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To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher.Intention-to-treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures. Subgroup analyses with factors for baseline HbA1c categories and their interaction with treatment group, as well as analyses within the HbA1c subgroups, were conducted. Additionally, sensitivity analyses were performed for baseline HbA1c subgroups of 6.5% or less and more than 6.5%.Of the 9876 eligible participants, 3921 and 5955 had a baseline HbA1c of less than 7% and 7% or higher, respectively. Mean baseline HbA1c was 6.3% and 8.0% and the mean duration of diabetes was 9.0 and 11.6 years in the respective subgroups. The less than 7% subgroup was slightly older and less frequently insulin-treated. There was no evidence of a differential dulaglutide treatment effect on body mass index (BMI) reduction, cardiovascular or safety outcomes of interest between the baseline HbA1c subgroups. Treatment-by-baseline HbA1c group interaction was significant for HbA1c change from baseline (P .001), with a greater reduction in the subgroup with higher baseline HbA1c values. Sensitivity analyses by baseline HbA1c subgroups of 6.5% or less and more than 6.5% showed similar results.The reduced incidence of cardiovascular events, and the reduction in BMI in participants treated with once-weekly dulaglutide, were independent of the baseline HbA1c level. Conversely, participants with a higher baseline HbA1c level had greater reductions in HbA1c. Dulaglutide has a positive benefit-risk profile and can be considered in patients with comparatively well-controlled HbA1c levels seeking optimal metabolic control and cardiovascular benefits.

Background In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D). Methods Data from the REWIND trial placebo group (N = 4952) were analyzed. All participants had T2D, age ≥ 50 years, had either a previous CV event or CV risk factors, and a BMI of ≥ 23 kg/m2. Cox proportional hazard models were used to investigate if BMI, waist-to-hip ratio (WHR), and waist circumference (WC) were significant risk factors for major adverse CV events (MACE)-3, CVD-related mortality, all-cause mortality, and heart failure (HF) requiring hospitalization. Models were adjusted for age, sex, and additional baseline factors selected by LASSO method. Results are presented for one standard deviation increase of the respective anthropometric factor. Results Participants in the placebo group experienced 663 MACE-3 events, 346 CVD-related deaths, 592 all-cause deaths, and 226 events of HF requiring hospitalization during the median follow-up of 5.4 years. WHR and WC, but not BMI, were identified as independent risk factors of MACE-3 (hazard ratio [HR] for WHR: 1.11 [95% CI 1.03 to 1.21]; p = 0.009; HR for WC: 1.12 [95% CI 1.02 to 1.22]; p = 0.012). WC adjusted for hip circumference (HC) showed the strongest association with MACE-3 compared to WHR, WC, or BMI unadjusted for each other (HR: 1.26 [95% CI 1.09 to 1.46]; p = 0.002). Results for CVD-related mortality and all-cause mortality were similar. WC and BMI were risk factors for HF requiring hospitalization, but not WHR or WC adjusted for HC (HR for WC: 1.34 [95% CI 1.16 to 1.54]; p Conclusions In this post hoc analysis of the REWIND placebo group, WHR, WC and/or WC adjusted for HC were risk factors for MACE-3, CVD-related mortality, and all-cause mortality; while BMI was only a risk factor for HF requiring hospitalization. These findings indicate the need for anthropometric measures that consider body fat distribution when assessing CV risk.

Background Patients with type 2 diabetes (T2D) treated with glucagon-like peptide-1 receptor agonists may experience reductions in weight and blood pressure. The primary objective of the current study was to determine the weight-dependent and weight-independent effects of ~ 6 months treatment with dulaglutide 1.5 mg treatment in participants with T2D. Methods Mediation analysis was conducted for five randomized, placebo-controlled trials of dulaglutide 1.5 mg to estimate the weight-dependent (i.e., mediated by weight) and weight-independent effects from dulaglutide vs. placebo on change from baseline for systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure. A random-effects meta-analysis combined these results. To investigate a dose response between dulaglutide 4.5 mg and placebo, mediation analysis was first conducted in AWARD-11 to estimate the weight-dependent and weight-independent effects of dulaglutide 4.5 mg vs. 1.5 mg, followed by an indirect comparison with the mediation result for dulaglutide 1.5 mg vs. placebo. Results Baseline characteristics were largely similar across the trials. In the mediation meta-analysis of placebo-controlled trials, the total treatment effect of dulaglutide 1.5 mg after placebo-adjustment on SBP was − 2.6 mmHg (95% CI − 3.8, − 1.5; p p p = 0.01), accounting for 36% and 64% of the total effect, respectively. For pulse pressure, the total treatment effect of dulaglutide (− 2.5 mmHg; 95% CI: − 3.5, − 1.5; p Conclusions Dulaglutide 1.5 mg reduced SBP and pulse pressure in people with T2D across the placebo-controlled trials in the AWARD program. While up to one third of the effect of dulaglutide 1.5 mg on SBP and pulse pressure was due to weight reduction, the majority was independent of weight. A greater understanding of the pleotropic effects of GLP-1 RA that contribute to reduction in blood pressure could support developing future approaches for treating hypertension. Trial registrations (clinicaltrials.gov) NCT01064687, NCT00734474, NCT01769378, NCT02597049, NCT01149421, NCT03495102

Introduction: This exploratory post hoc analysis investigated the relative changes in glycated haemoglobin (HbA1c) in patients with type 2 diabetes mellitus (T2DM) treated with dulaglutide versus active comparators across a continuous range of baseline HbA1c values using data from three phase III randomised controlled trials. Methods: Data from patients receiving once-weekly dulaglutide 0.75 and 1.5 mg, once-daily sitagliptin 100 mg, once-daily liraglutide 1.8 mg or twice-daily exenatide 10 ?g in the intent-to-treat populations in the AWARD-5, AWARD-6 and AWARD-1 trials were analysed using last observation carried forward analysis of covariance. Starting with the predefined statistical model from each study, the type of association between HbA1c baseline and change at 26 weeks was modelled. Consistency of treatment effect was assessed via treatment-by-baseline HbA1c interaction terms. Results: Improvements in HbA1c occurred in all treatment groups across the entire baseline HbA1c range. The relationship between HbA1c baseline and magnitude of change was linear in all treatment groups, with greater reductions in patients with higher baseline HbA1c values. Across the continuum of baseline HbA1c values, patients treated with dulaglutide 1.5 mg achieved a similar mean HbA1c reduction to patients receiving liraglutide 1.8 mg and a greater reduction than patients receiving twice-daily exenatide or sitagliptin. In AWARD-5, the treatment-by-baseline HbA1c interaction P value (0.001) demonstrated progressively greater HbA1c reduction in dulaglutide-treated compared with sitagliptin-treated patients as baseline HbA1c increased. Conclusion: Our results suggest that dulaglutide is an appropriate therapeutic option for patients with T2DM across a wide range of baseline HbA1c values, including those with poor metabolic control.

AIMS Insulin-treated patients with type 2 diabetes (T2D) and obesity are challenged in achieving body weight stability or reduction, in addition to glycaemic control. Post-hoc analyses of body weight and insulin dose data from the AWARD-4 trial involved comparison of treatment with once-weekly dulaglutide 1.5 mg (N = 295) or 0.75 mg (N = 293) and treatment with daily insulin glargine (N = 296), each with prandial insulin lispro (± metformin). MATERIALS AND METHODS Changes in weight and in the proportion of patients without weight gain or with weight loss of at least 3%, 5% or 10% or composites of HbA1c less than 7% without weight gain and weight loss of at least 3% after 52 weeks were compared between the dulaglutide (either dose) groups and the insulin glargine group, overall and by baseline BMI (

BACKGROUND We investigated the rate of severe hypoglycemic events and confounding factors in patients with type-2-diabetes treated with sulfonylurea (SU) at specialized diabetes centers, documented in the German/Austrian DPV-Wiss-database. METHODS Data from 29,485 SU-treated patients were analyzed (median[IQR] age 70.8[62.2-77.8]yrs, diabetes-duration 8.2[4.3-12.8]yrs). The primary objective was to estimate the event-rate of severe hypoglycemia (requiring external help, causing unconsciousness/coma/convulsion and/or emergency.hospitalization). Secondary objectives included exploration of confounding risk-factors through group-comparison and Poisson-regression. RESULTS Severe hypoglycemic events were reported in 826(2.8%) of all patients during their most recent year of SU-treatment. Of these, n = 531(1.8%) had coma, n = 501(1.7%) were hospitalized at least once. The adjusted event-rate of severe hypoglycemia [95%CI] was 3.9[3.7-4.2] events/100 patient-years (coma: 1.9[1.8-2.1]; hospitalization: 1.6[1.5-1.8]). Adjusted event-rates by diabetes-treatment were 6.7 (SU + insulin), 4.9 (SU + insulin + other OAD), 3.1 (SU + other OAD), and 3.8 (SU only). Patients with ≥1 severe event were older (p 60 mL/min: 3.9). CONCLUSIONS These real-life data showed a rate of severe hypoglycemia of 3.9/100 patient-years in SU-treated patients from specialized diabetes centers. Higher risk was associated with known risk-factors including lack of diabetes-education, older age, and decreased eGFR, but also with lower BMI and lower triglyceride-levels, suggesting that SU-treatment in those patients should be considered with caution. This article is protected by copyright. All rights reserved.

Resumen Antecedentes y objetivo El estudio INSTIGATE evalua los costes directos sanitarios y los resultados clinicos en pacientes con diabetes mellitus tipo 2 que inician insulinoterapia en Espana, durante 24 meses. Material y metodo Estudio observacional, no intervencionista, prospectivo y multicentrico. En cada visita se evaluaron los costes incurridos durante los 6 meses previos. Resultados En total se evaluaron 172 pacientes durante al menos 12 o un maximo de 24 meses con un indice de masa corporal medio de 29,6 kg/m 2 , una duracion media [desviacion estandar] de la enfermedad de 10,9 [7,0] anos y un porcentaje de hemoglobina A 1c de 9,2% [1,5%]. Un total de 116 pacientes (67,4%) iniciaron insulina de accion prolongada/intermedia solamente. Los cambios medios intraindividuales en los valores iniciales de hemoglobina A 1c tras 6, 12 y 24 meses de la insulinoterapia fueron, respectivamente, -1,9 [1,65%], -1,6 [1,73%] y -1,5% [1,76%]. La media (mediana) del total de los costes directos sanitarios por paciente aumento de 659 € (527 €) a 1.085 € (694 €) 6 meses despues del inicio de la insulinoterapia, bajo a 646 € (531 €) despues de 12 meses, y 24 meses despues aumento nuevamente a 667 € (539 €). A los 24 meses, los costes de insulina/antidiabeticos orales, medicina general/especializada, y monitorizacion de la glucemia representaron el 41, 26 y 19%, respectivamente, de los costes totales. Conclusiones Los parametros clinicos de estos pacientes con diabetes mellitus tipo 2 mejoraron tras iniciar la insulinoterapia. Tras un incremento temporal, los costes directos sanitarios del tratamiento de la diabetes volvieron a los valores basales al final del periodo de seguimiento.

At the time of diagnosis of type 2 diabetes (T2D), patients already have varying degrees of beta-cell dysfunction and insulin resistance and the defects continue to deteriorate despite treatment. We examined insulin secretion impairment and insulin resistance in overweight patients with T2D who had metformin failure, with elevated HbA1c at maximal metformin dose. Patients (N = 1,039) were examined at entry to the European Exenatide (EUREXA) clinical trial of add-on exenatide versus sulphonylurea. Mean (±SD) age was 57 ± 10 years, and BMI was 32.4 ± 4.1 kg/m(2). All patients underwent an oral glucose tolerance test; HOMA-IR, HOMA-B, ∆I(30)/∆G(30), disposition index and pro-insulin/insulin ratio were evaluated in relation to stratified HbA1c levels (≤7.3, >7.3-8.2, >8.2%) and duration of diabetes (

This study aimed to assess the relative contributions of postprandial and fasting glucose concentrations to overall hyperglycaemia.Patients with type 2 diabetes (n=973) carried out self-monitored blood glucose (SMBG) profiles on entry into the European Exenatide (EUREXA) trial. Glucose area under the curve was calculated for postprandial excursions (AUC(ppg)) and total daytime concentrations6.1 mmol/L (AUC(total)), as well as for the percentage of glycaemia due to postprandial excursions (%(ppg)). In addition, OGTT scores were assessed for each patient. Results were evaluated according to defined HbA(1c) categories.There was a significant linear relationship between HbA(1c) and the derived variables of AUC(ppg), AUC(total) and %(ppg) (P0.001 for each), with explained variance greatest for AUC(total) (r(2)=37.4%). AUC(ppg) increased only slightly up to an HbA(1c) of 7.0%, but showed a steeper increase in higher HbA(1c) categories. Also, the increase in AUC(total) with increasing HbA(1c) was much more pronounced. As a result, the postprandial glucose excursion as a proportion of total glucose (%(ppg)) decreased across HbA(1c) categories from 61.0% at HbA(1c)6.5% to 22.0% at HbA(1c)≥9.0%. HOMA-IR remained virtually unchanged through all HbA(1c) categories, while HOMA-B showed no large changes up to HbA(1c) 7.0%, but then decreased at higher HbA(1c) values. The ΔI30/ΔG30 ratio decreased in the HbA(1c) 7.0-7.9% category, but did not change greatly at higher HbA(1c) categories.With increasing HbA(1c), there was a decrease in the contribution of postprandial hyperglycaemia to total glycaemia, and fasting hyperglycaemia became more important. This is consistent with impaired insulin release, particularly first-phase release, at higher HbA(1c) levels.

ObjectiveInitial GH-induced catch up growth is highly variable in short children born small for gestational age (SGA) and mainly influenced by age at start of therapy and GH dose. This study compared the first year growth-promoting effect of an individually adjusted GH dose (IAD) versus a fixed high GH dose (FHD) in pre-pubertal children born SGA with severe short stature.DesignThis was a randomized, open-label, multi-center study.MethodsThe FHD group received 0.067 mg/kg per day GH throughout the 12-month study. The IAD group initially received 0.035 mg/kg per day GH; at 3 months the Cologne growth-prediction model for first year change in height SDS was applied; if predicted change was ResultsIn the IAD group, 38 out of the 80 patients required the higher GH dose from month 3. From an ANCOVA for non-inferiority, mean difference in change in height SDS between IAD and FHD groups was −0.24 (95% confidence interval (CI) −0.35: −0.12), the CI for height SDS being above the pre-defined non-inferiority margin of −0.5. GH dose reductions due to IGF-I SDS >0.5 and IGFBP-3 SDS ConclusionWith a mean treatment group difference of 1 cm in 12-month growth response, although statistically significant, the IAD group was considered non-inferior compared with the FHD group. Early growth prediction can be used to tailor the dose to the individual patient's needs, resulting in lower overall GH dose.

Introduction To examine changes in insulin regimens and glycemic control during the 24 months after initiation of insulin in patients with type 2 diabetes mellitus. Methods Data were collected over a 24-month period from patients requiring insulin initiation as part of usual care, in a prospective, observational study. Changes in insulin regimens and hemoglobin A1c (HbA1c) were examined within countries (Germany, Greece, Spain) and overall. Results Prandial insulin only was most commonly initiated in Germany, while basal or premixed formulations were initiated in Greece and Spain. In Germany, compared with Greece or Spain, the patients were slightly younger and had a shorter diabetes duration when initiating insulin. For patients overall, 76.1% did not change their insulin regimen between initiation and 24 months. The most obvious change was a shift from prandial to basal/bolus in Germany, with almost doubling of mean daily insulin dose; in Greece and Spain, more patients stopped using insulin and the trend to more complex regimens was not seen. Overall, mean (SD) HbA1c decreased from baseline (9.4 [1.7]%) to 6 months (7.2 [1.0]%), but with little further change through 24 months (7.2 [1.1]%). HbA1c change with basal/bolus insulin (−2.6 [2.0]%, baseline 10.1%) was greater than with basal only (−2.0 [1.8]%, baseline 9.3%). Mean HbA1c less than 7% was achieved and maintained over 24 months in Germany, but was not achieved at any time in Greece or Spain. Conclusions Within 24 months of insulin initiation, the majority of patients with type 2 diabetes remained on the same insulin regimen initially instigated, despite the well-established progressive loss of prandial and basal endogenous insulin secretion. Adequate glycemic control was best achieved where insulin dosage adjustments and insulin intensification took place.

AIM To describe the rationale for the European Exenatide (EUREXA) clinical study and describe the characteristics of the patient cohort. METHODS EUREXA is a multinational study of long-term effects of add-on exenatide vs. glimepiride in patients with type 2 diabetes and failure of diet/lifestyle plus metformin monotherapy. Metformin failure was defined as hemoglobin A1c (HbA1c) > or = 6.5% and patients were overweight/obese (BMI > or = 25 to < 40 kg/m(2)). The primary end point is time to failure of combination treatment, defined from HbA1c concentration according to current criteria. At baseline, an oral glucose tolerance test (OGTT) was performed, fasting blood was taken for lipid profile and patients were randomized to add-on exenatide (5 microg b.i.d. for 4 weeks then 10 microg b.i.d.) or glimepiride (1 mg/day titrated to maximum dose). RESULTS A total of 1039 patients were entered in the study, with mean (+/- s.d.) age 57.2 +/- 9.6 years, body mass index (BMI) 32.4 +/- 4.1 kg/m(2), duration of diabetes 5.6 +/- 4.5 years and HbA1c 7.4 +/- 0.7%. A history of cardiovascular disease (CVD) was present for 64.8% of patients overall and duration of diabetes was statistically significantly longer for patients with CVD than without (p = 0.010). Lipid abnormalities were reported for 48.9% of patients and 40.9% were taking at least one lipid-lowering medication. CONCLUSION Patients included in the EUREXA study had early failure of glucose control with metformin and presented typical features of type 2 diabetes: overweight/obesity and high prevalence of lipid abnormalities and CVD. In this population, the effects of exenatide vs. glimepiride will be evaluated over at least 2.5 years.

Objective: The aim of the study was to assess the influence of overweight and obesity on the risk of calcium oxalate stone formation. Research Methods and Procedures: BMI, 24-hour urine, and serum parameters were evaluated in idiopathic calcium oxalate stone formers (363 men and 164 women) without medical or dietetic pretreatment. Results: Overweight and obesity were present in 59.2% of the men and in 43.9% of the women in the study population. Multiple linear regression analysis revealed a significant positive relationship between BMI and urinary uric acid, sodium, ammonium, and phosphate excretion and an inverse correlation between BMI and urinary pH in both men and women, whereas BMI was associated with urinary oxalate excretion only among women and with urinary calcium excretion only among men. Serum uric acid and creatinine concentrations were correlated with BMI in both genders. Because no association was established between BMI and urinary volume, magnesium, and citrate excretion, inhibitors of calcium oxalate stone formation, the risk of stone formation increased significantly with increasing BMI among both men and women with urolithiasis (p = 0.015). The risk of calcium oxalate stone formation, median number of stone episodes, and frequency of diet-related diseases were highest in overweight and obese men. Discussion: Overweight and obesity are strongly associated with an elevated risk of stone formation in both genders due to an increased urinary excretion of promoters but not inhibitors of calcium oxalate stone formation. Overweight and obese men are more prone to stone formation than overweight women.

Introduction L’exenatide (EXE) ameliore chez les patients diabetiques de type 2 (DT2), le controle metabolique et reduit le poids corporel (PC). Ces donnees sont issues de l’etude « EURopean EXenAtide » (EUREXA), etude prospective a long terme, en ouvert qui compare les effets de l’EXE versus le Glimepiride (GLIM) sur le maintient du controle glycemique. Un addendum de l’etude EUREXA est de comparer les effets de l’EXE et du GLIM, en ajout a la metformine, sur la composition corporelle et la distribution de la masse grasse, a l’inclusion et apres 9 mois de traitement, dans un sous-groupe de patients. Materiels et Methodes Sur les 1 039 patients randomises, 35 sont entres dans l’addendum et 33 patients DT2 en surpoids (IMC moyen : 32,8 ± 3,98 kg/m2) etaient eligibles. Les patients etaient randomises pour recevoir soit l’EXE (n = 15) soit le GLIM (n = 18). La composition corporelle etait analysee par Impetance Bioelectrique (BIA) et la distribution de la masse grasse abdominale par IRM. Resultats A l’inclusion, les patients avaient un PC de 96,7 (13,55) kg dans le groupe EXE, de 98,0 (10,76) kg dans le groupe GLIM et une HbA1c respectivement de 7,5 % (0,55) et de 7,6 % (0,72) ; les variations moyennes [SEM] d’HbA1c etaient de −0,80 % [0,27] et de −0,71 % [0,24] respectivement (p = 0,796). Les variations du PC etaient de −5,26 [1,03] kg et de +2,14 [0,94] respectivement (p Conclusion EXE et GLIM montrent un controle glycemique comparable apres 9 mois de traitement. Les patients sous GLIM ont augmente leur masse grasse au niveau abdominale. La perte de PC sous EXE chez les patients DT2 en surpoids etait principalement due a une perte de masse grasse abdominale avec aucun changement significatif sur la masse maigre.