Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono)

OBJECTIVE

To assess efficacy and safety of lixisenatide monotherapy in type 2 diabetes.

RESEARCH DESIGN AND METHODS

Randomized, double-blind, 12-week study of 361 patients not on glucose-lowering therapy (HbA_1c 7–10%) allocated to one of four once-daily subcutaneous dose increase regimens: lixisenatide 2-step (10 μg for 1 week, 15 μg for 1 week, and then 20 μg; n = 120), lixisenatide 1-step (10 μg for 2 weeks and then 20 μg; n = 119), placebo 2-step (n = 61), or placebo 1-step (n = 61) (placebo groups were combined for analyses). Primary end point was HbA_1c change from baseline to week 12.

RESULTS

Once-daily lixisenatide significantly improved HbA_1c (mean baseline 8.0%) in both groups (least squares mean change vs. placebo: −0.54% for 2-step, −0.66% for 1-step; P < 0.0001). Significantly more lixisenatide patients achieved HbA_1c <7.0% (52.2% 2-step, 46.5% 1-step) and ≤6.5% (31.9% 2-step, 25.4% 1-step) versus placebo (26.8% and 12.5%, respectively; P < 0.01). Lixisenatide led to marked significant improvements of 2-h postprandial glucose levels and blood glucose excursions measured during a standardized breakfast test. A significant decrease in fasting plasma glucose was observed in both lixisenatide groups versus placebo. Mean decreases in body weight (∼2 kg) were observed in all groups. The most common adverse events were gastrointestinal—nausea was the most frequent (lixisenatide 23% overall, placebo 4.1%). Symptomatic hypoglycemia occurred in 1.7% of lixisenatide and 1.6% of placebo patients, with no severe episodes. Safety/tolerability was similar for the two dose regimens.

CONCLUSIONS

Once-daily lixisenatide monotherapy significantly improved glycemic control with a pronounced postprandial effect (75% reduction in glucose excursion) and was safe and well tolerated in type 2 diabetes.In recent years, the use of glucagon-like peptide 1 (GLP-1) receptor agonists has become established as an important therapeutic option in the management of patients with type 2 diabetes (1,2). As a class, GLP-1 receptor agonists possess a number of favorable clinical characteristics in addition to their glucose-lowering effects, including a low propensity to cause hypoglycemia (as a result of their glucose-dependent action) and promotion of weight loss (3,4). Preclinical studies using in vitro and animal models also suggest that GLP-1 receptor agonists have the potential to preserve pancreatic islet β-cells, which may help to provide more stable metabolic control long term (5). As of today, three representatives of the GLP-1 receptor agonist class have been marketed: exenatide (twice-daily and once-weekly formulations) and liraglutide once daily.Lixisenatide (AVE0010) is a new selective once-daily GLP-1 receptor agonist in development for the treatment of type 2 diabetes mellitus (6–8). It is a 44-amino acid peptide that is amidated at the C-terminal end and shares some structural elements with exendin-4 (the main difference being the addition of 6 lysine residues at the C terminus) (9). Lixisenatide is highly selective for the GLP-1 receptor and exerts about fourfold higher affinity for the GLP-1 receptor than native human GLP-1 (9). The preclinical pharmacological profile of lixisenatide suggests that stimulation of insulin secretion by lixisenatide is strictly glucose dependent. In animal models, lixisenatide enhances insulin biosynthesis and stimulation of β-cell proliferation and delays gastric emptying and reduces food intake (9). In human islets, lixisenatide prevents lipotoxic islet insulin depletion and preserves insulin production, storage, and pancreatic β-cell function (9). Lixisenatide undergoes renal metabolism, but mild or moderate renal impairment does not appear to influence its pharmacokinetics or tolerability (10).In a 13-week, randomized, double-blind, placebo-controlled, parallel-group, phase II dose-ranging study, lixisenatide administered at doses of 5, 10, 20, or 30 μg once daily or twice daily in patients with type 2 diabetes inadequately controlled with metformin significantly improved HbA_1c compared with placebo (8). Dose-dependent improvements were also observed for fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) associated with the morning meal and average self-monitored seven-point blood glucose levels (7). The dose of 20 μg administered once daily was found to provide the optimal balance of efficacy and tolerability (8).Accordingly, in this Phase III study, we assessed the safety and efficacy of 20 μg lixisenatide once daily in a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group monotherapy trial in patients with type 2 diabetes not currently receiving glucose-lowering therapy.