original article Is insulin the most effective injectable antihyperglycaemic therapy?

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1 Diabetes, Obesity and Metabolism 17: , The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd. Is insulin the most effective injectable antihyperglycaemic therapy? J. B. Buse 1,A.Peters 2, D. Russell-Jones 3,S.Furber 4,M.Donsmark 5, J. Han 6, L. MacConell 6,, D. Maggs 6, &M.Diamant 7, 1 University of North Carolina School of Medicine, Medicine/Endocrinology, Chapel Hill, NC, USA 2 Keck School of Medicine, University of Southern California, Los Angeles, CA, USA 3 Endocrinology and Metabolism, Royal Surrey County Hospital, Guildford, UK 4 Novo Nordisk Pharmaceuticals, Sydney, Australia 5 Novo Nordisk A/S, Søborg, Denmark 6 Amylin Pharmaceuticals LLC, San Diego, CA, USA 7 VU University Medical Center, Diabetes Center, Department of Internal Medicine, Amsterdam, The Netherlands ORIGINAL ARTICLE Aims: The recent type 2 diabetes American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement suggested insulin is the most effective glucose-lowering therapy, especially when glycated haemoglobin (HbA1c) is very high. However, randomized studies comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly [OW; DURATION-3 (Diabetes therapy Utilization: Researching changes in A1c, weight, and other factors Through Intervention with exenatide ONce-Weekly)] and liraglutide once-daily [OD; LEAD-5 (Liraglutide Effect and Action in Diabetes)] with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c 8.3% (67mmol/mol). This post hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c, fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile. Methods: Descriptive statistics were provided for change in HbA1c, fasting glucose, weight, and insulin dose, and subjects (%) achieving HbA1c <7.0%, by baseline HbA1c quartile. Inferential statistical analysis on the effect of baseline HbA1c quartile was performed for change in HbA1c. An analysis of covariance (ANCOVA) model was used to evaluate similarity in change in HbA1c across HbA1c quartiles. Results: At 26 weeks, in both studies, HbA1c reduction, and proportion of subjects reaching HbA1c <7.0%, were similar or numerically greater with the GLP-1RAs than glargine for all baseline HbA1c quartiles. Fasting glucose reduction was similar or numerically greater with glargine. Weight decreased with both GLP-1RAs across all quartiles; subjects taking glargine gained weight, more at higher baseline HbA1c. Adverse events were uncommon although gastrointestinal events occurred more frequently with GLP-1RAs. Conclusions: HbA1c reduction with the GLP-1RAs appears at least equivalent to that with basal insulin, irrespective of baseline HbA1c. This suggests that liraglutide and exenatide OW may be appropriate alternatives to basal insulin in type 2 diabetes, including when baseline HbA1c is very high ( 9.0%). Keywords: basal insulin, exenatide, GLP-1 receptor agonists, HbA1c, liraglutide Date submitted 14 May 2014; date of first decision 7 July 2014; date of final acceptance 12 October 2014 Introduction The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) position statement on management of hyperglycaemia in type 2 diabetes designates insulin as the only antihyperglycaemic agent with highest efficacy for reduction of glycated haemoglobin A1c (HbA1c), an index of average glycaemia over the preceding 2 4 months [1]. Correspondence to: Dr J. B. Buse, Endocrinology and Metabolism, University of North Carolina School of Medicine, CB #7172, 8027 Burnett-Womack Building, Chapel Hill, NC , USA. jbuse@med.unc.edu Employed by Amylin LLC, a completely owned subsidiary of Bristol-Myers Squibb, at the time of writing this article. Michaela Diamant died in April 2014, but was completely involved in the preparation and submission of this article. This is an open access article under the terms of the Creative Commons Attribution- NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. Thisopinionwasbasedontheperceptionthatinpatientspresenting with high baseline HbA1c insulin is uniquely effective because of its limitless titration potential. However, studies of the glucagon-like peptide 1 receptor agonists (GLP-1RA) liraglutide and exenatide once-weekly (OW) showed that these GLP-1RAs are superior to insulin glargine with respect to HbA1c reduction [2,3]. However, because the average HbA1c in the populations studied was in the low 8% range, this leaves open the possibility that the overall result did not adequately reflect the effects of these agents in subjects with high baseline values, for example HbA1c >9%,inwhomthetheoretically infinite titration of insulin might prove advantageous. A study group was formed in 2012 to engage the manufacturersofmarketedglp-1rasinacollaborativeefforttoprovide further clarity on the relative efficacy and safety of basal insulin and GLP-1RAs with respect to HbA1c reduction. Of particular interest was the comparative efficacy of different treatment approaches in patients with high baseline HbA1c, who, if treated according to guidelines, would be candidates for insulin

2 DIABETES, OBESITY AND METABOLISM Table 1. Baseline characteristics of subjects enrolled in DURATION-3 and LEAD-5 trials. Duration-3 Exenatide 2 mg OW (N = 233) Insulin glargine OD (N = 223) LEAD-5 Liraglutide 1.8 mg OD (N = 230) Insulin glargine OD (N = 232) Age (years) 58 (10) 58 (9) 58 (10) 58 (11) Male (%) Body mass index (kg/m 2 ) 32 (5) 32 (5) 30 (5) 30 (5) HbA1c (%) 8.3 (1.1) 8.3 (1.0) 8.3 (0.9) 8.2 (0.9) HbA1c (mmol/mol) Fasting blood glucose (mmol/l)* 9.9 (2.5) 9.7 (2.7) 9.1 (2.1) 9.1 (2.0) Duration of diabetes (years) 8.0 (6.0) 7.8 (6.0) 9.2 (5.8) 9.7 (6.4) Prior therapy (N, %) Single OHA 164 (70) 157 (70) 15 (7) 12 (5) Combination (two) OHA 69 (30) 66 (30) 215 (94) 220 (95) Data are mean (s.d.) unless stated otherwise. HbA1c, glycated haemoglobin; OHA, oral antihyperglycaemic agents; OD, once-daily; OW, once-weekly. *Data are fasting serum glucose in DURATION-3 and fasting plasma glucose in LEAD-5. therapy. Here we report the results of a post hoc analysis of the efficacy and safety of liraglutide and exenatide OW compared to glargine across the spectrum of baseline HbA1c, using data from the previously published, open-label, DURATION-3 [2] and LEAD-5 [3] studies in subjects with type 2 diabetes. Materials and Methods The reader is referred to the previously published DURATION-3 [2] and LEAD-5 [3] reports for details of the respective study methods. In brief, DURATION-3 randomized subjects with suboptimal glycaemic control (HbA1c between 7.1 and 11.0%), despite maximum tolerated doses of metformin with or without a sulphonylurea, to exenatide OW 2mg(n= 233) or glargine (n = 223), for 26 weeks. In LEAD-5, subjects with HbA1c between 7.0 and 10.0% on combination therapy with metformin + sulphonylurea were randomized to liraglutide 1.8 mg OD (n = 232), liraglutide placebo (n = 115) or glargine (n = 234) for 26 weeks. In both trials glargine was titrated to achieve fasting glucose (FG) levels 5.5 mmol/l. For the purposes of this post hoc analysis we compared changes in HbA1c, fasting glucose, body weight, insulin dose and adverse events with long-acting GLP-1RAs and glargine intheduration-3andlead-5trials.thebaselinecharacteristics of subjects in both studies are presented in Table 1. In order to gain further understanding of the effect of baseline HbA1c on treatment outcomes, results were stratified by quartile (Q) of baseline HbA1c (Table 2). To investigate possible treatment interaction with baseline HbA1c quartile, inferential statisticalanalysisontheeffectofbaselinehba1cquartilewas performed only for change in HbA1c because of the fact that thesetwoparametersarehighlycorrelated.safetyanalyseswere carried out on the intent-to-treat (ITT) population, defined as allsubjectswhoreceivedatleastonedoseofstudymedication. Hypoglycaemia was classified as per the original studies and was based on symptoms and/or blood glucose measurement. Major hypoglycaemia comprised a symptomatic episode that required third-party assistance because of severe impairment in consciousness or behaviour. Minor hypoglycaemia was defined as symptomatic self-treated, blood glucose <3.0 mmol/l Table 2. Change in HbA1c from baseline and percentage of subjects reaching target HbA1c <7.0% according to baseline HbA1c quartile in DURATION-3 and LEAD-5. Baseline HbA1c quartile range (%) Estimated LS mean treatment difference (95%CI) in change in HbA1c (GLP-1RA glargine; HbA1c % points) Subjects reaching HbA1c <7% n/n (%) DURATION-3 Exenatide OW Glargine Q ( 0.52, 0.08) 48/56 (86) 39/49 (80) Q ( 0.51, 0.07) 42/55 (76) 34/61 (56) Q ( 0.23, 0.34) 27/60 (45) 26/59 (44) Q ( 0.56, 0.02) 24/61 (39) 10/54 (19) LEAD-5 Liraglutide Glargine Q ( 0.66, 0.06) 52/61 (85) 45/63 (71) Q ( 0.41, 0.19) 32/55 (58) 36/69 (52) Q ( 0.61, 0.08) 19/49 (39) 14/44 (32) Q ( 0.53, 0.11) 16/59 (27) 8/49 (16) ANCOVA, analysis of covariance; HbA1c, glycated haemoglobin. Note that subjects were allocated to HbA1c quartile according to HbA1c value at screening. *ANCOVA analysis with last observation carried forward (LOCF) imputation method. 146 Buse et al. Volume 17 No. 2 February 2015

3 DIABETES, OBESITY AND METABOLISM (DURATION-3) or self-treated plasma glucose <3.1 mmol/l (LEAD-5). Efficacy analyses were carried out on a modified ITT population, defined as all subjects who received at least one dose of study medication and had baseline, and at least one postbaseline, measurement of relevance. A last observation carried forward (LOCF) approach was used where postbaseline data were missing. Data Analysis Subjects in each trial were categorized by baseline HbA1c quartile. Descriptive statistics were provided for change in HbA1c, fasting glucose, body weight and insulin dose, as well as the percentage achievinghba1cgoal of<7.0%, by baseline HbA1c quartile. As the mixed model repeated measures (MMRM) introduced complexity in model converging when multiple interaction terms were included, particularly in light of the relatively small sample size, an alternative analysis of covariance (ANCOVA) model was used to evaluate the similarity in change in HbA1c at the endpoint (LOCF) across baseline HbA1c quartiles. In this model, treatment, baseline HbA1c quartile, country, background oral antihyperglycaemic agent (OHA) stratum (DURATION-3 only) and treatment-by-baseline HbA1c quartile interaction were included as fixed effects, and baseline HbA1c value as a covariate [4]. Data were analysed usingsasprocmixed(sas ; SAS Institute, Cary, NC, USA). These studies are registered with ClinicalTrials.gov, number NCT (DURATION-3) and NCT (LEAD-5). Results Baseline patient characteristics in DURATION-3 and LEAD-5 are published elsewhere [2,3] and summarized in Table 1. Population characteristics including age, body mass index (BMI) and baseline HbA1c were similar in the two studies. OHA therapy differed between studies as all subjects in LEAD-5 received sulphonylureas combined with metformin, whereas this is was only the case for 30% of the DURATION-3 population; the remaining 70% of DURATION-3 subjects received metformin alone. After 26 weeks, HbA1c reduction was significantly greater with exenatide OW than glargine [mean HbA1c at 26 weeks: 6.89 vs. 7.06%; mean change 1.42 vs. 1.25%; least squares (LS) mean treatment difference: 0.17%, P = 0.02; 95%CI: 0.31, 0.02] in DURATION-3. Similarly, HbA1c reduction was significantly greater with liraglutide than glargine (mean HbA1c at 26 weeks: 7.0 vs. 7.2%; mean change 1.33 vs. 1.09%; estimated treatment difference: 0.24% P = 0.002; 95%CI: 0.39, 0.08) in LEAD-5. In the analysis by baseline HbA1c quartile, HbA1c values decreased approximately in parallel across the 26-week study period, with numerically greater reductions in GLP-1RA treatment groups than with glargine in all quartiles, at most timepoints (8, 14, 18, 22 and 26 weeks in DURATION-3; 12, 18 and 26 weeks in LEAD-5; Figure S1, Supporting Information). At 26 weeks, HbA1c reduction was numerically similar or greater, and mean HbA1c tendedtobelower,withtheglp-1rasthanwithglarginein all baseline HbA1c quartiles (Figure 1; includes final HbA1c values at 26 weeks, by quartile). Results from the ANCOVA original article analyses showed no interaction between treatment and baseline HbA1c quartile (DURATION-3, P = 0.37; LEAD-5, P = 0.54), indicating that the estimated treatment differences between the GLP-1RAs and glargine were similar across all quartiles in both trials (Table 2).The proportion of subjects reaching target HbA1c (<7.0%) was numerically similar or greater with theglp-1rasthanwithglargineacrossallbaselinehba1c quartiles (Table 2); as expected, the proportion of subjects that reached the HbA1c target was highest in the lowest quartile of baseline HbA1c. After 26 weeks, fasting serum glucose (FSG) levels decreased to a similar (Q2) or lesser (Q1, Q3, Q4) extent with exenatide OW than glargine (DURATION-3) and fasting plasma glucose (FPG) to a similar (Q1, Q3) or lesser (Q2, Q4) extent with liraglutide than glargine (LEAD-5) across all HbA1c quartiles (Figure 1; includes final FSG values at 26 weeks, by quartile).the time course of fasting glucose reduction was similar across quartiles with the GLP-1RAs and glargine. Body weight decreased in subjects taking the GLP-1RAs across all HbA1c quartiles and increased with glargine (Figure 2; includes final body weight at 26 weeks, by quartile). Body weight gain with glargine tended to increase with increasing baseline HbA1c quartile. Mean daily dose of glargine increased with increasing baseline HbA1c quartile in both studies (Figure S2). Major hypoglycaemia occurred rarely in both trials. In DURATION-3, three events occurred that required assistance from another person, one in a patient taking exenatide OW without sulphonylureas and two in subjects taking glargine. In LEAD-5, there were six major hypoglycaemic events in five subjects taking liraglutide, all of whom were also taking sulphonylureas, and no events with glargine. No major hypoglycaemic events occurred in subjects in Q4. The incidence of minor hypoglycaemia was low with exenatide OW ( events/patient-year in all subjects; and events/patient-year in subjects taking and not taking sulphonylureas, respectively) and liraglutide ( events/patient-year in all subjects). In most instances, the rate of minor hypoglycaemia with both GLP-1RAs was numerically lower than that with glargine in all baseline quartiles (Figure 3). Adverse events (Table 1) occurred with similar frequency in both GLP-1RA groups ( 65 70% of subjects) and insulin groups ( 55 60%) in DURATION-3 and LEAD-5; serious events were reported in 4 8% of subjects across groups. As expected from the mode of action of GLP-1RAs, gastrointestinal adverse events, especially nausea, were more common with these agents than with glargine ( 14 vs. 1%, respectively). Injection site reactions were more common with exenatide OW (13%) than with other treatments ( 2%). Discussion Recent position statements [1] and essentially all texts on the subject suggest that insulin is unique among treatments for type 2 diabetes in its antihyperglycaemic efficacy. As a result, insulin therapy is often recommended in patients with HbA1c levels 9.0% who fail to achieve glycaemic control using other agents [1,5]. The post hoc analysis presented here suggests that the ability of the GLP-1RAs liraglutide and exenatide OW to reduce Volume 17 No. 2 February 2015 doi: /dom

4 DIABETES, OBESITY AND METABOLISM Figure 1. Mean (observed) glycated haemoglobin (HbA1c) reduction (%) (A, B) and fasting glucose reduction (mmol/l) (C, D) from baseline after 26 weeks across baseline HbA1c quartiles in DURATION-3, and LEAD-5 studies. Note: fasting glucose data are serum glucose (FSG) for DURATION-3 and plasma glucose (FPG) for LEAD-5. OW, once-weekly. HbA1c is no less than that of glargine in both head-to-head studies and across the spectrum of baseline HbA1c from 7.0 to 11.0%. Arguably, starting liraglutide or exenatide OW is therefore a reasonable alternative to basal insulin in these patients. Further, if HbA1c targets cannot be met, basal insulin may subsequently be added [6,7]. Additional benefits of a GLP-1RA over basal insulin include body weight loss, as opposed to gain; low rates of hypoglycaemia unless combined with sulphonylurea; easier dose titration driven only by tolerability and the lack of a requirement for self-monitoring of blood glucose. It should, however, be acknowledged that initiating treatment with a GLP-1RA or basal insulin is only a first step towards achieving HbA1c targets. Patients may require additional interventions to achieve their individual glycaemic goals. Clinical trials involving insulin are often criticized for lack of appropriate titration, although trials with varying (forced and non-forced) titration strategies, and a wide range of insulin doses (25 62 IU/day), have resulted in similar HbA1c reductions to those reported here [8 10]. In both studies examined here, basal insulin was increased to reach a fasting glucose target through a combination of patient self-titration and titration by study staff. Nonetheless, the fasting glucose levels achieved in DURATION-3 and LEAD-5 remained considerably higher than goal ( 5.5 mmol/l), limiting the potential for overall Figure 2. Mean (observed) change in body weight (kg) from baseline after 26 weeks, across baseline glycated haemoglobin (HbA1c) quartiles in (A) DURATION-3 and (B) LEAD-5. OW, once-weekly. 148 Buse et al. Volume 17 No. 2 February 2015

5 DIABETES, OBESITY AND METABOLISM original article Figure 3. Rates of minor hypoglycaemia (events/patient-year) across baseline glycated haemoglobin (HbA1c) quartiles. DURATION-3 data are shown (A) separately for all subjects; (B) subjects taking sulphonylurea at baseline (C) and subjects not taking sulphonylurea at baseline. Minor hypoglycaemia was defined as self-treated hypoglycaemia symptoms accompanied by blood glucose <3.0 mmol/l (DURATION-3) or fasting plasma glucose <3.1 mmol/l (LEAD-5). Note that in LEAD-5 all subjects were receiving sulphonylurea (D). OD, once-daily; OW, once-weekly; SU, sulphonylurea. glucose-lowering in the glargine arms of both trials. We believe that this is related to hypoglycaemia or other adverse events of therapy as the investigators were required by protocol to titrate to goal, except as limited by safety concerns. However, the percentage of subjects in the highest HbA1c quartile who achieved HbA1c <7.0% in DURATION-3 and LEAD-5 (19 and 16%, respectively) is much lower than that in a pooled analysis of basal insulin studies in which 41% of subjects with baseline HbA1c of %, and 34% of those with HbA1c >9.5%, reached HbA1c <7.0% [11]. This, along with the modest mean insulin doses at 26 weeks, supports the possibility that insulin titration could have been improved in both GLP-1RA studies. That said, even in the Efficacy Assessment of Insulin Glargine Versus LiraglutidE (EAGLE) trial, in which subjects started with a baseline HbA1c of 9%, very rigorous titration of glargine resulted in no significant difference in the proportion of participants reaching an HbA1c <7% (p = 0.44) [12]. Further, it is worth noting that the dosing simplicity and limited need for titration or glucose monitoring when using GLP-1RAs may provide advantages over basal insulin in managing uncontrolled patients in many clinical practice. Furthermore, although the degree of intervention and level of support in clinical trials generally are greater than in routine clinical practice, some medical practices may be able to achieve better relative performance with insulin glargine than that achieved on average across study sites. In both studies reported here withdrawal rates among GLP-1RA-treated subjects were numerically greater than with glargine, in part related to higher rates of adverse events, particularly of a gastrointestinal nature [2,3]. Rates of hypoglycaemia were similar when basal insulin and GLP1-RAs were added to existing therapy, including sulphonylurea. In subjects previously treated with metformin alone, hypoglycaemia was less common when adding GLP-1RA than glargine. This has implications for the management of uncontrolled hyperglycaemia in the outpatient setting. In our analysis, subjects using GLP-1RAs were able to achieve body weight loss across all glycaemic quartiles. This is an important distinction from basal insulin where we observed body weight gain across all glycaemic quartiles; whether the trend towards greater body weight gain in subjects with higher baseline HbA1c is due to a direct effect of increased insulin, increased calorie intake to mitigate hypoglycaemia or perceived risk thereof, correction of more significant hyperglycaemia or a combination of factors is unclear. There are various limitations to this analysis. First, these data represent post hoc analysis of short-term, open-label clinical trials. The study population was limited to those with type 2 diabetes treated with metformin (with or without sulphonylurea) and screening HbA1c between 7.0 and 11.0%, and excluded those with new-onset diabetes, type 1 diabetes, intercurrent illness or suspected issues with adherence. Extrapolationtootherpopulationsoroveralongertimeperiod should be made with caution. In the general population with HbA1c >9.0%, in whom we are suggesting GLP-1RA treatment could be considered a reasonable alternative to basal insulin therapy, many are treated with other background therapies or have new-onset disease, insulin-deficient diabetes, intercurrent illnessorevenpoorerglycaemiccontrolthaninthesestudies. Furthermore, HbA1c and fasting glucose values in the highest HbA1c quartiles of DURATION-3 and LEAD-5 were not extremely high, and results may be different in patients with HbA1c >11.0% and/or fasting glucose >12mmol/l. Thus, these datamayaddanewperspectiveastherearenorandomized Volume 17 No. 2 February 2015 doi: /dom

6 studies in the recent past that have evaluated the optimal management of poorly controlled outpatients. Second, because of the relatively small number of subjects in each quartile group (n= 44 69), the power to detect treatment difference byquartilewaslimited.thus,whereastheoriginalreportof thecompletedatasetshowedsuperiorityofliraglutideand exenatide OW over glargine in HbA1c reduction, we only can suggest similar HbA1c lowering of the three agents across quartiles, even among those with HbA1c >9%.Furthermore,with only 26 weeks of treatment and observation, these data represent a relatively limited number of patient-years of follow-up; examination of change-over-time graphs (Figure S1) show how early discrepancies between groups may even out over time. Third, the resources available when managing subjects in clinical trials are generally more robust than those available in clinical practice. This analysis did not address the resource implications of the two treatment strategies examined and such an evaluation would be worthwhile. We would counsel clinicians who are considering the use of GLP-1RAs instead of basal insulin in patients with HbA1c >9.0% to provide comprehensive patient education; important points to address include potential deterioration of control despite intervention and the need to call or return to clinic if adverse events arise or glycaemia does not improve relatively quickly and consistently. Importantly, we do not intend these post hoc data be used to change policy but rather to alert clinicians to the fact that the long-held belief that insulin is the only appropriate treatment for poorly controlled diabetes may not be supported by current data from trials involving novel agents. Conclusion This post hoc analysis shows similar or numerically greater HbA1c reduction with GLP-1RA as compared to glargine in people with type 2 diabetes, even at baseline HbA1c levels as high as 11.9%. Although data are derived from two different clinical trials involving two long-acting GLP-1RAs, the resultsareremarkablysimilar.thissuggeststhatglp-1rasand insulin may both be appropriate initial treatment choices in selected patients with type 2 diabetes and HbA1c levels above 9.0% despite treatment with oral agents. Acknowledgements Henrik Thomsen of Novo Nordisk is thanked for statistical analyses of LEAD-5. Esther Nathanson, Watermeadow Medical, Witney, UK, funded by Novo Nordisk A/S, is thanked for her contributions to drafting and editing this manuscript under guidance from the authors. Conflict of Interest J. B. B. is an investigator and/or consultant without any direct financial benefit under contracts between his employer and the following companies: Amylin Pharmaceuticals, Inc., Andromeda, AstraZeneca, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Dance Biopharm, Elcelyx DIABETES, OBESITY AND METABOLISM Therapeutics Inc., Eli Lilly and Company, GI Dynamics, GlaxoSmithKline, Halozyme Therapeutics, F. Hoffmann-La Roche Ltd., Intarcia Therapeutics, Johnson & Johnson, Lexicon, LipoScience, Medtronic, Merck, Metavention, Novo Nordisk, Orexigen Therapeutics Inc., Osiris Therapeutics Inc., Pfizer Inc., PhaseBio Pharmaceuticals Inc, Quest Diagnostics, Sanofi, Santarus, Scion NeuroStim, Takeda, ToleRx and TransTech Pharma. J. B. B. is a consultant to PhaseBio Pharmaceuticals Inc and has personally received stock options and payments for that work. A. P. has served as a speaker and/or consultant for Abbott, Amylin, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Dexcom, Genetech, Janssen, Lifescan, Lilly, Medtronic, Merck, Novo Nordisk, Roche, Sanofi, Takeda. M. D. is a shareholder and employee of Novo Nordisk. S. F. is a shareholder and employee of Novo Nordisk. J. H. is a full-time employee of Amylin Pharmaceuticals, LLC, and a fully owned subsidiary of Bristol-Myers Squibb. L. M. and D. M. were full-time employees of Amylin LLC, a fully owned subsidiary of Bristol-Myers Squibb, at the time of writing this article. M. Di. was consultant for Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Poxel Pharma and Sanofi; wasspeakerforaz-bms,elililly,mercksharp&dohme, Novo Nordisk and Sanofi. Through M. Di., the VU University Medical Centre received research grants from Amylin/BMS, Boehringer Ingelheim, Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi. M. Di. received no personal payments in connection to the above-mentioned activities, but all paymentsweredirectlytransferredtothenon-profitinstitutional Research Foundation. M. Di. and D. R-.J. were signatory investigators for the DURATION-3 and LEAD-5 studies, respectively. All authors had complete access to primary data for both DURATION-3 and LEAD-5 studies and provided input on content and publication submission. J. H. and Henrik Thomsen (see Acknowledgement) performed analyses for DURATION-3 and LEAD-5, respectively. All authors contributed to developing the analysis plan, data interpretation, writing and editing of the manuscript and approved the final manuscript. Sponsors were involved in the study design, protocol development, collection, review, and analysis of the data and writing of the report. J. B. B. and M. Di. had final responsibility for the decision to submit for publication. Supporting Information Additional Supporting Information may be found in the online version of this article: Figure S1. Mean glycated haemoglobin ± standard mean error (HbA1c ± s.e.m.) over time according to treatment and baseline HbA1c quartile in (A) DURATION-3 and (B) LEAD-5. OD, once-daily; OW, once-weekly. Figure S2. Final daily insulin glargine dose ± standard deviation (s.d.) (IU) after 26 weeks, across baseline glycated haemoglobin (HbA1c) quartiles for (A) DURATION-3 and (B) LEAD-5. Table S1. Adverse events occurring overall and among 5% of subjects enrolled in DURATION-3 and LEAD-5 studies. 150 Buse et al. Volume 17 No. 2 February 2015

7 DIABETES, OBESITY AND METABOLISM References 1. Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: Diamant M, Van Gaal L, Stranks S et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet 2010; 375: Russell-Jones D, Vaag A, Schmitz O et al., Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+ SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+ SU): a randomised controlled trial. Diabetologia 2009; 52: Qu Y. Issues for stratified randomization based on a factor derived from a continuous baseline variable. Pharm Statist 2011; 10: Handelsman Y, Mechanick JI, Blonde L et al. AACE Task Force for Developing Diabetes Comprehensive Care Plan. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011; 17(Suppl. 2): Goldenberg R. Insulin plus incretin agent combination therapy in type 2 diabetes: a systematic review. Curr Med Res Opin 2014; 30: original article 7. Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014; DOI: /S (14) Yki-Järvinen H, Juurinen L, Alvarsson M et al. Initiate Insulin by Aggressive Titration and Education (INITIATE): a randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups. Diabetes Care 2007; 30: Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008; 51: Riddle MC, Rosenstock J, Gerich J, Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 2003; 26: Riddle M, Vlajnic A, Zhou R, Rosenstock J. Baseline HbA1c predicts attainment of 7.0% HbA1c target with structured titration of insulin glargine in type 2 diabetes: a patient-level analysis of 12 studies. Diabetes Obes Metab 2013; 15: Efficacy Assessment of Insulin Glargine Versus LiraglutidE After Oral Agents Failure (EAGLE). Available from URL: clinicaltrials.gov/ct2/show/nct Accessed 22 September Volume 17 No. 2 February 2015 doi: /dom