Several studies related to the GetGoal Program involving the investigational glucagon-like peptide (GLP)-1 agonist lixisenatide were presented at the 2012 ADA annual meeting. Glycemic control was improved in patients with type 2 diabetes with once-daily lixisenatide added to various antidiabetes medications, including basal insulin in the GetGoal-L study, pioglitazone in the GetGoal-P study, and insulin glargine and oral agents in the GetGoal Duo 1 study.
More patients achieved hemoglobin (Hb) A1c target levels of <7.0% or ≤6.5% with lixisenatide compared with placebo in these studies. This novel GLP-1 agonist was safe and well tolerated in these 24-week, randomized, double-blind, parallel-group, placebo-controlled, multicenter studies.
GetGoal-L Study
Ronnie Aronson, MD, of the LMC Diabetes & Endocrinology in Toronto, Canada, presented results of the GetGoal-L study. Patients insufficiently controlled with basal insulin, with or without metformin, were randomized to lixisenatide (20 mcg) to placebo once daily after breakfast. The mean HbA1c was 8.4%, and the body mass index was 32.1 kg/m2. Previous insulin therapy (mean, 55 U/day) included glargine, neutral protamine Hagedorn, detemir, and premix. By protocol, the insulin dose was to be reduced by 20% for an HbA1c ≤7.5% to limit hypoglycemia.
At 24 weeks there was a significant reduction in HbA1c, the primary end point, to 7.8% with lixisenatide compared with 8.1% with placebo, from the mean baseline level of 8.4% in both groups. Of the patients receiving lixisenatide, 28% achieved an HbA1c <7.0% compared with 12% of the patients receiving placebo.
Greater reductions with lixisenatide were also found in postprandial glucose (PPG) and body weight. The PPG level 2 hours after breakfast was reduced by 5.54 mmol/L with lixisenatide and by 1.72 mmol/L with placebo, and weight was reduced by 1.80 kg from 87.4 kg and by 0.52 kg from 89.1 kg, respectively.
The frequency of adverse events (AEs) and serious AEs was similar in the 2 groups. Discontinuation because of an AE was 7.6% with lixisenatide, primarily because of gastrointestinal (GI) problems, and 4.8% with placebo.
GetGoal-P Study
The patient population was similar in the GetGoal-P study; patients taking pioglitazone, with or without metformin, were randomized to lixisenatide or to placebo. More than 80% of patients were taking metformin at baseline. The study was presented by Dr Aronson and Michel Pinget, MD, University Hospital of Strasbourg in France.
The HbA1c target <7.0% was achieved by 52.3% of the patients taking lixisenatide and by 26.4% taking placebo. More patients taking lixisenatide (28.9%) also achieved an HbA1c target <6.5% compared with placebo (10.1%).
Other key findings with lixisenatide in GetGoal-P include a significantly larger reduction in fasting plasma glucose (FPG) by 1.16 mmol/L versus 0.32 mmol/L with placebo. Patients receiving lixisenatide lost 0.21 kg in body weight, but those using a placebo gained 0.21 kg.
There was less of a need for rescue therapy by patients receiving lixisenatide (3.8%) compared with 11.3% of patients receiving placebo.
AEs and drug discontinuation were similar in the 2 groups. GI events were the primary cause of the 2.8% drug discontinuation in the patients taking lixisenatide compared with 0.6% in those taking placebo; 6.5% and 5.0% of patients in these groups, respectively, stopped taking their study drug.
GetGoal Duo 1 Study
In the GetGoal Duo 1 study reported by Julio Rosenstock, MD, Director, Dallas Diabetes and Endocrine Center, Texas, targeting PPG glucose with the GLP-1 agonist in patients with uncontrolled type 2 diabetes significantly improved HbA1c levels and reduced PPG level, without affecting weight.
In this randomized, double-blind, multicenter trial, lixisenatide was added to insulin glargine and to oral antidiabetic agents. During the 12-week run-in phase, glargine was titrated to achieve a FPG of 80 to 100 mg/dL. A total of 446 patients with an HbA1c ≥7.5% were evenly randomized to lixisenatide or to placebo once daily in the morning and were followed for 24 weeks. All patients were taking metformin and 12% were receiving a thiazolidinedione. Sulfonylurea therapy was stopped at randomization.
During the randomized follow-up, HbA1c was reduced to 6.96% with lixisenatide and to 7.30% with placebo (P <.001). More patients taking lixisenatide achieved an HbA1c <7.0% (56%) than patients taking placebo (39%).
At study end, FPG values were 6.56 mmol/L and 6.69 mmol/L in the lixisenatide and placebo groups, respectively, and were reduced to 6.70 mmol/L and 6.86 mmol/L, respectively.
A robust reduction in the PPG was seen with lixisenatide, stated Dr Rosenstock. PPG measured 2 hours after a standardized breakfast was reduced with lixisenatide from 13.02 mmol/L at baseline to 9.87 mmol/L at 24 weeks but increased from 12.85 mmol/L to 13.04 mmol/L with placebo.
There was a trend toward greater weight loss with lixisenatide. Only a small increase in the insulin dose was found in both arms, suggesting that the patients could not be titrated, or that there was more potential effect with more aggressive titration, Dr Rosenstock stated.
AEs occurred more frequently (80%) in the lixisenatide group versus placebo (68%) and were the usual GLP-1–related events of nausea and vomiting, which abated as the study progressed. Drug discontinuation because of AEs was higher in the lixisenatide group. Hypoglycemia was more frequent with lixisenatide, but the overall numbers were low.
After treatment, a blood glucose level <60 mg/dL was measured in 26% of the placebo group and in 45% of the lixisenatide group. The number of events per patient annually was 0.44 in the placebo group and 0.80 in the lixisenatide group. Severe hypoglycemia was reported in only 1 patient (in the lixisenatide group).
Dr Rosenstock noted that the composite end points showed more benefit with the GLP-1 receptor. More patients in the lixisenatide than in the placebo group achieved an HbA1c of <7% without hypoglycemia (44% vs 34%, respectively), an HbA1c of <7% without weight gain (34% vs 20%), and an HbA1c of <7% without hypoglycemia or weight gain (28% vs 18%).