Chronic obstructive pulmonary disease (COPD) induces serious social and economic burdens due to its high disability and mortality, the pathogenesis of which is highly involved with inflammation, oxidative stress (OS), and mechanism of mucin 5AC (MUC5AC) secretion. Lixisenatide is a selective glucagon-like peptide 1 receptor agonist recently reported to have anti-inflammatory properties. Our study will focus on the potential impact of lixisenatide on lipopolysaccharide (LPS)-induced mucin secretion and inflammation in 16 human bronchial epithelial (16HBE) cells to check its potential function in COPD. 16HBE cells were treated with LPS, with or without lixisenatide (10 and 20 nM) for 1 day. Remarkably declined cell viability, enhanced lactate dehydrogenase release, activated OS, and elevated release of inflammatory cytokines were observed in LPS-treated 16HBE cells, accompanied by the activation of nuclear factor-κB signaling, all of which were signally reversed by lixisenatide. Moreover, elevated expression and release of MUC5AC were observed in LPS-treated 16HBE cells but were markedly repressed by lixisenatide. Furthermore, the repressed nuclear factor erythroid 2-related factor 2 (Nrf2) level in LPS-treated 16HBE cells was notably rescued by lixisenatide. Lastly, following the knockdown of Nrf2, the protective function of lixisenatide on LPS-triggered MUC5AC release in 16HBE cells was significantly abrogated. Collectively, lixisenatide ameliorated LPS-induced expression of mucin and inflammation in bronchial epithelial cells by regulating Nrf2.

BACKGROUND: The Chinese Diabetes Society recommends basal insulin and glucagon-like peptide-1 receptor agonists as an add-on therapy to first-line oral antihyperglycemic drugs for people with type 2 diabetes (T2D). Fixed-ratio combination of insulin glargine 100 U/ml (iGlar) and lixisenatide (iGlarLixi) is known to improve glycemic control in adults with T2D. However, the pharmacokinetics of iGlarLixi has not been evaluated in Chinese participants. The present study evaluated pharmacokinetics and safety of two iGlarLixi (10 U/10 μg and 30 U/15 μg) doses following single subcutaneous administration in healthy Chinese participants.
METHODS: This was a Phase 1, single-center, open-label, parallel-group, randomized study in healthy Chinese adults who were randomized to receive a single dose of iGlarLixi with either 1:1 (10 U/10 μg) or 2:1 (30 U/15 μg) ratio of iGlar and lixisenatide. Primary objectives include assessment of pharmacokinetics of iGlar in iGlarLixi 30 U/15 μg group and the pharmacokinetics of lixisenatide in both the groups (iGlarLixi 10 U/10 μg and iGlarLixi 30 U/15 μg). Safety and tolerability were also assessed.
RESULTS: In iGlarLixi 30 U/15 μg group, iGlar concentrations were low and quantifiable in three of ten participants, while its main metabolite (M1) was quantifiable in all participants, reflecting rapid conversion of iGlar to M1. Median INS-tmax was 14.00 h for iGlar and 13.00 h post-dose for M1. Absorption of lixisenatide was similar in both dose groups with median tmax of 3.25 and 2.00 h post-dose in both groups. The exposure increase was dose proportionate with a 1.5-fold increase in the lixisenatide dose. Adverse events observed were consistent with those previously reported with iGlar or lixisenatide.
CONCLUSIONS: iGlarLixi administration resulted in early absorption of both iGlar and lixisenatide with a good tolerability profile in healthy Chinese participants. These results are consistent with the previously published data from other geographic regions.
BACKGROUND: U1111-1194-9411.

To evaluate the efficacy of iGlarLixi in the Asian Pacific (AP) population with type 2 diabetes (T2D) using derived time-in-ranges calculated from seven-point self-measured blood glucose.
Two phase III trials were analysed. LixiLan-O-AP was performed in insulin-naive T2D patients (n = 878) randomized to iGlarLixi, glargine 100 units/mL (iGlar) or lixisenatide (Lixi). LixiLan-L-CN was performed in insulin-treated T2D patients (n = 426) randomized to iGlarLixi or iGlar. Changes in derived time-in-ranges from baseline to end-of-treatment (EOT) and estimated treatment differences (ETDs) were analysed. The proportions of patients achieving 70% or higher derived time-in-range (dTIR), 5% or higher dTIR improvement, and the composite triple target (≥ 70% dTIR, < 4% derived time-below-the-range [dTBR] and < 25% derived time-above-the-range [dTAR]) were calculated.
The changes from baseline to EOT in dTIR with iGlarLixi were greater versus iGlar (ETD1 : 11.45% [95% CI, 7.66% to 15.24%]) or Lixi (ETD2 : 20.54% [95% CI, 15.74% to 25.33%]) in LixiLan-O-AP, and versus iGlar (ETD: 16.59% [95% CI, 12.09% to 21.08%]) in LixiLan-L-CN. In LixiLan-O-AP, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT with iGlarLixi were 77.5% and 77.8%, respectively, higher than with iGlar (61.1% and 75.3%) or Lixi (47.0% and 53.0%). In LixiLan-L-CN, the proportions of patients achieving 70% or higher dTIR or 5% or higher dTIR improvement at EOT were 71.4% and 59.8% with iGlarLixi, greater than with iGlar (45.4% and 39.5%). More patients achieved the triple target with iGlarLixi compared with iGlar or Lixi.
iGlarLixi achieved greater improvements in dTIR parameters versus iGlar or Lixi in insulin-naïve and insulin-experienced AP people with T2D.

BACKGROUND: This analysis investigated the efficacy and safety of add-on lixisenatide by disease duration in Asian people with type 2 diabetes inadequately controlled with basal insulin ± oral antidiabetic drugs.
METHODS: Data for Asian participants in the GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C studies were pooled and categorized by diabetes duration: < 10 years (group 1), 10 to < 15 years (group 2), and ≥ 15 years (group 3). Efficacy and safety of lixisenatide versus placebo were evaluated by subgroup. The potential influence of diabetes duration on efficacy was examined using multivariable regression analyses.
RESULTS: A total of 555 participants were included (mean age 53.9 years, 52.4% male). No significant differences in treatment effect between the duration subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), PPG excursion, body weight or body mass index, or the proportion of participants with HbA1c < 7% at 24 weeks (all P values for interaction > 0.1). Change in insulin dosage (U/day) was significantly different between subgroups (P = 0.038). Multivariable regression analysis showed participants in group 1 had a smaller change in body weight and basal insulin dose over the 24-week treatment period than participants in group 3 (P = 0.014 and 0.030, respectively) and were less likely to achieve an HbA1c < 7% than participants in group 2 (P = 0.047). No severe hypoglycemia was reported. A higher proportion of participants in group 3 versus the other groups had symptomatic hypoglycemia, for both lixisenatide and placebo, and T2D duration had a significant effect on hypoglycemia risk (P = 0.001).
CONCLUSIONS: Lixisenatide improved glycemic control in Asian individuals regardless of diabetes duration, without increasing the risk of hypoglycemia. Individuals with longer disease duration had a greater risk of symptomatic hypoglycemia than individuals with shorter disease duration regardless of treatment. No additional safety concerns were observed.
BACKGROUND: GetGoal-Duo 1, ClinicalTrials.gov record NCT00975286; GetGoal-L, ClinicalTrials.gov record NCT00715624; GetGoal-L-C, ClinicalTrials.gov record NCT01632163.

The preferable choice of sustained peptide delivery systems is generally polymer-based microspheres in which their large particle size, wide size distribution, low drug encapsulation efficacy, poor colloidal stability, and undesirable burst release eventually hinder their clinical translation. In this study, a nanoscale ternary Lixisenatide (Lix) sustained delivery system based on strong multivalent interactions (electrostatic and coordination complexation) among small molecular phytic acid (PA), Lix and Fe3+ was developed. Flash nanocomplexation (FNC) was utilized to facilitate the rapid and efficient mixing of the three components and kinetically control the assembly process that enabled dynamic balance of two competitive chemical reactions with different kinetic rates (slow chemical reaction of PA/Lix and fast chemical reaction of PA/Fe3+) to generate structural uniform ternary nanoparticles and avoid heterogeneous complexes. By tuning the mixing conditions (i.e., flow rate, mass ratio, concentration, pH value, etc.), the ternary PA/Lix/Fe3+ nanoparticles were assembled with reproducible production in a manner of high uniformity and scalability, achieving small size (∼50 nm), uniform composition (PDI: ∼0.12), favourable colloidal stability, high encapsulation efficiency (∼100%), and tunable drug release kinetics. The optimized formulation exhibited a minor Lix release (<20%) in the first day and extended peptide release period over 8 days. Unexpectedly, upon a single injection administration, the as-prepared formulation (600 μg/kg) rapidly brought the high BGL (∼30 mmol/L) back to normal range (<10 mmol/L) within the initial 6 h and achieved a 180 h glycemic control in T2D mouse model. Moreover, this sustained peptide delivery system demonstrated a repeatable hypoglycemic effects and significantly suppressed the pathological damage of major organs following multiple injection. This sustained peptide delivery system with aqueous, facile and reproducible preparation process possesses good biocompatibility, tunable release kinetics, and prolonged hypoglycemic effects, portending its great translational potential in the chronic disease treatment.

OBJECTIVE: The prevalence and pathophysiological background of type 2 diabetes mellitus vary across ethnicities, and can affect treatment responses. Adding lixisenatide to basal insulin (BI) in type 2 diabetes mellitus patients has shown improvements in glycated hemoglobin (HbA1c) and postprandial glycemic (PPG) excursions, without increasing hypoglycemic events. We aim to compare the efficacy of lixisenatide in Asian and white patients inadequately controlled with basal insulin.
METHODS: An individual-level pooled analysis of two multi-national phase III studies, GetGoal-L and GetGoal-L-C, was carried out to assess the efficacy of lixisenatide versus placebo as an add-on treatment to BI ± metformin in Asian and white patients with type 2 diabetes mellitus. Change in HbA1c, 2-h PPG and PPG excursion were analyzed, along with possible predictors of glycemic control.
RESULTS: Pooled data showed that baseline characteristics were similar between Asian and white patients with the exception of bodyweight, body mass index and BI dose being higher in white patients. After 24 weeks, lixisenatide reduced HbA1c in both ethnic groups, with no statistically significant difference between the two groups (Asian patients least squares mean difference -0.49, 95% confidence interval -0.68 to - 0.30 and white patients least squares mean difference -0.45, 95% confidence interval -0.63 to - 0.26; P = 0.6287). Similarly, no significant difference was found in 2-h PPG reduction between both groups (least squares mean difference for Asian vs white patients: -3.37 vs -3.93; P = 0.3203). Treatment with lixisenatide contributed to HbA1c reduction of -0.56% after adjustment of baseline HbA1c level in Asian patients, and -0.41% in white patients.
CONCLUSIONS: Adding lixisenatide to BI significantly reduced HbA1c and 2-h PPG levels in both Asian and white participants with type 2 diabetes mellitus. No differences in treatment effect were observed between the two populations.

Convergent lines of evidence indicate a striking correlation between olfactory deficits and depressive symptoms. However, the effectiveness of intranasal treatment of antidepressant or other neurotrophic agents remains poorly understanding. Here in this study, we created depression mouse model and explored the antidepressant effects of GLP-1 analog lixisenatide (LXT) with intranasal treatment. Consecutive intranasal treatment of LXT remarkably reduced the depressive and anxiety behaviors. Meanwhile, it also improved the olfactory memory and olfactory sensitivity. Immunofluorescent analysis demonstrated the LXT improved the adult neurogenesis in olfactory system and hippocampus. Inhibition of adult neurogenesis with TMZ caused the compromised effects of LXT in improving emotional and olfactory functions, suggesting the vital role of adult neurogenesis in LXT induced depression therapeutic effects. Treatment of LXT resulted in the increased phosphorylation of CREB protein in hippocampal tissue, indicating CREB plays important roles in antidepressant effects of LXT intranasal treatment. Inhibiting CREB with chemical approach decreased effects of LXT in reserving depression induced emotional and olfactory functions. In conclusion, our study suggests intranasal treatment of LXT could be a potential antidepressant to improve the olfactory functions as well as the emotional behaviors.

Objective: To compare the cost per responder of lixisenatide versus insulin glulisine once daily (basal-plus) and three times daily (basal-bolus) on top of basal insulin for the treatment of patients with type 2 diabetes mellitus (T2DM) inadequately controlled by basal insulin in China.Methods: The cost per responder was estimated based on clinical data obtained from the GetGoal Duo-2 clinical trial and direct medical costs from the perspective of the Chinese healthcare system over a 52-week time horizon. The response was assessed at week 26 in the clinical trial, which was extrapolated to 52 weeks to estimate the annual cost per responder. Responders were primarily defined using a composite endpoint that based on an HbA1c ≤ 7.0% threshold AND no weight gain With or Without no documented symptomatic hypoglycemia. Composite endpoints with varied HbA1c thresholds were defined in secondary analyses.Results: For the composite endpoint of HbA1c threshold ≤7.0% AND no weight gain, the annual cost per responder results were 96,722 CNY, 122,552 CNY and 135,926 CNY (14,616, 18,520 and 20,541 US dollars) for lixisenatide combined with basal insulin, basal-plus, and basal-bolus, respectively. For the composite endpoint of HbA1c threshold ≤7.0% AND no weight gain AND no documented symptomatic hypoglycemia, the annual cost per responder results were 136,290 CNY, 231,487 CNY and 222,424 CNY (20,596, 34,982 and 33,612 US dollars) for lixisenatide combined with basal insulin, basal-plus, and basal-bolus, respectively. The secondary analyses proved similar results.Conclusion: Lixisenatide combined with basal insulin is associated with a lower cost per responder compared with basal-plus and basal-bolus for T2DM patients inadequately controlled by basal insulin in China.

Diabetes and its complications have become a global challenge of public health. Herein, we aimed to develop a long-acting delivery system of lixisenatide (Lixi), a glucose-dependent antidiabetic peptide, based on an injectable hydrogel for the synchronous treatment of type 2 diabetes mellitus (T2DM) and associated complications. Two triblock copolymers, poly(ε-caprolactone-co-glycolic acid)-poly(ethylene glycol)-poly(ε-caprolactone-co-glycolic acid) and poly(d,l-lactic acid-co-glycolic acid)-poly(ethylene glycol)-poly(d,l-lactic acid-co-glycolic acid) possessing temperature-induced sol-gel transitions, were synthesized by us. Compared to the two single-component hydrogels, their 1/1 mixture hydrogel not only maintained the temperature-induced gelation but also exhibited a steadier degradation profile in vivo. Both in vitro and in vivo release studies demonstrated that the mixture hydrogel provided the sustained release of Lixi for up to 9 days, which was attributed to balanced electrostatic interactions between the positive charges in the peptide and the negative charges in the polymer carrier. The hypoglycemic efficacy of Lixi delivered from the mixture hydrogel after a single subcutaneous injection into diabetic db/db mice was comparable to that of twice-daily administrations of Lixi solution for up to 9 days. Furthermore, three successive administrations of the abovementioned gel system within a month significantly increased the plasma insulin level, lowered glycosylated hemoglobin, and improved the pancreatic function of the animals. These results were superior or equivalent to those of twice-daily injections of Lixi solution for 30 days, but the number of injections was markedly reduced from 60 to 3. Finally, an improvement in hyperlipidemia, augmentation of nerve fiber density, and enhancement of motor nerve conduction velocity in the gel formulation-treated db/db mice indicated that the sustained delivery of Lixi arrested and even ameliorated diabetic complications. These findings suggested that the Lixi-loaded mixture hydrogel has great potential for the treatment of T2DM with significant improvements in the health and quality of life of patients.

Rheumatoid arthritis (RA) is a major debilitating systemic disease characterized by chronic inflammation of the synovium and joint destruction. Despite major advancements in our understanding of RA in recent decades, it remains a disease of unknown etiology. To our knowledge, this is the first study exploring the effects of agonism of the glucagon-like peptide-1 (GLP-1) receptor using lixisenatide, a licensed drug used for the treatment of type II diabetes, on the pathological characteristics of RA in human fibroblast-like synoviocytes. Our findings indicate that lixisenatide inhibited the inflammatory response through downregulation of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and interleukin-8 (IL-8); inhibition of matrix metalloproteinases (MMPs); and blockade of cellular signaling pathways, including the c-Jun N-terminal kinase (JNK), activator protein 1 (AP-1), and nuclear factor κ B (NF-κB) pathways. Furthermore, lixisenatide improved oxidative stress, rescued mitochondrial membrane potential (ΔΨm), and prevented cell death in fibroblast-like synoviocytes. These findings suggest that agonism of the GLP-1 receptor using lixisenatide may serve as a novel therapeutic option for the treatment and prevention of RA.