Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1)

Abstract

Objective: When oral therapy for type 2 diabetes is ineffective, adding basal insulin improves glycemic control. However, when glycated hemoglobin (HbA1c) remains elevated because of postprandial hyperglycemia, the next therapeutic step is controversial. We examined the efficacy and safety of lixisenatide in patients with HbA1c still elevated after initiation of insulin glargine.

Research design and methods: This double-blind, parallel-group trial enrolled patients with HbA1c 7-10% despite oral therapy. Insulin glargine was added and systematically titrated during a 12-week run-in, after which candidates with fasting glucose ≤ 7.8 mmol/L and HbA1c 7-9% were randomized to lixisenatide 20 µg or placebo for 24 weeks while insulin titration continued. The primary end point was HbA1c change after randomization.

Results: The randomized population (n = 446) had mean diabetes duration of 9.2 years, BMI 31.8 kg/m(2), and daily glargine dosage of 44 units. HbA1c had decreased during run-in from 8.6 to 7.6%; adding lixisenatide further reduced HbA1c by 0.71 vs. 0.40% with placebo (least squares mean difference, -0.32%; 95% CI, -0.46 to -0.17; P < 0.0001). More participants attained HbA1c <7% with lixisenatide (56 vs. 39%; P < 0.0001). Lixisenatide reduced plasma glucose 2 h after a standardized breakfast (difference vs. placebo -3.2 mmol/L; P < 0.0001) and had a favorable effect on body weight (difference vs. placebo -0.89 kg; P = 0.0012). Nausea, vomiting, and symptomatic hypoglycemia <3.3 mmol/L were more common with lixisenatide.

Conclusions: Adding lixisenatide to insulin glargine improved overall and postprandial hyperglycemia and deserves consideration as an alternative to prandial insulin for patients not reaching HbA1c goals with recently initiated basal insulin.

Trial registration: ClinicalTrials.gov NCT00975286.

Figure 1

Clinical responses to therapy from baseline to week 24 and end point with last observation carried forward (LOCF). A: Mean HbA_1c (%) by visit. B: Mean fasting plasma glucose (mmol/L) by visit. C: Mean change in body weight (kg) from baseline by visit. D:Mean daily basal insulin dose (units/day) by visit. Values are mean ± SE. The end point with LOCF calculation used the modified intention-to-treat population. All analyses excluded measurements after the introduction of rescue medication or after treatment cessation plus 14 days, or both.

Figure 2

Mean seven-point SMPG (mmol/L) at baseline and week 24 or end point with last observation carried forward (LOCF). A: Before and after treatment profiles for the insulin glargine plus metformin (with or without TZDs) plus lixisenatide group. B: Profiles for insulin glargine plus metformin (with or without TZDs) plus placebo. The dashed lines show the profiles at baseline and the solid lines show those after treatment. Values are mean ± SE. Calculations used the modified intention-to-treat population.