BRENZAVVY Safety and Effectiveness Compared to Glimepiride as an Adjunct to Metformin for Treatment of Type 2 Diabetes Mellitus in Adults
Study Design
A phase 3, randomized, double-blind, active-controlled, parallel-group designed trial compared the safety and effectiveness of BRENZAVVY, 20 mg, to glimepiride, optimally titrated up to 6 mg, in adults with type 2 diabetes mellitus medicated with metformin (≥ 1500 mg day-1) for at least 8 weeks prior to the screening visit. Patients were eligible if their antidiabetic regimen included another oral hypoglycemic agent (OHA), if they discontinued the second agent for at least 6 weeks prior to entering the 2-week, single blind placebo run-in period that all subjects underwent. 426 adults received BRENZAVVY or glimepiride in addition to ongoing metformin for up to 96 weeks. Eligible patients were stratified based on their baseline HbA1c (> 8.5% or not), treatment history (metformin only or metformin plus another OHA), and their renal function at the screening visit (eGFR 60 to < 90 mL min-1 per 1.73 m2 or ≥ 90 mL min-1 per 1.73 m2). The primary endpoint was the intergroup difference in HbA1c from baseline to week 60. Participants remained enrolled through a safety monitoring period of an additional 36 weeks to allow for assessment of the durability of the treatment effect and the identification of any adverse treatment-related sequelae.
Study Population
The study population had a mean age of 59.6 years, a mean duration of disease of 8.7 years and body mass of 89.1 kg. The mean HbA1c at baseline was 8.01% and a majority had a treatment history of metformin only (64.3%) while the remainder had received metformin and another OHA prior to randomization (35.7%). Most of the population had near-normal renal function with a mean eGFR of 91.4 mL min-1 per 1.73 m2. 70% of subjects resided in Europe while 30% were from the United States.
HbA1c
BRENZAVVY was noninferior to glimepiride for the management of type 2 diabetes mellitus in a population poorly controlled by metformin or metformin plus one other OHA. The model-adjusted mean change in HbA1c from baseline to week 60 was −0.70% in the BRENZAVVY arm and −0.66% in the glimepiride arm. The improvement in glycemic control was clinically meaningful. At week 60, 70 adults in the BRENZAVVY arm (36.3%) and 65 subjects in the glimepiride arm (34.0%) had achieved an HbA1c < 7.0%.
Body Mass
BRENZAVVY was superior to glimepiride for the reduction in body mass from baseline to week 60 for study participants with a BMI ≥ 25 kg m-2 at baseline (94.6% of the study population). Following 60 weeks of treatment with BRENZAVVY, the intergroup model-adjusted difference for those treated with glimepiride was −4.31 kg.
Systolic Blood Pressure
BRENZAVVY was superior to glimepiride for the reduction in systolic blood pressure from baseline to week 60 for study participants with an SBP ≥ 140 mmHg at baseline. Patients in the BRENZAVVY-treated arm had a change in SBP of −13.48 mmHg compared to −6.95 mmHg in the glimepiride-treated arm. The intergroup difference of −6.53 mmHg favoring the BRENZAVVY arm was statistically significant.
Hypoglycemia Events
BRENZAVVY was superior to glimepiride for the proportion of patients experiencing documented symptomatic hypoglycemia (symptoms accompanied by a measured plasma glucose concentration ≤ 70 mg dL1) and no patients experienced severe hypoglycemia in either treatment arm. 7 patients (3.3%) in the BRENZAVVY arm experienced documented symptomatic hypoglycemia compared to 44 patients (20.8%) in the glimepiride arm.
Renal Function
The mean change from baseline eGFR for BRENZAVVY minus the mean change from baseline for glimepiride was 3.14 mL min-1 per 1.73m2 at 96 weeks. During the treatment period, participants in the BRENZAVVY arm experienced a change in eGFR of −1.33 mL min-1 per 1.73 m2 whereas those in the glimepiride arm experienced a change of −4.47 mL min-1 per 1.73m2. At the follow-up visit conducted 2 weeks after last dose, BRENZAVVY-treated patients exhibited a mean increase in eGFR of 1.38 mL min-1 per 1.73 m2 from the baseline value whereas glimepiride-treated patients exhibited a mean decrease of 4.67 mL min-1 per 1.73 m2 from baseline.
REFERENCES: 1. Halvorsen YD, Lock JP, Frias JP, et al. A 96-week, double-blind, randomized controlled trial comparing bexagliflozin to glimepiride as an adjunct to metformin for the treatment of type 2 diabetes in adults. Diabetes Obes Metab. 2023;25(1):293-301. doi:10.1111/dom.14875; PMID: 36178197.