title: 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.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01952145.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas2Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Lingvay
authors.affiliation: Centro de Investigaciones Metabolicas, Buenos Aires, Argentina.
authors.forename: Federico
authors.initials: F
authors.lastname: Pérez Manghi
authors.affiliation: Servicio de Endocrinologia, Hospital Universitario de Monterrey "Dr José Eleuterio-González," Nuevo León, México.
authors.forename: Pedro
authors.initials: P
authors.lastname: García-Hernández
authors.affiliation: Valley Research, Fresno, California.
authors.forename: Paul
authors.initials: P
authors.lastname: Norwood
authors.affiliation: Novo Nordisk A/S, Søborg, Denmark.
authors.forename: Lucine
authors.initials: L
authors.lastname: Lehmann
authors.affiliation: Novo Nordisk A/S, Søborg, Denmark.
authors.forename: Mads Jeppe
authors.initials: MJ
authors.lastname: Tarp-Johansen
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill.
authors.forename: John B
authors.initials: JB
authors.lastname: Buse
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis*; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000069036:Insulin Glargine / Q000008:administration & dosage* / Q000009:adverse effects; D049528:Insulin, Long-Acting / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008687:Metformin / Q000008:administration & dosage* / Q000009:adverse effects; D008875:Middle Aged; D015430:Weight Gain; D015431:Weight Loss
chemical_list: D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting; D008687:Metformin; C571886:insulin degludec