Tirzepatide Demonstrates Superior Glycemic Control, Weight Loss, and Cardiovascular Safety Versus Insulin Glargine in High-Risk Type 2 Diabetes Patients: SURPASS-4 Phase 3 Results Published in The Lancet

October 21, 2021 /BioonBIOON/ --Eli Lilly(Eli Lilly) recently announced the evaluation of the dual GIP and GLP-1 receptor agonist tirzepatide (LY3298176) for the treatment of type 2# Diabetesof Phase 3 SURPASS-4 (NCT03730662)Clinical TrialThe detailed results have been published in the leading international medical journal *The Lancet* (The Lancet). For details, see:Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial。

Data show,In type 2 diabetes with elevated cardiovascular (CV) riskDiabetes mellitusIn adult patients, all three doses of tirzepatide demonstrated superiority in lowering blood glucose and body weight compared with titrated insulin glargine.: After 52 weeks of treatment, using an efficacy estimand statistical analysis, the highest dose of tirzepatide (15 mg once weekly) reduced A1C levels by 2.58% from baseline and reduced body weight by 11.7 kg (25.8 lb, 13.0%) from baseline, whereas titrated insulin glargine reduced A1C by 1.44% from baseline and increased body weight by 1.9 kg (4.2 lb, 2.2%) from baseline.

SURPASS-4 is the largest and longest trial to date in the SURPASS program, and is the fifth and final completed trial evaluating tirzepatide for the treatment of type 2 diabetes.Diabetesglobal registration study. The primary endpoint was assessed at 52 weeks, with patients continuing treatment for 104 weeks or until study completion. The completion of the study was triggered by the accrual of major adverse cardiovascular events (MACE) to assess CV risk. In the recently published data from the post-52-week treatment period, patients treated with tirzepatide maintained A1C and weight control for up to 2 years.

The overall safety profile of tirzepatide assessed throughout the study was consistent with the safety findings observed at 52 weeks, with no new safety signals identified over the 104-week period. Gastrointestinal adverse events were the most frequently reported, typically occurring during the dose-escalation phase and decreasing in frequency over time.

tirzepatide is developed byEli LillyA novel 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. GIP and GLP-1 are both hormones secreted by the intestine that stimulate insulin secretion.Tirzepatide integrates two insulinotropic effects into a single molecule, representing a treatment for type 2Diabetesa novel class of drugs.

The SURPASS Phase 3 global clinical development program has already been initiated in 10Clinical TrialOver 13,000 patients with type 2 diabetes were enrolled in the program, including five global registration studies. The program was initiated in late 2018, and all five global registration trials have been completed.

tirzepatide (LY3298176, image sourced from literature: PMID-31686879)

SURPASS-4 was an open-label, global trial conducted in 2002 adults with type 2 diabetes who had increased cardiovascular (CV) risk and inadequately controlled blood glucose levels despite treatment with 1–3 oral glucose-lowering medications (metformin, sulfonylureas, SGLT2 inhibitors), evaluating the efficacy and safety of three doses of tirzepatide (5 mg, 10 mg, 15 mg) versus titrated insulin glargine. Among all randomized patients, 1819 (91%) completed the initial 52-week follow-up, and 1706 (85%) completed study treatment. The median study duration was 85 weeks, and 202 (10%) completed the 2-year study.

In this study, the mean duration of diabetes was 11.8 years, baseline A1C was 8.52%, and baseline body weight was 90.3 kg, with 85% of patients having a history of cardiovascular disease. In the insulin glargine group, insulin doses were titrated according to a treat-to-target algorithm, with a target fasting blood glucose of less than 100 mg/dL. The starting dose of insulin glargine was 10 units/day, and the mean dose at week 52 was 43 units/day.

In this study, two estimands (efficacy estimand and treatment-regimen estimand) were used to compare treatment differences.The Efficacy estimand refers to the efficacy prior to 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 the use of rescue therapy for persistent severe hyperglycemia.

The results showed that,Using two estimation methods, the study met both the primary and key secondary endpoints: compared with insulin glargine, at week 52, all three doses of tirzepatide (5 mg, 10 mg, and 15 mg) demonstrated statistically significant reductions in blood glucose (A1C) and body weight.

Efficacy assessment results showed that all three doses of tirzepatide were superior to insulin glargine in reducing A1C and body weight.: (1) A1C reduction: -2.24% (5 mg), -2.43% (10 mg), -2.58% (15 mg), -1.44% (insulin glargine); (2) Weight loss: -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg), -11.7 kg (-13.0%, 15 mg), +1.7 kg (+2.2%, insulin glargine); (3) Proportion of patients with A1C <7%: 81.0% (5 mg), 88% (10 mg), 91% (15 mg), 51% (insulin glargine); (4) Proportion of patients with A1C <5.7%: 23% (5 mg), 33% (10 mg), 43% (15 mg), 3% (insulin glargine); (5) Level 2 hypoglycemic events (<54 mg/dL) during the 52-week treatment period: incidence was lower across all tirzepatide dose groups at 6.7% (5 mg), 5.5% (10 mg), and 6.5% (15 mg), compared with 15.0% in the insulin glargine group. Hypoglycemic episodes were more common in patients on background sulfonylurea therapy.

TreatTreatment regimen evaluation results showed that three doses of tirzepatide were superior to insulin glargine in reducing A1C and body weight.: (1) A1C reduction: -2.11% (5 mg), -2.30% (10 mg), -2.41% (15 mg), -1.39% (insulin glargine); (2) Weight loss: -6.4 kg (5 mg), -8.9 kg (10 mg), -10.6 kg (15 mg), +1.7 kg (insulin glargine); (3) Proportion of patients with A1C <7%: 75% (5 mg), 83% (10 mg), 85% (15 mg), 49% (insulin glargine).

Exploratory analysis shows that patients treated with tirzepatide maintained A1C and weight control for up to 2 years.: (1) Mean A1c levels at 52 and 104 weeks: at 52 weeks (N=1750), 6.3% (5 mg), 6.1% (10 mg), 6.0% (15 mg), 7.1% (insulin glargine); at 104 weeks (N=199), 6.4% (5 mg), 6.1% (10 mg), 6.1% (15 mg), 7.5% (insulin glargine); (2) Change in body weight at 52 and 104 weeks: at 52 weeks (N=1755), -7.1 kg (-8.1%, 5 mg), -9.5 kg (-10.7%, 10 mg), -11.7 kg (-13.0%, 15 mg), +1.9 kg (+2.2%, insulin glargine), at 104 weeks (N=202), -5.8 kg (-8.6%, 5 mg), -10.4 kg (-10.8%, 10 mg), -11.1 kg (-12.8%, 15 mg), +2.3 kg (+2.3%, insulin glargine).

Throughout the study period, 8.8% (5 mg), 6.1% (10 mg), and 8.0% (15 mg) of patients in the three tirzepatide dose groups, respectively, and 19.1% of patients in the insulin glargine group experienced hypoglycemia <54 mg/dL. Hypoglycemic episodes were more common in patients receiving background sulfonylurea therapy.

At another study endpoint,At week 52, all three doses of tirzepatide resulted in favorable changes from baseline in fasting lipid levels.。Specifically, at the highest dose of tirzepatide (15 mg): total cholesterol decreased by 5.6%, triglycerides decreased by 22.5%, low-density lipoprotein (LDL) cholesterol decreased by 7.9%, very-low-density lipoprotein (VLDL) cholesterol decreased by 21.8%, high-density lipoprotein (HDL) cholesterol increased by 10.8%.

Throughout the study, the most common adverse events were gastrointestinal-related and generally mild to moderate in severity. Compared with insulin glargine (nausea 2%, diarrhea 4%, vomiting 2%), the incidence of nausea (12%, 16%, 23%), diarrhea (13%, 20%, 22%), and vomiting (5%, 8%, 9%) was higher in patients treated with tirzepatide (5 mg, 10 mg, and 15 mg, respectively). Throughout the study, the discontinuation rates due to adverse events were 7.3% (5 mg), 7.9% (10 mg), and 8.9% (15 mg), respectively, compared with 1.9% in the insulin glargine group.

A safety analysis evaluated MACE-4 (a composite endpoint of cardiovascular or unexplained death, myocardial infarction, stroke, and hospitalization for unstable angina). In the SUPERSES-4 trial,Pooled analysis: Compared with insulin glargine, tirzepatide was not associated with an increased cardiovascular risk; the observed hazard ratio (HR) was 0.74 (95% CI: 0.51–1.08).. (Bioon.com)

Original Source:Tirzepatide results published in The Lancet show superior A1C and body weight reductions compared to insulin glargine in adults with type 2 diabetes with increased cardiovascular risk