This retrospective, observational post-marketing database study was conducted using the Medical Data Vision (MDV) database (Medical Data Vision Co., Ltd, Tokyo, Japan), the largest acute-care hospital database encompassing 42.56 million patients treated at 475 hospitals in Japan.

The first analysis set (Cohort 1) included data from people aged ≥ 15 years with T2D who had received a new prescription for iGlarLixi or iGlar-100 ± OADs between 1 June 2020 and 31 May 2023. Individuals had ≥ 90 days of previous treatment records before their first prescription and no prior prescription of iGlarLixi or iGlar-100 within 90 days before the initial prescription (Fig. 1). People who had a type 1 diabetes (T1D) diagnosis, were prescribed other insulin preparations or GLP-1 RAs, or had a previous record of treatment-associated hypoglycaemia within 90 days before the first prescription of iGlarLixi or iGlar-100 were excluded.

Disposition of Cohort 1 included in the first analysis set. *Seven people were included in both treatment groups. iGlar-100 insulin glargine 100 U/mL, GLP-1 RA glucagon-like peptide-1 receptor agonist, iGlarLixi insulin glargine 100 U/mL plus lixisenatide, OAD oral antidiabetic drug, T1D type 1 diabetes, T2D type 2 diabetes

In the second analysis set, evaluations were conducted in two subcohort sets that enrolled people aged ≥ 15 years with T2D who were newly prescribed iGlarLixi between 1 June 2020 and 31 May 2023. In the first subcohort (Cohort 2A), individuals had a prior prescription of GLP-1 RA ± OADs or of OADs alone within 90 days of the first iGlarLixi prescription (Fig. 2). In the second subcohort (Cohort 2B), individuals had a prior prescription of GLP-1 RA and long-acting insulin ± OADs or of long-acting insulin ± OADs within 90 days of the first iGlarLixi prescription (Fig. 3). The second analysis set excluded: people with a T1D diagnosis (both subcohorts); those with T2D who were prescribed any insulin preparations (Cohort 2A) or insulin preparations other than long-acting insulin (Cohort 2B) within 90 days before the first iGlarLixi prescription; those with T2D who were prescribed GLP-1 RAs (Cohort 2A) and/or other insulin preparations (Cohort 2B) on the same day as the first iGlarLixi prescription; and those who had a previous record of hospital-treated hypoglycaemia or severe hyperglycaemia requiring inpatient treatment within 90 days of first iGlarLixi prescription (both subcohorts).

Disposition of Cohort 2A included in the second analysis set (first subcohort set). iGlar-100 insulin glargine 100 U/mL, GLP-1 RA glucagon-like peptide-1 receptor agonist, iGlarLixi insulin glargine 100 U/mL plus lixisenatide, OAD oral antidiabetic drug, T1D type 1 diabetes, T2D type 2 diabetes

Disposition of Cohort 2B included in the second analysis set (second subcohort set). iGlar-100 insulin glargine 100 U/mL, GLP-1 RA glucagon-like peptide-1 receptor agonist, iGlarLixi insulin glargine 100 U/ml plus lixisenatide, OAD oral antidiabetic drug, T1D type 1 diabetes, T2D type 2 diabetes

This database study covered a data period from 1 December 2019 to 31 May 2023. These dates were selected to ensure a sufficient look-back period for people who were first prescribed iGlarLixi around the time it had received marketing authorisation (8 June 2020) to confirm the presence of ≥ 90 days of enrolment data before the prescription.

The date of the first prescription of iGlarLixi or iGlar-100 was defined as the index date. The follow-up period was defined as the period from the index date to the earliest of the following: the date before the prescription date of any other antidiabetic drug(s) that fell in the category of GLP-1 RAs or insulin, including iGlarLixi or iGlar-100 if switched; the date of the last prescription of iGlarLixi or iGlar-100 plus a 44-day grace period multiplied by the number of pens prescribed; the end date of the observation period; or the first occurrence of one of the outcomes of interest. The grace period was used because the actual duration of a prescription was not available from the health insurance claims records (only the number of pens prescribed was available) and was set at 44 days [maximum number of days of treatment on the smallest dose plus the number of days that the treatment remained effective (i.e. 1 day)].

For each person, the following information was extracted from the database: age, classification of inpatient and outpatient services at index date, hospital size, comorbidities and previous and concomitant medications (presence/absence, type and number of antidiabetic and other related drugs), as well as glycated haemoglobin (HbA1c), blood glucose, estimated glomerular filtration rate (eGFR) and body mass index (BMI) where data were available.

For Cohort 1, the study objective was to determine the occurrence of hospital-treated hypoglycaemia in individuals newly prescribed iGlarLixi (± OADs) versus iGlar-100 (± OADs).

For Cohort 2A, the objective was to determine the occurrence of hospital-treated hypoglycaemia and severe hyperglycaemia requiring inpatient treatment in people who had switched to iGlarLixi from a GLP-1 RA ± OADs versus from OADs.

For Cohort 2B, the objective was to determine the occurrence of hospital-treated hypoglycaemia or severe hyperglycaemia requiring inpatient treatment in people who had switched to iGlarLixi from a GLP-1 RA and long-acting insulin ± OADs versus from a long-acting insulin ± OADs.

The definition of hospital-treated hypoglycaemia included the presence of: (1) an International Classification of Diseases, Tenth Revision (ICD-10) code representing hypoglycaemia (Supplementary Table S1); (2) an insurance claims code related to the administration of a 20% or 50% intravenous (IV) glucose solution (Supplementary Table S2); and/or (3) an insurance claims code related to the use of simple blood glucose monitoring (Supplementary Table S3). Primary (broad definition) and secondary (narrower definition) outcomes of hospital-treated hypoglycaemia that were used for all the cohorts are described in detail in Table 1.

Severe hyperglycaemia requiring inpatient treatment was defined by the ICD-10 codes corresponding to hyperosmolar hyperglycaemic syndrome (HHS; Supplementary Table S4) or diabetic ketoacidosis (DKA; Supplementary Table S5). Primary (broad definition) and secondary (narrower definition) outcomes of severe hyperglycaemia requiring inpatient treatment are described in Table 1.

Due to the descriptive nature of this study, no calculation of sample size was conducted, and all eligible people were included.

For all cohorts, individual characteristics, including age, sex, comorbidities and concomitant medications and study outcomes were summarised using means, standard deviations (SDs), medians and ranges for continuous variables, and numbers and proportions for categorical variables. t tests or U tests were used to compare continuous data, and the Fisher's exact test was used to compare categorical data. A p value of < 0.05 was considered statistically significant. The incidence rate and 95% confidence intervals (CI) for the outcomes in each cohort were calculated per person-year of follow-up.

SAS software, version 9.4 (SAS Institute, Cary, NC, USA) was used for statistical analyses.

The study was conducted in accordance with the Japanese Ministerial Ordinance on Good Post-Marketing Study Practice (Ministry of Health, Labour and Welfare Ordinance No. 171, December 20, 2004) and the ethical guidelines for medical and health research involving human subjects. Under these Japanese regulations, this study was conducted without the review or approval by the ethics committee of the participating medical institutions. All data were collected from the MDV database; the authors had no access to individuals’ medical records.