Glucagon-like Peptide-1 Receptor Agonist Lixisenatide Research Articles

The effect of GLP-1 receptor agonist lixisenatide on experimental diabetic retinopathy.

Glucagon-like peptide-1 receptor agonists are effective treatments for type 2 diabetes, effectively lowering glucose without weight gain and with low risk for hypoglycemia. However, their influence on the retinal neurovascular unit remains unclear. In this study, we analyzed the effects of the GLP-1 RA lixisenatide on diabetic retinopathy. Vasculo- and neuroprotective effects were assessed in experimental diabetic retinopathy and high glucose-cultivated C. elegans, respectively. In STZ-diabetic Wistar rats, acellular capillaries and pericytes (quantitative retinal morphometry), neuroretinal function (mfERG), macroglia (GFAP western blot) and microglia (immunohistochemistry) quantification, methylglyoxal (LC-MS/MS) and retinal gene expressions (RNA-sequencing) were determined. The antioxidant properties of lixisenatide were tested in C. elegans. Lixisenatide had no effect on glucose metabolism. Lixisenatide preserved the retinal vasculature and neuroretinal function. The macro- and microglial activation was mitigated. Lixisenatide normalized some gene expression changes in diabetic animals to control levels. Ets2 was identified as a regulator of inflammatory genes. In C. elegans, lixisenatide showed the antioxidative property. Our data suggest that lixisenatide has a protective effect on the diabetic retina, most likely due to a combination of neuroprotective, anti-inflammatory and antioxidative effects of lixisenatide on the neurovascular unit.

Pharmacokinetics of Lixisenatide, a GLP-1 Receptor Agonist, Determined by a Novel Liquid Chromatography–Tandem Mass Spectrometry Analysis in Rats

Because of its greater binding affinity and longer half-life than native glucagon-like peptide-1 (GLP-1), the GLP-1 receptor agonist lixisenatide is commonly used to treat type 2 diabetes mellitus. This study aimed to establish a simple and robust liquid chromatography–tandem mass spectrometry (LC–MS/MS) approach for lixisenatide for in vivo pharmacokinetic investigation. Methanol-based protein precipitation with formic acid was exploited for plasma sample extraction, using esomeprazole as the internal standard. Gradient elution with 0.1% formic acid in distilled water and acetonitrile was utilized for chromatographic separation. Mass spectrometry was used to monitor the MRM transition at m/z 810.8 → 129.2 for lixisenatide. In rat plasma, lixisenatide had a lower limit of quantification of 10 ng/mL. The LC–MS/MS was applied to describe the pharmacokinetics of lixisenatide in rats following intravenous and subcutaneous dosing. The average half-life of lixisenatide was 0.37 ± 0.06 h after intravenous injection. The estimated subcutaneous bioavailability of lixisenatide was 2.17%. This LC–MS/MS analysis might be relevant in future research to create novel dosage formulations of lixisenatide and other GLP-1 receptor agonists with optimal therapeutic effectiveness.

Findings for iGlarLixi versus BIAsp 30 confirmed in groups of people with type 2 diabetes with different biomedical characteristics.

To report prespecified and post hoc analyses of the SoliMix dataset exploring the impact of baseline participant characteristics on the original SoliMix study outcomes, to enable informed treatment choices for people with different biomedical characteristics. SoliMix (EudraCT 2017-003370-13) compared once-daily iGlarLixi (a fixed-ratio combination of insulin glargine 100 U/mL and the glucagon-like peptide-1 receptor agonist lixisenatide) with twice-daily BIAsp 30 (30% insulin aspart and 70% insulin aspart protamine). In this analysis, the original primary outcomes of noninferiority of iGlarLixi versus BIAsp 30 in terms of glycated haemoglobin (HbA1c) change and superiority in terms of body weight change, together with change in basal insulin dose and hypoglycaemia outcomes, were investigated by baseline age, duration of diabetes, insulin dose, HbA1c level, body mass index (BMI), and renal function. No evidence of difference in comparative treatment effect was detected across baseline age, duration of diabetes, insulin dose, HbA1c level, BMI and renal function subgroups for any endpoint (all heterogeneity P> 0.05), except American Diabetes Association Level 2 hypoglycaemia event rate when stratified by insulin dose (P= 0.011), which may be a chance difference given multiple testing and the small numbers of Level 2 events. Treatment effects of iGlarLixi were consistent irrespective of baseline HbA1c, insulin dose, BMI, age, duration of diabetes and renal function, supporting the use of iGlarLixi as an efficacious and well-tolerated treatment option in people with type 2 diabetes with a wide range of biomedical characteristics.

Use of iGlarLixi for Management of Type 2 Diabetes in Japanese Clinical Practice: SPARTA Japan, a Retrospective Observational Study.

Many individuals with type 2 diabetes (T2D) experience suboptimal glycemic control. Treatment intensification options include fixed-ratio combination products containing a basal insulin and a glucagon-like peptide-1 receptor agonist, such as iGlarLixi (insulin glargine 100U/mL and lixisenatide). This study aimed to provide real-world evidence of the effect of iGlarLixi in Japanese clinical practice. SPARTA Japan was a non-comparative, observational study conducted at 27 institutions in Japan. Anonymized individual-level data from adults with T2D receiving iGlarLixi in routine clinical practice were retrospectively collected. The primary study objective was to assess the impact of iGlarLixi on the change in glycated hemoglobin (HbA1c) at 6months' post-treatment initiation, with preplanned subanalyses to determine the influence of baseline characteristics. Secondary and exploratory endpoints included assessment of the proportion of individuals achieving HbA1c targets, change in body weight, and incidence and severity of hypoglycemia and gastrointestinal events. The full analysis set included 432 individuals, with data available at 6months for 426. Of the 432 individuals, the mean (SD) age at baseline was 61.6 (12.8) years and the majority had a T2D duration of ≥ 10years [mean (SD) 13.3 (10.4) years]. At 6months, HbA1c had significantly decreased versus baseline ( -0.85%; P < 0.0001), with a greater decrease in those aged < 65years, with a shorter duration of T2D and higher baseline HbA1c. A significant increase in the proportion of participants achieving age-specific HbA1c versus baseline was observed. Mean body weight decreased by 0.5kg (P = 0.0034 versus baseline). There were few hypoglycemia and gastrointestinal events (in individuals with HbA1c data); no severe hypoglycemic events were reported. The results of this real-world study indicate that iGlarLixi may improve glycemic control without serious adverse events in Japanese individuals with T2D who have suboptimal glycemic control on current treatment regimens and switch to iGlarLixi. UMIN-CTR Trials Registry, UMIN000044126; registered 10 May 2021.

Acute Administration of the GLP-1 Receptor Agonist Lixisenatide Diminishes Postprandial Insulin Secretion in Healthy Subjects But Not in Type2 Diabetes, Associated with Slowing of Gastric Emptying.

IntroductionIt is uncertain whether lixisenatide has postprandial insulinotropic effects when its effect on slowing gastric emptying is considered, in healthy subjects and type 2 diabetes mellitus (T2DM). We evaluated the effects of single administration of 10 μg sc lixisenatide on glycaemia, insulin secretion and gastric emptying (GE), measured using the ‘gold standard’ technique of scintigraphy following an oral glucose load (75 g glucose).MethodsFifteen healthy subjects (nine men, six women; age 67.2 ± 2.3 years) and 15 patients with T2DM (nine men, six women; age 61.9 ± 2.3 years) had measurements of GE, plasma glucose, insulin and C-peptide for 180 min after a radiolabeled 75 g glucose drink on two separate days. All subjects received lixisenatide (10 μg sc) or placebo in a randomised, double-blind, crossover fashion 30 min before the drink. Insulin secretory response (ISR) was determined using the C-peptide deconvolution method.ResultsGE was markedly slowed by lixisenatide compared with placebo in both healthy subjects (1.45 ± 0.10 kcal/min for placebo vs. 0.60 ± 0.14 kcal/min for lixisenatide) and diabetes (1.57 ± 0.06 kcal/min for placebo vs. 0.75 ± 0.13 kcal/min for lixisenatide) (both P < 0.001) with no difference between the two groups (P = 0.42). There was a moderate to strong inverse correlation between the early insulin secretory response calculated at 60 min and gastric retention at 60 min with lixisenatide treatment in healthy subjects (r = − 0.8, P = 0.0003) and a trend in type 2 diabetes (r = − 0.4, P = NS), compared with no relationships in the placebo arms (r = − 0.02, P = NS, healthy subjects) and (r = − 0.16, P = NS, type 2 diabetes).ConclusionThe marked slowing of GE of glucose induced by lixisenatide is associated with attenuation in the rise of postprandial glucose in both healthy subjects and diabetes and early insulin secretory response in healthy subjects.Clinical Trials Registration NumberNCT02308254.

Statement of Retraction

This article refers to:RETRACTED ARTICLE: GLP-1 receptor agonist lixisenatide protects against high free fatty acids-induced oxidative stress and inflammatory response

Glucagon-like peptide-1 receptor agonists, selection within the class. The rational combination of insulin glargine 100 + lixisenatide

Type 2 diabetes mellitus (T2DM) is a progressive disease accompanied by a gradual worsening of β-cell function. With a long course of T2DM, a significant proportion of patients develop absolute insulinopenia and there is a need to transfer the patient from oral hypoglycemic drugs (OHD) to basal insulin therapy in combination with OHD or to the basal-bolus regimen of insulin therapy (IT). More than 80% of patients with T2DM are obese or overweight and the addition of insulin, which is a lipogenetic hormone, to the therapy contributes to even greater weight gain, which serves as a prerequisite for increasing cardiovascular risks, as well as the appearance and progression of biomechanical problems such as arthrosis of the joints, venous insufficiency. In this review article, we will consider and evaluate the benefits of administering combinations of basal insulin glargine in combination with glucagonlike peptide-1 receptor agonists (GLP-1ra) lixisenatide to one of the most rational treatment regimens for patients with T2DM insulin deficiency and persistent insulin resistance. Also, the article focuses on the variability of glycemia, which according to research can play an important role in the pathogenesis of atherosclerosis and can be an independent risk factor for cardiovascular complications in patients with diabetes. Due to the fact that glycemic control is based on the determination of predominantly glycated hemoglobin (HbA1c) as a measure of average glucose concentration, it is known that this marker does not accurately reflect glycemic variability, which is characterized by the amplitude, frequency and duration of hypo- and hyperglycemic fluctuations. A fixed combination of insulin preparations glargin 100 and GLP-1ra lixisenatide allows to select individually effective dosage for a patient with type 2 diabetes and obesity, will help to achieve several goals at the same time - from improving glycemic parameters without increasing body weight and without increasing the risk of hypoglycemia, to significantly reduce the need for insulin with its previous use, as well as reduce the risk of cardiovascular complications.

The GLP-1 receptor agonist lixisenatide reduces postprandial glucose in patients with diabetes secondary to total pancreatectomy: a randomised, placebo-controlled, double-blinded crossover trial.

Treatment of diabetes secondary to total pancreatectomy remains a challenge and insulin constitutes the only glucose-lowering treatment for these patients. We hypothesised that the glucagon-like peptide 1 (GLP-1) receptor agonist lixisenatide would improve postprandial glucose tolerance in totally pancreatectomised patients. In a double-blinded, randomised, crossover study, 12 totally pancreatectomised individuals (age: 65.0 ± 9.5 mean±SD years; BMI: 22.9 ± 3.9kg/m2) and 12 healthy control individuals (age 66.1 ± 7.6years; BMI: 24.0 ± 2.9kg/m2) underwent two 3h liquid mixed-meal tests (with paracetamol for assessment of gastric emptying) after single-dose injection of 20μg of lixisenatide or placebo. Basal insulin was given the night before each experimental day; no insulin was given during study days. Compared with placebo, lixisenatide reduced postprandial plasma glucose excursions in the pancreatectomy group (baseline-subtracted AUC [bsAUC] [mean±SEM]: 548 ± 125 vs 1447 ± 95mmol/l × min, p < 0.001) and in the control group (-126 ± 12 vs 222 ± 51mmol/l × min, p < 0.001). In the pancreatectomy group a mean peak glucose concentration of 23.3 ± 1.0mmol/l was reached at time point 134 ± 11min with placebo, compared with a mean peak glucose concentration of 18 ± 1.4mmol/l (p = 0.008) at time point 148 ± 13min (p = 0.375) with lixisenatide. In the control group a mean peak concentration of 8.2 ± 0.4mmol/l was reached at time point 70 ± 13min with placebo, compared with a mean peak concentration of 5.5 ± 0.1mmol/l (p < 0.001) at time point 8 ± 25min (p = 0.054) with lixisenatide. Lixisenatide also reduced gastric emptying and postprandial glucagon responses in the pancreatectomy group (66 ± 84 vs 1190 ± 311pmol/l × min, p = 0.008) and in the control group (141 ± 100 vs 190 ± 100pmol/l × min, p = 0.034). In the pancreatectomy group, C-peptide was undetectable in plasma. In the control group, postprandial plasma C-peptide responses were reduced with lixisenatide (18 ± 17 vs 189 ± 31nmol/l × min, p < 0.001). The GLP-1 receptor agonist lixisenatide reduces postprandial plasma glucose excursions in totally pancreatectomised patients. The mode of action seems to involve deceleration of gastric emptying and reduced postprandial responses of gut-derived glucagon. ClinicalTrials.gov NCT02640118. This study was funded by an unrestricted investigator-initiated study grant from Sanofi. Support was also received from from the Novo Nordisk Foundation Center for Basic Metabolic Research, the A.P. Møller Foundation for the Advancement of Medical Science and the Faculty of Health and Medical Sciences, University of Copenhagen.

The protective effects of GLP-1 receptor agonist lixisenatide on oxygen-glucose deprivation/reperfusion (OGD/R)-induced deregulation of endothelial tube formation.

Acute myocardial infarction (AMI) is a complication of atherosclerosis that takes place in coronary arteries. Cardiac endothelial cells play a significant role in the pathogenesis of AMI. Oxygen-glucose deprivation/reperfusion (OGD/R) is widely used as a model to simulate AMI in vitro. Recently, antidiabetic GLP-1 receptor agonists have been shown to exert pleiotropic effects that modulate cardiovascular complications. In this study, we investigated the vascular effect of lixisenatide. We show that pre-treatment of endothelial cells with lixisenatide protected them from OGD/R-induced cytotoxicity and improved their viability. Pre-treatment with lixisenatide ameliorated OGD/R-induced ROS accumulation and disturbed endothelial tube formation. At the molecular level, lixisenatide mitigated OGD/R-induced reduced eNOS expression and NO production but further promoted the expression of the anti-oxidant regulators Nrf2 and HO-1. Mechanistically, we confirmed that the PI3K/Akt pathway is essential for mediating the effects of lixisenatide, and blockage of PI3K/Akt using the inhibitor LY294002 abolished the ameliorative effect of lixisenatide on ROS production and impaired tube formation. These data indicate that lixisenatide possesses a beneficial effect on the vasculature in a model of ischemia-induced endothelial injury. We conclude that the GLP-1 receptor agonist lixisenatide has pleiotropic properties that can modulate vascular function independent of its anti-glycemic effect.

Effects of sequential treatment with lixisenatide, insulin glargine, or their combination on meal-related glycaemic excursions, insulin and glucagon secretion, and gastric emptying in patients with type 2 diabetes.

To examine the glucose-lowering mechanisms of the glucagon-like peptide-1 receptor agonist lixisenatide after two subsequent meals and in combination with basal insulin. Twenty-eight metformin-treated patients with type 2 diabetes were randomly assigned to treatment sequences with either lixisenatide or insulin glargine alone for 4 weeks, and a combination of both treatments for 4 weeks. Metabolic examinations were performed before and after each treatment period following breakfast and a late lunch 8 hours later. Lixisenatide mainly reduced postprandial glycaemia, while insulin glargine mainly reduced fasting glucose after breakfast (P < 0.05). This was partially preserved after a late lunch (P < 0.05). After breakfast, lixisenatide reduced insulin secretion and glucagon levels significantly. These effects were lost after a late lunch. Insulin glargine did not significantly reduce glucagon or insulin secretion. Gastric emptying was slowed by lixisenatide, but not by insulin glargine after breakfast. After the late lunch, lixisenatide slightly accelerated gastric emptying. Lixisenatide decelerates gastric emptying after breakfast, thereby reducing glycaemic excursions, insulin secretion and glucagon levels. The glycaemic reduction persists until after a late lunch, despite accelerated gastric emptying. The combination with insulin glargine enhances the glucose-lowering effect because of complementary modes of action.

Clinical Characteristics and Glycemic Outcomes of Patients with Type 2 Diabetes Requiring Maximum Dose Insulin Glargine/Lixisenatide Fixed-Ratio Combination or Insulin Glargine in the LixiLan-L Trial.

IntroductioniGlarLixi is a titratable, fixed-ratio combination of insulin glargine (iGlar, 100 units/ml) and the glucagon-like peptide-1 receptor agonist lixisenatide for the treatment of patients with type 2 diabetes. This post hoc analysis of the phase 3 LixiLan-L trial (NCT02058160) investigated baseline characteristics, glycemic control, and safety outcomes in participants who received the study-specified maximum dose (60 units/day) of iGlarLixi or iGlar vs. those who received < 60 units/day.MethodsOutcomes were compared for participants receiving 60 or < 60 units/day at week 30. Endpoints analyzed included change in A1C, fasting plasma glucose (FPG), 2-h postprandial glucose (2-h PPG), body weight, proportion of participants achieving A1C < 7.0%, proportion of participants receiving rescue therapy, documented symptomatic hypoglycemia, and gastrointestinal adverse event (GI AE) incidence.ResultsBy week 30, 27% (iGlarLixi) and 31% (iGlar) of participants received the maximum dose. Participants on 60 vs. < 60 units/day were younger and had higher body weight, body mass index (BMI), FPG, and baseline insulin dose. In both dose groups, A1C change from baseline was significantly greater with iGlarLixi vs. iGlar, and more participants treated with iGlarLixi vs. iGlar achieved A1C < 7.0%. No significant differences were observed in change from baseline for A1C, FPG, 2-h PPG, or GI AE incidence between insulin dose groups, regardless of treatment. In both treatment arms, incidence of symptomatic hypoglycemia was lower in participants receiving 60 units/day vs. those receiving < 60 units/day. Participants treated with iGlarLixi (< 60 or 60 units/day) had modest weight loss over 30 weeks vs. an increase in weight compared with iGlar.ConclusionsMaximum doses of iGlarLixi were required in participants with a more insulin-resistant clinical phenotype (younger, higher BMI, FPG, and insulin doses). Benefits were observed with iGlarLixi vs. iGlar, even at 60 units/day, with more participants achieving glycemic goals, no increase in symptomatic hypoglycemia, and a modest reduction in body weight.FundingSanofi US, Inc.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-019-01033-1) contains supplementary material, which is available to authorized users.

RETRACTED ARTICLE: GLP-1 receptor agonist lixisenatide protects against high free fatty acids-induced oxidative stress and inflammatory response

We, the Editors, Authors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article: Qini Zhao, Haiming Xu, Lirong Zhang, Long Liu & Libo Wang (2019) GLP-1 receptor agonist lixisenatide protects against high free fatty acids-induced oxidative stress and inflammatory response. Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 2325–2332, DOI: 10.1080/21691401.2019.1620248 Since publication, the authors continued their study and found that the original experimental results were unverifiable. The authors checked their data and confirmed there are fundamental errors present. Therefore, they have agreed to the retraction of this article. The authors apologise for this oversight. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

Effects of lixisenatide on postprandial blood pressure, gastric emptying and glycaemia in healthy people and people with type 2 diabetes.

To evaluate the effects of the prandial glucagon-like peptide-1 receptor agonist lixisenatide on gastric emptying and blood pressure (BP) and superior mesenteric artery (SMA) blood flow, and the glycaemic responses to a 75-g oral glucose load in healthy people and those with type 2 diabetes (T2DM). Fifteen healthy participants (nine men, six women; mean ± SEM age 67.2 ± 2.3 years) and 15 participants with T2DM (nine men, six women; mean ± SEM age 61.9 ± 2.3 years) underwent measurement of gastric emptying, BP, SMA flow and plasma glucose 180 minutes after a radiolabelled 75-g glucose drink on two separate days. All participants received lixisenatide (10 μg subcutaneously) or placebo in a randomized, double-blind, crossover fashion 30 minutes before the glucose drink. Lixisenatide slowed gastric emptying (retention at 120 minutes, P < 0.01), attenuated the rise in SMA flow (P < 0.01) and markedly attenuated the decrease in systolic BP (area under the curve [AUC] 0-120 minutes, P < 0.001) compared to placebo in healthy participants and those with T2DM. Plasma glucose (incremental AUC 0-120 minutes) was greater in participants with T2DM (P < 0.005) than in healthy participants, and lower after lixisenatide in both groups (P < 0.001). In healthy participants and those with T2DM, the marked slowing of gastric emptying of glucose induced by lixisenatide was associated with attenuation of the increments in glycaemia and SMA flow and decrease in systolic BP. Accordingly, lixisenatide may be useful in the management of postprandial hypotension.

Lixisenatide requires a functional gut-vagus nerve-brain axis to trigger insulin secretion in controls and type 2 diabetic mice.

Endogenous glucagon-like peptide-1 (GLP-1) regulates glucose-induced insulin secretion through both direct β-cell-dependent and indirect gut-brain axis-dependent pathways. However, little is known about the mode of action of the GLP-1 receptor agonist lixisenatide. We studied the effects of lixisenatide (intraperitoneal injection) on insulin secretion, gastric emptying, vagus nerve activity, and brain c-Fos activation in naive, chronically vagotomized, GLP-1 receptor knockout (KO), high-fat diet-fed diabetic mice, or db/db mice. Lixisenatide dose-dependently increased oral glucose-induced insulin secretion that is correlated with a decrease of glycemia. In addition, lixisenatide inhibited gastric emptying. These effects of lixisenatide were abolished in vagotomized mice, characterized by a delay of gastric emptying and in GLP-1 receptor KO mice. Intraperitoneal administration of lixisenatide also increased the vagus nerve firing rate and the number of c-Fos-labeled neurons in the nucleus tractus solitarius (NTS) of the brainstem. In diabetic mouse models, lixisenatide increased the firing rate of the vagus nerve when administrated simultaneously to an intraduodenal glucose. It increased also insulin secretion and c-Fos activation in the NTS. Altogether, our findings show that lixisenatide requires a functional vagus nerve and neuronal gut-brain-islets axis as well as the GLP-1 receptor to regulate glucose-induced insulin secretion in healthy and diabetic mice. NEW & NOTEWORTHY Lixisenatide is an agonist of the glucagon-like protein (GLP)-1 receptor, modified from exendin 4, used to treat type 2 diabetic patients. However, whereas the mode of action of endogenous GLP-1 is extensively studied, the mode of action of the GLP-1 analog lixisenatide is poorly understood. Here, we demonstrated that lixisenatide activates the vagus nerve and recruits the gut-brain axis through the GLP-1 receptor to decrease gastric emptying and stimulate insulin secretion to improve glycemia.

IGlarLixi Effectively Reduces Residual Hyperglycemia in Patients with Type 2 Diabetes on Basal Insulin—A Post-Hoc Analysis from the LixiLan-L Study

Residual hyperglycemia (glycated hemoglobin [HbA1c] over target despite fasting plasma glucose [FPG] at target) presents an obstacle in achieving glycemic control in T2D. GLP-1 receptor agonist (RA) therapy can target excessive postprandial glycemia (PPG) and thereby address residual hyperglycemia. This analysis investigated the effect of iGlarLixi, a fixed-ratio combination of insulin glargine (iGlar) U100 and the GLP-1 RA lixisenatide (Lixi), on the proportion of patients with T2D with discordant HbA1c/FPG (HbA1c ≥7% and FPG &amp;lt;140 mg/dL) in the LixiLan-L trial. Patients who had suboptimal glycemic control despite basal insulin ± oral antidiabetes drugs (OADs) stopped all OADs but metformin and, after 6 weeks of iGlar run-in, were randomized to iGlarLixi or iGlar for 30 weeks (N=736). At baseline (post-run-in), proportions with discordant HbA1c/FPG were similar in the two arms. After 12-week randomized treatment, proportions with discordant HbA1c/FPG were 32.1% (iGlarLixi) and 49.9% (iGlar; p&amp;lt;0.0001; Figure). After 30 weeks, the prevalence of discordant HbA1c/FPG was further reduced with iGlarLixi vs. iGlar (22.7% vs. 45.9%; p&amp;lt;0.0001). In conclusion, iGlarLixi reduces the proportion of T2D patients with discordant HbA1c/FPG levels more than iGlar does, reflecting its capacity to address residual hyperglycemia by targeting both FPG and PPG. Disclosure F. Giorgino: Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim GmbH. Research Support; Self; Eli Lilly and Company, Johnson &amp; Johnson Services, Inc.. Consultant; Self; MedImmune, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care Health and Digital Solutions, Sanofi. Research Support; Self; Takeda Development Centre Europe Ltd. R. Retnakaran: Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Sanofi, Eli Lilly and Company. J. Vidal: None. V. Aroda: Consultant; Self; Novo Nordisk Inc.. Research Support; Self; Novo Nordisk Inc., AstraZeneca, Calibra Medical, Eisai Inc., Sanofi. Consultant; Self; Sanofi. Research Support; Self; Theracos, Inc.. Employee; Spouse/Partner; Merck &amp; Co., Inc.. Other Relationship; Self; American Diabetes Association. Consultant; Self; ADOCIA. A. Saremi: Employee; Self; Sanofi US. M. Liu: Employee; Self; Sanofi.

IGlarLixi: A New Once-Daily Fixed-Ratio Combination of Basal Insulin Glargine and Lixisenatide for the Management of Type 2 Diabetes.

Background.Patients with type 2 diabetes require treatment intensification to maintain glycemic control. Clinician reluctance, patient injection fears, hypoglycemia, weight gain, or other objections may lead to clinical inertia, whereby therapy is not intensified and patients live with uncontrolled hyperglycemia and increased risk for complications. Initiation of injectable therapy with a glucagon-like peptide (GLP)-1 receptor agonist and/or basal insulin is a recommended option for patients with type 2 diabetes inadequately controlled on one or more oral agents.Purpose.This article reviews clinical evidence and provides information on dosing and administration of iGlarLixi, a titratable fixed-ratio combination of insulin glargine and the GLP-1 receptor agonist lixisenatide that effectively lowers both fasting and postprandial glucose levels.Findings.In phase 3 trials, iGlarLixi provided greater A1C reduction than insulin glargine or lixisenatide alone, without increased hypoglycemia risk compared with insulin glargine. iGlarLixi did not lead to weight gain versus insulin glargine and was associated with a lower frequency of gastrointestinal adverse effects than lixisenatide. iGlarLixi was recently approved by the U.S. Food and Drug Administration to improve glycemic control in adults with type 2 diabetes inadequately controlled on basal insulin (<60 units daily) or lixisenatide. iGlarLixi is administered by subcutaneous injection once daily, and the dose is titrated based on each patient’s insulin needs using a simple titration algorithm.Conclusion.iGlarLixi offers an effective and well-tolerated treatment option for patients with type 2 diabetes requiring additional glycemic control, with comparable or improved safety outcomes than its separate components. Because of its simple regimen and low rate of adverse effects, iGlarLixi may improve adherence and, consequently, therapeutic outcomes.

Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease

Type 2 diabetes mellitus (T2DM) has been identified as a high risk factor for Alzheimer's disease (AD). The impairment of insulin signaling has been found in AD brain. Glucagon-like peptide-1 (GLP-1) is an incretin hormone, normalises insulin signaling and acts as a neuroprotective growth factor. We have previously shown that the long-lasting GLP-1 receptor (GLP-1R) agonist lixisenatide plays an important role in memory formation, synaptic plasticity and cell proliferation of rats. In the follow-up study, we analysed the neuroprotective effect and mechanism of lixisenatide, injected for 60 days at 10 nmol/kg i.p. once daily in APP/PS1/tau female mice and C57BL/6J female mice (as control) aged 12 month. The results showed that lixisenatide could reduce amyloid plaques, neurofibrillary tangles and neuroinflammation in the hippocampi of 12-month-old APP/PS1/tau female mice; activation of PKA-CREB signaling pathway and inhibition of p38-MAPK might be the important mechanisms in the neuroprotective function of lixisenatide. The study demonstrated that GLP-1R agonists such as lixisenatide might have the potential to be developed as a novel therapy for AD.

The combination therapy of basal insulin and lixisenatide in Asian diabetic patients

The pathophysiology of Asian diabetic patients differs from that in Western patients. However, the majority of studies for treatment in type 2 diabetes have been performed predominantly in Western populations, and the researches in Chinese or Asian patients are limited. We discuss the mechanisms of different glucagon-like peptide 1 receptor agonist(GLP-1RA), and describe the available clinical data for the treatment of basal insulin in combination with the short-acting GLP-1RA lixisenatide, especially for Asian patients with type 2 diabetes mellitus.The current paper is a Chinese translation of a review entitled as What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus published in 《Journal of Diabetes》 (2017, 9: 562-574) with the permission from the the journal. (Chin J Endocrinol Metab, 2017, 33: 790-797) Key words: Insulin; Lixisenatide; Diabetes mellitus, type 2

Inhibition of plaque progression and promotion of plaque stability by glucagon-like peptide-1 receptor agonist: Serial in vivo findings from iMap-IVUS in Watanabe heritable hyperlipidemic rabbits

Background and aimsGlucagon-like peptide-1 (GLP-1) is thought to inhibit development of aortic atherosclerosis and plaque formation. However, whether GLP-1 stabilizes fully developed atherosclerotic plaque or alters the complicated plaque composition remains unclarified. MethodsTen Watanabe heritable hyperlipidemic (WHHL) rabbits were divided into GLP-1 receptor agonist treatment group and control group. After confirmation of atherosclerotic plaques in brachiocephalic arteries by iMap intravascular ultrasound (iMAP-IVUS), GLP-1 receptor agonist lixisenatide was administered to WHHL rabbits at 30 nmoL/kg/day for 12 weeks by osmotic pump. An equal volume of normal saline was administered in a control group. After evaluation by iMAP-IVUS at 12 weeks, brachiocephalic arteries were harvested for pathological histological analysis. ResultsiMAP-IVUS analysis revealed larger fibrotic plaque components and smaller necrotic and calcified plaque components in the GLP-1 group than in the control group; %fibrotic area: 66.30 ± 2.06% vs. 75.14 ± 2.62%, p < 0.01, %necrotic area: 23.25 ± 1.87% vs. 16.17 ± 2.27%, p = 0.02, %calcified area: 2.15 ± 0.24% vs. 1.00 ± 0.18%, p < 0.01), indicating that GLP-1 receptor agonist might modify plaque composition and increase plaque stability. Histological analysis confirmed that GLP-1 receptor agonist treatment improved smooth muscle cell (SMC)-rich plaque with increased fibrotic content. Furthermore, plaque macrophage infiltration and calcification were significantly reduced by GLP-1 receptor agonist treatment; %SMC area: 6.93 ± 0.31% vs. 8.14 ± 0.48%, p = 0.02; %macrophage area: 9.11 ± 0.80% vs. 6.19 ± 0.85%, p < 0.01; %fibrotic area: 54.75 ± 1.63% vs. 69.60 ± 2.12%, p = 0.02; %calcified area: 3.25 ± 0.67% vs. 0.75 ± 0.15%, p = 0.02). ConclusionsGLP-1 receptor agonist inhibited plaque progression and promoted plaque stabilization by inhibiting plaque growth and modifying plaque composition.

Switch to Combined GLP1 Receptor Agonist Lixisenatide with Basal Insulin Glargine in Poorly Controlled T2DM Patients with Premixed Insulin Therapy: A Clinical Observation and Pilot Study in Nine Patients.

IntroductionTo prove the feasibility and safety of a conversion to once-daily injected GLP1 agonist (lixisenatide) and long-acting basal insulin analogue (glargine) in patients with T2DM and poorly controlled glycemia previously treated with multiple injections of premixed insulins (iPremix) in an outpatient setting.MethodsNine patients with T2DM currently receiving iPremix formulations and poor glycemic control were switched to once-daily injected lixisenatide (Lixi) and basal insulin analogue glargine (iGlar) for a 12-week period. Efficacy was defined as A1c reduction of at least 0.4% and weight loss of 0.5 kg or higher.ResultsFive of nine patients achieved A1c reductions of 0.4% (4 mmol/mol) or higher and six of nine patients a weight loss of 0.5 kg or higher. A mean A1C reduction of 0.5% ± 0.5% (6 mmol/mol) and mean weight loss of −1.4 ± 3.6 kg were observed in all patients. Total daily insulin dose after 12 weeks declined from 56 ± 26 IU with iPremix formulations to 47 ± 17 IU in patients taking combined iGlar and Lixi. Corrections with fast acting insulin glulisine (iGlu) were necessary in two patients on a regular basis and in four patients on an irregular basis (2.3 IU mean total daily dose). Two patients did not need additional iGlu. Postprandial glucose profiles were lower in the combined group compared with iPremix throughout the day, which resolved in the afternoon. No metabolic derangements occurred. Mild hypoglycemia and gastrointestinal symptoms were the most often reported adverse events affecting three patients.ConclusionThe conversion to once-daily injected GLP1 agonist Lixi and basal iGlar could safely be performed in an outpatient setting and was associated with better postprandial glycemic control throughout the day, except dinner, compared to iPremix. Clinical Trial Registration: EU clinical trials register EudraCT number 2013-005334-37 and ClinicalTrials.gov NCT02168491. Funding: Sponsored by the Medical University of Vienna and in part supported by Sanofi-Aventis.