Modeling the Effect of Subcutaneous Lixisenatide on Glucoregulatory Endocrine Secretions and Gastric Emptying in Type 2 Diabetes to Simulate the Effect of iGlarLixi Administration Timing on Blood Sugar Profiles.

Background: As type 2 diabetes (T2D) progresses, intensification to combination therapies, such as iGlarLixi (a fixed-ratio GLP-1 RA and basal insulin combination), may be required. Here a simulation study was used to assess the effect of iGlarLixi administration timing (am vs pm) on blood sugar profiles.

Methods: Models of lixisenatide were built with a selection procedure, optimizing measurement fits and model complexity, and were included in a pre-existing T2D simulation platform containing glargine models.

iGlarLixi effectively reduces residual hyperglycaemia in patients with type 2 diabetes on basal insulin: A post hoc analysis from the LixiLan-L study.

Globally, nearly half of patients with type 2 diabetes (T2D) do not successfully achieve target HbA1c with basal insulin, despite meeting fasting plasma glucose (FPG) targets. In this post hoc analysis of the LixiLan-L study, we determined whether iGlarLixi, a fixed-ratio combination of insulin glargine Gla-100 (iGlar) and the glucagon-like peptide-1 receptor agonist lixisenatide (Lixi), addresses the challenge of reducing residual hyperglycaemia in patients with T2D. In LixiLan-L, a randomized, open-label study, 1018 patients with T2D on basal insulin for ≥6 months ± oral antidiabetes drugs entered a 6-week run-in period, during which they were switched to and/or optimized for a daily dose of iGlar while continuing only metformin.

Impact of disease duration and β-cell reserve on the efficacy of switching to iGlarLixi in adults with type 2 diabetes on glucagon-like peptide-1 receptor agonist therapy: Exploratory analyses from the LixiLan-G trial.

Aim: To evaluate the efficacy of iGlarLixi by C-peptide levels and duration of diabetes in an exploratory analysis of the LixiLan-G study.

Methods: LixiLan-G was a 26-week, randomized, open-label study in adults with type diabetes (T2D) inadequately controlled while on a glucagon-like peptide-1 receptor agonist (GLP-1 RA), with metformin, with or without pioglitazone and/or a sodium-glucose co-transporter-2 inhibitor. This analysis investigated the efficacy of switching to iGlarLixi by fasting baseline quartile C-peptide levels and baseline quartile of duration of T2D compared with continued GLP-1 RA use.

Fixed-Ratio Combination of Insulin and GLP-1 RA in Patients with Longstanding Type 2 Diabetes: A Subanalysis of LixiLan-L.

Introduction: With longer duration and progression of type 2 diabetes (T2D), β-cell function deteriorates and insulin therapy often becomes necessary. Glucagon-like peptide-1 receptor agonists such as lixisenatide that do not rely only on β-cell function and glucagon suppression primarily, but also lower glucose by other (insulin-independent) mechanisms such as delayed gastric emptying, may be appropriate adjuvant therapy to basal insulin in patients with longstanding T2D.

Methods: We assessed the efficacy and safety of insulin glargine (iGlar) versus iGlarLixi, a fixed-ratio combination of iGlar and lixisenatide, stratified by quartiles (Q) of T2D duration (≤ 7.

Efficacy and Safety of iGlarLixi, Fixed-Ratio Combination of Insulin Glargine and Lixisenatide, Compared with Basal-Bolus Regimen in Patients with Type 2 Diabetes: Propensity Score Matched Analysis.

Introduction: Basal-bolus (BB) regimens are generally used to intensify basal insulin therapy in patients with type 2 diabetes (T2D) not meeting glycemic targets. However, drawbacks include multiple injection burden and risk of weight gain and hypoglycemia. A once-daily titratable fixed-ratio combination of insulin glargine 100 U/mL and lixisenatide (iGlarLixi) may provide a simple, well-tolerated, and efficacious alternative.

Achievement of glycaemic control is associated with improvements in lipid profile with iGlarLixi versus iGlar: A post hoc analysis of the LixiLan-L trial.

Diabetic dyslipidaemia is a major risk factor for accelerated atherosclerosis. Glycaemic treatments that improve dyslipidaemia may help reduce the burden of atherosclerosis. This analysis investigated the effect of iGlarLixi [insulin glargine U100 (iGlar) and lixisenatide] versus iGlar on lipid profiles in patients with type 2 diabetes uncontrolled on basal insulin.

EFFICACY AND SAFETY OF IGLARLIXI IN HISPANICS AND NON-HISPANIC WHITES WITH TYPE 2 DIABETES.

Type 2 diabetes (T2D) is more common in Hispanic than non-Hispanic white (NHW) populations worldwide, and ethnicity, among other factors, may affect response to therapy. The efficacy and safety of insulin glargine 100 units/mL (iGlar) and the fixed-ratio combination of iGlar and the glucagon-like peptide 1 receptor agonist lixisenatide (iGlarLixi) was assessed in Hispanic and NHW patients with T2D from 25 countries. In this post hoc analysis, data from two 30-week randomized controlled trials comparing iGlar and iGlarLixi in patients with T2D uncontrolled on basal insulin ± oral antidiabetes drugs (OADs; LixiLan-L: NCT02058160) or uncontrolled on metformin ± OADs (LixiLan-O: NCT02058147) were evaluated.

CXCL4L1 Promoter Polymorphisms Are Associated with Improved Renal Function in Type 1 Diabetes.

Inflammation is a recognized mechanism underlying the pathogenesis of renal dysfunction in type 1 diabetes. Evidence suggests that genetic factors modulate the expression of inflammatory genes, which may lead to an enhanced predisposition to developing renal complications in patients with diabetes. In this study, we examined 55 genetic variants from 16 human candidate inflammatory genes for associations with renal function expressed as the estimated glomerular filtration rate in 1540 participants from the Genetics of Kidneys in Diabetes study.

Correction to: Bedtime-to-Morning Glucose Difference and iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of LixiLan-L.

In the original publication, the text in abstract section under the 'Results' section is incorrectly published as 'higher proportion of patients reached a BeAM value < 55 mg/dL.

Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial.

Background: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes.

Methods: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries.

Bedtime-to-Morning Glucose Difference and iGlarLixi in Type 2 Diabetes: Post Hoc Analysis of LixiLan-L.

Introduction: A difference of ≥ 50-55 mg/dL between bedtime and morning glucose (BeAM) values in patients with type 2 diabetes (T2D) on basal insulin is an indicator of poor postprandial glucose control. This analysis compared the effect of treatment with a fixed-ratio combination of insulin glargine/lixisenatide (iGlarLixi) vs insulin glargine (iGlar) on BeAM values, and evaluated the impact of BeAM values on glycemic and safety endpoints.

Methods: In this post hoc analysis of 517 participants from the LixiLan-L trial, change in BeAM values and composite efficacy and safety endpoints stratified by BeAM value < 55 mg/dL or ≥ 55 mg/dL were evaluated in patients with T2D uncontrolled on basal insulin randomized to iGlarLixi or iGlar over 30 weeks (LixiLan-L).

Advanced Glycation End Products, Oxidation Products, and Incident Cardiovascular Events in Patients With Type 2 Diabetes.

Objective: The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes.

Research Design And Methods: Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: ) a subcohort of the Veterans Affairs Diabetes Trial (VADT) ( = 445) and ) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study ( = 271).

Results: Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A.

Advanced Glycation End Products, Oxidation Products, and the Extent of Atherosclerosis During the VA Diabetes Trial and Follow-up Study.

Objective: To determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study.

Research Design And Methods: Baseline plasma levels of methylglyoxal hydroimidazolone, Nε-carboxymethyl lysine, Nε-carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide were measured in a total of 411 participants, who underwent ultrasound assessment of carotid intima-media thickness (CIMT), and computed tomography scanning of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) after an average of 10 years of follow-up.

Results: In risk factor-adjusted multivariable regression models, G-H1 was associated with the extent of CIMT and CAC.

Machine learning to predict rapid progression of carotid atherosclerosis in patients with impaired glucose tolerance.

Objectives: Prediabetes is a major epidemic and is associated with adverse cardio-cerebrovascular outcomes. Early identification of patients who will develop rapid progression of atherosclerosis could be beneficial for improved risk stratification. In this paper, we investigate important factors impacting the prediction, using several machine learning methods, of rapid progression of carotid intima-media thickness in impaired glucose tolerance (IGT) participants.

A Link Between Hypoglycemia and Progression of Atherosclerosis in the Veterans Affairs Diabetes Trial (VADT).

Objective: To determine whether a link exists between serious hypoglycemia and progression of atherosclerosis in a substudy of the Veterans Affairs Diabetes Trial (VADT) and to examine whether glycemic control during the VADT modified the association between serious hypoglycemia and coronary artery calcium (CAC) progression.

Research Design And Methods: Serious hypoglycemia was defined as severe episodes with loss of consciousness or requiring assistance or documented glucose <50 mg/dL. Progression of CAC was determined in 197 participants with baseline and follow-up computed tomography scans.

The effect of intensive glucose lowering therapy among major racial/ethnic groups in the Veterans Affairs Diabetes Trial.

Objective: To examine the effect of intensive glycemic control on cardiovascular disease events (CVD) among the major race/ethnic groups in a post-hoc analysis of the VADT.

Materials And Methods: Participants included 1111 non-Hispanic Whites, 307 Hispanics and 306 non-Hispanic Blacks randomized to intensive or standard glucose treatment in VADT. Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups.

The effect of intensive glucose lowering on lipoprotein particle profiles and inflammatory markers in the Veterans Affairs Diabetes Trial (VADT).

Objective: Intensive glucose-lowering therapy (INT) did not reduce macrovascular events in the recent randomized trials, possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors.

Research Design And Methods: Standard plasma lipids, cholesterol content of lipoprotein subfractions, and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial (VADT) participants (n = 266) at baseline and after 9 months of INT or standard therapy.

Results: INT lowered glycated hemoglobin (by a median of 2% vs.

Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors.

Objective: To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes.

Methods And Results: CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.

Progression of vascular calcification is increased with statin use in the Veterans Affairs Diabetes Trial (VADT).

Objective: To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM).

Research Design And Methods: Progression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM.

Results: After adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.

Acute effects of interleukin-6 infusion on apo-B-containing lipoprotein subclasses in humans.

IL-6 is believed to mediate the elevation in plasma TG and VLDL lipids in patients with sepsis. Previous studies of lipoprotein density fractions do not reveal the extent to which cytokines change the immunochemically distinct TG-rich (LpB:C, LpB:C:E, LpAII:B:C:D:E) and cholesterol-rich (LpB, LpB:E) apoB-containing subclasses present in VLDL. Therefore, we have directly measured these subclasses following their isolation by sequential immunoprecipitation in seven healthy male subjects during a 3-h infusion with recombinant human (rh) IL-6.

Rates and determinants of coronary and abdominal aortic artery calcium progression in the Veterans Affairs Diabetes Trial (VADT).

Objective: To determine the predictors of progression of calcified atherosclerosis and the effect of intensive glycemic control on this process in patients with type 2 diabetes.

Research Design And Methods: As part of the Risk Factors, Atherosclerosis, and Clinical Events in Diabetes (RACED) substudy of the Veterans Affairs Diabetes Trial (VADT), 197 and 189 individuals with type 2 diabetes received baseline and follow-up computed tomographic scans for measurement of coronary and abdominal artery calcium, respectively. Standard and novel risk factors were assessed at baseline, and progression of calcified atherosclerosis was determined by several methods.

Preliminary report: hepatic fat and inflammation in type 2 diabetes mellitus.

Although the association between inflammation and hepatic fat is fairly established, it remains unclear whether this association is independent of general measures of obesity and standard cardiovascular risk factors. Therefore, the aim of this study was to investigate the contribution of hepatic steatosis as an independent predictor of chronic inflammation in 281 subjects with type 2 diabetes mellitus. Reduced hepatic steatosis significantly (P < .

Association between IL-6 and the extent of coronary atherosclerosis in the veterans affairs diabetes trial (VADT).

Aims: The aim of the present study was to investigate the association of high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6) and lipoprotein-associated phospholipase A2 (Lp-PLA2) with the extent of calcified coronary atherosclerosis in patients with type 2 diabetes mellitus (T2DM).

Materials And Results: This is a cross-sectional study of 306 subjects aged 40years or older who were enrolled into the veterans affairs diabetes trial (VADT). Calcified coronary atherosclerosis was assessed using electron beam computed tomography scored by the Agatston method.

Periodontal disease and mortality in type 2 diabetes.

Objective: Periodontal disease may contribute to the increased mortality associated with diabetes.

Research Design And Methods: In a prospective longitudinal study of 628 subjects aged > or =35 years, we examined the effect of periodontal disease on overall and cardiovascular disease mortality in Pima Indians with type 2 diabetes. Periodontal abnormality was classified as no or mild, moderate, and severe, based on panoramic radiographs and clinical dental examinations.