Diabetes Ther (2022) 13:57–73 https://doi.org/10.1007/s13300-021-01179-8 ORIGINAL RESEARCH Does Gender Influence the Effectiveness and Safety of Insulin Glargine 300 U/ml in Patients with Uncontrolled Type 2 Diabetes? Results from the REALI European Pooled Analysis Pierre Gourdy . Riccardo C. Bonadonna . Nick Freemantle . Didac Mauricio . Dirk Müller-Wieland . Gregory Bigot . Celine Mauquoi . Alice Ciocca . Mireille Bonnemaire Received: October 1, 2021 / Accepted: October 27, 2021 / Published online: November 16, 2021 Ó The Author(s) 2021 ABSTRACT initiated on insulin glargine 300 U/ml (Gla- 300). Introduction: Gender differences in risk factors Methods: Data were pooled from 14 multicen- and treatment outcomes for type 2 diabetes tre, prospective, interventional and non-inter- mellitus (T2DM) may exist. We used the REALI ventional studies. Impact of gender on European database to investigate whether there glycaemic control, insulin dose, body weight were gender-specific differences in baseline and hypoglycaemia was evaluated after 12 and characteristics and clinical outcomes among 24 weeks of Gla-300 treatment. patients with inadequately controlled T2DM P. Gourdy D. Müller-Wieland Endocrinology, Diabetology and Nutrition Department of Medicine I, University Hospital Department, Toulouse University Hospital, Aachen, Aachen, Germany Toulouse, France G. Bigot P. Gourdy IVIDATA, Paris, France Institute of Metabolic and Cardiovascular Diseases, UMR1297 INSERM/UPS, Toulouse University, C. Mauquoi Toulouse, France IDDI, Louvain-la-Neuve, Belgium R. C. Bonadonna A. Ciocca  M. Bonnemaire (&) Azienda Ospedaliero-Universitaria di Parma, Parma, General Medicines, Sanofi, Paris, France Italy e-mail: mireille.bonnemaire@sanofi.com R. C. Bonadonna Department of Medicine and Surgery, University of Parma, Parma, Italy N. Freemantle Institute of Clinical Trials and Methodology, University College London, London, UK D. Mauricio Department of Endocrinology and Nutrition, CIBERDEM, Hospital de la Santa Creu i Sant Pau Institut de Recerca, Barcelona, Spain 58 Diabetes Ther (2022) 13:57–73 Results: Women (N = 3857) were older than men (N = 4376) (median age, 65.0 versus Key Summary Points 63.0 years), with greater mean body mass index (32.5 versus 31.6 kg/m2) and lower median Why carry out this study? estimated glomerular filtration rate (77.5 versus 84.0 ml/min/1.73 m2). Peripheral arterial dis- Increasing evidence suggests that gender ease and a history of myocardial infarction were affects the pathophysiology, more frequent in men (20.1% versus 11.7% and epidemiology, symptoms, course and 12.0% versus 5.8%, respectively). At baseline, response to therapy in type 2 diabetes mean haemoglobin A1c (HbA1c) was 8.74% in mellitus (T2DM). men and 8.79% in women. Least square (LS) Insulin glargine 300 U/ml (Gla-300) is a mean (95% CI) reduction in HbA1c from base- second-generation, long-acting basal line to week 24 was - 1.17% (- 1.21 to - 1.13) insulin analogue that has been extensively in men and - 1.07% (- 1.11 to - 1.02) in evaluated in several large, multicentre, women, resulting in a LS mean difference of randomised controlled trials; there is - 0.10% (- 0.15 to - 0.05; p \ 0.0001). At however a dearth of data describing the 24 weeks, 21.6% of women and 27.2% of men impact of gender on the effectiveness and achieved target HbA1c of \ 7.0% (p \ 0.001; safety of Gla-300, particularly in settings chi-square). Reported incidence for symp- close to clinical practice. tomatic (8.5% versus 8.7%) and severe (0.3% versus 0.5%) any-time-of-the-day or symp- What was learned from the study? tomatic (2.4% versus 1.8%) and severe (0.1% In the REALI pooled analysis of 14 versus 0.2%) nocturnal hypoglycaemia was interventional and non-interventional overall low and comparable between men and studies conducted among European women. Changes in daily Gla-300 dose and patients with uncontrolled T2DM, both body weight were also similar. men and women achieved clinically Conclusion: Despite some gender differences in important improvements in glycaemic baseline characteristics, Gla-300 treatment control after Gla-300 treatment initiation, improved glycaemic control, with overall low without notable gender differences in hypoglycaemia incidences in both men and reported hypoglycaemia event rates and women. However, women had statistically sig- incidence, body weight and insulin dose nificantly lower HbA1c reductions than men, changes. although these differences were clinically modest. Our findings support the use of Gla-300 in both women and men with inadequately Keywords: Europe; Gender differences; controlled T2DM; however, to optimise Glycaemic control; Insulin glargine 300 U/ml; diabetic management, an individualised Pooled analysis; Type 2 diabetes treatment approach taking gender into account may still be considered. Diabetes Ther (2022) 13:57–73 59 INTRODUCTION multicentre, randomised controlled trials (RCTs) [14], there is currently a dearth of data Increasing evidence suggests that gender affects describing the impact of gender on the effec- the pathophysiology, epidemiology, symptoms, tiveness and safety of Gla-300, particularly in course and response to therapy in type 2 dia- settings close to clinical practice. Accordingly, betes mellitus (T2DM) [1–5]. For instance, we used the REALI European database to eval- women with T2DM generally have poorer gly- uate the association of gender with response to caemic control and are less likely to reach the Gla-300 therapy, based on data from 14 non- goals for haemoglobin A1c (HbA1c) compared interventional and interventional studies con- with men [1, 2, 6]. In addition, more women ducted in patients with T2DM uncontrolled on than men die of diabetes on a global scale: 2.3 previous glucose-lowering therapy who initi- versus 1.9 million in 2019 [7]. The relative risk ated or switched to Gla-300. of diabetes-related vascular complications is also substantially higher in women than men [8]. METHODS The mechanisms underlying gender-related Study Designs and Patient Populations differences of glycaemic control have several determinants, including gender-based differ- ences in body fat distribution and hormones as This analysis included pooled data from 14 well as slower glucose absorption in women multicentre, prospective, open-label studies [1, 2, 8, 9]. Varying disease outcomes may also [15–29] of a minimum duration of 24 weeks be due to differences in treatment response and conducted among European adult patients with psychological factors as well as health care dis- inadequately controlled T2DM who initiated parities between the genders [6, 10]. Not only Gla-300 treatment (Table 1). The rationale, are women with T2DM more likely to experi- methodology and a detailed description of the ence side effects from glucose-lowering agents variables have been already provided in the such as hypoglycaemia, but some data indicated published protocol of the REALI project [30]. they were also less likely to be adherent to For most included studies in the REALI treatment than men [1, 10, 11]. In addition, pooled analysis, poor glycaemic control was women with T2DM appear to fare worse psy- defined as an HbA1c between 7.5 and 10.0%. In chologically and suffer more from depression, each study, Gla-300 was injected subcuta- anxiety and low energy levels compared with neously once daily, using a pre-filled insulin men, potentially contributing to the lower pen at the same time of the day ± 3 h if needed, degree of achievement of HbA1c targets as specified in the summary of product charac- [10, 12]. Women have also experienced a poorer teristics [31]. Two of the included studies (Take quality of diabetes care than men, with a lower Control [22] and ITAS [23, 29]) were interven- likelihood to be monitored for diabetes com- tional, single-drug, two-arm studies, in which plications [13]. Despite the potential role of patients were randomised (1:1) according to gender in glycaemic control, there are currently Gla-300 titration to either a self- or physician- no specific treatment guidelines differentiating managed titration algorithm of Gla-300, between genders [6, 10]. whereas the others were non-interventional, Insulin glargine 300 U/ml (Gla-300) is a new single-arm studies, in which Gla-300 was initi- generation, long-acting basal insulin analogue ated and titrated according to real-world clinical providing similar glycaemic control to that practice. All studies were performed in the achieved with insulin glargine 100 U/ml (Gla- ambulatory care setting, except COBALTA [24], 100), with a lower risk of hypoglycaemia and which included a Gla-300 initiation at the less weight gain [14]. Although the efficacy and hospital followed by an ambulatory use after safety of Gla-300 in people living with diabetes discharge. have been evaluated in several large, Patients included within the REALI analysis were either insulin-naı̈ve or previously treated 60 Table 1 Characteristics of the studies included in the REALI pooled analysis Study name Location(s) Study period Study aim Key inclusion criteria Sample Gender distribution Non-interventional studies Toujeo-Neo Germany August 2015 To assess real-world effectiveness Adults with T2DM previously 1213 627 men and (ISRCTN number: to March and safety of switching the basal treated with any basal insulin 586 women ISRCTN93674355) 2017 component of any BOTplus or except Gla-300, and with an (male:female basal-bolus insulin regimen to HbA1c C 7.5% and B 10.0% ratio: 1.1) Gla-300 and a FPG [ 130 mg/dl OPTIN-D [25] The Netherlands October To document changes over time Adults with T2DM previously 162 87 men and 75 2015 to in PROs (emotional wellbeing, treated with basal women September adherence, sleep quality) insulin ± prandial insulin (male:female 2017 for C 6 months prior to Gla- ratio: 1.2) 300 initiation To-Goal [26] Serbia November To evaluate real-life effectiveness Adults with T2DM previously 367 161 men and 2017 to and safety of Gla-300 treated with insulin (basal/bolus 206 women October or premixed insulin) in (male:female 2018 combination with OADs ratio: 0.8) TOP-2 [16] Germany, Austria, June 2015 to To evaluate real-world Adults with T2DM previously 1643 923 men and and Switzerland December effectiveness and safety of Gla- treated with any basal insulin 720 women 2016 300 in patients uncontrolled on except Gla-300, and with an (male:female previous BOT HbA1c C 7.5% and B 10.0% ratio: 1.3) Toujeo-BB [17] Hungary March 2016 To evaluate real-world Adults with T2DM previously 229 116 men and to April effectiveness of Gla-300? treated with a basal-bolus 113 women 2017 insulin glulisine in patients regimen (NPH ? regular (male:female uncontrolled on their previous insulin), with HbA1c C 8.0% ratio: 1.0) basal-bolus regimen or C 3 hypoglycaemic events per month requiring correction Diabetes Ther (2022) 13:57–73 Table 1 continued Study name Location(s) Study period Study aim Key inclusion criteria Sample Gender distribution Toujeo-1 [18, 19] Germany and June 2015 to To evaluate real-world Adult, insulin-naı̈ve patients with 1550 886 men and Switzerland December effectiveness and safety of T2DM previously treated with 664 women 2017 initiating a BOT regimen with OADs, with an HbA1c C 7.5% (male:female Gla-300 and B 10.0% ratio: 1.3) Diabetes Ther (2022) 13:57–73 TOPAZ [20] Czech Republic May 2016 to To evaluate clinical effectiveness Adults with T2DM previously 300 169 men and March and safety of Gla-300 treated with basal insulin with 131 women 2018 or without OADs, and with an (male:female HbA1c [ 7.6% or repeated ratio: 1.3) hypoglycaemia MAGE [21] Belgium June 2016 to To assess treatment satisfaction, Adults with T2DM for [ 1 year, 93 63 men and 30 August efficacy, and safety of Gla-300 with an HbA1c C 7.0% women 2018 in a real-world setting and B 10.0%, previously treated (male:female with any basal insulin except ratio: 2.1) Gla-300 plus mealtime insulin GOAL_RO [27] Romania May 2017 to To evaluate real-life effectiveness Adult, insulin-naı̈ve patients with 1095 487 men and June 2018 and safety of Gla-300 T2DM, with an 608 women HbA1c C 7.0% on prior OADs (male:female ratio: 0.8) ToUPGRADE [28] Bulgaria October To evaluate real-life effectiveness Adults with T2DM previously 286 126 men and 2017 to and safety of Gla-300 treated with NPH ± prandial 160 women April 2019 insulin or premixed insulin with (male:female or without OADs, with an ratio: 0.8) HbA1c [ 9.0% COBALTA [24] Spain June 2016 to To evaluate efficacy and safety of Hospitalised adults with T2DM 112 68 men and 44 (EudraCT number: July 2018 Gla-300 during hospitalisation who were C 3 months on women 2015-004715-20) and therapy intensification at treatment with basal insulin (male:female discharge with or without OADs, with an ratio: 1.5) HbA1c C 8.0 and B 10.0% 61 62 Table 1 continued Study name Location(s) Study period Study aim Key inclusion criteria Sample Gender distribution TRANSITION 2 France January 2016 To evaluate efficacy and safety of Adults with T2DM previously 193 124 men and [15] to July Gla-300 in patients with treated with basal insulin with 69 women (ClinicalTrials.gov 2017 suboptimal glucose control on or without other antidiabetics, (male:female identifier: another basal insulin for whom HbA1c [ 7.5%, and fasting ratio: 1.8) NCT02967237) therapeutic change was SMPG [ 130 mg/dl (mean of indicated last 3 measures) Interventional studies Take Control [22] Greece, Spain, February To compare efficacy and safety of Adults with T2DM for C 1 year, 631 317 men and (EudraCT number: Czech Republic, 2016 to self- versus physician-managed who were on C 6 months on 314 women 2015-001626-42) Switzerland, June 2017 titration of Gla-300 treatment with C 1 OAD, with (male:female Poland, Denmark, or without a basal insulin, and ratio: 1.0) Slovenia, Slovakia, with an HbA1c C 7.0% Croatia, UK and B 10.0% for patients taking basal insulin, or C 7.5% and B 11.0% for insulin-naı̈ve patients ITAS [23, 29] Italy September To compare efficacy and safety of Adult, insulin-naı̈ve patients with 359 222 men and (EudraCT Number: 2015 to self- versus physician-managed T2DM for C 1 year, with an 137 women 2015-001167-39) October titration of Gla-300 HbA1c C 7.5% and B 10.0% (male:female 2017 on OADs and/or non-insulin ratio: 1.6) injectables BOT basal insulin-supported oral therapy, BOTplus basal insulin-supported oral therapy plus a single or double dose of prandial insulin, FPG fasting plasma glucose, Gla-300 insulin glargine 300 U/ml, HbA1c haemoglobin A1c, NPH neutral protamine Hagedorn, OADs oral antidiabetic agents, PROs patient-reported outcomes, SMPG self-monitored plasma glucose, T2DM type 2 diabetes mellitus Diabetes Ther (2022) 13:57–73 Diabetes Ther (2022) 13:57–73 63 with insulin (basal insulin ± prandial insulin) The pooled analysis also evaluated changes with or without non-insulin glucose-lowering in body weight and in the daily dose of Gla-300 agents. There were no upper age limit restric- from baseline to week 12 and week 24 of Gla- tions in any trial. Common exclusion criteria 300 treatment. included a diagnosis of type 1 diabetes, preg- nancy and/or breastfeeding, a history of alcohol Statistical Analyses or drug abuse, the presence of any clinically relevant somatic or mental disease, stage 5 All outcome measures were analysed according chronic kidney disease, known hypersensitivity to gender. The changes in HbA1c and FPG from or intolerance to Gla-300 or any of its excipi- baseline to weeks 12 and 24 of Gla-300 treat- ents, and inability to self-measure blood glucose ment were analysed using a mixed model for levels. repeated measures, with fixed categorical effects Protocols for all included studies were of visit and gender as well as continuous fixed approved by the appropriate ethics committees, covariates of baseline HbA1c or FPG, baseline and the studies were conducted according to HbA1c or FPG value-by-visit interaction and Good Clinical Practice and the Declaration of gender-by-visit interaction. For these two effi- Helsinki. All patients provided written informed cacy endpoints, the least square (LS) mean dif- consent. In this analysis, patient-level raw data ferences between men and women and two- were pooled from the multiple studies. The raw, sided 95% confidence intervals (CIs) were de-identified datasets obtained were standard- estimated. ised for consistency in coding prior to pooling. All other efficacy and safety endpoints as well as baseline demographic and disease char- Outcomes acteristics were assessed descriptively, with cat- egorical variables presented as counts and Efficacy outcomes evaluated in the pooled percentages, and continuous variables as mean, analysis were the changes in HbA1c and fasting standard deviation (SD), median, and first and plasma glucose (FPG) from baseline to week 12 third quartiles. and week 24 of Gla-300 treatment as well as the Efficacy and safety assessments were based proportion of patients achieving HbA1c targets on all included patients who received at least of \ 7.0% (53.0 mmol/mol), \ 7.5% one Gla-300 dose. There were missing patient (58.5 mmol/mol) and \ 8.0% (63.9 mmol/mol) baseline characteristics and missing outcome at week 24. data in some studies; no imputation of missing Safety endpoints included percentages of data was performed. All statistical tests were patients having at least one hypoglycaemic two-sided, with a p value \ 0.05 considered event at any time of day or during the night and statistically significant. All analyses were per- hypoglycaemia event rates (events per patient- formed using SAS, version 9.4 (SAS Institute year). Nocturnal hypoglycaemia was evaluated Inc., Cary, NC, USA). to exclude potential confounders relating to daytime activities and meal intake. The defini- tions of hypoglycaemia were predetermined in RESULTS the present pooled analysis. Severe hypogly- caemia was defined as any event requiring Baseline Characteristics assistance from another person to actively administer carbohydrates or glucagon or to take A total of 8233 patients from 20 European other corrective actions [32]. Symptomatic countries comprised the pooled study popula- hypoglycaemia was defined as an event during tion (4376 men [53.2%] and 3857 women which typical symptoms of hypoglycaemia [46.8%]), with a male:female ratio of 1.1. The occurred (e.g., sweating, hunger, shakiness, gender ratio largely varied across the included palpitations). studies, with the male:female ratio ranging 64 Diabetes Ther (2022) 13:57–73 Table 2 Baseline characteristics according to gender Men Women Total (N = 4376) (N = 3857) (N = 8233) Age, years Mean ± SD 63.3 ± 9.5 64.3 ± 9.9 63.8 ± 9.7 Median (Q1–Q3) 63.0 65.0 (57.0–71.0) 64.0 (57.0–71.0) (57.0–70.0) Body weight, mean ± SD, kg 95.2 ± 16.4 85.9 ± 15.8 90.9 ± 16.8 2 Body mass index, mean ± SD, kg/m 31.6 ± 5.1 32.5 ± 5.7 32.0 ± 5.4 eGFRd, median (Q1–Q3), ml/min/1.73 m2 84.0 77.5 (61.1–93.9) 81.0 (64.9–97.0) (69.0–99.0) Diabetes duration, median (Q1–Q3), years 10.0 (6.0–15.0) 10.0 (6.0–16.0) 10.0 (6.0–15.0) Previous insulin use, n (%) 2660 (60.8) 2327 (60.3) 4987 (60.6) Prior basal insulin use, n (%)a 2388 (54.6) 2074 (53.8) 4462 (54.2) Insulin glargine 100 U/ml 1115 (46.7) 841 (40.5) 1956 (43.8) NPH insulin 676 (28.3) 605 (29.2) 1281 (28.7) Insulin detemir 319 (13.4) 301 (14.5) 620 (13.9) Insulin degludec 154 (6.4) 163 (7.9) 317 (7.1) Duration of previous basal insulin therapy, median (Q1–Q3), 1.7 (0.6–3.9) 1.6 (0.7–3.7) 1.7 (0.7–3.8) years Prior basal insulin dose, mean ± SD, U/day 37.3 ± 24.58 34.7 ± 22.12 36.1 ± 23.53 Prior rapid-acting insulin use, n (%)b 480 (11.0) 509 (13.2) 989 (12.0) Insulin aspart 127 (26.5) 115 (22.6) 242 (24.5) Insulin glulisine 49 (10.2) 46 (9.0) 95 (9.6) Insulin lispro 57 (11.9) 56 (11.0) 113 (11.4) Other insulin 185 (38.5) 188 (36.9) 373 (37.7) c Previous non-insulin glucose-lowering drugs, n (%) 3178 (72.6) 2569 (66.6) 5747 (69.8) Biguanides 2371 (74.6) 1867 (72.7) 4238 (73.7) Dipeptidyl peptidase-4 inhibitors 1009 (31.7) 843 (32.8) 1852 (32.2) Sulphonylurea 700 (22.0) 630 (24.5) 1330 (23.1) SGLT-2 inhibitors 547 (17.2) 395 (15.4) 942 (16.4) Glucagon-like peptide-1 receptor agonists 200 (6.3) 168 (6.5) 368 (6.4) Patients with C 1 diabetic complication, n (%) 1043 (23.8) 982 (25.5) 2025 (24.6) Diabetic neuropathy 674 (15.4) 724 (18.8) 1398 (17.0) Diabetic retinopathy 337 (7.7) 294 (7.6) 631 (7.7) Diabetic nephropathy 306 (7.0) 230 (6.0) 536 (6.5) Diabetes Ther (2022) 13:57–73 65 Table 2 continued Men Women Total (N = 4376) (N = 3857) (N = 8233) Patients with C 1 CV event or risk factor, n (%) 3405 (77.8) 3045 (78.9) 6450 (78.3) Hypertension 3014 (68.9) 2746 (71.2) 5760 (70.0) Dyslipidaemia 1700 (38.8) 1540 (39.9) 3240 (39.4) Peripheral arterial disease 881 (20.1) 452 (11.7) 1333 (16.2) History of myocardial infarction 526 (12.0) 225 (5.8) 751 (9.1) History of stroke 314 (7.2) 246 (6.4) 560 (6.8) Other ischaemic heart disease 405 (9.3) 348 (9.0) 753 (9.1) Haemoglobin A1c, mean ± SD, % 8.74 ± 1.84 8.79 ± 1.31 8.77 ± 1.61 Fasting plasma glucose, mean ± SD, mg/dl 181.16 ± 54.65 181.95 ± 54.62 181.48 ± 54.63 Gla-300 daily initiation dose, mean ± SD, U/kg/day 0.29 ± 0.18 0.31 ± 0.18 0.30 ± 0.18 N refers to all patients from the pooled REALI database included in each gender subgroup; means and percentages are calculated based on data available for each variable CV cardiovascular, eGFR estimated glomerular filtration rate, Gla-300 insulin glargine 300 U/ml, NPH neutral protamine Hagedorn, Q1 first quartile, Q3 third quartile, SD standard deviation, SGLT-2 sodium glucose co-transporter-2 a The total number of patients who were previously treated with basal insulin in each gender subgroup was used as the denominator to calculate the percentages of patients who received prior insulin glargine, NPH, detemir or degludec b The total number of patients who were previously treated with rapid-acting insulin in each gender subgroup was used as the denominator to calculate the percentages of patients who received prior insulin aspart, glulisine, lispro or other c The total number of patients who were previously treated with non-insulin glucose-lowering drugs in each gender subgroup was used as the denominator to calculate the percentages of patients in each drug class d Data on baseline eGFR were available for only 1712/8233 (20.8%) patients from 0.8 to 2.1 (Table 1). Of the 8233 patients, gender subgroups, with a mean daily basal 8046 (97.7%) received at least one dose of Gla- insulin dose higher in men. More men (72.6%) 300 and were consequently included in the than women (66.6%) were treated with non- efficacy and safety analyses. insulin glucose-lowering agents at baseline Patients’ baseline demographic and disease (most commonly with metformin), and this characteristics are summarised in Table 2. type of treatment did not notably change dur- Compared to men, women had a higher median ing the 24-week Gla-300 treatment period. age as well as a higher mean body mass index at Peripheral arterial disease (PAD) and a his- baseline. In addition, median levels of esti- tory of myocardial infarction (MI) were more mated glomerular filtration rate were lower in frequent in men than in women (20.1% versus women compared to men. The study popula- 11.7% and 12.0% versus 5.8%, respectively). By tion was characterised by a history of long-s- contrast, female patients had a higher preva- tanding T2DM, with more than half of women lence of diabetic neuropathy, hypertension and (54.7%) and men (52.1%) having a diabetes dyslipidaemia. Compared to men, there was a duration C 10 years. Gla-100 was the most trend for slightly higher baseline HbA1c and commonly used prior basal insulin across both FPG levels in women (Table 2). 66 Diabetes Ther (2022) 13:57–73 Table 3 Change in HbA1c (%) from baseline to weeks 12 and 24 of Gla-300 treatment in both men and women Men Women (N = 4262) (N = 3784) Mean ± SD HbA1c 8.76 ± 1.25 8.82 ± 1.34 at baseline Mean ± SD HbA1c 7.77 ± 1.08 7.91 ± 1.06 at week 12 Change from baseline n = 1418 n = 1287 to week 12 LS mean ± SE - 0.95 ± 0.02 - 0.86 ± 0.03 (95% CI) (- 0.99 to (- 0.91 to Fig. 1 Percentage (%) of men and women achieving haemoglobin A1c targets \ 7.0%, \ 7.5% and \ 8.0% at - 0.90) - 0.81) week 24 of the study. P values were determined using LS mean ± SE - 0.09 ± 0.03 (- 0.15 to Pearson’s chi-squared test difference (95% - 0.03) CI) men versus men and women of - 0.10% (95% CI - 0.15 to women - 0.05; p \ 0.0001). The decrease in HbA1c in both gender subgroups happened mainly in the P value 0.0054 first 12 weeks of Gla-300 treatment and con- Mean ± SD HbA1c 7.63 ± 1.10 7.75 ± 1.09 tinued afterwards, as reported in Table 3. at week 24 Moreover, at week 24, more men than women achieved HbA1c targets of \ 7.0% (p \ 0.0001; Change from baseline n = 3263 n = 2952 chi-square), \ 7.5% and \ 8.0% (Fig. 1). to week 24 The LS mean (95% CI) decrease in FPG from LS mean ± SE - 1.17 ± 0.02 - 1.07 ± 0.02 baseline to week 24 was - 40.32 mg/dl (- 42.84 (95% CI) (- 1.21 to (- 1.11 to to - 37.80) in men and - 36.00 mg/dl (- 38.65 - 1.13) - 1.02) to - 33.36) in women, resulting in a LS mean difference between men and women of LS mean ± SE - 0.10 ± 0.03 (- 0.15 to - 4.32 mg/dl (95% CI - 7.48 to - 1.16; difference (95% - 0.05) p = 0.0073). In line with changes in HbA1c, the CI) men versus reduction in FPG in both gender subgroups women happened mainly in the first 12 weeks and continued afterwards (Table 4). P value \ 0.0001 CI confidence interval, Gla-300 insulin glargine 300 U/ml, Hypoglycaemic Events HbA1c haemoglobin A1c, LS least squares, SD standard deviation, SE standard error During the 24-week Gla-300 treatment period, 10.7% of men and 10.6% of women reported at least one episode of any-time-of-the-day hypo- Glycaemic Control glycaemia of any type. Nocturnal hypogly- caemia of any type was reported by 2.9% of men and 2.1% of women. Incidence and event rates The LS mean (95% CI) reduction in HbA1c from for symptomatic and severe any-time-of-the- baseline to week 24 was - 1.17% (- 1.21 to day hypoglycaemia as well as symptomatic and - 1.13) in men and - 1.07% (- 1.11 to - 1.02) severe nocturnal hypoglycaemia were overall in women, with a LS mean difference between Diabetes Ther (2022) 13:57–73 67 Table 4 Change in fasting plasma glucose (mg/dl) from Insulin Dose and Body Weight baseline to weeks 12 and 24 of Gla-300 treatment in both men and women Mean ± SD Gla-300 dose increased from Men Women 0.29 ± 0.18 and 0.31 ± 0.18 U/kg/day at base- (N = 4262) (N = 3784) line to 0.40 ± 0.20 and 0.41 ± 0.20 U/kg/day at week 12 in men and women, respectively. Mean ± SD FPG 181.33 ± 54.02 182.47 ± 53.85 Changes in the daily dose of Gla-300 remained at baseline comparable in both gender subgroups Mean ± SD FPG 140.67 ± 41.74 143.02 ± 44.00 throughout the 24-week treatment period at week 12 despite slightly lower levels at week 24 in men (0.36 ± 0.20) than in women (0.40 ± 0.21 Change from n = 1643 n = 1389 U/kg/day). baseline to week The mean ± SD change in body weight from 12 baseline to week 12 and week 24 of Gla-300 treatment was marginal in both gender sub- LS mean ± SE - 37.28 ± 1.15 - 35.82 ± 1.23 groups: 0.12 ± 2.83 and 0.08 ± 4.21 kg for men (95% CI) (- 39.54 to (- 38.23 to and - 0.08 ± 2.32 and - 0.06 ± 3.64 kg for - 35.02) - 33.41) women, respectively. LS mean ± SE - 1.46 ± 1.44 (- 4.28 to 1.36) difference (95% DISCUSSION CI) men versus women The REALI pooled analysis revealed that despite P value 0.31 some differences in baseline demographic and clinical characteristics, both men and women Mean ± SD FPG 140.23 ± 42.26 145.22 ± 64.80 with inadequately controlled T2DM achieved at week 24 clinically important improvements in gly- Change from n = 2360 n = 2057 caemic control after Gla-300 treatment initia- baseline to week tion, without notable gender differences in reported hypoglycaemia event rates or inci- 24 dence, body weight change and insulin dose LS mean ± SE - 40.32 ± 1.29 - 36.00 ± 1.35 change. However, male gender was associated (95% CI) (- 42.84 to (- 38.65 to with a statistically significantly greater reduc- - 37.80) - 33.36) tion in HbA1c and FPG from baseline compared with female gender, and women were also less LS mean ± SE - 4.32 ± 1.61 (- 7.48 to likely than men to achieve HbA1c target levels difference (95% - 1.16) after 6 months of treatment, independently of CI) men versus different HbA1c target thresholds. The LS mean women differences in HbA1c and FPG reductions P value 0.0073 between the gender subgroups were however only - 0.10% (95% CI - 0.15 to - 0.05) and CI confidence interval, FPG fasting plasma glucose, Gla- - 4.32 (95% CI - 7.48 to - 1.16) mg/dl, 300 insulin glargine 300 U/ml, LS least squares, SD respectively, which renders the clinical rele- standard deviation, SE standard error vance of these findings uncertain. To date, studies on gender differences in glycaemic control have shown inconsistent results. In a 2013 pooled analysis [33] of nine low, with no notable differences between men RCTs, evaluating treatment outcomes with Gla- and women (Table 5). 100 versus an active comparator treatment (i.e., neutral protamine Hagedorn [NPH] insulin, 68 Diabetes Ther (2022) 13:57–73 Table 5 Incidence and event rate of hypoglycaemic events Table 5 continued in both men and women Men Women Men Women (N = 4262) (N = 3784) (N = 4262) (N = 3784) Total number of events 6 (0.003) 8 (0.005) Total patient-year 1832.06 1649.82 (event rate) exposure Any-time-of-the-day hypoglycaemia The event rate is calculated as the total number of events divided by total patient-year exposure. Event rates are Any hypoglycaemia expressed as number of events per patient-year Patients with C 1 457 (10.7) 402 (10.6) Symptomatic hypoglycaemia was defined as an event dur- ing which typical symptoms of hypoglycaemia occurred event, n (%) (e.g., sweating, hunger, shakiness, palpitations). Severe Total number of events 2227 (1.216) 1888 (1.144) hypoglycaemia was defined as any event requiring assis- (event rate) tance from another person to actively administer carbo- hydrates, glucagon or take other corrective actions Symptomatic hypoglycaemia Patients with C 1 361 (8.5) 329 (8.7) event, n (%) insulin lispro, premixed insulin, oral antidia- Total number of events 1477 (0.806) 1348 (0.817) betic agents, dietary intervention) in 2938 (event rate) patients with T2DM (1651 men and 1287 women), Gla-100-treated men were more likely Severe hypoglycaemia to achieve HbA1c levels B 7.0% than women Patients with C 1 14 (0.3) 20 (0.5) after 24 weeks of treatment (60.8% versus event, n (%) 54.3%; p = 0.016). Gla-100-treated men also experienced a 0.07 percentage point greater Total number of events 23 (0.013) 29 (0.018) reduction in HbA1c levels from baseline com- (event rate) pared with women that was also statistically Nocturnal hypoglycaemia significant (p = 0.037) but clinically modest. Interestingly, the FPG reduction was 3.1 mg/dl Any hypoglycaemia greater in female than in male patients [33]. Patients with C 1 123 (2.9) 81 (2.1) Likewise, in another patient-level pooled anal- event, n (%) ysis [1] of six RCTs of Gla-100 versus NPH insulin administered for 24–36 weeks in 2600 Total number of events 285 (0.156) 199 (0.121) insulin-naı̈ve, inadequately controlled patients (event rate) with T2DM (1349 men and 1251 women), sig- Symptomatic hypoglycaemia nificantly more men than women achieved the HbA1c target level of \ 7.0% during either Patients with C 1 101 (2.4) 70 (1.8) insulin treatment (33.0% versus 26.5%; event, n (%) p \ 0.001). A statistically significantly greater Total number of events 187 (0.102) 167 (0.101) HbA1c reduction was also observed in men than (event rate) in women (- 1.36 versus - 1.22; p = 0.002); however, the difference between the genders in Severe hypoglycaemia HbA1c reduction was clinically modest. Reduc- Patients with C 1 3 (0.1) 6 (0.2) tions in FPG levels were, by contrast, signifi- event, n (%) cantly greater in women (- 4.33 versus - 3.93 mmol/l; p = 0.009) [1]. On the other hand, a population-based, cross-sectional study from the US conducted in 1178 insulin-treated Diabetes Ther (2022) 13:57–73 69 patients with T2DM identified female sex as a Previous studies have reported differences in predictor of good glycaemic control [34]. In the prevalence of several cardiovascular risk another retrospective, population-based study factors such as overweight/obesity, hyperten- from the UK in 6032 patients with T2DM who sion and dyslipidaemia between men and initiated insulin therapy, gender was not a sig- women [2, 36]. Consistent with REALI in which nificant predictor of insulin responders who female patients had a higher prevalence of were defined as having an HbA1c \ 7.5% and/ hypertension and dyslipidaemia, a 2006 meta- or HbA1c reduction by [ 1% at 12 months post- analysis [37] of 37 prospective cohort studies insulin initiation [35]. This inconsistency found that women with diabetes not only have between the different studies may be partly significantly higher blood pressure and lipid attributed to different population characteris- levels than men with diabetes, but that the tics and study settings, or probably to a random difference in the levels among people with and chance observation of a significant difference in without diabetes was significantly greater in response to insulin therapy. women than it was in men [37]. In REALI, a In REALI, similar rates of hypoglycaemia history of MI was substantially more common occurring at any time of the day or during the in men compared to women. This is an expec- night were reported in both gender subgroups. ted finding, since the prevalence of symp- In the two aforementioned pooled analyses tomatic or severe PAD seems to be higher [1, 33], significantly higher annual rates of among men than women in the general popu- symptomatic and severe hypoglycaemia occur- lation [38]. By contrast, asymptomatic PAD has ring during the night or at any time of the day been reported to be more frequent in women were found among female patients. Such dif- than in men, which often leads to delayed ferences in the risk of hypoglycaemia between diagnosis and under-recognition of PAD in REALI and the two previous pooled analyses women [39]. Regarding MI, its risk has been [1, 33] could be related, at least in part, to dif- estimated to be, on average, three times higher ferent baseline population characteristics as in men than in women [40]. well as patient differences in self-monitoring of The causes of the gender differences in the blood glucose. The smoother and more even prevalence of cardiovascular risk factors are not pharmacokinetic and pharmacodynamic pro- completely understood. Gender differences in files as well as the low within-day variability of body anthropometry and storage patterns of Gla-300 used in REALI compared to Gla-100 and adipose tissue might partly explain the differ- the other first-generation insulins used once to ences between men and women in the burden twice daily in the aforementioned pooled anal- and complications of T2DM [6, 8]. The prefer- yses may have also partially contributed to the ential deposition of excess fat in visceral and overall low and similar rates of hypoglycaemia ectopic tissues in men could lead to a faster reported in both gender subgroups of REALI transition to insulin resistance and diabetes, [14]. Of note, REALI is, to the best of our whereas women may need to gain more weight knowledge, the first pooled analysis assessing and related metabolic risk factors may need to gender differences in glycaemic and safety out- worsen to a greater extent than in men to reach comes following Gla-300 treatment initiation. the same levels of visceral and ectopic fat that Gla-300 had a weight neutral effect for both are required to develop insulin resistance and men and women, suggesting that weight gain is T2DM [8]. In addition, a sex-stratified Men- not an issue of concern when initiating Gla-300 delian randomisation study found that the in either gender. Similarly, the Gla-300 daily genetic risk of T2DM increased the odds of dose increased during the first 12-week treat- cardiovascular diseases such as coronary heart ment and remained relatively stable up to disease for both genders (odds ratio of 1.13 24 weeks in both men and women. These safety [95% CI 1.08–1.18]) and 1.21 [1.17–1.26] per findings are key factors that influence patients’ 1-log unit increase in odds of T2DM in women adherence and quality of life, regardless of their and men, respectively) [41]. These findings gender. suggest to grant equal priority in both genders 70 Diabetes Ther (2022) 13:57–73 for cardiovascular disease prevention in the CONCLUSIONS management of T2DM [41]. There is currently a dearth of data regarding the role of Gla-300 in Both men and women with uncontrolled T2DM men and women with a variable cardiovascular achieved clinically important improvements in risk factor presentation, despite the fact that glycaemic control after Gla-300 treatment ini- Gla-300 has shown efficacy and safety across a tiation, without notable gender differences in broad spectrum of T2DM populations, includ- reported hypoglycaemia event rates or inci- ing patients with cardiovascular risk factors dence, body weight and insulin dose changes. such as chronic kidney disease and advanced However, female patients treated with Gla-300 age [14, 42]. Nevertheless, further research is over a 24-week period were less likely to achieve needed to evaluate Gla-300 in high-risk T2DM HbA1c target levels and had statistically signif- populations and to specifically assess the impact icantly lower, although clinically modest, of Gla-300 therapy on cardiovascular outcomes reductions in HbA1c and FPG than male and on endpoints such as micro- and patients. In any case, adopting an individu- macrovascular complications [14, 43]. alised treatment approach that considers dif- The present analysis has several strengths ferent patient characteristics, including gender, including the large sample size, the prospective may add value in the management of patients nature of the evaluated trials, and the inclusion with T2DM. of adequate and balanced numbers of men and women allowing for a robust evaluation of the impact of gender on treatment outcomes in T2DM. In addition, the REALI analysis applied ACKNOWLEDGEMENTS standardised endpoint definitions to reduce study-specific differences. There are also limita- Funding. This study was funded by Sanofi tions to the current pooled analysis, such as the (Paris, France). The journal’s Rapid Service Fee combination of interventional and non-inter- was also funded by Sanofi (Paris, France). ventional study data, which could increase the heterogeneity of the findings. However, this is Medical Writing Support. Medical writing unlikely, as the two included interventional support in accordance with Good Publication studies (Take Control [22] and ITAS [23, 29]) are Practice (GPP3) guidelines (http://www.ismpp. phase IV, single-drug, two-arm RCTs, with ran- org/gpp3) was provided by Thomas Rohban, domisation performed according to Gla-300 MD, and Magalie El Hajj, PharmD, of Partner 4 titration approach, i.e., patient-managed versus Health (Paris, France) and was funded by Sanofi. physician-managed titration. Another limita- tion may be the presence of a potential report- Authorship. All named authors meet the ing bias, which is inherent to observational International Committee of Medical Journal studies and which could result in under- or Editors (ICMJE) criteria for authorship for this overreporting of adverse events including article, take responsibility for the integrity of hypoglycaemia by the participating physicians the work as a whole, and have given their involved in diabetes care and by the patients. approval for this version to be published. Nevertheless, REALI adds great value to the lit- erature on gender differences in T2DM treat- Authors’ Contributions. All authors con- ment outcomes and supports the need to tributed to the project design and the analysis individualise diabetes therapy taking into plan. Celine Mauquoi performed the statistical account all specificities including but not lim- analysis of the data. All authors were involved ited to gender differences. REALI data further in the interpretation of the data, writing and support the initiation of Gla-300 in both reviewing drafts of the manuscript, and women and men with inadequately controlled approved the final version for submission. T2DM. Diabetes Ther (2022) 13:57–73 71 Prior Presentation. Preliminary results were Open Access. This article is licensed under a presented at the 55th Annual Meeting of the Creative Commons Attribution-NonCommer- European Association for the Study of Diabetes, cial 4.0 International License, which permits 16–20 September 2019, Barcelona, Spain. any non-commercial use, sharing, adaptation, distribution and reproduction in any medium Disclosures. Pierre Gourdy has received or format, as long as you give appropriate credit advisory board and speaker honoraria from to the original author(s) and the source, provide Abbott, Amgen, AstraZeneca, Novo Nordisk, a link to the Creative Commons licence, and Boehringer Ingelheim, Eli Lilly, Merck Sharp & indicate if changes were made. The images or Dohme, Mundipharma, Organon, Sanofi, and other third party material in this article are Servier. Riccardo C. Bonadonna has served on included in the article’s Creative Commons the speaker bureau for Sanofi, Merck Sharp & licence, unless indicated otherwise in a credit Dohme, Bristol-Myers Squibb, AstraZeneca and line to the material. If material is not included Janssen, and has served on the advisory panel in the article’s Creative Commons licence and for Merck Sharp & Dohme, Eli Lilly, Sanofi and your intended use is not permitted by statutory Johnson & Johnson. Nick Freemantle has regulation or exceeds the permitted use, you received research support and acted as a con- will need to obtain permission directly from the sultant for Allergan, Ipsen, Sanofi, AstraZeneca copyright holder. To view a copy of this licence, and Novartis. Didac Mauricio has acted as a visit http://creativecommons.org/licenses/by- consultant and has served on the speaker nc/4.0/. bureau for Almirall, Ascensia, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Eli Lilly, Ferrer, Janssen, Menarini, Merck Sharp & Dohme, Novartis, Novo Nordisk and Sanofi. REFERENCES Dirk Müller-Wieland has acted as a consultant and has served on the speaker bureau for 1. Kautzky-Willer A, Kosi L, Lin J, Mihaljevic R. 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