Effect of Insulin Glargine Up-titration vs Insulin Degludec/Liraglutide on Glycated Hemoglobin Levels in Patients With Uncontrolled Type 2 Diabetes
Authors: Ildiko Lingvay, Federico Pérez Manghi, Pedro García-Hernández, Paul Norwood, Lucine Lehmann, Mads Jeppe Tarp-Johansen, John B. Buse
Journal: JAMA (2016)

<h3>Importance</h3> Achieving glycemic control remains a challenge for patients with type 2 diabetes, even with insulin therapy. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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 (HbA<sub>1c</sub>) levels of 7% to 10% and a body mass index of 40 or lower. <h3>Interventions</h3> 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. <h3>Main Outcomes and Measures</h3> Primary outcome measure was change in HbA<sub>1c</sub>level after 26 weeks, with a noninferiority margin of 0.3% (upper bound of 95% CI, &lt;0.3%). If noninferiority of degludec/liraglutide was achieved, secondary end points were tested for statistical superiority and included change in HbA<sub>1c </sub>level, change in body weight, and rate of confirmed hypoglycemic episodes. <h3>Results</h3> 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 HbA<sub>1c</sub>level was 8.4% for the degludec/liraglutide group and 8.2% for the glargine group. HbA<sub>1c</sub>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 (<i>P</i> &lt; .001), and also meeting criteria for statistical superiority (<i>P</i> &lt; .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]<sub>,</sub><i>P</i> &lt; .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]<sub>,</sub><i>P</i> &lt; .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). <h3>Conclusions and Relevance</h3> Among patients with uncontrolled type 2 diabetes taking glargine and metformin, treatment with degludec/liraglutide compared with up-titration of glargine resulted in noninferior HbA<sub>1c</sub>levels, with secondary analyses indicating greater HbA<sub>1c</sub>level reduction after 26 weeks of treatment. Further studies are needed to assess longer-term efficacy and safety. <h3>Trial Registration</h3> clinicaltrials.gov Identifier:NCT01952145