BACKGROUND: Insulin efsitora alfa (efsitora), a once-weekly basal insulin, has the potential to reduce the treatment burden of people with type 2 diabetes who require insulin. We aimed to assess the efficacy and safety of once-weekly efsitora compared with insulin glargine U100 in adults with type 2 diabetes treated with basal and prandial insulin.
METHODS: This phase 3, randomised, 26-week, parallel-design, open-label, treat-to-target, non-inferiority study was done at 78 outpatient clinics and hospitals in Argentina, Germany, India, Italy, Mexico, Spain, and the USA (including Puerto Rico). Participants with type 2 diabetes (glycated haemoglobin [HbA] 7·0-10·0%) treated with basal and prandial insulin and up to three non-insulin glucose-lowering agents were randomly assigned (1:1) to efsitora or glargine U100, both with prandial insulin lispro. Randomisation was stratified by country, baseline HbA(<8% vs ≥8%; <63·9 mmol/mol vs ≥63·9 mmol/mol), and routine use of personal continuous glucose monitoring or flash glucose monitoring at randomisation (yes vs no). The primary endpoint was HbAchange from baseline to week 26 (non-inferiority margin 0·4%). The completed trial is registered at ClinicalTrials.gov (NCT05462756). 1c1c1c
FINDINGS: Between Aug 11, 2022, and Feb 27, 2024, 1037 study participants were screened and 730 were randomly assigned to efsitora (n=365) or glargine U100 (n=365). 369 (51%) of 730 participants were female and 361 (49%) were male, the mean participant age was 58·9 years (SD 10·5), and the mean participant BMI was 31·85 kg/m(SD 5·47). Using the treatment regimen estimand, the least-squares mean baseline HbAwas 8·18% (SE 0·04; 65·9 mmol/mol [SE 0·47]) in the efsitora group and 8·18% (0·04; 65·9 mmol/mol [0·47]) in the glargine U100 group. At week 26, the least-squares mean HbAwas 7·17% (SD 0·05; 54·8 mmol/mol [0·51]) in the efsitora group and 7·18 (0·05; 55·0 mmol/mol [0·51]) in the glargine U100 group. The change from baseline to week 26 using the treatment regimen estimand was -1·01 percentage points for the efsitora group and -1·00 percentage points for the glargine U100 group, indicating non-inferiority of efsitora versus glargine U100. Rates of overall and nocturnal level 2 (<54 mg/dL; 3·0 mmol/L) or level 3 (severe) hypoglycaemia during the treatment period were similar for efsitora versus glargine U100 (6·6 vs 5·9 events per patient-year of exposure, estimated rate ratio [ERR] 1·11, 95% CI 0·85-1·44; p=0·44; 0·67 vs 1·00 events per patient-year of exposure, ERR 0·67, 95% CI 0·44-1·01; p=0·058), respectively. Adverse event occurrence was similar between efsitora and glargine U100. Serious adverse events were reported by 25 (7%) of 365 participants in the efsitora group and 23 (6%) of 365 participants in the glargine U100 group. 2 1c1c
INTERPRETATION: Efsitora showed non-inferior HbAreductions and similar rates of combined clinically significant or severe hypoglycaemia versus glargine U100 in participants with type 2 diabetes treated with basal and prandial insulin. These findings show that efsitora is a well tolerated and efficacious once-weekly alternative to daily basal insulin, with a reduced injection frequency, for the treatment of adults with type 2 diabetes. 1c
FUNDING: Eli Lilly and Company.
