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Figure 1.
Flow of Patients Through the DUAL V Trial
Flow of Patients Through the DUAL V Trial

FPG indicates fasting plasma glucose; SMBG, self-measured blood glucose.

aPatients could have more than 1 exclusion or inclusion criteria. Details only provided for criteria accounting for more than 5% screening failure rate.

bInitiation of any systemic treatment with products that, in the investigator’s opinion, could interfere with glucose metabolism.

cFasting SMBG or FPG limits leading to withdrawal were 270 mg/dL (to convert FPG to mmol/L, multiply by 0.0555) from baseline to week 6, 240 mg/dL from week 7 to week 12, and 200 mg/dL from week 13 to week 26.

Figure 2.
Change in HbA1c Levels and Body Weight, and Cumulative Incidence of Confirmed Hypoglycemia Over Time for Degludec/Liraglutide vs Glargine
Change in HbA1c Levels and Body Weight, and Cumulative Incidence of Confirmed Hypoglycemia Over Time for Degludec/Liraglutide vs Glargine

ANCOVA indicates analysis of covariance; HbA1c, glycated hemoglobin. Time 0 indicates randomization. Error bars indicate 95% CIs. Panel A, The American Diabetes Association and European Association for the Study of Diabetes HbA1c target was less than 7.0%; the American Association of Clinical Endocrinologists HbA1c target was 6.5% or less (dashed lines). The estimated treatment difference (ETD) at 26 weeks was –0.59% (95% CI, –0.74% to –0.45%), P < .001 (1-sided, superiority), estimated from an ANCOVA analysis based on the full analysis set. Change in HbA1c level for insulin degludec/liraglutide was −1.81; for insulin glargine, −1.13. B, The ETD at 26 weeks was –3.20 kg (95% CI, –3.77 to –2.64), P < .001 (1-sided, superiority), estimated from an ANCOVA analysis based on the full analysis set. Change in body weight for degludec/liraglutide was −1.4; for glargine, 1.8. A and B are based on observed values with missing data imputed by last observation carried forward for the full analysis set. C, Mean cumulative number of events per patient were based on the safety analysis set. The estimated rate ratio, 0.43 (95% CI, 0.30 to 0.61), P < .001 (1-sided, superiority), is the ETD of the linear predictor of a negative binomial regression model, back transformed to event per time scale, based on the full analysis set. The number of patients with 1 episode or more was 79 for degludec/liraglutide and 137 for glargine. There were 289 events, with a rate of 2.23 per patient-year of exposure for degludec/liraglutide and 683 events with a rate of 5.05 per patient-year of exposure for glargine.

Figure 3.
Change in Fasting Plasma Glucose, 9-Point SMBG Profile, Nocturnal Hypoglycemia, and Insulin Dose Over Time for Degludec/Liraglutide vs Glargine
Change in Fasting Plasma Glucose, 9-Point SMBG Profile, Nocturnal Hypoglycemia, and Insulin Dose Over Time for Degludec/Liraglutide vs Glargine

ANCOVA indicates analysis of covariance; SMBG, self-measured blood glucose. To convert glucose to mmol/L, multiply by 0.0555. Time 0 indicates randomization. Error bars indicate 95% CIs. A, Based on observed values with missing data imputed by last observation carried forward for the full analysis set. The estimated treatment difference (ETD) at 26 weeks was –0.015 mg/dL (95% CI, –6.28 to 5.99), P = .96, estimated from an ANCOVA analysis based on the full analysis set. Change in mean fasting blood glucose for insulin degludec/liraglutide was −50.9 mg/dL; for insulin glargine, −49.9 mg/dL. B, Mean observed values were based on the full analysis set and missing values were imputed by last observation carried forward. At week 26, for breakfast, 90 minutes after lunch, dinner, 90 minutes after dinner, and breakfast the next day, P < .05 for degludec/liraglutide vs glargine based on linear mixed-model with an unstructured residual covariance matrix. C, Mean cumulative number of events per patient were based on the safety analysis set. The estimated rate ratio, 0.17 (95% CI, 0.10 to 0.31), P < .001, is the ETD of the linear predictor of a negative binomial regression model, back transformed to event per time scale, based on the full analysis set. Nocturnal was defined as between 12:01 am to 5:59 am (both inclusive). The number of patients with 1 episode or more was 17 for degludec/liraglutide and 68 for glargine. There were 29 events, with a rate of 0.22 per patient-year of exposure for degludec/liraglutide and 166 events with a rate of 1.23 per patient-year of exposure for glargine. D, Based on observed values with missing data imputed by last observation carried forward for the safety analysis set. The ETD at week 26 was –25.47 U (95% CI, –28.90 to –22.05), P < .001, estimated from an ANCOVA analysis based on the full analysis set. The degludec/liraglutide dose was capped at 50 dose steps; there was no maximum dose for glargine.

Table 1.  
Baseline Demographics and Patient Characteristics of the Full Analysis Set
Baseline Demographics and Patient Characteristics of the Full Analysis Set
Table 2.  
Summary of Primary and Secondary End Points for Degludec/Liraglutide vs Glargine
Summary of Primary and Secondary End Points for Degludec/Liraglutide vs Glargine
Table 3.  
Proportion of Patients Achieving HbA1c and Composite Targets
Proportion of Patients Achieving HbA1c and Composite Targets
1.
Curtis  B, Lage  MJ.  Glycemic control among patients with type 2 diabetes who initiate basal insulin: a retrospective cohort study. J Med Econ. 2014;17(1):21-31.
PubMedArticle
2.
Blak  BT, Smith  HT, Hards  M, Curtis  BH, Ivanyi  T.  Optimization of insulin therapy in patients with type 2 diabetes mellitus: beyond basal insulin. Diabet Med. 2012;29(7):e13-e20.
PubMedArticle
3.
Inzucchi  SE, Bergenstal  RM, Buse  JB,  et al.  Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
PubMedArticle
4.
Clinicaltrials.gov. A clinical trial comparing efficacy and safety of insulin degludec/liraglutide (IDegLira) vs basal-bolus therapy in subjects with type 2 diabetes mellitus.https://clinicaltrials.gov/ct2/show/NCT02420262. Accessed December 10, 2015.
5.
US Department of Health and Human Services. Guidance for industry diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention.http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071624.pdf. Accessed February 4, 2016.
6.
Abdi  H. Holm’s sequential Bonferroni procedure. In: Salkind  N, ed. Encyclopedia of Research Design. Thousand Oaks, CA: Sage; 2010.
7.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed February 4, 2016.
8.
Luo  J, Qu  Y.  Analysis of hypoglycemic events using negative binomial models. Pharm Stat. 2013;12(4):233-242.
PubMedArticle
9.
O’Kelly  M, Ratitch  B. Clinical Trials With Missing Data: A Guide for Practitioners. West Sussex, United Kingdom: John Wiley & Sons; 2014.
10.
Koch  GG.  Comments on “current issues in noninferiority trials” by Thomas R. Fleming, statistics in medicine. Stat Med. 2008;27(3):333-342.
PubMedArticle
11.
Keene  ON, Roger  JH, Hartley  BF, Kenward  MG.  Missing data sensitivity analysis for recurrent event data using controlled imputation. Pharm Stat. 2014;13(4):258-264.
PubMedArticle
12.
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;384(9961):2228-2234.
PubMedArticle
13.
Kunt  T, Snoek  FJ.  Barriers to insulin initiation and intensification and how to overcome them. Int J Clin Pract Suppl. 2009;62(164):6-10.
PubMedArticle
14.
Peyrot  M, Barnett  AH, Meneghini  LF, Schumm-Draeger  PM.  Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabet Med. 2012;29(5):682-689.
PubMedArticle
15.
Carver  C.  Insulin treatment and the problem of weight gain in type 2 diabetes. Diabetes Educ. 2006;32(6):910-917.
PubMedArticle
16.
Vijan  S, Hayward  RA, Ronis  DL, Hofer  TP.  Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens. J Gen Intern Med. 2005;20(5):479-482.
PubMedArticle
17.
Cuddihy  RM, Philis-Tsimikas  A, Nazeri  A.  Type 2 diabetes care and insulin intensification: is a more multidisciplinary approach needed? results from the MODIFY survey. Diabetes Educ. 2011;37(1):111-123.
PubMedArticle
18.
Liu  FP, Dong  JJ, Yang  Q,  et al.  Glucagon-like peptide 1 receptor agonist therapy is more efficacious than insulin glargine for poorly controlled type 2 diabetes: a systematic review and meta-analysis. J Diabetes. 2015;7(3):322-328.
PubMedArticle
19.
Zinman  B, Gerich  J, Buse  JB,  et al; LEAD-4 Study Investigators.  Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32(7):1224-1230.
PubMedArticle
20.
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(10):2046-2055.
PubMedArticle
21.
Buse  JB, Vilsbøll  T, Thurman  J,  et al; NN9068-3912 (DUAL-II) Trial Investigators.  Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014;37(11):2926-2933.
PubMedArticle
Original Investigation
March 1, 2016

Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 DiabetesThe DUAL V Randomized Clinical Trial

Author Affiliations
  • 1Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
  • 2Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas
  • 3Centro de Investigaciones Metabolicas, Buenos Aires, Argentina
  • 4Servicio de Endocrinologia, Hospital Universitario de Monterrey “Dr José Eleuterio-González,” Nuevo León, México
  • 5Valley Research, Fresno, California
  • 6Novo Nordisk A/S, Søborg, Denmark
  • 7University of North Carolina School of Medicine, Chapel Hill
JAMA. 2016;315(9):898-907. doi:10.1001/jama.2016.1252
Abstract

Importance  Achieving glycemic control remains a challenge for patients with type 2 diabetes, even with insulin therapy.

Objective  To assess whether a fixed ratio of insulin degludec/liraglutide was noninferior to continued titration of insulin glargine in patients with uncontrolled type 2 diabetes treated with insulin glargine and metformin.

Design, Setting, and Participants  Phase 3, multinational, multicenter, 26-week, randomized, open-label, 2-group, treat-to-target trial conducted at 75 centers in 10 countries from September 2013 to November 2014 among 557 patients with uncontrolled diabetes treated with glargine (20-50 U) and metformin (≥1500 mg/d) with glycated hemoglobin (HbA1c) levels of 7% to 10% and a body mass index of 40 or lower.

Interventions  1:1 randomization to degludec/liraglutide (n = 278; maximum dose, 50 U of degludec/1.8 mg of liraglutide) or glargine (n = 279; no maximum dose), with twice-weekly titration to a glucose target of 72 to 90 mg/dL.

Main Outcomes and Measures  Primary outcome measure was change in HbA1c level after 26 weeks, with a noninferiority margin of 0.3% (upper bound of 95% CI, <0.3%). If noninferiority of degludec/liraglutide was achieved, secondary end points were tested for statistical superiority and included change in HbA1c level, change in body weight, and rate of confirmed hypoglycemic episodes.

Results  Among 557 randomized patients (mean: age, 58.8 years; women, 49.7%), 92.5% of patients completed the trial and provided data at 26 weeks. Baseline HbA1c level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA1c level reduction was greater with degludec/liraglutide vs glargine (−1.81% for the degludec/liraglutide group vs −1.13% for the glargine group; estimated treatment difference [ETD], –0.59% [95% CI, –0.74% to –0.45%]), meeting criteria for noninferiority (P < .001), and also meeting criteria for statistical superiority (P < .001). Treatment with degludec/liraglutide was also associated with weight loss compared with weight gain with glargine (–1.4 kg for degludec/liraglutide vs 1.8 kg for glargine; ETD, –3.20 kg [95% CI, –3.77 to –2.64],P < .001) and fewer confirmed hypoglycemic episodes (episodes/patient-year exposure, 2.23 for degludec/liraglutide vs 5.05 for glargine; estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61],P < .001). Overall and serious adverse event rates were similar in the 2 groups, except for more nonserious gastrointestinal adverse events reported with degludec/liraglutide (adverse events, 79 for degludec/liraglutide vs 18 for glargine).

Conclusions and Relevance  Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA1c levels, with secondary analyses indicating greater HbA1c level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety.

Trial Registration  clinicaltrials.gov Identifier: NCT01952145

Introduction

Quiz Ref IDAchieving optimal glucose control is a challenge for the majority of patients with type 2 diabetes, with less than one-third of patients treated with basal insulin reaching a glycated hemoglobin (HbA1c) level of less than 7.0%.1 Despite this, many patients continue basal insulin without treatment intensification.2 Traditionally, such patients and their clinicians intensify the insulin regimen, generally by further up-titration of the basal insulin dose or with the addition of 1 or more mealtime insulin injections. Both options increase the risk of hypoglycemia and weight gain. In addition, there may be a practical limit to the glucose-lowering efficacy achievable with insulin titration alone, irrespective of the regimen. Recently, combinations of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and basal insulin have been recommended as an alternative in international guidelines, extending the intensification options available.3

In this trial, we addressed the practical and patient-centered question of the relative efficacy and safety of optimized and unlimited titration of a once-daily injection of basal insulin (glargine) vs a once-daily injection of the fixed-ratio combination of basal insulin degludec (dose limit of 50 U) and the GLP-1RA liraglutide (dose limit of 1.8 mg) (hereafter referred to as degludec/liraglutide). Although comparisons of degludec/liraglutide to more complex insulin regimens are being studied in an ongoing trial,4 the use of basal insulin in combination with oral agents is the dominant treatment strategy for refractory hyperglycemia and the most relevant comparator for clinicians.

The primary objective of this trial was to determine whether degludec/liraglutide was noninferior to up-titration of glargine in change from baseline in HbA1c level in patients with uncontrolled type 2 diabetes treated with glargine and metformin. If the primary objective was met, secondary objectives were to assess whether degludec/liraglutide was statistically superior compared with glargine in change from baseline of HbA1c level, body weight, and rate of confirmed hypoglycemia.

Methods

The trial was reviewed and approved by institutional review boards, and all patients provided written, informed consent forms prior to participation. DUAL V was a phase 3, multinational, multicenter, randomized clinical trial conducted from September 2013 to November 2014 with a total length of 29 weeks (2 weeks from screening to randomization, 26-week treatment period, and 1 week posttreatment follow-up). This treat-to-target trial enrolled adults (aged ≥18 years) with type 2 diabetes with an HbA1c level of 7% to 10% (inclusive), who were taking a stable dose of glargine (total daily dose, 20-50 U, inclusive, allowing individual fluctuations of ±10% for at least 56 days prior to screening), with stable daily dosing of metformin (≥1500 mg or maximum tolerated dose), body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 40 or lower, and able to adhere to the protocol. The trial protocol and statistical analysis plan are available in Supplement 1.

Interventions

Patients were randomized 1:1 via an interactive voice/web response system to receive degludec/liraglutide or continued glargine, each treatment titrated to the same fasting glucose target. Patients randomized to degludec/liraglutide discontinued glargine and initiated degludec/liraglutide at 16 dose steps (16 U of degludec/0.6 mg of liraglutide), irrespective of the dose of glargine at the time of randomization, and dosed once daily at any time of day, preferably at the same time every day. The maximum allowed dose was 50 dose steps providing 50 U of degludec and 1.8 mg of liraglutide (the maximum dose of liraglutide approved for the type 2 diabetes indication).

Patients randomized to glargine continued treatment with their pretrial dosing, with no maximum daily dose during the trial period. Glargine was dosed once daily according to the locally approved prescribing information.

Quiz Ref IDIn both groups, target-driven titration was performed twice weekly based on the mean of 3 previous daily self-monitored prebreakfast blood glucose measurements. If this mean was above or below the 72 to 90 mg/dL target (to convert glucose to mmol/L, multiply by 0.0555), patients were to respectively increase or decrease their dose by 2 dose steps or 2 U.

Main Outcomes and Measures

The primary end point was change in HbA1c level from baseline to 26 weeks. Secondary end points were change from baseline in body weight and number of treatment-emergent hypoglycemic episodes during 26 weeks. Exploratory prespecified end points included insulin dose, change from baseline in fasting plasma glucose (FPG) level, 9-point self-measured blood glucose (SMBG) profile, responders for HbA1c level (predefined targets of <7.0% and ≤6.5%), and for composite targets based on HbA1c level without hypoglycemia and/or without weight gain. Time points included in the 9-point SMBG profile were breakfast, 90 minutes after breakfast, lunch, 90 minutes after lunch, dinner, 90 minutes after dinner, bedtime, 4:00 am, and breakfast the next day. Post-hoc analysis of mean blood glucose at each time point in the 9-point SMBG profile and analysis of confirmed hypoglycemia by end of treatment HbA1c level were also performed. Safety end points included number of treatment-emergent adverse events and nocturnal hypoglycemic episodes during the 26-week treatment period, change from baseline in standard laboratory analyses (including lipid profile, amylase, lipase, and calcitonin), blood pressure, electrocardiogram, and pulse.

Confirmed hypoglycemic episodes were defined as episodes in which plasma glucose was biochemically confirmed as less than 56 mg/dL, with or without symptoms or in which the patient required assistance. A hypoglycemic episode was classified as severe if the patient required assistance, and nocturnal if it occurred between 12:01 am and 05:59 am (both inclusive). Patient-reported outcomes were measured using the Treatment-Related Impact Measure for Diabetes (TRIM-D) and 36-Item Short Form Survey (SF-36).

Ethnicity and race were recorded to meet regulatory requirements and were self-reported by the participant from a predefined list.

All collected blood samples were processed and shipped immediately to a central laboratory (Quintiles), where all parameters were analyzed.

Statistical Analysis

The trial was powered to the primary objective of demonstrating noninferiority using a t test under the following assumptions: no treatment difference, a noninferiority margin of 0.3%, 1:1 randomization, nominal power of 90%, standard deviation of 1%, and 15% drop out. The noninferiority margin of 0.3% was selected based on existing US Food and Drug Administration (FDA) guidance, and is considered in the field the minimal clinically significant change for HbA1c level.5

In total, 554 patients were planned to be randomized. The primary end point was analyzed using a standard analysis of covariance (ANCOVA) model, including treatment and region as fixed factors and baseline HbA1c level as covariate. For secondary end points the family-wise type I error was controlled using 1-sided testing at the 2.5% level using the following prespecified test procedure that combines hierarchical testing and the Holm-Bonferroni method. First, the primary end point was tested for noninferiority using 1-sided testing at the 2.5% level. Second, if statistical significance was obtained, testing proceeded (hierarchical part) to the secondary end points. In turn, these end points were tested by the Holm-Bonferroni method comparing 1-sided P values against 2.5% significance levels adjusted for multiplicity.6 Exploratory end points were tested 2-sided at the 5% level and not adjusted for multiplicity.

Continuous end points were analyzed by ANCOVA with treatment and region as fixed factors and corresponding baseline value as covariate (plus baseline HbA1c level for dose); fasting lipid laboratory analyses were log-transformed prior to the analysis. The 9-point SMBG profile values were analyzed jointly using a linear mixed-model with an unstructured residual covariance matrix for measurements within patient and with treatment, time point, region, and interaction between treatment and time point as fixed effects and baseline 9-point SMBG profile values as covariates. Hypoglycemic episodes were analyzed using a negative binomial regression model with a log-link function and log of the exposure time as offset that included treatment and region as fixed factors. Responder end points (proportion of patients achieving HbA1c level <7.0%, HbA1c level ≤6.5%, and the composite end points described previously) were analyzed by a generalized linear model with binomial distribution and identity link that included treatment as a fixed factor. The choice of ANCOVA for continuous end points was based on European Medicines Agency (EMA)/FDA guidance and wide acceptance, and the negative binomial analysis of hypoglycemic events is widely accepted for diabetes trials.5,7,8 Models were checked by residual plots and diagnostic statistics. Statistical analyses were based on the full analysis set (all randomized patients); efficacy and safety end point descriptive statistics are based on the full analysis set and safety analysis set (all patients receiving at least 1 dose of trial product), respectively (Figure 1). For the full analysis set analyses and descriptive statistics, a patient contributed with treatment “as randomized” (intention-to-treat principle). For safety analysis set descriptive statistics, a patient contributed with treatment “as treated” (principle of safety attributable to drug). In this particular trial, the 2 analysis sets are identical (ie, all randomized patients were exposed to their randomized treatment). Data are reported as mean (SD) unless otherwise noted. The estimated treatment differences (ETD) were calculated from the point estimates of the 2 treatments from the ANCOVA model (treatment factor levels) and associated standard error and covariance.

Sensitivity analyses were performed for secondary end points. For continuous end points (HbA1c level and weight) repeated measures and 2 multiple imputation–based methods with sequential ANCOVAs were conducted.9,10 Hypoglycemic episodes were analyzed by multiple imputation method using a posterior Bayesian approach.11

All statistical analyses were performed using SAS (SAS Institute), version 9.3.

Results
Patient Population

Patients from 10 countries were included, 767 were screened, and 557 were randomized and exposed to the trial products (Figure 1) from September 20, 2013, through November 4, 2014. Of the 557 patients randomized (mean: age 58.8 years; women, 49.7%), 92.5% completed the trial and provided data at 26 weeks. The treatment groups were comparable at baseline with respect to demographics and characteristics (Table 1). In total, 239 of 278 patients receiving degludec/liraglutide (86%) and 255 of 279 patients receiving glargine (91%) attended all scheduled visits from week 0 to 26.

Primary Objective

HbA1c level decreased from baseline for the degludec/liraglutide group (8.4% [SD, 0.9%]) and glargine group (8.2% [SD, 0.9%]) over the first 16 weeks of treatment and stabilized at 6.6% for the degludec/liraglutide group (SD, 0.9%) and 7.1% for the glargine group (SD, 0.9%) by week 26. After 26 weeks of treatment, mean HbA1c level had decreased by 1.81% for the degludec/liraglutide group (SD, 1.08%) and by 1.13% for the glargine group (SD, 0.98%) with glargine corresponding to an ETD of –0.59% (95% CI, –0.74% to –0.45%) (Table 2 and Figure 2A), demonstrating noninferiority of degludec/liraglutide (upper bound of the 95% CI, –0.45%; less than the noninferiority margin of 0.3%, 1-sided P for noninferiority < .001) compared with glargine.

Secondary End Points

The ETD for change in HbA1c level (–0.59% [95% CI, –0.74% to –0.45%], 1-sided P < .001) also met criteria for statistical superiority of degludec/liraglutide vs glargine (Table 2 and Figure 2A). A reduction in body weight of 1.4 kg (SD, 3.5) was observed in the degludec/liraglutide group from 88.3 kg (SD, 17.5) to 86.9 kg (SD, 17.2), whereas the glargine group had an increase in body weight of 1.8 kg (SD, 3.6) from 87.3 kg (SD, 15.8) to 89.1 kg (SD, 15.9); ETD, –3.20 kg (95% CI, –3.77 to –2.64), 1-sided P < .001 (Table 2 and Figure 2B). Confirmed hypoglycemia occurred in fewer patients receiving degludec/liraglutide than those receiving glargine (28.4% for the degludec/liraglutide group and 49.1% for the glargine group), with reduced rates of 2.23 episodes vs 5.05 episodes per patient-year of exposure (PYE) (estimated rate ratio, 0.43 [95% CI, 0.30 to 0.61], 1-sided P < .001) (Table 2; Figure 2C). One severe hypoglycemic episode was reported in the trial, which was in the glargine group. Sensitivity analyses all demonstrated similar results in terms of statistical significance and effect sizes (eTable 1 in Supplement 2).

Exploratory Prespecified End Points

FPG level had decreased in both groups after 26 weeks of treatment to 109.5 mg/dL (SD, 38.4) for the degludec/liraglutide group and 110.2 mg/dL (SD, 38.6) for the glargine group; ETD, –0.15 mg/dL (95% CI, –6.28 to 5.99), P = .96 (Figure 3A). Mean SMBG levels measured for dose adjustment decreased in both groups over the first 12 weeks (more rapidly with degludec/liraglutide) and stabilized until week 26 at 105.8 mg/dL (SD, 26.0) for the degludec/liraglutide group and at 100.7 mg/dL (SD, 23.7) for the glargine group, as expected in a treat-to-target trial.

At week 26, the mean of the 9-point SMBG measurements had decreased in both groups, by 45.6 mg/dL (SD, 44.9) from baseline to 136.5 mg/dL (SD, 34.6) at 26 weeks for degludec/liraglutide and by 42.6 mg/dL (SD, 49.5) from baseline to 141.4 mg/dL (SD, 33.8) at 26 weeks for glargine. The between-group ETD was –4.0 mg/dL (95% CI, –9.6 to 1.6), P = .16 (Figure 3B).

More patients randomized to degludec/liraglutide achieved HbA1c targets (specifically, <7.0% as well as ≤6.5%) than with glargine, and did so without weight gain and/or hypoglycemia (P < .001 for all) (Table 3).

In the glargine group, 24.4% of patients reported nocturnal confirmed hypoglycemic episodes, as did 6.1% in the degludec/liraglutide group, with event rates per PYE of 1.23 for the glargine group and 0.22 for the degludec/liraglutide group. The estimated rate ratio for nocturnal hypoglycemia was 0.17 (95% CI, 0.10 to 0.31),P < .001 (Figure 3C).

After 26 weeks, there were increases in the mean daily dose of degludec/liraglutide to 41 dose steps (41 U of degludec/1.48 mg of liraglutide) (range, 16–50) and to 66 U for glargine (range, 17–153) (Figure 3D). The between-group ETD insulin dose was –25.47 U (95% CI, –28.90 to –22.05), P < .001. Approximately 40% of patients in the degludec/liraglutide group received the maximum 50 dose steps after 26 weeks, of which 68% achieved an HbA1c level less than 7% compared with 74% of those who used less than the maximum allowed degludec/liraglutide dose.

Patient-Reported Outcomes

The physical component score of the SF-36 questionnaire improved with degludec/liraglutide (from 47.4 [95% CI, 46.4 to 48.5] at baseline to 49.0 [95% CI, 48.0 to 50.0] at week 26) and worsened with glargine (from 47.7 [95% CI, 46.7 to 48.7] at baseline to 47.2 [95% CI, 46.1 to 48.3] at week 26); ETD, 1.9 [95% CI, 0.8 to 3.1], P < .001 (eTable 2 in Supplement 2). This was also the case with physical functioning (ETD, 1.4 [95% CI, 0.0 to 2.7], P = .045) and bodily pain (ETD, 2.0 [95% CI, 0.4 to 3.6], P = .01) subdomains; the general health subdomain score increased more with degludec/liraglutide (from 42.9 [95% CI, 41.9 to 44.0] at baseline to 46.2 [95% CI, 45.2 to 47.3] at week 26) than with glargine (from 43.6 [95% CI, 42.5 to 44.7] at baseline to 45.0 [95% CI, 43.9 to 46.1] at week 26; ETD, 1.7 [95% CI, 0.4 to 2.9], P = .008). There was no between-group difference in overall mental score (ETD, –0.1 [95% CI, –1.5 to 1.3], P = .93) or any component subdomains. Patient-reported outcome scores using the TRIM-D questionnaire improved in all subdomains and in total score in both groups. The increase in total score was greater with degludec/liraglutide (from 74.6 [95% CI, 73.1 to 76.2] at baseline to 82.1 [95% CI, 80.6 to 83.7] at week 26) compared with glargine (from 73.6 [95% CI, 72.1 to 75.1] at baseline to 78.9 [95% CI, 77.4 to 80.4] at week 26; ETD, 2.8 [95% CI, 0.9 to 4.7], P = .003), largely driven by higher scores than glargine in the treatment burden (ETD, 3.7 [95% CI, 0.7 to 6.8], P = .02) and diabetes management (ETD, 7.2 [95% CI, 4.2 to 10.2], P < .001) subdomains, indicating higher treatment satisfaction with degludec/liraglutide (eTable 2 in Supplement 2).

Post Hoc Analyses

The lower rate of confirmed hypoglycemia observed with degludec/liraglutide compared with glargine was also seen irrespective of end-of-trial HbA1c level (eFigure 1 in Supplement 2). Post hoc analysis of the 9-point SMBG measurements, using a linear mixed-model, showed a statistically significantly lower blood glucose level 90 minutes after lunch (ETD, –11.54 mg/dL [95% CI, –19.83 to –3.25], P = .006), before dinner (ETD, –12.48 mg/dL [95% CI, –20.05 to –4.92], P = .001), and after dinner (ETD, –10.24 mg/dL [95% CI, –19.45 to –1.02], P = .03), but a higher blood glucose level before breakfast (ETD, 8.28 mg/dL [95% CI, 2.98 to 13.59], P = .002) and before breakfast on the following day (ETD, 7.23 mg/dL [95% CI, 1.42 to 13.04], P = .02) for degludec/liraglutide than with glargine; blood glucose levels were similar at the other 4 time points.

Vital Parameters

After 26 weeks of treatment, heart rate increased in the degludec/liraglutide group and remained similar to baseline with glargine (ETD, 3.71 beats/min [95% CI, 2.33 to 5.08], P < .001). Systolic blood pressure decreased with degludec/liraglutide and remained unchanged with glargine (ETD, –3.57 mm Hg [95% CI, –5.54 to –1.59], P < .001). There was no difference in the change in diastolic blood pressure between the groups (ETD, 0.91 mm Hg [95% CI, –0.28 to 2.10], P = .14), which remained similar to baseline (eTable 3 in Supplement 2).

Laboratory Measurements

After 26 weeks of treatment, total cholesterol (estimated treatment ratio [ETR], 0.95 [95% CI, 0.92 to 0.98], P <.001), low-density lipoprotein cholesterol (ETR, 0.92 [95% CI, 0.88 to 0.97], P <.001) and free fatty acids (ETR, 0.85 [95% CI, 0.80 to 0.92], P <.001) were lower with degludec/liraglutide than with glargine. No differences were observed for high-density lipoprotein, very low–density lipoprotein, and triglycerides between the groups at the end of trial.

There were increases in mean lipase (17.6 U/L [SD, 37.0]; to convert to μkat/L, multiply by 0.0167) and amylase (10.7 U/L [SD, 22.1]; to convert to μkat/L, multiply by 0.0167) activity during the treatment period in the degludec/liraglutide group and minimal change in the glargine group (–2.2 U/L [SD, 29.2] for lipase and 2.2 U/L [SD, 18.4] for amylase).

Calcitonin levels were similar between the degludec/liraglutide and glargine groups throughout the trial and there was no clinically relevant change from baseline at week 26 in either group: median change from baseline 0.0 pg/mL (range, –3.4-47.7) for the degludec/liraglutide group and 0.0 pg/mL (range, –20.5-8.0) for the glargine group (to convert to pmol/L, multiply by 0.292).

Adverse Events

The overall rate of adverse events per 100 PYE was 343.3 for the degludec/liraglutide group and 286.4 for the glargine group. Serious adverse events per 100 PYE were 3.9 for the degludec/liraglutide group and 6.7 for the glargine group. The majority of adverse events were mild and judged to be unlikely related to the trial products by the investigator. A higher proportion of adverse events were judged related to the trial product in the degludec/liraglutide group, these were mainly gastrointestinal disorders. Accordingly, nausea was reported by more patients in the degludec/liraglutide group (9.4%; n = 26; 26.2 events per 100 PYE) than the glargine group (1.1%; n = 3; 2.2 events per 100 PYE). However, no more than 4% of patients experienced nausea with degludec/liraglutide at any given week during the trial (eFigure 2 in Supplement 2).

Of 5 cardiovascular events sent for adjudication, 4 were confirmed by the external blinded event adjudication committee, 2 of which were major cardiovascular events (defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) (1 in each group). A patient treated with glargine died of hemorrhagic stroke, and a patient treated with degludec/liraglutide had an ischemic stroke followed by full recovery. Both events were considered unlikely related to the trial product by the investigator. Seven potential events of neoplasm were sent to the event adjudication committee for adjudication; 3 were confirmed (rectal adenocarcinoma, prostate cancer, and metastatic pancreatic carcinoma; the latter diagnosed 9 days after stopping treatment [day 54 of the trial]), all in the degludec/liraglutide group and all considered unlikely related to the trial product by the investigator. Two thyroid disease events were sent for adjudication; neither were confirmed as thyroid neoplasms. The single event of pancreatitis sent for adjudication was not confirmed by the event adjudication committee.

Discussion

Quiz Ref IDAmong patients with uncontrolled type 2 diabetes treated with glargine and metformin, degludec/liraglutide achieved noninferior HbA1c level reduction (primary objective), and subsequently statistically greater HbA1c level reduction (secondary objective) compared with continued glargine titration, when both products were titrated to the same fasting glycemic target. Further analyses demonstrated that degludec/liraglutide was associated with weight loss compared with weight gain with glargine and a lower rate of hypoglycemia.

Despite the initial reduction in insulin dose for patients randomized to the degludec/liraglutide group, from a mean of 31 U to 16 dose steps (including a liraglutide component of 0.6 mg), there was no deterioration in mean SMBG measurement immediately following this switch. The mean SMBG measurement decrease following randomization was greater in the degludec/liraglutide group, indicating a faster therapeutic response to degludec/liraglutide initiation compared with glargine up-titration. The maximum allowed dose of degludec/liraglutide was 50 dose steps, whereas there was no predefined maximum daily dose of glargine. Despite the dosing cap, a statistically and clinically significantly greater HbA1c level reduction was achieved in the degludec/liraglutide group compared with the glargine group (final dose 41 U in the degludec/liraglutide group vs 66 U in the glargine group). The majority of patients treated with degludec/liraglutide met the less than 7.0% and 6.5% or less HbA1c level targets, more than those in the glargine group, with a lower rate of hypoglycemia. These findings highlight the therapeutic benefits of the liraglutide component and its insulin-sparing effect.

The combination of basal insulin and GLP-1RA as a treatment option is well established.3,12 Concern about hypoglycemia is a barrier to good glycemic control, rendering patients unwilling to optimize treatment with insulin13 and clinicians reticent to recommend more aggressive treatment targets.14 The burden of treatment complexity13,14 and concerns about weight gain15 may contribute to poor patient adherence to treatment intensification.16 Equally, physicians cite lack of experience and time to educate patients as a barrier to initiating, modifying, and intensifying insulin treatment.17Quiz Ref ID As a once daily, single injection that is effective, associated with weight loss, and a low risk of hypoglycemia, degludec/liraglutide may overcome many of the barriers to treatment intensification in patients treated with basal insulin. This suggestion is supported by the patient-reported outcome results.

Gastrointestinal complications are well-known adverse effects of treatment with GLP-1RA.18 In the liraglutide clinical development program, nausea was reported by between 14% and 40% of patients treated with 1.2 mg and 1.8 mg of liraglutide compared with glargine and placebo.19,20 In this trial, a lower proportion of patients treated with degludec/liraglutide reported 1 or more episodes of nausea (9.4%). This is likely due to a more gradual titration regimen for degludec/liraglutide compared with that customarily used for liraglutide (0.6 mg weekly). The liraglutide component in degludec/liraglutide is up-titrated in smaller increments (up to 0.072 mg twice weekly) with the titration scheme used, contributing to the tolerability of the product. The open-label nature of this trial could have introduced an unconscious bias resulting in overreporting of these events, as even fewer patients reported nausea (6.5%) in a double-blinded trial comparing degludec/liraglutide with insulin degludec.21

This study had several important limitations. It was necessary to perform the trial with an open-label design as the maximum dose of degludec/liraglutide was 50 dose steps and otherwise a double-dummy design would have been required with patients administering 2 injections daily in unlabeled syringes. The open-label nature of the trial may have biased reporting of adverse events by investigators or patient-reported outcomes scoring by patients. However, the event adjudication committee, who adjudicated cardiovascular, neoplasm, thyroid disease, or pancreatitis events were blinded to randomized treatment. Quiz Ref IDThe clinical applicability of this trial is limited to those who fit the inclusion and exclusion criteria. In clinical practice, this means that care must be taken to avoid extrapolating expectations from these results to patients with diabetes who were, for example, previously uncontrolled on a higher dose of basal insulin (ie, >50 U) or basal insulin in combination with therapies other than metformin. Though the fasting glucose level achieved by study end is similar between groups and to other treat to target trials and though the differences of rates of hypoglycemia were substantial, the mean glargine dose did not reach a plateau at study end; this does raise the possibility that with longer treatment duration or alternative insulin regimens differences in HbA1c level may have been minimized, but at the expense of greater differences in hypoglycemia and weight gain.

Further research is indicated to evaluate the durability of the effects of degludec/liraglutide in longer-term studies, in clinical practice, and to assess whether patients and physicians consider degludec/liraglutide a suitable treatment option to overcome barriers to treatment intensification.

Conclusions

Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA1c levels, with secondary analyses indicating greater HbA1c level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety.

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Article Information

Corresponding Author: John B. Buse, MD, PhD, University of North Carolina School of Medicine, 160 Dental Cir, CB# 7172, Burnett-Womack 8027, Chapel Hill, NC 27599-7172 (jbuse@med.unc.edu).

Correction: This article was corrected for an error in a collaborator’s name on May 17, 2016.

Author Contributions: Drs Lingvay and Buse had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Lehmann.

Acquisition, analysis, or interpretation of data: Lingvay, Manghi, Garcia-Hernández, Norwood, Lehmann, Tarp-Johansen, Buse.

Drafting of the manuscript: Lehmann, Tarp-Johansen.

Critical revision of the manuscript for important intellectual content: Lingvay, Manghi, Garcia-Hernández, Norwood, Lehmann, Tarp-Johansen, Buse.

Statistical analysis: Tarp-Johansen.

Study supervision: Lingvay, Garcia-Hernández, Norwood, Lehmann.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Lingvay reports receiving grants from Novo Nordisk, Pfizer/Merck, and GI Dynamics; personal fees from AstraZeneca, Boehringer-Ingelheim, and Janssen; editorial assistance from Sanofi. Dr García-Hernández reports receiving grants and consulting fees from Ely Lilly, Pfizer/Merck, and Amgen. Dr Lehmann reports being an employee of and holding shares in Novo Nordisk. Dr Tarp-Johansen reports being an employee of Novo Nordisk. Dr Buse reports receiving grants, nonfinancial support, and personal fees from Novo Nordisk, Eli Lilly, Bristol-Myers Squibb, GI Dynamics, Orexigen, Merck, PhaseBio, AstraZeneca, Takeda, Sanofi, and Lexicon; nonfinancial support and personal fees from Elcylex, Metavention, vTv Pharma, Dance Biopharm, and Quest; grants from Medtronic Minimed, Tolerex, Osiris, Halozyme, Johnson & Johnson, Andromeda, Boehringer-Ingelheim, GlaxoSmithKline, Astellas, MacroGenics, Intarcia Therapeutics, and Scion NeuroStim; and being a member of a variety of nonprofit boards. No other disclosures are reported.

Funding/Support: This study was funded by Novo Nordisk.

Role of the Funder/Sponsor: Novo Nordisk was involved in the study design and protocol development, provided logistical support, and obtained the data, which were evaluated jointly by the authors and the sponsor. All authors interpreted the data and wrote the manuscript together with the sponsor's medical writing services. The sponsor did not have the right to suppress or veto publications.

Group Information: The DUAL V investigators: Argentina: Federico Perez Manghi, Centro de Investigaciones Metabólicas, Capital Federal; Virginia Visco, DIM Clinica Privada, Buenos Aires; Silvia Saavedra, Sanatorio Parque SA, Salta; Marisa Vico, Instituto de Investigaciones Clinicas Zarate, Zarate; Silvia Lapertosa, Hospital Central “Dr Jose Ramón Vidal,” Corrientes. Australia: Michael D’Emden, Royal Brisbane & Women’s Hospital Endocrinology Research Unit, Herston, QLD; Robert Moses, Illawarra Diabetes Service Clinical Trials & Research Unit, Wollongong, NSW; Roger Chen, Specialist Medical Centre, Blacktown, NSW; Mark Forbes, Robina Hospital Division of Medicine & Research, Robina, QLD; Murray Gerstman, Eastern Clinical Research Unit, Ringwood East, VIC; Thomas Nathow, Ipswich Research Institute, Ipswich, QLD. Greece: Alexandra Bargiota, U.H. of Larissa, Larissa; Ioannis Ioannidis, G.H. of N. Ionia “Agia Olga,” Nea Ionia; Kyparissia Karatzidou, G.H. of Thessaloniki “Papageorgiou,” Thessaloniki; Emmanouil Pagkalos, Clinic "Thermi," Thessaloniki; Christos Sambanis, G.H. of Thessaloniki “Ippokrateio,” Thessaloniki; Nikolaos Tentolouris, G.H. of Athens “Laiko,” Athens; Stelios Tigas, U.H. of Ioannina, Ioannina. Hungary: Mihály Dudás, Pándy Kálmán Megyei Kórház Belgyógyászati Osztály, Gyula; Eleonóra Harcsa, Markhot Ferenc Oktatókórház és Rendelőintézet Belgyógyászati Osztály, Eger; Iván Őry, MH Egészségügyi Központ Belgyógyászati Osztály, Budapest; Barnabás Bakó, BAZ megyei Kórház és Egyetemi Oktató Kórház Belgyógyászati Osztály, Miskolc; Tibor Hidvégi, Petz Aladár Megyei Oktató Kórház, Győr. Mexico: Leobardo Sauque Reyna, Instituto de Diabetes, Obesidad y Nutrición S.C., Morelos; Israel Olvera Álvarez, Clínicos Asociados BOCM, S.C., Mexico City; Marco Antonio Morales de Teresa, Resultados Médicos, Desarrollo e Investigación S.C., Hidalgo; Guadalupe Morales Franco, Centro de Diabetes de Durango, Durango; Pedro Alberto García Hernández, Hospital Universitario “Dr. José Eleuterio González,” Nuevo León. Russia: Nina Petunina, I.M. Sechenov First Moscow State Medical University, Moscow; Alsou Zalevskaya, City Multifield Hospital #2, St Petersburg; Gagik Galstyan, Endocrinology Research Centre, Moscow; Vladimir Potin, Research Institute of Obstetrics and Gynecology, St Petersburg; Alexander Sobolev, Kirov Clinical Hospital #7, Kirov; Yulia Samoilova, Siberian State Medical University, Tomsk; Marina Kharakhulakh, Tomsk Regional Clinical Hospital, Tomsk; Vadim Klimontov, Institute of Clinical and Experimental Lymphology SB RAMS, Novosibirsk; Sergei Nedogoda, Volgograd State Medical University, Volgograd; Svetlana Zyangirova, City Endocrinology Dispensary, Kazan; Diana Alpenidze, City polyclinic #117, St Petersburg; Fatima Khetagurova, Vsevolozhsk Central Regional Clinical Hospital, Vsevolozhsk; Irina Ipatko, Consultative Diagnostic Center of Komi Republic, Syktyvkar. Slovakia: Emil Martinka, Národný endokrinologický a diabetologický ústav n.o., Diabetologické oddelenie, Ľubochňa; Jozef Lacka, JAL s.r.o. Diabetologická ambulancia, Trnava; Karol Rummer, Diabetologická ambulancia Komárňanská, Veľký Meder; Ján Truban, ENDIAMED s.r.o. Odbojárov, Dolný Kubín; Lucia Gajdošíkova s.r.o. Diabetologická ambulancia Nemocničná, Považská Bystrica; Adriana Philippiová, DIADA s.r.o. Bezručová, Bardejov; Milan Běhunčík, Železničné zdravotníctvo Košice s.r.o. Diabetologická ambulancia, Košice; Anna Vargová, DIA-KONTROL s.r.o. Ambulancia diabetológie poruchy látkovej premeny avýživy, Levice; Emília Pastrnáková, Interná ambulancia AGTO s.r.o. Trieda; Košice; Monika Košíková, DIAKOM s.r.o. diabetologická ambulancia Mnoheľová 2, Poprad; Jana Džuponová, DIA-CLARUS s.r.o. Hviezdoslavova, Prievidza; Emília Pastrnáková, EMPA s.r.o., diabetologicka ambulancia Mojzesova, Kosice. Spain: Pedro Mezquita Raya, Servicio de Endocrinologia, Clinica San Pedro, Almeria; Margarita Rivas Fernández, Servicio de Endocrinologia, Hospital Infanta Luisa San Jacinto, Sevilla; Santiago Tofé, Servicio Endocrinologia, Clinica Juaneda, Palma de Mallorca; Carmen de la Cuesta, Clinica Nuevas Tecnologias en Diabetes y Endocrinologia, Sevilla; Juan Francisco Merino Torres, El Servicio de Endocrino y Nutrición, Universitari i Politècnic La Fe, Valencia; Manuel Muñoz, Consultas Ext. Endocrinología, Hospital Universitario San Cecilio, Granada. South Africa: Johanna Adriana Kok, Union Hospital, Alberton; Andrew Jacovides, Health Emporium, Midrand; Hans Hendrik Snyman, Armansis Medical Centre, Brits North West; Deenadalayan Pillay, Stanger. United States: Neil Farris, Research Group of Lexington; Kevin Cannon, PMG Research of Wilmington; Lon Lynn, Clinical Research of West Florida; Gary Bedel, Prestige Clinical Research; Louis Chaykin, Meridien Research; Clinton Corder, COR Clinical Research; Raul Gaona, Briggs Clinical Research; Judith Kirstein, Advanced Clinical Research; Wilfred McKenzie, M&O Clinical Research; Emily Morawski, Holston Medical Group; Ikeadi Ndukwu, Laporte County Institute for Clinical Research; Joseph Risser, San Diego Family Care; Jerry Thurman, SSM Medical Group; David Winslow, Kentucky Research Group; Kenneth Blaze, South Broward Research; Guenther Boden, Temple University Hospital; Michael Jardula, Desert Medical Group; Leslie Klaff, Rainier Clinical Research Center; Paul Norwood, Valley Research; Henry Stamps, Collierville Medical Specialists; Ileana Tandron; Gary Tarshis, ExpressCare Clinical Research; Lawrence Levinson, Tipton Medical & Diagnostic Center; John Agaiby, Clinical Investigation Specialists; Etsegenet Ayele, Pacific Clinical Studies; Sean Hurley, Rowan Research; Anthony Inzerello, Clinical Research Advantage/Family Medicine Associates; James Lane, Harold Hamm Diabetes Center; Kari Uusinarkaus, Clinical Research Advantage/Colorado Springs Health Partners; Ildiko Lingvay, University of Texas Southwestern Medical Center.

Additional Contributions: We thank Henrik Jarlov, MD (Novo Nordisk), for his review and input to the manuscript, and Helen White, PhD, and Gabrielle Parker, BSc (both from Watermeadow Medical), for medical writing and editorial assistance. All contributors received compensation from Novo Nordisk.

References
1.
Curtis  B, Lage  MJ.  Glycemic control among patients with type 2 diabetes who initiate basal insulin: a retrospective cohort study. J Med Econ. 2014;17(1):21-31.
PubMedArticle
2.
Blak  BT, Smith  HT, Hards  M, Curtis  BH, Ivanyi  T.  Optimization of insulin therapy in patients with type 2 diabetes mellitus: beyond basal insulin. Diabet Med. 2012;29(7):e13-e20.
PubMedArticle
3.
Inzucchi  SE, Bergenstal  RM, Buse  JB,  et al.  Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149.
PubMedArticle
4.
Clinicaltrials.gov. A clinical trial comparing efficacy and safety of insulin degludec/liraglutide (IDegLira) vs basal-bolus therapy in subjects with type 2 diabetes mellitus.https://clinicaltrials.gov/ct2/show/NCT02420262. Accessed December 10, 2015.
5.
US Department of Health and Human Services. Guidance for industry diabetes mellitus: developing drugs and therapeutic biologics for treatment and prevention.http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071624.pdf. Accessed February 4, 2016.
6.
Abdi  H. Holm’s sequential Bonferroni procedure. In: Salkind  N, ed. Encyclopedia of Research Design. Thousand Oaks, CA: Sage; 2010.
7.
European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Accessed February 4, 2016.
8.
Luo  J, Qu  Y.  Analysis of hypoglycemic events using negative binomial models. Pharm Stat. 2013;12(4):233-242.
PubMedArticle
9.
O’Kelly  M, Ratitch  B. Clinical Trials With Missing Data: A Guide for Practitioners. West Sussex, United Kingdom: John Wiley & Sons; 2014.
10.
Koch  GG.  Comments on “current issues in noninferiority trials” by Thomas R. Fleming, statistics in medicine. Stat Med. 2008;27(3):333-342.
PubMedArticle
11.
Keene  ON, Roger  JH, Hartley  BF, Kenward  MG.  Missing data sensitivity analysis for recurrent event data using controlled imputation. Pharm Stat. 2014;13(4):258-264.
PubMedArticle
12.
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;384(9961):2228-2234.
PubMedArticle
13.
Kunt  T, Snoek  FJ.  Barriers to insulin initiation and intensification and how to overcome them. Int J Clin Pract Suppl. 2009;62(164):6-10.
PubMedArticle
14.
Peyrot  M, Barnett  AH, Meneghini  LF, Schumm-Draeger  PM.  Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabet Med. 2012;29(5):682-689.
PubMedArticle
15.
Carver  C.  Insulin treatment and the problem of weight gain in type 2 diabetes. Diabetes Educ. 2006;32(6):910-917.
PubMedArticle
16.
Vijan  S, Hayward  RA, Ronis  DL, Hofer  TP.  Brief report: the burden of diabetes therapy: implications for the design of effective patient-centered treatment regimens. J Gen Intern Med. 2005;20(5):479-482.
PubMedArticle
17.
Cuddihy  RM, Philis-Tsimikas  A, Nazeri  A.  Type 2 diabetes care and insulin intensification: is a more multidisciplinary approach needed? results from the MODIFY survey. Diabetes Educ. 2011;37(1):111-123.
PubMedArticle
18.
Liu  FP, Dong  JJ, Yang  Q,  et al.  Glucagon-like peptide 1 receptor agonist therapy is more efficacious than insulin glargine for poorly controlled type 2 diabetes: a systematic review and meta-analysis. J Diabetes. 2015;7(3):322-328.
PubMedArticle
19.
Zinman  B, Gerich  J, Buse  JB,  et al; LEAD-4 Study Investigators.  Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32(7):1224-1230.
PubMedArticle
20.
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(10):2046-2055.
PubMedArticle
21.
Buse  JB, Vilsbøll  T, Thurman  J,  et al; NN9068-3912 (DUAL-II) Trial Investigators.  Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care. 2014;37(11):2926-2933.
PubMedArticle
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