Efficacy and Safety of Lixisenatide in Japanese Patients with Type 2 Diabetes Insufficiently Controlled with Basal Insulin±Sulfonylurea: A Subanalysis of the GetGoal-L-Asia Study.

The aim of the study was to evaluate the efficacy and safety of once-daily lixisenatide 20 µg as add-on to basal insulin with or without sulfonylurea in Asian patients with type 2 diabetes mellitus. The study as a subanalysis of the 159 Japanese patients from the 24-week double-blind GetGoal-L-Asia study (NCT00866658) who received once-daily lixisenatide or placebo. The primary endpoint was change from baseline in HbA1c evaluated using analysis of covariance. Once-daily lixisenatide significantly reduced mean HbA1c [least squares mean difference vs. placebo - 1.1% (- 12 mmol/mol); p<0.0001]. Significantly more patients in the lixisenatide group reached HbA1c targets of < 7% (53 mmol/mol; 31.4 vs. 2.3% for placebo; p<0.0001) and ≤ 6.5% (48 mmol/mol; 12.9 vs. 1.2% for placebo; p=0.0028). Lixisenatide significantly reduced 2-h postprandial plasma glucose (least squares mean difference vs. placebo-8.64 mmol/l; p<0.0001), glucose excursion (least squares mean difference vs. placebo - 7.80 mmol/l; p<0.0001) and fasting plasma glucose (least squares mean difference vs. placebo - 0.96 mmol/l; p=0.0126). Body weight was reduced with lixisenatide but with no significant difference vs. placebo. Gastrointestinal adverse events were more frequent with lixisenatide (61.1 vs. 11.5% for placebo) but were generally transient and mild-to-moderate in intensity. The incidence of symptomatic hypoglycemia was 39.0 vs. 13.5% in patients receiving sulfonylureas and 32.3 vs. 22.9% in those not receiving sulfonylureas, for lixisenatide and placebo, respectively. In Japanese patients with type 2 diabetes mellitus, once-daily lixisenatide was well tolerated and led to significant and clinically relevant improvement in glycemic control, with a pronounced effect on postprandial plasma glucose.

Pharmacodynamics of the glucagon-like peptide-1 receptor agonist lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus poorly controlled on sulphonylureas with/without metformin.

AIMS: The PDY6797 study evaluated efficacy, safety and pharmacodynamics of lixisenatide in Japanese and Caucasian patients with type 2 diabetes mellitus (T2DM) insufficiently controlled with sulphonylureas with/without metformin. METHODS: This randomized, double-blind, placebo-controlled trial comprised a single-dose assessment of lixisenatide 5 and 10 µg, and a 5- to 6-week repeated dose-escalation assessment of lixisenatide 5 to 30 µg once (QD) or twice daily (BID). The primary endpoint was change in postprandial plasma glucose (PPG) area under the curve (AUC)[0:29-4:30 h] after a standardized breakfast at the highest tolerated lixisenatide dose. Change from baseline in glycated haemoglobin (HbA1c), 2-h PPG and fasting plasma glucose (FPG) were assessed, as were adverse events. RESULTS: Change from baseline in PPG AUC[0:29-4:30 h] with lixisenatide QD and BID was significantly greater than placebo (p < 0.0001 for all study populations), with particularly prominent effects in Japanese patients. Greater reductions in PPG AUC[0:29-4:30 h] were seen with lixisenatide QD versus BID, while the totality of evidence suggested that the lixisenatide 20 µg dose was optimal. In the overall population, changes from baseline for 2-h PPG, HbA1c and FPG were significant with lixisenatide QD and BID versus placebo (p < 0.01 for all). Lixisenatide was well tolerated. CONCLUSIONS: Lixisenatide significantly reduced PPG AUC[0:29-4:30 h] versus placebo at the highest well-tolerated dose in patients with T2DM treated with sulphonylureas with/without metformin and had a good safety and tolerability profile. Japanese patients experienced particular benefits with lixisenatide in terms of reductions in PPG excursions.

Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1).

AIMS: To assess the efficacy and safety of one- and two-step dose-increase regimens of lixisenatide once daily in participants with Type 2 diabetes mellitus insufficiently controlled with metformin. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre study enrolling participants with Type 2 diabetes (n = 484) treated with metformin. Participants were randomized to receive either lixisenatide in a one-step dose increase or a two-step dose increase vs. placebo for 24 weeks, followed by a ≥ 52-week variable double blind period. Primary outcome was HbA1c reduction at week 24. RESULTS: Lixisenatide one-/two-step once daily significantly improved HbA1c at week 24 compared with placebo (P < 0.0001) and allowed more participants to achieve HbA1c < 53 mmol/mol (< 7.0%) (P ≤ 0.0005). Improvements were observed in fasting plasma glucose (-0.5/-0.6 vs. +0.1 mmol/l; P < 0.001) and body weight (-2.6/-2.7 vs. -1.6 kg; P < 0.005). At week 24, adverse events were reported by 67.7/70.8/65.6% of participants treated with lixisenatide one-/two-step/placebo, respectively--nausea and vomiting being reported most frequently. Symptomatic hypoglycaemia occurred in 1.9/2.5% of participants on one-/two-step lixisenatide and 0.6% with placebo, with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable double-blind extension period of at least 52 weeks. CONCLUSIONS: Lixisenatide one- or two-step dose-increase regimens significantly improved glycaemic control and decreased body weight over 24 weeks and during a long-term extension period without increasing hypoglycaemia. The study confirmed that tolerability in the one-step group was at least similar to the two-step dose increase, with nausea/vomiting and hypoglycaemia frequency being lower in the one-step regimen.

Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P).

AIMS: To compare the efficacy and safety of once-daily prandial lixisenatide with placebo in type 2 diabetes mellitus (T2DM) insufficiently controlled by pioglitazone ± metformin. METHODS: This randomized, double-blind study included a 24-week main treatment period and a ≥52-week variable extension period. Patients were randomized 2 : 1 to receive lixisenatide 20 µg once daily or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) at week 24. RESULTS: In total, 484 patients were randomized: 323 to lixisenatide; 161 to placebo. After 24 weeks, lixisenatide once daily significantly improved HbA1c (-0.56% vs. placebo; p < 0.0001) and increased the proportion of patients achieving HbA1c <7% compared with placebo (52.3% vs. 26.4%, respectively; p < 0.0001) and significantly improved fasting plasma glucose (-0.84 mmol/l vs. placebo; p < 0.0001). There was a small decrease in body weight with lixisenatide once daily and a small increase with placebo, with no statistically significant difference between the two groups. Overall, lixisenatide once daily was well tolerated, with a similar proportion of treatment-emergent adverse events (TEAEs) and serious TEAEs between groups (lixisenatide: 72.4% and 2.5%; placebo: 72.7% and 1.9%). Symptomatic hypoglycaemia rates were also relatively low in both groups (lixisenatide 3.4% and placebo 1.2%), with no severe episodes. Lixisenatide continued to be efficacious and well tolerated during the variable extension period. CONCLUSIONS: Lixisenatide once daily significantly improved glycaemic control with a low risk of hypoglycaemia, and was well tolerated over 24 weeks and during the long-term, double-blind extension period in patients with T2DM insufficiently controlled on pioglitazone ± metformin.

Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia).

AIMS: To assess the efficacy and safety of once-daily lixisenatide versus placebo in Asian patients with type 2 diabetes insufficiently controlled on basal insulin ± sulfonylurea. METHODS: In this 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicentre study, participants (mean baseline HbA(1c) 8.53%) from Japan, Republic of Korea, Taiwan and the Philippines received lixisenatide (n = 154) or placebo (n = 157) in a stepwise dose increase to 20 µg once daily. The primary endpoint was HbA(1c) change from baseline to week 24. RESULTS: Once-daily lixisenatide significantly improved HbA(1c) versus placebo (LS mean difference vs. placebo = -0.88% [95%CI= -1.116, -0.650]; p < 0.0001), and allowed more patients to achieve HbA(1c) <7.0% (35.6 vs. 5.2%) and ≤ 6.5% (17.8 vs. 1.3%). Lixisenatide also significantly improved 2-h postprandial plasma glucose and glucose excursion, average 7-point self-monitored blood glucose and fasting plasma glucose. Lixisenatide was well tolerated; 86% of patients on lixisenatide completed the study versus 92% on placebo. Ten (6.5%) lixisenatide and 9 (5.7%) placebo patients experienced serious adverse events. More lixisenatide patients [14 (9.1%)] discontinued for adverse events versus placebo [5 (3.2%)], mainly with gastrointestinal causes. Nausea and vomiting were reported in 39.6 and 18.2% of patients on lixisenatide versus 4.5 and 1.9% on placebo. Symptomatic hypoglycaemia was more frequent with lixisenatide (42.9%) versus placebo (23.6%), but was similar between groups (32.6 vs. 28.3%, respectively), in those not receiving sulfonylureas. No severe hypoglycaemia was reported. CONCLUSIONS: In an Asian type 2 diabetes population insufficiently controlled by basal insulin ± sulfonylurea, once-daily lixisenatide significantly improved glycaemic control, with a pronounced postprandial effect, and was well tolerated.