kg.

In this study, two types of estimands (Efficacy estimand and Treatment-regimen estimand) were used to compare treatment differences. The Efficacy estimand refers to the efficacy before discontinuation of the study drug or initiation of rescue therapy for persistent severe hyperglycemia. The Treatment-regimen estimand refers to the efficacy regardless of adherence to the study drug or use of rescue therapy for persistent severe hyperglycemia.

The results demonstrated that the study met both the primary and key secondary endpoints using two assessment methods: all three doses of tirzepatide achieved superior reductions in glycated hemoglobin (A1C) and body weight compared with titrated insulin degludec (mean dose of 48.8 units/day at week 52). Among patients treated with all three doses of tirzepatide, 92.6% achieved an A1C level <7% (the treatment target for patients with diabetes recommended by the American Diabetes Association [ADA]). Furthermore, regarding a secondary endpoint, 48.4% of patients receiving tirzepatide achieved an A1C level <5.7% (the A1C level observed in healthy individuals).

In treatment regimen assessment, compared with titrated insulin degludec, each dose of tirzepatide significantly reduced A1C and body weight: (1) A1C reduction: -1.85% (5 mg), -2.01% (10 mg), -2.14% (15 mg), -1.25% (insulin degludec); (2) Body weight loss: -7.0 kg (5 mg), -9.6 kg (10 mg), -11.3 kg (15 mg), +1.9 kg (insulin degludec); (3) Proportion of patients with A1C <7%: 79.2% (5 mg), 81.5% (10 mg), 83.5% (15 mg), 58.0% (insulin degludec). (4) The incidence of Level 2 hypoglycemic events (<54 mg/dL) was 1.4% (5 mg), 1.1% (10 mg), and 2.2% (15 mg) in the respective tirzepatide dose groups, versus 7.3% in the insulin degludec group.

The Most Common in the Tirzepatide GroupAdverse ReactionsGastrointestinal-related adverse events were generally mild to moderate in severity, typically occurred during the dose-escalation period, and decreased with continued dosing. Compared with patients in the insulin degludec titration group (1.7% [nausea], 3.9% [diarrhea], 1.1% [vomiting]), those treated with tirzepatide (5 mg, 10 mg, 15 mg) experienced higher rates of nausea (11.5%, 22.5%, 23.7%), diarrhea (15.4%, 16.7%, 15.6%), and vomiting (5.9%, 9.4%, 10.0%). Discontinuation rates due to adverse events were 7.2% (5 mg), 9.7% (10 mg), 10.9% (15 mg), and 1.4% (insulin degludec), respectively.

Dr. Bernhard Ludvik, Associate Professor of Medicine at the Landstrasse Clinic in Vienna and lead investigator of the SURPASS-3 study, stated, “For patients with type 2 diabetes whose disease has progressed to the point where injectable therapy is being initiated, these positive results underscore the potential of tirzepatide in reducing A1C and body weight. Throughout the one-year study, tirzepatide provided sustained A1C reduction and progressive weight loss, with a low incidence of secondary hypoglycemia, which is an important consideration for patients with diabetes and their clinicians.” (Bioon.com)

Original Source: Tirzepatide significantly reduced A1C and body weight in people with type 2 diabetes in two phase 3 trials from Lilly's SURPASS program