Current Medical Research and Opinion ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/icmo20 Real-world outcomes of treatment with insulin glargine 300 U/mL versus standard-of-care in people with uncontrolled type 2 diabetes mellitus Nick Freemantle, Didac Mauricio, Andrea Giaccari, Timothy Bailey, Ronan Roussel, Denise Franco, Baptiste Berthou, Valerie Pilorget, Jukka Westerbacka, Zsolt Bosnyak, Mireille Bonnemaire, Anna M. G. Cali, My-Liên Nguyên-Pascal, Alfred Penfornis, Manuel Perez-Maraver, Jochen Seufert, Sean D. Sullivan, John Wilding, Carol Wysham & Melanie Davies on behalf of the REACH and REGAIN investigators To cite this article: Nick Freemantle, Didac Mauricio, Andrea Giaccari, Timothy Bailey, Ronan Roussel, Denise Franco, Baptiste Berthou, Valerie Pilorget, Jukka Westerbacka, Zsolt Bosnyak, Mireille Bonnemaire, Anna M. G. Cali, My-Liên Nguyên-Pascal, Alfred Penfornis, Manuel Perez-Maraver, Jochen Seufert, Sean D. Sullivan, John Wilding, Carol Wysham & Melanie Davies on behalf of the REACH and REGAIN investigators (2020) Real-world outcomes of treatment with insulin glargine 300 U/mL versus standard-of-care in people with uncontrolled type 2 diabetes mellitus, Current Medical Research and Opinion, 36:4, 571-581, DOI: 10.1080/03007995.2019.1708287 To link to this article: https://doi.org/10.1080/03007995.2019.1708287 © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. View supplementary material Published online: 19 Jan 2020. Submit your article to this journal Article views: 3651 View related articles View Crossmark data Citing articles: 10 View citing articles Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=icmo20 CURRENT MEDICAL RESEARCH AND OPINION 2020, VOL. 36, NO. 4, 571–581 https://doi.org/10.1080/03007995.2019.1708287 Article RT-0537.R1/1708287 ORIGINAL ARTICLE Real-world outcomes of treatment with insulin glargine 300 U/mL versus standard-of-care in people with uncontrolled type 2 diabetes mellitus Nick Freemantlea , Didac Mauriciob, Andrea Giaccaric, Timothy Baileyd, Ronan Roussele,f,g, Denise Francoh, Baptiste Berthoui, Valerie Pilorgetj, Jukka Westerbackak, Zsolt Bosnyakk, Mireille Bonnemairek, Anna M. G. Calik, My-Li^ en Nguy^ en-Pascalj, Alfred Penfornisl, Manuel Perez-Maraverm, Jochen Seufertn, Sean D. Sullivano, John Wilding , Carol Wyshamq and Melanie Daviesr; on behalf of the REACH and REGAIN investigators p a Institute of Clinical Trials and Methodology, University College London, London, UK; bDepartment of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, CIBERDEM, Barcelona, Spain; cCenter for Endocrine and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCSS, Universita Cattolica del Sacro Cuore, Rome, Italy; dAMCR Institute, Escondido, CA, USA; eDepartment of Diabetology, Endocrinology, and Nutrition, Bichat Hospital, AP-HP, Paris, France; fINSERM U1138, Centre de Recherche des Cordeliers, Paris, France; gUFR de Medecine, Paris University, Paris, France; hCPCLIN Clinical Research Center, S~ao Paulo, Brazil; iIT&M Stats, Paris, France; jSanofi, Chilly- Mazarin, France; kSanofi, Paris, France; lDepartment of Diabetes, Sud-Francilien Hospital, Corbeil-Essonnes and Universite Paris Sud, Paris, France; mServei dEndocrinologia i Nutricio, Hospital Universitari Bellvitge, L’Hospitalet de Llobregat, IDIBELL, Barcelona, Spain; nFaculty of Medicine, Division of Endocrinology and Diabetology, Department of Medicine II, University Hospital of Freiburg, University of Freiburg, Freiburg, Germany; oThe CHOICE Institute, School of Pharmacy, University of Washington, Seattle, WA, USA; pObesity and Endocrinology Clinical Research, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK; qDiabetes and Endocrinology Center, Multicare Rockwood Clinic, Spokane, WA, USA; rDiabetes Research Centre, Leicester General Hospital, University of Leicester, Leicester, UK ABSTRACT ARTICLE HISTORY Objective: To compare real-world outcomes with newer (insulin glargine 300 U/mL; Gla-300) versus Received 27 September 2019 standard of care (SoC) basal insulins (BIs) in the REACH (insulin-naïve; NCT02967224) and REGAIN Revised 13 December 2019 (basal insulin-treated; NCT02967211) studies in participants with uncontrolled type 2 diabetes (T2DM) Accepted 17 December 2019 in Europe and Brazil. KEYWORDS Methods: In these open-label, parallel-group, pragmatic studies, patients (HbA1c > 7.0%) were Clinical trial; insulin; drug randomized to Gla-300 or SoC BI for a 6-month treatment period (to demonstrate non-inferiority of therapy; type 2 Gla-300 vs SoC BIs for HbA1c change [non-inferiority margin 0.3%]) and a 6-month extension period diabetes mellitus (continuing with their assigned treatment). Insulin titration/other medication changes were at investi- gator/patient discretion post-randomization. Results: Overall, 703 patients were randomized to treatment in REACH (Gla-300, n ¼ 352; SoC, n ¼ 351) and 609 (Gla-300, n ¼ 305, SoC, n ¼ 304) in REGAIN. The primary outcome, non-inferiority of Gla-300 versus SoC for HbA1c change from baseline to month 6, was met in REACH (least squares [LS] mean difference 0.12% [95% CI –0.046 to 0.281]) but not REGAIN (LS mean difference 0.17% [0.015–0.329]); no between-treatment difference in HbA1c change was shown after 12 months in either study. BI dose increased minimally from baseline to 12 months in REACH (Gla-300, þ0.17 U/kg; SoC, þ0.15 U/kg) and REGAIN (Gla-300, þ0.11 U/kg; SoC, þ0.07 U/kg). Hypoglycemia incidence was low and similar between treatment arms in both studies. Conclusions: In both REACH and REGAIN, no differences in glycemic control or hypoglycemia out- comes with Gla-300 versus SoC BIs were seen over 12 months. However, the suboptimal insulin titra- tion in REACH and REGAIN limits comparisons of outcomes between treatment arms and suggests that more titration instruction/support may be required for patients to fully derive the benefits from newer basal insulin formulations. Introduction injectable therapy option2, basal insulins still play a key role Many people with type 2 diabetes (T2DM) who initially in the management of people with T2DM who are uncon- achieve glycemic control with oral antihyperglycemic drugs trolled on OADs with or without GLP-1 RAs3. In clinical prac- (OADs) eventually require basal insulin, either alone or in tice, basal insulin initiation is frequently delayed until combination with other agents1. Although a recent ADA/ glycated hemoglobin (HbA1c) is >9% (>75 mmol/mol)4. EASD consensus report recommends that glucagon-like pep- Newer second-generation basal insulin analogs such as tide-1 receptor agonists (GLP-1 RAs) be used as the first insulin glargine 300 U/mL (Gla-300) were developed to CONTACT Nick Freemantle nicholas.freemantle@ucl.ac.uk Institute of Clinical Trials and Methodology, University College London, 90 High Holborn, Holborn, London WC1V 6LJ, UK Supplemental data for this article is available online at https://doi.org/10.1080/03007995.2019.1708287. ß 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. www.cmrojournal.com 572 N. FREEMANTLE ET AL. optimize glycemic control while minimizing the risk of hypo- active-controlled, 2-arm, parallel-group, comparative, pragmatic glycemia. Gla-300 provides a more constant and prolonged real-world studies in patients with uncontrolled T2DM who pharmacokinetic and pharmacodynamic profile than insulin were either insulin-naïve but considered eligible for basal insu- glargine 100 U/mL (Gla-100, a standard of care [SoC] in basal lin therapy (REACH; conducted in Brazil, France, Germany, Italy, insulin treatment5), and equivalent glycemic control with Romania, Spain, United Kingdom) or already on basal insulin reduced risk of anytime (24 h) or nocturnal hypoglycemia, in therapy (REGAIN; conducted in Brazil, Finland, France, Italy, randomized controlled trials (RCTs) of people with T2DM6–9. Romania, Spain, Switzerland, United Kingdom). Participants Furthermore, a lower risk of hypoglycemia with Gla-300 dur- underwent a 1-week screening period, followed by a 6-month ing the initial weeks of treatment (the titration period) has treatment period (for assessment of the primary outcome) and been consistently shown in regulatory RCTs versus Gla-100, a 6-month extension period (during which patients continued and has also been demonstrated versus insulin degludec6–10. within their assigned treatment arm) (Supplementary Figure 1), Consistent with RCTs, Gla-300 has shown comparable HbA1c to evaluate durability of clinical benefit, as well as patient- reduction with fewer hypoglycemic episodes versus first- reported outcomes (PROs) and healthcare resource utilization. generation basal insulin analogs in retrospective, non-inter- Patients attended four study visits during the 12-month ran- ventional real-world evidence (RWE) studies11,12. domization period. Both trials were approved by local/national Even after initiation, those using basal insulin frequently institutional review boards/independent ethics committees, as experience poor glycemic control, which may be related to appropriate, and were performed in accordance with the insulin dose up-titration13, that is often suboptimal in real-world Declaration of Helsinki and the International Conference on practice4,14. Such therapeutic inertia (a phenomenon that Harmonization guidelines for Good Clinical Practice. All partici- includes delayed therapy initiation, lack of dose adjustment pants provided written informed consent. and delayed therapy intensification13), which probably contrib- Participants were aged 18 years with uncontrolled T2DM utes to the low level of HbA1c target achievement in routine (HbA1c >7.0%) after 6 months of treatment with or clinical practice4,15, may be related to perceived barriers such without GLP-1RA therapy and either (i) current OADs as hypoglycemia and weight gain13,14,16–18. We hypothesized (REACH) or (ii) basal insulin therapy with/without OADs that the use of newer basal insulin (such as Gla-300) in clinical (REGAIN). Permitted OADs were metformin, sulfonylureas practice may allow people with T2DM to titrate appropriately (SU), thiazolidinediones, dipeptidyl peptidase 4 (DPP-4) to achieve glycemic control with minimal hypoglycemia, inhibitors, sodium-glucose co-transporter 2 (SGLT-2) inhibi- thereby overcoming therapeutic inertia. However, although tors, glinides, a-glucosidase inhibitors. SoC basal insulin results from non-interventional real-world studies are interesting therapy included Gla-100, insulin detemir, neutral protamine and may better reflect clinical practice than regulatory RCTs, Hagedorn (NPH) insulin or insulin degludec. Participants in comparisons between treatments in such studies may be con- REGAIN were also required to have a fasting plasma glucose founded even if factors are fully controlled by appropriate stat- (FPG) concentration of >130 mg/dL (>7.2 mmol/L) to justify istical methods such as propensity score matching. the need to intensify the current basal insulin treatment. Here we present the results of two studies that combine Exclusion criteria included the presence of any clinically sig- real-world relevance with the advantages of randomization, a nificant abnormality that would restrict successful participation methodology which, uniquely, is a perfect instrument to in the study, use of OADs not specified in the inclusion criteria, address confounding. These studies aim to evaluate the real- use of GLP-1RA not approved for use with insulin, or use of world effectiveness of newer basal insulin, Gla-300, compared any drug in the context of a clinical trial within 3 months prior with other SoC basal insulins, in insulin-naïve (the REACH to screening. Participants in REGAIN were also excluded if they CONTROL trial) and basal insulin-treated (the REGAIN had received short-/rapid-acting insulin (e.g. human recombin- CONTROL trial) participants with uncontrolled T2DM. REACH ant insulin, insulin lispro, insulin aspart, insulin glulisine, inhaled and REGAIN are the first randomized real-life studies (often human insulin, pre-mix insulin, and biosimilars) during the known as pragmatic studies as they aim to assess the out- 3 months prior to screening, other than for temporary use dur- comes of treatment in routine clinical practice, rather than in ing hospitalization. Additional exclusion criteria are listed in the the controlled explanatory setting of a regulatory RCT19) Supplementary Material. using basal insulin treatments in Europe and Brazil, and the first such studies in the field of basal insulin therapy. The studies were intended to allow for direct treatment compari- Randomization and treatment sons in a real-life setting, and also provide an opportunity to determine whether this pragmatic study design is a valid Randomization (1:1) either to Gla-300 or to any SoC basal approach to investigate the impact of novel therapies on insulin (all commercially available long- or intermediate-act- therapeutic inertia. ing basal insulins, chosen at the investigator’s discretion based on their clinical practice) was performed centrally by an interactive response technology (IRT) system; the investi- Materials and methods gator called the IRT system after the screening visit for allo- cation of the patient number, and again on Day 1 when the Study design and participants system randomized the patients to one of the treatment REACH CONTROL (NCT02967224) and REGAIN CONTROL arms. Randomization was stratified according to HbA1c cat- (NCT02967211) were multicenter, open-label, randomized, egory (<9% or 9%) at screening, SU use at the time of CURRENT MEDICAL RESEARCH AND OPINION 573 randomization, and GLP-1RA use within 6 months prior to <7.0%, <7.5% and <8.0%) at months 6 and 12, the percent- randomization. Gla-300 was to be self-administered once- age of participants whose HbA1c decreased by 1% (REACH) daily at approximately the same time of day. SoC basal insu- or 0.5% (REGAIN) at months 6 and 12, change in FPG from lins were to be administered once- or twice-daily according baseline to months 6 and 12 and the proportion of partici- to approved labeling and clinical practice. If needed, partici- pants remaining on assigned basal insulin therapy during the pants randomized to SoC basal insulin could switch to any 6- and 12-month randomized periods, with or without intensi- other SoC basal insulin, except Gla-300, during the treatment fication (defined as addition of any OAD, GLP1-RA and/or period. Where available, participants were offered either a rapid-acting insulin medication, or an increase in dose of anti- specific, designated patient support program (PSP) (Gla-300 hyperglycemic medication already in use). arm only) or a PSP as per the investigator’s usual practice Safety outcomes included hypoglycemia episodes, includ- (any patient assigned to SoC), to help them achieve success- ing incidence of nocturnal (00.00am–05.59am) and anytime ful insulin initiation and overall self-management, but this (24 h) hypoglycemic events, and documented symptomatic was not compulsory. The PSP for Gla-300 (COACH) has been or severe events. Hypoglycemia was classified according to described previously20,21, and includes tailored disease edu- ADA criteria24, similar to the definition used in the pivotal cation, product support, and encouragement for lifestyle studies of Gla-3006,7. Documented symptomatic hypogly- changes, but does not include specific titration support. cemia was defined as an event with typical symptoms of The approved insulin delivery devices for study drugs hypoglycemia accompanied by a PG concentration of were distinguishable; therefore, this was an open-label study. 70 mg/dL, (3.9 mmol/L) (<54 mg/dL [<3.0 mmol/L] was However, HbA1c and FPG were analyzed in central laborato- also analyzed). Severe hypoglycemia was defined as an event ries that were blinded to study drug received by the patient, requiring assistance from a third party to administer carbohy- and the sponsor and investigators were blinded to the drate, glucagon or other resuscitative actions. Other safety results prior to database lock. outcomes included adverse events (AEs) and serious adverse events (SAEs), injection-site and hypersensitivity reactions, vital signs and change in body weight from baseline to Dose and titration months 6 and 12. Although not classified as a safety out- The administered dose of Gla-300 or SoC basal insulin was at come, basal insulin dose (U and U/kg) was also assessed. the investigator’s discretion according to their standard prac- tice and the patient’s characteristics and requirements, and Statistical methods dependent on self-monitored plasma glucose data and occurrence of hypoglycemia. The recommended starting For REACH and REGAIN, a sample size of 340 and 290 patients, dose of Gla-300 was in line with the country-specific label, respectively, per treatment group was determined in order to taking into account glucose control and patterns of hypogly- provide 90% power to ensure that the upper confidence limit cemia in each patient. In brief, the starting dose of Gla-300 of the 2-sided 95% confidence interval (CI) for the mean differ- was to be 0.2 U/kg in REACH and the same dose as the pre- ence between Gla-300 and an SoC basal insulin did not exceed viously used basal insulin (adapted as per the Gla-300 label 0.3% (a non-inferiority margin recommended by the EMA25), in those previously on a twice-daily regimen) in REGAIN. The assuming a particular standard deviation (SD) (1.4% in REACH recommended target range for FPG was 80–130 mg/dL and 1.3% in REGAIN) and that the true difference in HbA1c (4.4–7.2 mmol/L), as per American Diabetes Association (ADA) between Gla-300 and a SoC basal insulin was 0.05%. The guidelines22. Insulin dose could be adjusted in order to power calculation was based on a 2-sample t-test for mean dif- achieve this target or other local practice guidelines, and gly- ference and was performed using the PROC POWER procedure cemic targets could be adapted if it was deemed necessary in SAS software version 9.3, SAS Institute Inc., Cary, NC, USA. by the investigator according to individual participant con- The primary analysis was conducted on all randomized siderations. Importantly and in keeping with the real-world patients following the intent-to-treat (ITT) principle. Change in nature of the study, no protocol-recommended titration algo- HbA1c from baseline to month 6 was analyzed in the ITT rithm or oversight of titration outside of local clinical practice population using a mixed-effect model with repeated measures was performed. It was recommended that Gla-300 dose (MMRM), with fixed categorical effects of treatment arm, visit, changes did not occur more frequently than every 3–4 days, treatment-by-visit interaction, multi-country organisation, ran- in line with the EU label23. Modification of concomitant anti- domization strata of SU use (yes/no), randomization strata of hyperglycemic medication use (i.e. discontinuation or initi- GLP-1 receptor agonist use (yes/no), as well as continuous ation) was performed according to local clinical practice and fixed covariates of baseline HbA1c and baseline HbA1c value- based on the investigator’s discretion. by-visit interaction. The same model was used to analyze HbA1c change to month 12, with the exception that one additional level was added to the “visit” factor. For the Outcomes primary endpoint, a stepwise closed testing approach was The primary outcome was change in HbA1c from baseline to used to assess non-inferiority and superiority sequentially. month 6, to demonstrate the non-inferiority of Gla-300 versus Non-inferiority (and superiority, if non-inferiority was shown) of SoC basal insulin therapy. Secondary outcomes included the Gla-300 versus SoC basal insulin was demonstrated if the proportion of participants reaching HbA1c targets (<6.5%, upper bound of the 2-sided 95% CI for the between-treatment 574 N. FREEMANTLE ET AL. Table 1. Demographics and baseline characteristics of study participants in REACH and REGAIN (randomized population). REACH REGAIN Parameter Gla-300 SoC basal insulin Total Gla-300 SoC basal insulin Total (n ¼ 352) (n ¼ 351) (N ¼ 703) (n ¼ 305) (n ¼ 304) (N ¼ 609) Age, years 61.4 ± 9.9 61.4 ± 10.0 61.4 ± 10.0 62.1 ± 10.1 62.0 ± 9.6 62.0 ± 9.9 Gender, male, n (%) 205 (58.2) 199 (56.7) 404 (57.5) 163 (53.4) 168 (55.3) 331 (54.4) Weight, kg 87.7 ± 20.6 87.1 ± 18.5 87.4 ± 19.5 87.9 ± 19.9 88.2 ± 19.3 88.1 ± 19.6 Body mass index, kg/m2 31.2 ± 6.1 31.1 ± 5.8 31.1 ± 5.9 32.0 ± 6.1 32.0 ± 6.1 32.0 ± 6.1 Duration of diabetes, years 11.2 ± 7.4 10.9 ± 7.1 11.0 ± 7.2 13.8 ± 7.4 13.6 ± 7.8 13.7 ± 7.6 HbA1c % 8.99 ± 1.40 9.08 ± 1.49 9.04 ± 1.45 8.58 ± 1.10 8.51 ± 1.18 8.55 ± 1.14 mmol/mol 74.8 ± 15.3 75.8 ± 16.3 75.3 ± 15.8 70.2 ± 12.0 69.6 ± 12.9 69.9 ± 12.5 FPG mg/dL 210.1 ± 61.9 209.9 ± 70.5 210.0 ± 66.3 177.4 ± 56.8 181.4 ± 56.5 179.4 ± 56.6 mmol/L 11.7 ± 3.4 11.7 ± 3.9 11.7 ± 3.7 9.9 ± 3.2 10.1 ± 3.1 10.0 ± 3.1 Baseline anti-hyperglycemic medication, n (%) Biguanides 308 (87.5) 320 (91.2) 628 (89.3) 268 (87.9) 264 (86.8) 532 (87.4) Sulfonylureas 197 (56.0) 197 (56.1) 394 (56.0) 104 (34.1) 100 (32.9) 204 (33.5) DPP-4 inhibitors 148 (42.0) 152 (43.3) 300 (42.7) 86 (28.2) 80 (26.3) 166 (27.3) GLP-1 RAs 56 (15.9) 57 (16.2) 113 (16.1) 59 (19.3) 59 (19.4) 118 (19.4) SGLT2 inhibitors 26 (7.4) 32 (9.1) 58 (8.3) 43 (14.1) 34 (11.2) 77 (12.6) Glinides 26 (7.4) 20 (5.7) 46 (6.5) 30 (9.8) 18 (5.9) 48 (7.9) Thiazolidinediones 18 (5.1) 6 (1.7) 24 (3.4) 5 (1.6) 6 (2.0) 11 (1.8) Alpha-glucosidase inhibitors 8 (2.3) 15 (4.3) 23 (3.3) 1 (0.3) 7 (2.3) 8 (1.3) None 1 (0.3) 0 (0) 1 (0.1) 4 (1.3) 5 (1.6) 9 (1.5) Diabetes complications, n (%) Neuropathy 74 (21.0) 87 (24.8) 161 (22.9) 78 (25.6) 75 (24.7) 153 (25.1) Nephropathy 62 (17.6) 53 (15.1) 115 (16.4) 67 (22.0) 58 (19.1) 125 (20.5) Retinopathy 44 (12.5) 32 (9.1) 76 (10.8) 69 (22.6) 73 (24.0) 142 (23.3) Prescribed basal insulin, n (%)† Glargine 300 U/mL 350 (100) 0 (0) n/a 304 (100) 0 (0) n/a Glargine 100 U/mL n/a 259 (74.0) n/a n/a 204 (67.1) n/a Detemir n/a 35 (10.0) n/a n/a 29 (9.5) n/a Degludec n/a 18 (5.1) n/a n/a 28 (9.2) n/a NPH n/a 38 (10.9) n/a n/a 43 (14.1) n/a Information about diabetes complications was obtained from patient records/history at the screening visit, using pre-defined terms in the case report form. †Data regarding basal insulin prescriptions are from the safety population, and represent insulin prescribed during the studies, not only at baseline. Data are presented as mean ± SD unless otherwise stated. Abbreviations. DPP-4, dipeptidyl peptidase-4; FPG, fasting plasma glucose; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HbA1c, glycated hemoglobin; n/a, not applicable; SD, standard deviation; SGLT2, sodium-glucose co-transporter 2; SoC, standard of care. difference in mean change of HbA1c from baseline to month 6 October 2017. Baseline characteristics for the overall study was less than the predefined margin of 0.3% (or <0% for populations of REACH (N ¼ 703) and REGAIN (N ¼ 609) are superiority). The test for the primary outcome was performed presented in Table 1. The REGAIN population had longer one-sided at level a ¼ 0.025. mean duration of diabetes, a lower proportion who were Secondary outcomes were analyzed descriptively in the ITT receiving SUs or DPP-4 inhibitors at baseline and a higher population, where appropriate using either a mixed-effect proportion receiving SGLT2 inhibitors at baseline compared model with repeated measures or a logistic regression with the REACH population. Patient disposition throughout approach, and no multiplicity adjustments were made. Safety both studies is shown in Supplementary Figure 2. Among outcomes were assessed descriptively, with no statistical test- patients who did not complete the 12-month randomized ing, in the safety population, comprising all randomized partici- period in REACH (n ¼ 30) and REGAIN (n ¼ 28), there were 4 pants who received  1 dose of study insulin. Participants were (Gla-300, n ¼ 2; SoC basal insulin, n ¼ 2) and 5 (Gla-300, analyzed according to treatment actually received, irrespective n ¼ 3; SoC basal insulin, n ¼ 2) deaths, respectively. The num- of the randomized treatment arm. Odds ratios (ORs) and rate ber of patients taking concomitant short-acting insulin, ratios (RRs) for Gla-300 versus SoC basal insulins and their cor- mainly for intensification, during the 12-month randomized responding 95% CIs were provided, where applicable and esti- periods were as follows: REACH, 21 patients (6.0%) in the mated using logistic and log binomial regression approaches, Gla-300 group and 31 patients (8.8%) in the SoC group; respectively. The difference in the annualized rate of hypogly- REGAIN, 16 patients (5.2%) in the Gla-300 group and cemic events was evaluated using an over-dispersed Poisson 14 patients (4.6%) in the SoC group. The most commonly used SoC basal insulin over 12 months was Gla-100 in both regression model. All analyses were undertaken using SAS soft- REACH (74%) and REGAIN (67%). ware version 9.3, SAS Institute Inc., Cary, NC, USA. Outcomes Results Change in HbA1c and insulin dose Study participants In REACH, mean baseline HbA1c values were 8.99 (SD 1.40) % REACH was conducted between November 2015 and (74.7 [15.3] mmol/mol) with Gla-300 and 9.08 (1.49) % (75.7 October 2017 and REGAIN between December 2015 and [16.3] mmol/mol) with SoC BIs. There was a similar change in CURRENT MEDICAL RESEARCH AND OPINION 575 (a) (b) LS mean difference (95% CI) M6 M12 LS mean difference (95% CI) M6 M12 Gla-300 vs SoC BI: Gla-300 vs SoC BI: 0.12 % 0.07 % 0.17 % -0.03 % (-0.046 to 0.281) (-0.087 to 0.227) (0.015 to 0.329) (-0.199 to 0.145) 1.31 mmol/mol 0.77 mmol/mol 1.86 mmol/mol 0.33 mmol/mol (-0.50 to 3.13) (-0.95 to 2.48) (-0.16 to 3.60) (-2.18 to 1.59) 0.8 7 0.8 7 0.4 0.4 HbA1c change (mmol/mol) HbA1c change (mmol/mol) 2 2 0.0 0.0 HbA1c change (%) HbA1c change (%) -3 -3 LS mean ± SE LS mean ± SE LS mean ± SE LS mean ± SE -0.4 -0.4 -0.8 Non-inferiority: p=0.0145 -8 -0.8 -8 Non-inferiority: p=0.0554 -1.2 -13 -1.2 -13 -1.6 -1.6 -18 -18 -2.0 -2.0 Gla-300 (n=352) -23 Gla-300 (n=305) -23 -2.4 -2.4 SoC BI (n=351) SoC BI (n=304) -2.8 -28 -2.8 -28 BL M3 M6 M12 BL M3 M6 M12 Gla-300: n=346 n=340 n=342 n=330 Gla-300: n=299 n=297 n=291 n=281 SoC: n=344 n=343 n=340 n=333 SoC: n=300 n=297 n=296 n=287 (c) (d) 0.20 0.20 Gla-300 (n=350) Gla-300 (n=304) Insulin dose change (U/kg) Insulin dose change (U/kg) SoC BI (n=350) SoC BI (n=304) 0.15 0.15 mean ± SE mean ± SE 0.10 0.10 0.05 0.05 0.00 0.00 BL M3 M6 M9 M12 BL M3 M6 M9 M12 Gla-300: n=350 n=342 n=341 n=336 n=332 Gla-300: n=304 n=300 n=294 n=289 n=284 SoC: n=349 n=339 n=337 n=333 n=333 SoC: n=304 n=300 n=296 n=289 n=290 Figure 1. LS mean (±SE) change from baseline in HbA1c by visit during the 12-month randomized period in (a) REACH and (b) REGAIN and change in insulin dose in (c) REACH and (d) REGAIN (ITT populations). Abbreviations. BI, basal insulin; CI, confidence interval; HbA1c, glycated hemoglobin; ITT, intent-to-treat; LS, least squares; M, month; SE, standard error; SoC, standard of care. HbA1c in both groups, with values decreasing to 7.65 (1.19) % however, by 12 months the difference in HbA1c between (60.1 [13.0] mmol/mol) with Gla-300 and 7.54 (1.17) % (58.9 treatment groups was observed to be nominally within the [12.8] mmol/mol) with SoC basal insulins at month 6. HbA1c non-inferiority margins (LS mean difference 0.03 [95% CI remained stable through to month 12, when values were 7.64 0.199 to 0.145]% [0.3 (2.2 to 1.6) mmol/mol]) (Figure 1(b)). (1.09) % (60.0 [11.9] mmol/mol) with Gla-300 and 7.59 (1.16) % In both studies, the degree of insulin titration reflected by (59.4 [12.7] mmol/mol) with SoC basal insulins. REACH met its dose changes was low in the Gla-300 and SoC basal insulin primary outcome, demonstrating non-inferiority of Gla-300 ver- treatment arms (Figure 1(c,d)). In REACH, mean (SD) daily dose sus SoC basal insulins in terms of HbA1c change from baseline increased from baseline values of 0.18 (0.07) U/kg for Gla-300 to month 6 (LS mean difference between groups 0.12; [95% CI and 0.17 (0.07) U/kg for SoC basal insulin, to month 6 values 0.046 to 0.281]% [1.3 (0.5 to 3.1) mmol/mol]) (Figure 1(a)). of 0.32 (0.18) U/kg for Gla-300 and 0.30 (0.18) U/kg for SoC There was also no difference between the groups in HbA1c basal insulins (mean increases of 0.14 and 0.13 U/kg, respect- change from baseline to month 12 (LS mean difference 0.07 ively). In REGAIN, mean (SD) daily dose increased from baseline [95% CI 0.087 to 0.227]% [0.8 (1.0 to 2.5) mmol/mol]) values of 0.41 (0.21) U/kg for Gla-300 and 0.41 (0.23) U/kg for (Figure 1(a)). SoC basal insulins, to month 6 values of 0.49 (0.27) U/kg for In REGAIN, mean (SD) baseline HbA1c values were 8.58 (1.10) Gla-300 and 0.46 (0.26) U/kg for SoC basal insulins (mean % (70.3 [12.0] mmol/mol) with Gla-300 and 8.51 (1.18) % (69.5 increases of 0.08 and 0.06 U/kg, respectively). By month 12, the [12.9] mmol/mol) with SoC basal insulins. There was only a daily dose had increased to 0.35 (0.19) U/kg for Gla-300 and modest decrease in HbA1c from baseline in both treatment 0.33 (0.20) U/kg for SoC basal insulins in REACH (mean groups, to 6-month values of 8.32 (1.24) % (67.4 [13.6] increases of 0.17 and 0.15 U/kg, respectively), and to 0.52 (0.28) mmol/mol) with Gla-300 and 8.11 (1.18) % (65.1 [12.9] mmol/mol) U/kg for Gla-300 and 0.48 (0.26) U/kg for SoC basal insulins in with SoC BIs. From month 6 onwards there was further HbA1c REGAIN (mean increases of 0.11 and 0.07 U/kg, respectively). reduction in the Gla-300 group (to 8.17 [1.19] % [65.8 (13.0) mmol/mol] at month 12), but little change in the SoC basal HbA1c targets insulins group (month 12 value of 8.17 [1.28] % [65.8 (14.0) mmol/mol]). In REGAIN, the primary 6-month outcome did not The proportion of patients who achieved the HbA1c target achieve statistical non-inferiority of Gla-300 versus SoC basal <7.0% was low and similar in the Gla-300 and SoC basal insulins in terms of HbA1c change from baseline (LS mean dif- insulin arms during the 12-month period in both REACH and ference 0.17 [95% CI 0.015–0.329]% [1.9 (0.2–3.6) mmol/mol]); REGAIN (Table 2). In REACH, the percentage of patients with 576 N. FREEMANTLE ET AL. Table 2. Proportion of patients at HbA1c target during the 12-month randomized period by visit (ITT population). REACH REGAIN Patients at HbA1c target, n (%) Gla-300 (n ¼ 352) SoC basal insulin (n ¼ 351) Gla-300 (n ¼ 305) SoC basal insulin (n ¼ 304) Baseline <6.5% 0 (0) 0 (0) 0 (0) 0 (0) <7.0% 4 (1.1) 2 (0.6) 1 (0.3) 2 (0.7) <7.5% 40 (11.4) 35 (10.0) 36 (11.8) 54 (17.8) <8.0% 89 (25.3) 83 (23.6) 105 (34.4) 119 (39.1) Imputed as failure 0 (0) 0 (0) 0 (0) 0 (0) Month 3 <6.5% 34 (9.7) 35 (10.0) 3 (1.0) 7 (2.3) <7.0% 80 (22.7) 113 (32.2) 19 (6.2) 36 (11.8) <7.5% 159 (45.2) 174 (49.6) 65 (21.3) 81 (26.6) <8.0% 228 (64.8) 232 (66.1) 128 (42.0) 147 (48.4) Imputed as failure 12 (3.4) 8 (2.3) 8 (2.6) 7 (2.3) Month 6 <6.5% 42 (11.9) 53 (15.1) 11 (3.6) 7 (2.3) <7.0% 102 (29.0) 107 (30.5) 26 (8.5) 44 (14.5) <7.5% 175 (49.7) 189 (53.8) 71 (23.3) 92 (30.3) <8.0% 231 (65.6) 247 (70.4) 119 (39.0) 157 (51.6) Imputed as failure 10 (2.8) 11 (3.1) 14 (4.6) 8 (2.6) Month 12 <6.5% 31 (8.8) 38 (10.8) 9 (3.0) 12 (3.9) <7.0% 85 (24.1) 102 (29.1) 34 (11.1) 31 (10.2) <7.5% 166 (47.2) 176 (50.1) 87 (28.5) 93 (30.6) <8.0% 231 (65.6) 228 (65.0) 137 (44.9) 151 (49.7) Imputed as failure 22 (6.3) 18 (5.1) 24 (7.9) 17 (5.6) Abbreviations. HbA1c, glycated hemoglobin; ITT, intent-to-treat; SoC, standard of care a 1% decrease in HbA1c at month 6 that was maintained at Hypoglycemia month 12 was similar in both treatment groups (Gla-300, Incidence and rates of anytime (24 h) hypoglycemia were low 44.0% (155/352); SoC basal insulin, 47.9% (168/351)). In and similar in the Gla-300 and SoC basal insulin arms in REGAIN, the percentage of patients with a 0.5% decrease REACH and REGAIN (Table 3). Benefits were observed for in HbA1c at month 6 that was maintained at month 12 was Gla-300 versus SoC basal insulins in REGAIN, for nocturnal similar in both treatment groups (Gla-300, 26.9% (82/305); (00.00am–05.59am) symptomatic documented (3.9 mmol/L) SoC basal insulin, 27.3% (83/304)). hypoglycemia (OR 0.48 [95% CI 0.26–0.87]; RR 0.45 [0.20–0.97]) and severe and/or symptomatic documented FPG changes (3.9 mmol/L) hypoglycemia (OR 0.47 [0.27–0.84]; RR 0.42 In REACH, mean (SD) baseline FPG was 11.62 (3.43) mmol/L [0.20–0.87])(Table 4). (209.3 [61.9] mg/dL) with Gla-300 and 11.67 (3.80) mmol/L (210.2 [68.5] mg/dL) with SoC basal insulins. FPG decreased similarly in both groups to month 6 values of 8.70 (2.49) Bodyweight changes mmol/L (156.7 [44.9] mg/dL) with Gla-300 and 8.42 (2.55) In both REACH and REGAIN, the LS mean change in patients’ mmol/L (151.7 [45.9] mg/dL) with SoC basal insulins, and to body weight from baseline to month 12 was modest and month 12 values of 8.25 (2.40) mmol/L (148.7 [43.2] mg/dL) similar in both treatment groups (Figure 2). with Gla-300 and 8.35 (2.62) mmol/L (150.5 [47.2] mg/dL) with SoC basal insulins. In REGAIN, mean baseline FPG was 9.85 (3.16) mmol/L (177.5 Incidence of adverse events [57.0] mg/dL) with Gla-300 and 10.03 (3.12) mmol/L (180.7 [56.2] mg/dL) with SoC basal insulins, decreasing to 9.21 (2.75) In both REACH and REGAIN, the AE profile was similar mmol/L (165.9 [49.5] mg/dL) and 8.74 (2.91) mmol/L between treatment arms. In REACH, 208 (59.4%) and 194 (157.5 [52.5] mg/dL) at month 6, and to 8.62 (3.04) mmol/L (55.4%) patients in the Gla-300 and SoC basal insulin arms, (155.4 [54.9] mg/dL) and 8.67 (3.14) mmol/L (156.2 [56.7] respectively, had a treatment-emergent AE (TEAE), of whom 14 mg/dL) at month 12, respectively. (4.0%) in each treatment arm had a TEAE considered as related In both REACH and REGAIN, LS mean FPG change from to study drug. Two (0.6%) patients in each treatment arm had baseline to month 12 was similar across treatment arms a TEAE leading to death. Two (0.6%) (Gla-300) and 3 (0.9%) (REACH, 3.32 mmol/L [59.9 mg/dL] with Gla-300 and patients (SoC basal insulins) discontinued treatment due to 3.27 mmol/L [58.8 mg/dL] with SoC basal insulins; REGAIN, TEAEs. In REGAIN, 184 (60.5%) and 170 (55.9%) patients in the 1.30 mmol/L [23.5 mg/dL] with Gla-300 and 1.26 mmol/L Gla-300 and SoC basal insulin arms, respectively, had a TEAE, [22.8 mg/dL] with SoC basal insulins). In both studies, the of whom 6 (2.0%) (Gla-300) and 2 (0.7%) (SoC basal insulins) month 12 FPG values in either treatment arm were above had a TEAE considered as related to study drug. Two (0.7%) the ADA FPG target range specified in the protocol. patients in each treatment arm had a TEAE leading to death. CURRENT MEDICAL RESEARCH AND OPINION 577 Table 3. Hypoglycemia events occurring at any time of day (24 h) during the 12-month on-treatment period in REACH and REGAIN (safety population). REACH REGAIN Type of hypoglycemia event Gla-300 SoC basal insulin Gla-300 vs SoC Gla-300 SoC basal insulin Gla-300 vs SoC (n ¼ 350) (n ¼ 350) basal insulin (n ¼ 304) (n ¼ 304) basal insulin Participants experiencing  1 OR (95% CI) OR (95% CI) hypoglycemic event, n (%) Any hypoglycemia 117 (33.4) 110 (31.4) 1.10 (0.80–1.52) 113 (37.2) 113 (37.2) 1.00 (0.72–1.39) Severe hypoglycemia 8 (2.3) 5 (1.4) 1.62 (0.52–5.01) 8 (2.6) 11 (3.6) 0.72 (0.29–1.82) Symptomatic hypoglycemia Documented 3.9 mmol/L 73 (20.9) 65 (18.6) 1.16 (0.80–1.70) 80 (26.3) 76 (25.0) 1.07 (0.74–1.54) (70 mg/dL) Documented < 3.0 mmol/L 19 (5.4) 20 (5.7) 0.95 (0.50–1.81) 32 (10.5) 28 (9.2) 1.17 (0.68–2.00) (<54 mg/dL) Severe and/or symptomatic hypoglycemia Documented  3.9 mmol/L 79 (22.6) 67 (19.1) 1.24 (0.86–1.80) 83 (27.3) 81 (26.6) 1.03 (0.72–1.48) (70 mg/dL) Documented < 3.0 mmol/L 26 (7.4) 24 (6.9) 1.09 (0.61–1.94) 38 (12.5) 36 (11.8) 1.07 (0.65–1.74) (<54 mg/dL) Number of events (events per RR (95% CI) RR (95% CI) patient-year) Total patient years 337.21 335.52 295.05 294.14 Any hypoglycemia 573 (1.70) 664 (1.98) 0.87 (0.56–1.33) 688 (2.33) 675 (2.29) 1.02 (0.68–1.53) Severe hypoglycemia 15 (0.04) 11 (0.03) 1.36 (0.41–4.46) 9 (0.03) 27 (0.09) 0.33 (0.10–1.11) Symptomatic hypoglycemia Documented  3.9 mmol/L 310 (0.92) 315 (0.94) 0.98 (0.55–1.76) 258 (0.87) 366 (1.24) 0.70 (0.44–1.11) (70 mg/dL) Documented < 3.0 mmol/L 41 (0.12) 42 (0.13) 0.97 (0.45–2.08) 63 (0.21) 70 (0.24) 0.90 (0.48–1.70) (<54 mg/dL) Severe and/or symptomatic hypoglycemia Documented  3.9 mmol/L 325 (0.96) 326 (0.97) 1.00 (0.57–1.75) 267 (0.90) 393 (1.34) 0.67 (0.43–1.05) (70 mg/dL) Documented < 3.0 mmol/L 56 (0.17) 53 (0.16) 1.05 (0.51–2.18) 72 (0.24) 97 (0.33) 0.74 (0.42–1.30) (<54 mg/dL) Abbreviations. CI, confidence interval; OR, odds ratio; RR, rate ratio; SoC, standard of care. The 12-month on-treatment period was defined as the time from the first study drug intake until one day after last injection of the study drug. ORs and their corresponding 95% CIs are based on a logistic regression with treat- ment arm as a fixed effect and adjusting for randomization strata: HbA1c (<9%/>9%), sulfonylurea use (yes/no) and GLP-1 RA use (yes/no). Estimated RRs and their corresponding 95% CIs are based on an over-dispersed Poisson regression model with a log-link function and with treatment arm as a fixed effect, adjust- ing for randomization strata: HbA1c (<9%/9%), SU use (yes/no) and GLP-1RA use (yes/no). Eight (2.6%) (Gla-300) and 2 (0.7%) patients (SoC basal insulins) larger real-world evidence program (including another prag- discontinued treatment due to TEAEs. matic study, ACHIEVE-CONTROL26, in 3300 insulin-naïve T2DM patients in North America). In both studies, the pri- Patient support program (PSP) mary outcome was non-inferiority of Gla-300 versus In REACH, 44.3% (155/350) of patients in the Gla-300 group SoC basal insulin in terms of HbA1c change from baseline to month 6. The primary outcome was met in REACH but not in at least partially participated in the core PSP, and 8.6% REGAIN, although only a modest HbA1c reduction was seen (30/350) of patients in the SoC basal insulin group at least in both treatment arms over the full study period in REGAIN, partially participated in any PSP. In REGAIN, 51.0% (155/304) and no difference in HbA1c change between the groups was of patients in the Gla-300 group and 2.6% (8/304) of patients shown after 12 months in either study. It may be notable in the SoC basal insulin group participated in a PSP. that overall basal insulin dose increases were minimal in both studies, particularly in REGAIN. Discussion The failure to achieve non-inferiority for the difference in REACH and REGAIN are the first randomized pragmatic stud- HbA1c change in REGAIN compared to SoC was unexpected. ies in T2DM to allow for direct treatment comparisons of It is possible that this simply reflects no benefit, or even a patient outcomes in a real-life setting, and are part of a lack of parity, with Gla-300 versus other SoC BIs in a real- 578 N. FREEMANTLE ET AL. Table 4. Nocturnal (00.00am–05.59am) hypoglycemia events occurring during the 12-month on-treatment period in REACH and REGAIN (safety population). REACH REGAIN Type of hypoglycemia event Gla-300 SoC basal insulin Gla-300 vs SoC Gla-300 SoC basal insulin Gla-300 vs SoC (n ¼ 350) (n ¼ 350) basal insulin (n ¼ 304) (n ¼ 304) basal insulin Participants experiencing  1 OR (95% CI) OR (95% CI) hypoglycemic event, n (%) Any hypoglycemia 35 (10.0) 25 (7.1) 1.45 (0.85–2.48) 34 (11.2) 48 (15.8) 0.67 (0.42–1.08) Severe hypoglycemia 1 (0.3) 3 (0.9) 0.33 (0.03–3.18) 2 (0.7) 5 (1.6) 0.39 (0.08–2.07) Symptomatic hypoglycemia Documented  3.9 mmol/L 20 (5.7) 15 (4.3) 1.36 (0.68–2.72) 18 (5.9) 35 (11.5) 0.48 (0.26–0.87) (70 mg/dL) Documented < 3.0 mmol/L 8 (2.3) 7 (2.0) 1.15 (0.41–3.21) 9 (3.0) 10 (3.3) 0.90 (0.38–2.16) (<54 mg/dL) Severe and/or symptomatic hypoglycemia Documented  3.9 mmol/L 21 (6.0) 18 (5.1) 1.18 (0.62–2.26) 20 (6.6) 39 (12.8) 0.47 (0.27–0.84) (70 mg/dL) Documented < 3.0 mmol/L 9 (2.6) 10 (2.9) 0.90 (0.36–2.24) 11 (3.6) 15 (4.9) 0.72 (0.33–1.61) (<54 mg/dL) Number of events (events per RR (95% CI) RR (95% CI) patient-year) Total patient-years 337.21 335.52 295.05 294.14 Any hypoglycemia 83 (0.25) 51 (0.15) 1.63 (0.87–3.05) 100 (0.34) 132 (0.45) 0.75 (0.42–1.36) Severe hypoglycemia 1 (0.00) 5 (0.01) 0.20 (0.00–12.72) 2 (0.01) 11 (0.04) 0.18 (0.01–5.25) Symptomatic hypoglycemia Documented  3.9 mmol/L 43 (0.13) 29 (0.09) 1.48 (0.68–3.21) 39 (0.13) 87 (0.30) 0.45 (0.20–0.97) (70 mg/dL) Documented < 3.0 mmol/L 10 (0.03) 7 (0.02) 1.42 (0.51–3.92) 11 (0.04) 18 (0.06) 0.61 (0.25–1.51) (<54 mg/dL) Severe and/or symptomatic hypoglycemia Documented  3.9 mmol/L 44 (0.13) 34 (0.10) 1.29 (0.62–2.70) 41 (0.14) 98 (0.33) 0.42 (0.20–0.87) (70 mg/dL) Documented < 3.0 mmol/L 11 (0.03) 12 (0.04) 0.92 (0.36–2.32) 13 (0.04) 29 (0.10) 0.45 (0.18–1.12) (<54 mg/dL) CI: confidence interval; OR: odds ratio; RR: rate ratio; SoC: standard of care. The 12-month on-treatment period was defined as the time from the first study drug intake until one day after last injection of the study drug. ORs and their corresponding 95% CIs are based on a logistic regression with treatment arm as a fixed effect and adjusting for randomization strata: HbA1c (<9%/>9%), sulfonylurea use (yes/no) and GLP-1RA use (yes/no). Estimated RRs and their correspond- ing 95% CIs are based on an over-dispersed Poisson regression model with a log-link function and with treatment arm as a fixed effect, adjusting for random- ization strata: HbA1c (<9%/9%), SU use (yes/no) and GLP-1 RA use (yes/no). Bold values represent p < 1. world scenario. However, given the results from previous treatment arms in REGAIN) compared with the EDITION RCTs RCTs6,7, we feel that this is unlikely. The EDITION program of that employed a treat-to-target approach; Gla-300 dose RCTs, with a treat-to-target approach, consistently demon- increase over 12 months was 0.17 U/kg in REACH versus strated non-inferiority of Gla-300 versus Gla-100 (the most 0.48 U/kg in EDITION 328 and 0.11 U/kg in REGAIN versus commonly used SoC basal insulin in both REACH and 0.33 U/kg in EDITION 26. Crucially, dose titration in REACH and REGAIN) in terms of HbA1c reduction, regardless of previous REGAIN was performed at the discretion of the investigators, insulin exposure27. Compared with these RCTs, REACH and without a predefined titration algorithm or a titration commit- REGAIN involved nearly no restriction to participation, did tee. In comparison, patients in the EDITION program were not include predefined titration regimens or mandated over- titrated to a fasting SMPG target of 4.4–5.6 mmol/L sight of titration during the studies, and involved less fre- (80–100 mg/dL; below the ADA target range), which translated quent contact between the patients and HCPs to ensure to greater increases in insulin dose and greater proportions of close titration support, so direct comparisons with REACH patients achieving glycemic targets, than was observed in and REGAIN are difficult. Moreover, in REACH and REGAIN, REACH or REGAIN. The minimal basal insulin dose increase in average baseline HbA1c (8.99 and 8.58%, respectively, in the REACH and REGAIN limited the ability to compare other out- Gla-300 arms) and FPG (11.62 and 9.85 mmol/L, respectively, comes across treatment arms and may also have driven the in the Gla-300 arms) was higher than seen in the EDITION low incidence of hypoglycemia compared with the EDITION program (HbA1c, 8.49% in EDITION 3 [insulin-naïve partici- program27 and the BRIGHT study (Gla-300 versus insu- pants] and 8.28% in EDITION 2 [basal insulin plus OADs]; lin degludec)10. FPG, 9.93 mmol/L in EDITION 3 and 8.24 mmol/L in EDITION Basal insulin titration in REGAIN was even more limited 2)6,28. The high baseline HbA1c levels are an indication of the than in REACH, in both treatment arms, and this overall difficulties associated with glycemic management in real-life therapeutic inertia may be related to the failure to achieve clinical practice. non-inferiority for the primary outcome at month 6. The Limited insulin titration was observed in REACH and REGAIN EDITION studies demonstrated that 12% more Gla-300 than (despite an apparent difference in dose increase between Gla-100 was required for equivalent glycemic control owing CURRENT MEDICAL RESEARCH AND OPINION 579 (a) 3 Gla-300 (n=350) HbA1c reduction with Gla-300, despite the availability of a Weight change (kg) SoC BI (n=350) PSP, maybe a further indication of substantial titration inertia. LS mean ± SE 2 However, although the Gla-300 PSP (COACH) has been shown to improve persistence and adherence to basal insulin 1 therapy20,21, it does not include any titration-to-target guid- ance. There is no evidence that the COACH PSP would influ- ence the outcomes of REACH and REGAIN, and so it should 0 not necessarily be expected to improve insulin dose titration. The impact of PSPs on outcomes in REACH and REGAIN was -1 not a predefined objective of either study and could not be BL M6 M12 analyzed because the use of a program was determined after randomization (patients could decide to use a PSP at any (b) 3 Gla-300 (n=304) point throughout the study), so this remains a poten- SoC BI (n=304) tial confounder. Weight change (kg) 2 In addition to real-life therapeutic inertia, the results pre- LS mean ± SE sented here may be partly influenced by the study design, 1 keeping in mind that REACH and REGAIN were the first randomized pragmatic studies in the field of basal insulin 0 treatment and so novel in this field. Power calculations for REACH and REGAIN were based on data from regulatory -1 RCTs and therefore assumed a slight benefit in favor of BL M6 M12 Gla-300, which may have unduly constrained patient num- Figure 2. LS mean (±SE) change in body weight from baseline to month 12 bers. HbA1c targets may require tailoring to the individual during the 12-month on-treatment period in REACH (a) and REGAIN (b) (safety patient and given the less-stringent inclusion criteria for populations). The 12-month on-treatment period was defined as the time from the first study drug intake until one day after last injection of the study drug. REACH and REGAIN compared with regulatory RCTs, the pre- Abbreviations. BI, basal insulin; LS, least squares; M, month; SE, standard error; defined targets (<7%) may have been too ambitious for SoC, standard of care. some patients. Such a shift towards patient-centered care is advocated in the recent ADA and EASD consensus report on to differences in bioavailability27, so a lack of titration could hyperglycemia management2, and future real-world studies have a greater impact on the outcomes of Gla-300. However, of basal insulins should consider individualized targets. It is it has not been determined if the dose requirements seen in notable that both REACH and REGAIN were initiated close to the EDITION RCTs are reflected in clinical practice. In addition the launch of Gla-300, therefore real-world experience of its to titration inertia, the lack of therapy intensification with use was lacking during the studies. Investigators may have short-acting insulins is notable in REGAIN, even though exercised caution in using new basal insulin but would likely investigators were allowed to intensify therapy with oral anti- have had long-term experience with the basal insulin used in hyperglycemic agents and/or injectable therapy as they do the SoC group. A potentially cautious approach to Gla-300 in their clinical practice. use could have been reinforced by the lack of an enforced There are many reasons why patients may not have up- titration algorithm. In addition, investigators may have been titrated their basal insulin dose to achieve glycemic control, more familiar with participating in regulatory RCTs, in which including perceived barriers such as hypoglycemia and visit frequency is higher and monitoring of study protocol weight gain13,14,16–18. However, it is likely that the lack of execution and oversight of dose titration and other proce- standardized titration-to-target algorithms for basal insulins dures is much stricter than in pragmatic studies. The wide is key to the suboptimal basal insulin titration seen in both range of concomitant antihyperglycemic therapies used by REACH and REGAIN and may highlight the need for tools to the heterogeneous populations included in REACH and facilitate such titration. The recent ADA/EASD consensus REGAIN, that may not reflect regulatory RCTs (for example, a report recognizes the necessity of titrating basal insulins to a relatively high proportion of people using DPP-4 inhibitors in fasting blood glucose target using an evidence-based algo- both studies), change in dose of these non-insulin anti- rithm2. Empowering patients to increase their own basal hyperglycemic therapies during the studies and the previous insulin dose is also important2, and self-titration has been basal insulin use in REGAIN (in particular whether a once- or shown to be superior to physician-led titration in the recent twice-daily regimen was used), may also have impacted TAKE CONTROL study29. In TAKE CONTROL, which included on outcomes. both insulin-naïve and insulin pre-treated participants with In contrast with the results presented here, other RWE T2DM, 72% of participants achieved the ADA-defined PG tar- studies employing retrospective analysis of electronic health get of 4.4–7.2 mmol/L (80–130 mg/dL) in the self-titra- records have demonstrated benefits of Gla-300 versus first- tion group. generation basal insulins in clinical practice, with comparable Substantially more people in the Gla-300 group than in glycemic improvement and lower hypoglycemia risk in pro- the SoC basal insulin group, in both REACH and REGAIN, uti- pensity score-matched cohorts11,12. In these RWE studies, the lized a PSP. The minimal basal insulin dose increases and investigators chose basal insulins based on patient 580 N. FREEMANTLE ET AL. characteristics, and there was no intervention that may have Pfizer and speaking engagements for Sanofi, Novo Nordisk, Eli Lilly, Merk led to a “study effect”; however, there was no randomization Sharp & Dohme, and Medtronic and has received research grants from Novo Nordisk, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Sanofi, to control for unknown confounders and no way to deter- Novartis, MSD, Boehringer Ingelheim, Amgen, and OPKO. BB is a consult- mine if more basal insulin titration occurred compared with ant for Sanofi. VP, JW, ZB, MB, AC, M-LN-P are employees and sharehold- REACH and REGAIN. ers of Sanofi. AP is an advisory panel member for AstraZeneca, MSD, and Novo Nordisk, and is a speaker for Abbott, Amgen, Bayer MSD, Sanofi, Novo Nordisk, Eli Lilly, and Medtronic. MP-M has acted as con- Conclusions sultant and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Novartis, MSD, Boehringer Ingelheim, and AstraZeneca and as an advisory board Therapeutic inertia is a global unmet medical need, one that member for Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, the ADA and EASD are seeking to address in their recent and AstraZeneca. JS has acted as an advisory board member for Abbott, consensus report. In both REACH and REGAIN, no differences AstraZeneca, Boehringer Ingelheim, GI-Dynamics, Janssen, LifeScan, in glycemic control or hypoglycemia outcomes were seen Mundipharma, Novartis, Novo Nordisk, and Sanofi-Aventis and as a speaker for Abbott, AstraZeneca, Bayer, Berlin Chemie, Boehringer between treatment arms over 12 months. However, the sub- Ingelheim, Bristol Myers Squibb, Janssen, Lilly, MSD, MedScape, Novartis, optimal basal insulin titration seen in both trials reflects con- Novo Nordisk, Omniamed, and Sanofi-Aventis. He has received grants in siderable therapeutic inertia, limiting the ability to compare support of investigator and investigator-initiated trials from AstraZeneca, outcomes between the newer basal insulin (Gla-300) and Boehringer Ingelheim, Bristol Myers Squibb, GI-Dynamics, Intarcia, Ipsen, SoC basal insulin arms. Results from REACH and REGAIN Janssen, Novartis, Novo Nordisk, Sanofi Aventis, and Ypsomed. SD has show that, in addition to appropriate insulin therapy, more received research support from Sanofi. JW has acted as a consultant and advisory board member for Astellas, AstraZeneca, Boehringer Ingelheim, dedicated basal insulin titration support using evidence- Janssen, Napp, Novo Nordisk, MSD, Mundipharma, Sanofi, and based algorithms may be required for patients and health- Wilmington Healthcare (paid into University funds). He has received care providers in order to help patients with uncontrolled grants for investigator-initiated trials from AstraZeneca and Novo T2DM to achieve glycemic targets. These studies also high- Nordisk and has acted as a speaker for AstraZeneca, Boehringer light the importance of appropriate patient selection and Ingelheim, Napp, Novo Nordisk, Mundipharma, Sanofi, and Takeda. CW has acted as an advisor, consultant, and/or speaker for Abbott, treatment. Appropriate titration of Gla-300 and other second- AstraZeneca, Boehringer Ingelheim, Eli Lilly, Insulet, Janssen, Novo generation basal insulin analogues may be required to real- Nordisk, and Sanofi. MD has acted as a consultant, advisory board mem- ize their potential clinical benefits of decreasing the risk of ber, and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, MSD, Boehringer hypoglycemia versus older basal insulins. Ingelheim, AstraZeneca, and Janssen; an advisory board member for Servier; and a speaker for Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in Transparency support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, and Janssen. Peer Declaration of funding reviewers on this manuscript have no relevant financial or other relation- ships to disclose. The REACH and REGAIN trials were sponsored by Sanofi. Sanofi was involved in designing the trials and conducted the trials and analyzed the data. The authors received editorial/writing support in the preparation of this manu- Author contributions script provided by Simon Rees, PhD, of Fishawack Communications Ltd, who was funded by Sanofi. NF, AMGC, and SDS were involved in the concept and design of both studies. BB performed statistical analyses. All authors were involved in the interpretation of the data, writing and reviewing drafts of the manu- Declaration of financial/other relationships script, and approved the final version for submission. NF has received research support from Sanofi-Aventis, AstraZeneca, Ipsen, Akcea, Takeda, Accelovance, Allergan, Biopharma, and Tesareo. He has served as a speaker for Sanofi-Aventis. DM has served on advisory Acknowledgements panels for Ferrer, Sanofi, AstraZeneca, Janssen, and Merck Sharp & None reported. Dohme (MSD) and received speakers’ bureau fees from Almirall, Boehringer Ingelheim, Menarini, GlaxoSmithKline, Eli Lilly, Sanofi, Novartis, Novo Nordisk, and MSD. Institutional research support was ORCID obtained from AstraZeneca, GlaxoSmithKline, Eli Lilly, Sanofi, Novo Nordisk, and MSD. AG has received honoraria or consulting fees from Nick Freemantle http://orcid.org/0000-0001-5807-5740 Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, and Sanofi and research funding from AstraZeneca. TB has received research sup- port from Abbott, Ascensia, BD, Boehringer Ingelheim, Calibra Medical, References Capillary Biomedical, Companion Medical, Dance Biopharm, Dexcom, Diasome, Eli Lilly, Glysens, Kowa, Lexicon, Medtronic, Novo Nordisk, [1] Horton ES. Defining the role of basal and prandial insulin for POPS! Diabetes Care, Sanofi, Senseonics, Taidoc, vTv Therapeutics, Xeris, optimal glycemic control. J Am Coll Cardiol. 2009;53(5):S21–S27. and Zealand; consulting honoraria from Abbott, Capillary Biomedical, Eli [2] Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyper- Lilly, Medtronic, and Sanofi; and speaking Honoraria from Abbott, glycemia in type 2 diabetes, 2018. A consensus report by the MannKind, Medtronic, Sanofi, and Senseonics. 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