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Original Investigation |

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

Ildiko Lingvay, MD, MPH, MSCS1,2; Federico Pérez Manghi, MD3; Pedro García-Hernández, MD4; Paul Norwood, MD5; Lucine Lehmann, MD6; Mads Jeppe Tarp-Johansen, PhD6; John B. Buse, MD, PhD7 ; for the DUAL V Investigators
[+] 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.
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Published online

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

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Figure 1.
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.

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Figure 2.
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.

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Figure 3.
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.

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