FDA approves lixisenatide for type 2 diabetes
In July, the FDA approved lixisenatide (Adlyxin; Sanofi-Aventis), for the treatment of type 2 diabetes in combination with diet and exercise. It is estimated that 29.1 million people in the U.S. have received a diagnosis of type 2 diabetes.
Various therapies exist to treat hyperglycemia associated with diabetes. Lixisenatide is a glucagon-like-peptide-1 receptor agonist (GLP-1 RA): these agents are associated with improved glycemic control, reduced weight, and a limited risk for hypoglycemia. However, lixisenatide significantly decreases postprandial glucose compared with other GLP-1 RAs.1
The approval of lixisenatide was based on the GetGoal clinical program, composed of 13 multinational clinical trials that evaluated lixisenatide against placebo as monotherapy and as adjunct therapy to both oral antidiabetics (OADs) and insulin. More than 5,000 adults were evaluated worldwide.2 GetGoal-Mono Japan3 evaluated lixisenatide in 361 and 69 patients, respectively, as monotherapy. Lixisenatide was evaluated in GetGoal-F1, GetGoal-M, GetGoal-M-Asia, GetGoal-S, and GetGoal-P for combination therapy with OADs.4-8 All studies evaluated patients whose diabetes was inadequately controlled on OADs. GetGoal-F1 and GetGoal-M evaluated 484 and 680 patients, respectively, who were receiving ≥1500 mg/d of metformin. GetGoal-M-Asia evaluated 391 patients receiving between 1000-1500 mg/d of metformin and/or sulfonylurea at a maximum effective dose. GetGoal-S evaluated 859 patients using sulfonylureas, and GetGoal-P evaluated 484 patients receiving pioglitazone, with or without metformin.
GetGoal-Duo 19 evaluated patients previously on OADs who had started taking insulin glargine for 12 weeks but who still had an A1c ≥7% but <9%. GetGoal-L10 evaluated uncontrolled patients on a stable dose of basal insulin with or without metformin ≥1500 mg/d. GetGoal-L-Asia11 evaluated uncontrolledAsian patients on a stable dose of basal insulin with or without a stable dose of a sulfonylurea. GetGoal-X12 compared lixisenatide once daily to exenatide twice daily, another GLP-1 RA, in 634 patients who were previously receiving metformin ≥1500 mg/d. GetGoal-Duo 213 compared lixisenatide to insulin glulisine, a rapid acting prandial insulin, in 894 patients receiving basal insulin with or without OADs where patients had a run-in phase resulting in the discontinuation of all oral agents other than metformin and optimization of insulin glargine.
In GetGoal-Mono, GetGoal-Mono Japan, and GetGoal-F1, patients were randomized into four groups: lixisenatide 10 mcg daily for 1 week, then 15 mcg daily for 1 week, then 20 mcg daily thereafter (2-step); lixisenatide 10 mcg daily for 2 weeks, then 20 mcg daily thereafter (1-step); placebo (2-step); or placebo (1-step). In GetGoal M, GetGoal-M-Asia, GetGoal-S, GetGoal-P, GetGoal-Duo 1, and GetGoal-L, patients were randomized to receive either lixisenatide 20 mcg daily or placebo. GetGoal-M further stratified patients to receive lixisenatide in the morning or evening. GetGoal-L-Asia randomized patients to receive a stepwise dose increase to 20 mcg daily of lixisenatide or placebo. GetGoal-X randomized patients to lixisenatide 20 mcg daily or exenatide 10 mcg twice daily. GetGoal-Duo 2 randomized patients to either lixisenatide 20 mcg daily (after a titration of 10 mcg daily x 2 weeks) or insulin glulisine daily or three times daily.
The primary endpoint for all studies was HbA1c reduction at 12 or 24 weeks. The GetGoal phase III clinical trial program showed that lixisenatide effectively reduced A1c (range: -0.7 to -1.0%), weight (range: -0.2 to -2.96 kg), and 2-hour postprandial glucose of the immediate meal following its administration (range: -3.1 to -7.96 mmol/L).
Lixisenatide is generally well tolerated. The most common adverse events (> 5%of patients) reported in the studies were nausea (25%), vomiting (10%), headache (9%), diarrhea (8%), dizziness (7%), and hypoglycemia (2% as monotherapy, 3% to 47% with combination therapy; more so in combination with basal insulin than OADs). Neither a one-step versus a two-step titration or morning versus evening administration appeared to have a significant impact on the rates of adverse events.