Michael Trautmann - Academia.edu (original) (raw)

Papers by Michael Trautmann

Research paper thumbnail of Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide

Diabetes Care, Aug 12, 2019

To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glu... more To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). RESEARCH DESIGN AND METHODS EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallelgroup, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo (n = 37), or liraglutide (£1.8 mg daily; n = 36). The primary efficacy end point was change in HbA 1c from baseline to week 13. RESULTS From a baseline HbA 1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ‡1 mg significantly reduced HbA 1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA 1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ‡1 mg than placebo achieved HbA 1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placeboadjusted LS mean differences 21.4 and 22.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. CONCLUSIONS Efpeglenatide once weekly led to significant reductions in HbA 1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.

Research paper thumbnail of Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline

BMJ open diabetes research & care, 2022

Introduction Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being develo... more Introduction Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being developed to improve glycemic control in type 2 diabetes (T2D). In the BALANCE 205 study (NCT02075281), efpeglenatide significantly reduced body weight versus placebo in patients with obesity, or overweight with comorbidities, and without T2D. These subanalyses explore the efficacy and safety of efpeglenatide in subgroups of patients with pre-diabetes and stratified by body mass index (BMI) or age from the BALANCE study. Research design and methods The 20-week BALANCE study randomized patients with BMI ≥30 kg/m 2 or ≥27 kg/ m 2 with comorbidities, and without diabetes, to efpeglenatide 4 mg or 6 mg once weekly, 6 mg or 8 mg once every 2 weeks, or placebo. For these subanalyses, patients were stratified by pre-diabetes status (glycated hemoglobin (HbA 1c) 5.7%−6.4% (39-46 mmol/mol) or fasting plasma glucose (FPG) 100-125 mg/dL) and by BMI or age < or ≥ median values (34.9 kg/ m 2 and 44 years, respectively) at baseline. Results In patients with pre-diabetes at baseline, all efpeglenatide doses led to greater proportions of patients reverting to normoglycemia (40.6%-64.3%) versus placebo (10.0%), and greater reductions in HbA 1c (0.30%-0.38%), FPG (7.7-14.1 mg/dL), and weight (5.6-7.3 kg) versus placebo (nominal p<0.05 for all). In patients with BMI or age < or ≥ median, greater reductions in weight were observed with all efpeglenatide doses versus placebo (nominal p<0.01 for all). The most common adverse events in patients receiving efpeglenatide across patient subgroups were gastrointestinal adverse events. Conclusions These results are consistent with the overall BALANCE population and suggest beneficial effects of efpeglenatide on glycemic control and body weight regardless of pre-diabetes status, age, or BMI at baseline. The effects of efpeglenatide on glycemic control in patients with pre-diabetes suggest it might help reduce the likelihood of at-risk patients developing diabetes. http://drc.bmj.com/

Research paper thumbnail of Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study

BMJ open diabetes research & care, Jun 1, 2021

et al. Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and be... more et al. Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study.

Research paper thumbnail of Encapsulation of Exenatide in Poly-(<scp>d,l</scp>-Lactide-Co-Glycolide) Microspheres Produced an Investigational Long-Acting Once-Weekly Formulation for Type 2 Diabetes

Diabetes Technology & Therapeutics, Nov 1, 2011

Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet... more Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This longacting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(d,l-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, *2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, *7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6-7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly.

Research paper thumbnail of Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1

Expert Opinion on Drug Discovery, Dec 12, 2012

The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from t... more The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic β-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss. This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials. GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.

Research paper thumbnail of Somatostatin analog Sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors

World Journal of Surgery, Jul 1, 1993

Research paper thumbnail of Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes

Diabetes Care, Mar 23, 2010

OBJECTIVE-To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic ... more OBJECTIVE-To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS-Obese subjects (n ϭ 152; age 46 Ϯ 12 years, female 82%, weight 108.6 Ϯ 23.0 kg, BMI 39.6 Ϯ 7.0 kg/m 2 , IGT or IFG 25%) were randomized to receive exenatide (n ϭ 73) or placebo (n ϭ 79), along with lifestyle intervention, for 24 weeks. RESULTS-Exenatide-treated subjects lost 5.1 Ϯ 0.5 kg from baseline versus 1.6 Ϯ 0.5 kg with placebo (exenatide Ϫ placebo, P Ͻ 0.001). Placebo-subtracted difference in percent weight reduction was Ϫ3.3 Ϯ 0.5% (P Ͻ 0.001). Both groups reduced their daily calorie intake (exenatide, Ϫ449 cal; placebo, Ϫ387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS-Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Research paper thumbnail of Somatostatin in der pr�operativen therapie und postoperativen diagnostik eines patienten mit Verner-Morrison-Syndrom

Langenbecks Archiv für Chirurgie, 1992

We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated... more We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated vipoma. Marked tumor-associated hypercalcemia could be treated successfully with somatostatin analogues prior to surgical therapy of the pancreatic tumor. Sixteen months after extirpation of the primary tumor recurrent tumor growth was diagnosed; at this time the patient was clinically asymptomatic and had no abnormal laboratory test results. Liver metastases and local metastases were identified using somatostatin receptor scintigraphy. We report and discuss the use of somatostatin in the treatment of tumor-associated symptoms in endocrine tumors and the possibility of identifying endocrine tumors by means of somatostatin receptor scintigraphy.

Research paper thumbnail of 1.3 Exenatide Once Weekly: Sustained Glycemic and Weight Control Through 3 Years Compared with Insulin Glargine (67-OR)

Nederlands tijdschrift voor diabetologie, Sep 1, 2013

De behandelingen van eenmaal per week (Dulaglutide) hebben een placebocontrole, terwijl juist de ... more De behandelingen van eenmaal per week (Dulaglutide) hebben een placebocontrole, terwijl juist de relevante vergelijking tussen Dulaglutide en Exenatide open label is met de bijbehorende risico's op een bias. Langetermijnstudies zijn nodig om het consistente eff ect van deze behandelingen op het beloop van de diabetes, de (macrovasculaire) complicaties en de levensverwachting te kunnen beoordelen.

Research paper thumbnail of Improved glycaemic control and treatment satisfaction with a simple wearable 3-day insulin delivery device among people with Type 2 diabetes

Diabetic medicine : a journal of the British Diabetic Association, Oct 1, 2018

To evaluate the PAQ (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that ... more To evaluate the PAQ (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes. Adults with Type 2 diabetes with HbA concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single-arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA , seven-point self-monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects. A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m , Type 2 diabetes duration 17 ± 8 years, HbA 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selecte...

Research paper thumbnail of Standardisiertes chirurgisches Konzept zur Diagnostik und Therapie des Zollinger-Ellison-Syndroms

Deutsche Medizinische Wochenschrift, Mar 25, 2008

ABSTRACT Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years... more ABSTRACT Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years) with Zollinger-Ellison syndrome (ZES) were treated according to a standardized surgical concept. The diagnostic work-up consisted of measuring serum gastrin levels, pre-operative localization by ultrasound and abdominal computed tomography, as well as extensive staging by laparotomy. As complete a tumour resection as possible was the aim of treatment in 15 patients, while in one patient it was to reduce the tumour mass. In six patients who had resection of a solitary tumour there was no evidence of recurrence after 6-42 months of follow-up. Exploration of the duodenum made it possible to identify and then remove a small gastrinoma of the duodenal wall in three patients. No gastrinoma was found in one patient despite extensive exploration. In a further four patients the laparotomy was purely exploratory, because diffuse metastasization was found. In four patients the primary tumour and, where present, the regional lymph nodes were removed, but the signs of ZES persisted, i.e. the intervention was merely palliative. In one female patient, reduction of tumour mass was necessary because the symptoms could not be controlled by conservative measures: she died postoperatively from toxic hepatitis. This experience indicates that standardized surgical intervention achieves potentially curative results in nearly 40% of patients. Including the duodenum in the surgical exploration allows the identification of even small gastrinomas of the duodenal wall. It is concluded that all patients with ZES but no evidence of diffuse metastases should undergo surgical treatment.

Research paper thumbnail of Early Pharmacodynamic Effects of Exenatide Once Weekly in Type 2 Diabetes Are Independent of Weight Loss: A Pooled Analysis of Patient-level Data

Clinical Therapeutics, 2016

Purpose: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved... more Purpose: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective ($ 50 pg/mL) and steady-state ($ 300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses. Methods: This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA 1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed. Findings: Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA 1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA 1c , FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not. Implications: Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.

Research paper thumbnail of Endokrin aktive Pankreastumoren aus internistischer Sicht

Research paper thumbnail of Exenatide und biphasisches Insulin Aspart bei Patienten mit Typ-2-Diabetes: Klinische Ergebnisse einer Nicht-Unterlegenheitsstudie

Diabetologie und Stoffwechsel, 2007

Research paper thumbnail of P39 Facteurs prédictifs d’atteinte de l’objectif glycémique chez des patients diabétiques de type 2 traités par exénatide ou insuline : résultats d’une méta-analyse

Diabetes & Metabolism, 2008

Introduction Dans 2 etudes comparatives, la baisse d’HbA1c apres 6 mois de traitement etait compa... more Introduction Dans 2 etudes comparatives, la baisse d’HbA1c apres 6 mois de traitement etait comparable avec l’exenatide (10 μg 2 fois par jour) et l’insuline (glargine ou asparte biphasique). L’objectif de la meta-analyse etait d’identifier les caracteristiques associees a une bonne reponse glycemique. Materiels et methodes Les donnees des 2 etudes on ete poolees (n = 1 050) pour determiner si les caracteristiques initiales des patients (HbA1c, glycemie a jeun [GAJ], poids, âge, anciennete du diabete, origine et sexe) etaient associees a une HbA1c en fin d’etude ≤ 6,5 % et ≤ 7 % avec l’exenatide ou l’insuline, associes au traitement oral pris avant l’etude (metformine + sulfamide Met+SU). Resultats Le taux moyen ( ± SD) initial d’HbA1c (8,4 ± 1,0 %) etait comparable entre les traitements qui n’etaient pas un facteur predictif d’obtention d’une HbA1c ≤ 7 %. En revanche, les patients traites par exenatide avaient 1,69 fois plus de chance d’atteindre une HbA1c ≤ 6,5 % que les patients traites par insuline (odds ratio (OR) IC95 % 1,21-2,35 ; p = 0,002). Avec exenatide, une HbA1c initiale plus basse (OR = 0,40 IC95 % 0,29-0,54) et une GAJ initiale plus basse (OR = 0,87 IC95 % 0,78-0,96) etaient des facteurs predictifs significatifs d’obtention d’une HbA1c ≤ 6,5 %. Une HbA1c initiale plus basse (OR = 0,47 IC95 % 0,36-0,62), une GAJ plus basse (OR = 0,87 IC95 % 0,79-0,96) et un âge plus avance (OR = 1,04 IC95 % 1,01-1,06) etaient des facteurs predictifs significatifs d’obtention d’une HbA1c ≤ 7 %. Avec l’insuline, seul un taux d’HbA1c initial plus bas etait un facteur predictif significatif associe a une HbA1c ≤ 6,5 % (OR- = 0,36 IC95 % 0,27-0,50) ou ≤ 7 % (OR = 0,30 IC95 % 0,23-0,40). Conclusion Chez des patients diabetiques de type 2 mal controles par MET+SU, candidats a la mise sous insuline, un plus grand pourcentage de patients atteignait une HbA1c ≤ 6,5 % avec l’exenatide compare a l’insuline, sans augmentation des hypoglycemies totales. Dans ces essais, l’exenatide etait associe a un plus faible taux d’hypoglycemie nocturne et en moyenne a une perte de poids, l’insuline etait associee a une prise de poids. Quelque soit le traitement, une HbA1c initiale plus basse etait associee a une plus grande probabilite d’atteindre l’objectif glycemique.

Research paper thumbnail of PO43 - Les anticorps anti-exénatide ne réagissent ni avec le GLP-1 humain, ni avec le glucagon et n’altèrent ni l’efficacité, ni la sécurité d’un traitement par exénatide

Diabetes & Metabolism, 2011

HbA1c > 6,5 %), soit 81 DT1 et 60 DT2. Nous n'avons exclu pour l'analyse les grossesses multiples... more HbA1c > 6,5 %), soit 81 DT1 et 60 DT2. Nous n'avons exclu pour l'analyse les grossesses multiples, et les MODY. Résultats : La prise de poids est moindre chez les DT2 de 6.5 ± 15,3 kg vs 13.5 ± 6,1 kg (DT1) (p < 0,001). le taux de programmation est de 60 % (DT1) vs 40 % (DT2), 60 % des DT2 ont débuté la grossesse sous antidiabétiques oraux (modification de traitement à 8SA en moyenne).78 % des DT1 et 9 % des DT2 sont traitées par pompe à Insuline. L'HbA1c (%) à chaque trimestre est 7,15/6,62/6,12 (DT1), et 7,29/6,3/6,02 (DT2). Les besoins journaliers en insuline sont 75 ± 35 U/j (DT1) vs 87 ± 68 U/j (DT2). Le poids de naissance est de 3225 g ± 579 (DT1) vs 3137 ± 671 g (DT2). nous n'avons pas trouvé de différence pour le taux de césariennes 57 % (DT1) vs 4 8 % (DT2), de transfert en néonatologie 20 % (DT1) vs 17 % (DT2) le nombre d'issues défavorables (FCS, MIU, IMG ou malformations sévères), 9 (11 %)1 DT1, 8 (13 %) DT2.L'HbA1c à la conception est plus élevée chez les patientes présentant une issue défavorable (8.47 ± 2.18 versus 7.02 ± 1.30, p = 0.0004). La prématurité est significativement associée, dans les deux types de diabète, à l'HbA1c au second trimestre de la grossesse (6,45 vs 5,97 p < 0,01). Conclusion : Si on ne retient que les diabètes type 2 « incontestables », les complications des grossesses sont aussi importantes dans le DT2 que dans le DT1. La précocité de la prise en charge effective, de l'insulinothérapie, et la programmation sont les facteurs primordiaux de la réussite de ces grossesses. PO43 Les anticorps anti-exénatide ne réagissent ni avec le GLP-1 humain, ni avec le glucagon et n'altèrent ni l'efficacité, ni la sécurité d'un traitement par exénatide

Research paper thumbnail of A systematic literature review and evidence synthesis of anti-diabetes treatments in type 2 diabetes mellitus patients: Indirect comparison of exenatide with metformin + sulphonylurea

Value in Health, 2014

ture between January 2006 and December 2011. Controls were matched with cases at a 4:1 ratio on t... more ture between January 2006 and December 2011. Controls were matched with cases at a 4:1 ratio on the following characteristics: gender, age, geographic region, and date of first dispensing of a TZD or insulin prescription. We conducted conditional logistic regression analyses to estimate the odds ratios (ORs) of having a fracture associated with the use of insulin compared to TZD while controlling for other covariates. Results: There were 2,842 cases matched to 8,238 controls. The mean (standard deviation) age of the study subjects was 46.5 years (0.9) and 57.6% were women. Among cases, 32.8% used insulin and 67.2% used TZDs, and for controls 30.3% used insulin and 69.7% used TZDs. The crude OR for insulin users compared with TZD was 1.14 (95% confidence interval [CI], 1.04-1.25). After adjustment for other antidiabetic drugs, comedication, and comorbidities, the OR was 1.28 (95% CI, 1.09-1.49). ConClusions: We found an association between use of insulin and fractures compared to TZDs in patients with COPD and DM. While further research is needed, clinicians and policy makers should assure that screening guidelines consider this relative risk in patients with COPD and DM. PDB4 CliniCal effiCaCy anD safety of insulin asPart ComPareD with regular human insulin in Patients with tyPe 1 anD tyPe 2 DiaBetes mellitus reCeiving PranDial insulin regimen-a systematiC review anD meta-analysis

Research paper thumbnail of Preclinical Effects of Efpeglenatide, a Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, Compared with Liraglutide and Dulaglutide

Diabetes, Jun 22, 2018

Efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in dev... more Efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in development for type 2 diabetes. The effects of efpeg vs. those of liraglutide (lira) and dulaglutide (dula) on glucodynamics and weight/lipid profiles were studied over 4 weeks in mouse models of diabetes (db/db) and obesity (diet-induced obesity [DIO]), respectively; doses tested wereefpeg 1.45, 2.89, or 4.35 nmol/kg once every 2 days (Q2D); twice-daily lira 30 nmol/kg (db/db study) or 50 nmol/kg (DIO study); dula 0.98 or 1.96 nmol/kg Q2D (equivalent human doses/key results in Table). At the highest doses tested, efpeg was significantly more effective at lowering blood glucose (vs. lira and dula) and reducing the increase in glycated hemoglobin (HbA1c) from Day 0 (vs. lira) in db/db mice. Efpeg also improved insulin sensitivity (vs. lira and dula) and postprandial glucose control (vs. dula). In DIO mice, efpeg significantly reduced body weight and mesenteric fat mass (vs. dula), and cholesterol (vs. lira and dula; at highest doses). Overall, efpeg showed greater reductions in blood glucose, HbA1c increase, weight, and cholesterol vs. other GLP-1 RAs in mice. These effects may be due to the distinct receptor binding properties of efpeg, which enhance intracellular signaling and insulin release in β-cells. Further studies are needed to assess the clinical relevance of these findings. Disclosure M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.

Research paper thumbnail of In Vitro Studies to Evaluate the Receptor Kinetics of Efpeglenatide vs. Other Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists

Diabetes, Jul 1, 2018

Efpeglenatide (efpeg) is a long-acting GLP-1 R agonist in development for the treatment of T2D. E... more Efpeglenatide (efpeg) is a long-acting GLP-1 R agonist in development for the treatment of T2D. Efpeg’s effects on the GLP-1 R suggest that it is a superagonist: a ligand that leads to greater maximal signaling and stimulation compared with its endogenous ligand. In vitro studies evaluated the superagonistic effects of efpeg and compared them to the effects of liraglutide (lira) and dulaglutide (dula) on GLP-1 R-binding kinetics and internalization, and cell signaling/desensitization. Efpeg had a higher dissociation constant vs. lira or dula (360.7 vs. 58.7 and 39.4 nmol/L, respectively) indicating a lower binding affinity for GLP-1 R (∼6.1 fold vs. lira, ∼9.2 vs. dula) and faster dissociation vs. lira (∼3.6 fold; p&lt;0.001) or dula (∼2.9 fold; p&lt;0.001). At 100nM, efpeg led to less receptor internalization vs. lira or dula (% of initial internalized receptor: 140% vs. 1191% and 714%, respectively; p&lt;0.001 each) and lower proportions of receptor lost from the cell surface (32% vs. 74% and 69%; p&lt;0.001). After pretreatment (4 or 24 h), efpeg led to significantly greater accumulation of cAMP and insulinotropic activity vs. lira or dula (Figure). The superagonistic effect of efpeg on GLP-1 R may be due to its specific binding characteristics, allowing more cell-surface receptor availability for intracellular signaling. The clinical relevance of these findings should be assessed further. Disclosure I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M. Moon: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.

Research paper thumbnail of Severe insulin resistance treated with insulin lispro

Research paper thumbnail of Once-Weekly Efpeglenatide Dose-Range Effects on Glycemic Control and Body Weight in Patients With Type 2 Diabetes on Metformin or Drug Naive, Referenced to Liraglutide

Diabetes Care, Aug 12, 2019

To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glu... more To explore the efficacy, safety, and tolerability of once-weekly efpeglenatide, a long-acting glucagon-like peptide 1 receptor agonist (GLP-1 RA), in early type 2 diabetes (T2D) (drug naive or on metformin monotherapy). RESEARCH DESIGN AND METHODS EXCEED 203 was a 12-week, randomized, placebo-controlled, double-blind, parallelgroup, dose-ranging study of efpeglenatide once weekly referenced to open-label liraglutide 1.8 mg (exploratory analysis). Participants, ∼90% on metformin monotherapy, were randomized to one of five efpeglenatide doses (0.3, 1, 2, 3, or 4 mg q.w.; n = 181), placebo (n = 37), or liraglutide (£1.8 mg daily; n = 36). The primary efficacy end point was change in HbA 1c from baseline to week 13. RESULTS From a baseline HbA 1c of 7.7-8.0% (61.0-63.9 mmol/mol), all efpeglenatide doses ‡1 mg significantly reduced HbA 1c versus placebo (placebo-adjusted least squares [LS] mean changes 0.6-1.2%, P < 0.05 for all) to a final HbA 1c of 6.3-6.8% (45.4-50.6 mmol/mol); masked efpeglenatide 4 mg was noninferior to open-label liraglutide. Greater proportions treated with efpeglenatide ‡1 mg than placebo achieved HbA 1c <7% (61-72% vs. 24%, P < 0.05 for all), and greater reductions in body weight were observed with efpeglenatide 3 and 4 mg versus placebo (placeboadjusted LS mean differences 21.4 and 22.0 kg, respectively, P < 0.05 for both). Rates of nausea and vomiting were consistent with other GLP-1 RAs and rapidly subsided after the initial 2 weeks. No neutralizing antibodies were detected with efpeglenatide. CONCLUSIONS Efpeglenatide once weekly led to significant reductions in HbA 1c and weight, with a safety profile consistent with the GLP-1 RA class in patients with early T2D mostly on metformin monotherapy.

Research paper thumbnail of Efficacy and safety of efpeglenatide in key patient subgroups from the BALANCE randomized trial, stratified by pre-diabetes status, BMI, and age at baseline

BMJ open diabetes research & care, 2022

Introduction Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being develo... more Introduction Efpeglenatide is a long-acting glucagon-like peptide-1 receptor agonist being developed to improve glycemic control in type 2 diabetes (T2D). In the BALANCE 205 study (NCT02075281), efpeglenatide significantly reduced body weight versus placebo in patients with obesity, or overweight with comorbidities, and without T2D. These subanalyses explore the efficacy and safety of efpeglenatide in subgroups of patients with pre-diabetes and stratified by body mass index (BMI) or age from the BALANCE study. Research design and methods The 20-week BALANCE study randomized patients with BMI ≥30 kg/m 2 or ≥27 kg/ m 2 with comorbidities, and without diabetes, to efpeglenatide 4 mg or 6 mg once weekly, 6 mg or 8 mg once every 2 weeks, or placebo. For these subanalyses, patients were stratified by pre-diabetes status (glycated hemoglobin (HbA 1c) 5.7%−6.4% (39-46 mmol/mol) or fasting plasma glucose (FPG) 100-125 mg/dL) and by BMI or age < or ≥ median values (34.9 kg/ m 2 and 44 years, respectively) at baseline. Results In patients with pre-diabetes at baseline, all efpeglenatide doses led to greater proportions of patients reverting to normoglycemia (40.6%-64.3%) versus placebo (10.0%), and greater reductions in HbA 1c (0.30%-0.38%), FPG (7.7-14.1 mg/dL), and weight (5.6-7.3 kg) versus placebo (nominal p<0.05 for all). In patients with BMI or age < or ≥ median, greater reductions in weight were observed with all efpeglenatide doses versus placebo (nominal p<0.01 for all). The most common adverse events in patients receiving efpeglenatide across patient subgroups were gastrointestinal adverse events. Conclusions These results are consistent with the overall BALANCE population and suggest beneficial effects of efpeglenatide on glycemic control and body weight regardless of pre-diabetes status, age, or BMI at baseline. The effects of efpeglenatide on glycemic control in patients with pre-diabetes suggest it might help reduce the likelihood of at-risk patients developing diabetes. http://drc.bmj.com/

Research paper thumbnail of Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study

BMJ open diabetes research & care, Jun 1, 2021

et al. Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and be... more et al. Effects of efpeglenatide versus liraglutide on gastric emptying, glucose metabolism and beta-cell function in people with type 2 diabetes: an exploratory, randomized phase Ib study.

Research paper thumbnail of Encapsulation of Exenatide in Poly-(<scp>d,l</scp>-Lactide-Co-Glycolide) Microspheres Produced an Investigational Long-Acting Once-Weekly Formulation for Type 2 Diabetes

Diabetes Technology & Therapeutics, Nov 1, 2011

Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet... more Exenatide once-weekly (EQW [2 mg s.c.]) is under development as monotherapy as an adjunct to diet and exercise or as a combination therapy with an oral antidiabetes drug(s) in adults with type 2 diabetes. This longacting formulation contains the active ingredient of the original exenatide twice-daily (EBID) formulation encapsulated in 0.06-mm-diameter microspheres of medical-grade poly-(d,l-lactide-co-glycolide) (PLG). After mechanical suspension and subcutaneous injection by the patient, EQW microspheres hydrate in situ and adhere to one another to form an amalgam. A small amount of loosely bound surface exenatide, typically less than 1%, releases in the first few hours, whereas drug located in deeper interstices diffuses out more slowly (time to maximum, *2 weeks). Fully encapsulated exenatide (i.e., drug initially inaccessible to diffusion) releases over a still longer period (time to maximum, *7 weeks) as the PLG matrix hydrolyzes into lactic acid and glycolic acid, which are subsequently eliminated as carbon dioxide and water. For EQW, plasma exenatide concentrations reach the therapeutic range by 2 weeks and steady state by 6-7 weeks. This gradual approach to steady state seems to improve tolerability, as nausea is less frequent with EQW than EBID. EQW administrations may be associated with palpable skin nodules that generally resolve without further medical intervention. In comparative trials, EQW improved hemoglobin A1c more than EBID, sitagliptin, pioglitazone, or insulin glargine and reduced fasting plasma glucose more than EBID. Weight loss due to EQW or EBID was similar. EQW is the first glucose-lowering agent that is administered once weekly.

Research paper thumbnail of Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1

Expert Opinion on Drug Discovery, Dec 12, 2012

The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from t... more The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic β-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss. This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials. GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.

Research paper thumbnail of Somatostatin analog Sandostatin and inhibition of tumor growth in patients with metastatic endocrine gastroenteropancreatic tumors

World Journal of Surgery, Jul 1, 1993

Research paper thumbnail of Effects of Exenatide and Lifestyle Modification on Body Weight and Glucose Tolerance in Obese Subjects With and Without Pre-Diabetes

Diabetes Care, Mar 23, 2010

OBJECTIVE-To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic ... more OBJECTIVE-To assess the effects of exenatide on body weight and glucose tolerance in nondiabetic obese subjects with normal or impaired glucose tolerance (IGT) or impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS-Obese subjects (n ϭ 152; age 46 Ϯ 12 years, female 82%, weight 108.6 Ϯ 23.0 kg, BMI 39.6 Ϯ 7.0 kg/m 2 , IGT or IFG 25%) were randomized to receive exenatide (n ϭ 73) or placebo (n ϭ 79), along with lifestyle intervention, for 24 weeks. RESULTS-Exenatide-treated subjects lost 5.1 Ϯ 0.5 kg from baseline versus 1.6 Ϯ 0.5 kg with placebo (exenatide Ϫ placebo, P Ͻ 0.001). Placebo-subtracted difference in percent weight reduction was Ϫ3.3 Ϯ 0.5% (P Ͻ 0.001). Both groups reduced their daily calorie intake (exenatide, Ϫ449 cal; placebo, Ϫ387 cal). IGT or IFG normalized at end point in 77 and 56% of exenatide and placebo subjects, respectively. CONCLUSIONS-Exenatide plus lifestyle modification decreased caloric intake and resulted in weight loss in nondiabetic obesity with improved glucose tolerance in subjects with IGT and IFG.

Research paper thumbnail of Somatostatin in der pr�operativen therapie und postoperativen diagnostik eines patienten mit Verner-Morrison-Syndrom

Langenbecks Archiv für Chirurgie, 1992

We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated... more We report the case of a patient with Verner-Morrison syndrome due to a malignant MEN I-associated vipoma. Marked tumor-associated hypercalcemia could be treated successfully with somatostatin analogues prior to surgical therapy of the pancreatic tumor. Sixteen months after extirpation of the primary tumor recurrent tumor growth was diagnosed; at this time the patient was clinically asymptomatic and had no abnormal laboratory test results. Liver metastases and local metastases were identified using somatostatin receptor scintigraphy. We report and discuss the use of somatostatin in the treatment of tumor-associated symptoms in endocrine tumors and the possibility of identifying endocrine tumors by means of somatostatin receptor scintigraphy.

Research paper thumbnail of 1.3 Exenatide Once Weekly: Sustained Glycemic and Weight Control Through 3 Years Compared with Insulin Glargine (67-OR)

Nederlands tijdschrift voor diabetologie, Sep 1, 2013

De behandelingen van eenmaal per week (Dulaglutide) hebben een placebocontrole, terwijl juist de ... more De behandelingen van eenmaal per week (Dulaglutide) hebben een placebocontrole, terwijl juist de relevante vergelijking tussen Dulaglutide en Exenatide open label is met de bijbehorende risico's op een bias. Langetermijnstudies zijn nodig om het consistente eff ect van deze behandelingen op het beloop van de diabetes, de (macrovasculaire) complicaties en de levensverwachting te kunnen beoordelen.

Research paper thumbnail of Improved glycaemic control and treatment satisfaction with a simple wearable 3-day insulin delivery device among people with Type 2 diabetes

Diabetic medicine : a journal of the British Diabetic Association, Oct 1, 2018

To evaluate the PAQ (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that ... more To evaluate the PAQ (CeQur SA, Horw, Switzerland), a wearable 3-day insulin delivery device that provides set basal rates and bolus insulin on demand, in people with Type 2 diabetes. Adults with Type 2 diabetes with HbA concentrations ≥53 and ≤97 mmol/mol (7.0 and 11.0%) while treated with ≥2 insulin injections/day were enrolled in two single-arm studies comprising three periods: a baseline (insulin injections), a transition and a PAQ treatment period (12 weeks). Endpoints included HbA , seven-point self-monitored blood glucose, total daily dose of insulin and body weight. Safety was assessed according to examination, hypoglycaemic episodes and adverse device effects. A total of 28 adults were enrolled (age 63 ± 7 years, 86% men, BMI 32.3 ± 4.3kg/m , Type 2 diabetes duration 17 ± 8 years, HbA 70 ± 12 mmol/mol (8.6 ± 1.1%), total daily insulin dose 58.7 ± 20.7 U), of whom 24 completed the studies. When transitioned to PAQ, 75% of participants continued on the first basal rate selecte...

Research paper thumbnail of Standardisiertes chirurgisches Konzept zur Diagnostik und Therapie des Zollinger-Ellison-Syndroms

Deutsche Medizinische Wochenschrift, Mar 25, 2008

ABSTRACT Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years... more ABSTRACT Between 1987 and 1991, 16 patients (13 females, three males; mean age 52.4 [33-73] years) with Zollinger-Ellison syndrome (ZES) were treated according to a standardized surgical concept. The diagnostic work-up consisted of measuring serum gastrin levels, pre-operative localization by ultrasound and abdominal computed tomography, as well as extensive staging by laparotomy. As complete a tumour resection as possible was the aim of treatment in 15 patients, while in one patient it was to reduce the tumour mass. In six patients who had resection of a solitary tumour there was no evidence of recurrence after 6-42 months of follow-up. Exploration of the duodenum made it possible to identify and then remove a small gastrinoma of the duodenal wall in three patients. No gastrinoma was found in one patient despite extensive exploration. In a further four patients the laparotomy was purely exploratory, because diffuse metastasization was found. In four patients the primary tumour and, where present, the regional lymph nodes were removed, but the signs of ZES persisted, i.e. the intervention was merely palliative. In one female patient, reduction of tumour mass was necessary because the symptoms could not be controlled by conservative measures: she died postoperatively from toxic hepatitis. This experience indicates that standardized surgical intervention achieves potentially curative results in nearly 40% of patients. Including the duodenum in the surgical exploration allows the identification of even small gastrinomas of the duodenal wall. It is concluded that all patients with ZES but no evidence of diffuse metastases should undergo surgical treatment.

Research paper thumbnail of Early Pharmacodynamic Effects of Exenatide Once Weekly in Type 2 Diabetes Are Independent of Weight Loss: A Pooled Analysis of Patient-level Data

Clinical Therapeutics, 2016

Purpose: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved... more Purpose: Exenatide once weekly, a glucagon-like peptide-1 receptor agonist (GLP-1RA), is approved as an adjunct to diet and exercise for the treatment of adults with type 2 diabetes mellitus. Exenatide acts by binding to and activating glucagon-like peptide-1 receptors, thereby stimulating glucose-dependent insulin secretion, suppressing glucose-dependent glucagon secretion, slowing gastric emptying, and increasing feelings of satiety. Gradual increases in drug level ("autotitration") after the initiation of a fixed exenatide 2-mg weekly dose achieve minimal effective ($ 50 pg/mL) and steady-state ($ 300 pg/mL) concentrations by 2 weeks and 6 to 8 weeks, respectively. The purpose of this study was to examine pharmacodynamic outcomes with exenatide once weekly and to determine whether changes are secondary to weight loss and thus delayed by the sequential nature of responses. Methods: This post hoc analysis evaluated trials in the exenatide once-weekly development program. Outcomes included glycosylated hemoglobin (HbA 1c), weight, fasting serum or plasma glucose (FG), lipids, and blood pressure (BP) at weeks 2, 4, and 24. Relationships between changes from baseline in these outcomes and changes in weight were examined. The effect of nausea and vomiting (adverse events characteristic of GLP-1RAs) on weight loss was also assessed. Findings: Pooled data were analyzed from 12 trials in which 2190 patients received exenatide once weekly. Patients had a mean HbA 1c level of 8.4% and weight of 87 kg at baseline. Exenatide once weekly produced significant improvements in HbA 1c , FG, weight, and systolic BP at weeks 2 and 4, with continuous improvements through week 24. There were no clinically meaningful correlations between weight loss and improvements in pharmacodynamic outcomes at weeks 2, 4, or 24. Patients had significant reductions in weight at weeks 2, 4, and 24 regardless of whether they experienced nausea and/or vomiting during the study, although patients with at least 1 nausea/vomiting event had greater weight loss at week 24 than those who did not. Implications: Improvements in pharmacodynamic end points occurred early in treatment with exenatide once weekly, before steady-state plasma concentrations. These early effects did not seem to be secondary to weight loss and are likely the direct effects of exenatide.

Research paper thumbnail of Endokrin aktive Pankreastumoren aus internistischer Sicht

Research paper thumbnail of Exenatide und biphasisches Insulin Aspart bei Patienten mit Typ-2-Diabetes: Klinische Ergebnisse einer Nicht-Unterlegenheitsstudie

Diabetologie und Stoffwechsel, 2007

Research paper thumbnail of P39 Facteurs prédictifs d’atteinte de l’objectif glycémique chez des patients diabétiques de type 2 traités par exénatide ou insuline : résultats d’une méta-analyse

Diabetes & Metabolism, 2008

Introduction Dans 2 etudes comparatives, la baisse d’HbA1c apres 6 mois de traitement etait compa... more Introduction Dans 2 etudes comparatives, la baisse d’HbA1c apres 6 mois de traitement etait comparable avec l’exenatide (10 μg 2 fois par jour) et l’insuline (glargine ou asparte biphasique). L’objectif de la meta-analyse etait d’identifier les caracteristiques associees a une bonne reponse glycemique. Materiels et methodes Les donnees des 2 etudes on ete poolees (n = 1 050) pour determiner si les caracteristiques initiales des patients (HbA1c, glycemie a jeun [GAJ], poids, âge, anciennete du diabete, origine et sexe) etaient associees a une HbA1c en fin d’etude ≤ 6,5 % et ≤ 7 % avec l’exenatide ou l’insuline, associes au traitement oral pris avant l’etude (metformine + sulfamide Met+SU). Resultats Le taux moyen ( ± SD) initial d’HbA1c (8,4 ± 1,0 %) etait comparable entre les traitements qui n’etaient pas un facteur predictif d’obtention d’une HbA1c ≤ 7 %. En revanche, les patients traites par exenatide avaient 1,69 fois plus de chance d’atteindre une HbA1c ≤ 6,5 % que les patients traites par insuline (odds ratio (OR) IC95 % 1,21-2,35 ; p = 0,002). Avec exenatide, une HbA1c initiale plus basse (OR = 0,40 IC95 % 0,29-0,54) et une GAJ initiale plus basse (OR = 0,87 IC95 % 0,78-0,96) etaient des facteurs predictifs significatifs d’obtention d’une HbA1c ≤ 6,5 %. Une HbA1c initiale plus basse (OR = 0,47 IC95 % 0,36-0,62), une GAJ plus basse (OR = 0,87 IC95 % 0,79-0,96) et un âge plus avance (OR = 1,04 IC95 % 1,01-1,06) etaient des facteurs predictifs significatifs d’obtention d’une HbA1c ≤ 7 %. Avec l’insuline, seul un taux d’HbA1c initial plus bas etait un facteur predictif significatif associe a une HbA1c ≤ 6,5 % (OR- = 0,36 IC95 % 0,27-0,50) ou ≤ 7 % (OR = 0,30 IC95 % 0,23-0,40). Conclusion Chez des patients diabetiques de type 2 mal controles par MET+SU, candidats a la mise sous insuline, un plus grand pourcentage de patients atteignait une HbA1c ≤ 6,5 % avec l’exenatide compare a l’insuline, sans augmentation des hypoglycemies totales. Dans ces essais, l’exenatide etait associe a un plus faible taux d’hypoglycemie nocturne et en moyenne a une perte de poids, l’insuline etait associee a une prise de poids. Quelque soit le traitement, une HbA1c initiale plus basse etait associee a une plus grande probabilite d’atteindre l’objectif glycemique.

Research paper thumbnail of PO43 - Les anticorps anti-exénatide ne réagissent ni avec le GLP-1 humain, ni avec le glucagon et n’altèrent ni l’efficacité, ni la sécurité d’un traitement par exénatide

Diabetes & Metabolism, 2011

HbA1c > 6,5 %), soit 81 DT1 et 60 DT2. Nous n'avons exclu pour l'analyse les grossesses multiples... more HbA1c > 6,5 %), soit 81 DT1 et 60 DT2. Nous n'avons exclu pour l'analyse les grossesses multiples, et les MODY. Résultats : La prise de poids est moindre chez les DT2 de 6.5 ± 15,3 kg vs 13.5 ± 6,1 kg (DT1) (p < 0,001). le taux de programmation est de 60 % (DT1) vs 40 % (DT2), 60 % des DT2 ont débuté la grossesse sous antidiabétiques oraux (modification de traitement à 8SA en moyenne).78 % des DT1 et 9 % des DT2 sont traitées par pompe à Insuline. L'HbA1c (%) à chaque trimestre est 7,15/6,62/6,12 (DT1), et 7,29/6,3/6,02 (DT2). Les besoins journaliers en insuline sont 75 ± 35 U/j (DT1) vs 87 ± 68 U/j (DT2). Le poids de naissance est de 3225 g ± 579 (DT1) vs 3137 ± 671 g (DT2). nous n'avons pas trouvé de différence pour le taux de césariennes 57 % (DT1) vs 4 8 % (DT2), de transfert en néonatologie 20 % (DT1) vs 17 % (DT2) le nombre d'issues défavorables (FCS, MIU, IMG ou malformations sévères), 9 (11 %)1 DT1, 8 (13 %) DT2.L'HbA1c à la conception est plus élevée chez les patientes présentant une issue défavorable (8.47 ± 2.18 versus 7.02 ± 1.30, p = 0.0004). La prématurité est significativement associée, dans les deux types de diabète, à l'HbA1c au second trimestre de la grossesse (6,45 vs 5,97 p < 0,01). Conclusion : Si on ne retient que les diabètes type 2 « incontestables », les complications des grossesses sont aussi importantes dans le DT2 que dans le DT1. La précocité de la prise en charge effective, de l'insulinothérapie, et la programmation sont les facteurs primordiaux de la réussite de ces grossesses. PO43 Les anticorps anti-exénatide ne réagissent ni avec le GLP-1 humain, ni avec le glucagon et n'altèrent ni l'efficacité, ni la sécurité d'un traitement par exénatide

Research paper thumbnail of A systematic literature review and evidence synthesis of anti-diabetes treatments in type 2 diabetes mellitus patients: Indirect comparison of exenatide with metformin + sulphonylurea

Value in Health, 2014

ture between January 2006 and December 2011. Controls were matched with cases at a 4:1 ratio on t... more ture between January 2006 and December 2011. Controls were matched with cases at a 4:1 ratio on the following characteristics: gender, age, geographic region, and date of first dispensing of a TZD or insulin prescription. We conducted conditional logistic regression analyses to estimate the odds ratios (ORs) of having a fracture associated with the use of insulin compared to TZD while controlling for other covariates. Results: There were 2,842 cases matched to 8,238 controls. The mean (standard deviation) age of the study subjects was 46.5 years (0.9) and 57.6% were women. Among cases, 32.8% used insulin and 67.2% used TZDs, and for controls 30.3% used insulin and 69.7% used TZDs. The crude OR for insulin users compared with TZD was 1.14 (95% confidence interval [CI], 1.04-1.25). After adjustment for other antidiabetic drugs, comedication, and comorbidities, the OR was 1.28 (95% CI, 1.09-1.49). ConClusions: We found an association between use of insulin and fractures compared to TZDs in patients with COPD and DM. While further research is needed, clinicians and policy makers should assure that screening guidelines consider this relative risk in patients with COPD and DM. PDB4 CliniCal effiCaCy anD safety of insulin asPart ComPareD with regular human insulin in Patients with tyPe 1 anD tyPe 2 DiaBetes mellitus reCeiving PranDial insulin regimen-a systematiC review anD meta-analysis

Research paper thumbnail of Preclinical Effects of Efpeglenatide, a Long-Acting Glucagon-Like Peptide-1 Receptor Agonist, Compared with Liraglutide and Dulaglutide

Diabetes, Jun 22, 2018

Efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in dev... more Efpeglenatide (efpeg) is a long-acting glucagon-like peptide-1 receptor agonist (GLP-1 RA) in development for type 2 diabetes. The effects of efpeg vs. those of liraglutide (lira) and dulaglutide (dula) on glucodynamics and weight/lipid profiles were studied over 4 weeks in mouse models of diabetes (db/db) and obesity (diet-induced obesity [DIO]), respectively; doses tested wereefpeg 1.45, 2.89, or 4.35 nmol/kg once every 2 days (Q2D); twice-daily lira 30 nmol/kg (db/db study) or 50 nmol/kg (DIO study); dula 0.98 or 1.96 nmol/kg Q2D (equivalent human doses/key results in Table). At the highest doses tested, efpeg was significantly more effective at lowering blood glucose (vs. lira and dula) and reducing the increase in glycated hemoglobin (HbA1c) from Day 0 (vs. lira) in db/db mice. Efpeg also improved insulin sensitivity (vs. lira and dula) and postprandial glucose control (vs. dula). In DIO mice, efpeg significantly reduced body weight and mesenteric fat mass (vs. dula), and cholesterol (vs. lira and dula; at highest doses). Overall, efpeg showed greater reductions in blood glucose, HbA1c increase, weight, and cholesterol vs. other GLP-1 RAs in mice. These effects may be due to the distinct receptor binding properties of efpeg, which enhance intracellular signaling and insulin release in β-cells. Further studies are needed to assess the clinical relevance of these findings. Disclosure M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. J. Kim: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.

Research paper thumbnail of In Vitro Studies to Evaluate the Receptor Kinetics of Efpeglenatide vs. Other Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists

Diabetes, Jul 1, 2018

Efpeglenatide (efpeg) is a long-acting GLP-1 R agonist in development for the treatment of T2D. E... more Efpeglenatide (efpeg) is a long-acting GLP-1 R agonist in development for the treatment of T2D. Efpeg’s effects on the GLP-1 R suggest that it is a superagonist: a ligand that leads to greater maximal signaling and stimulation compared with its endogenous ligand. In vitro studies evaluated the superagonistic effects of efpeg and compared them to the effects of liraglutide (lira) and dulaglutide (dula) on GLP-1 R-binding kinetics and internalization, and cell signaling/desensitization. Efpeg had a higher dissociation constant vs. lira or dula (360.7 vs. 58.7 and 39.4 nmol/L, respectively) indicating a lower binding affinity for GLP-1 R (∼6.1 fold vs. lira, ∼9.2 vs. dula) and faster dissociation vs. lira (∼3.6 fold; p&lt;0.001) or dula (∼2.9 fold; p&lt;0.001). At 100nM, efpeg led to less receptor internalization vs. lira or dula (% of initial internalized receptor: 140% vs. 1191% and 714%, respectively; p&lt;0.001 each) and lower proportions of receptor lost from the cell surface (32% vs. 74% and 69%; p&lt;0.001). After pretreatment (4 or 24 h), efpeg led to significantly greater accumulation of cAMP and insulinotropic activity vs. lira or dula (Figure). The superagonistic effect of efpeg on GLP-1 R may be due to its specific binding characteristics, allowing more cell-surface receptor availability for intracellular signaling. The clinical relevance of these findings should be assessed further. Disclosure I. Choi: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M. Moon: Employee; Self; Hanmi Pharmaceutical. Stock/Shareholder; Self; Hanmi Pharmaceutical. M.E. Trautmann: Consultant; Self; ProSciento. Stock/Shareholder; Self; Eli Lilly and Company. Consultant; Self; Hanmi Pharmaceutical, CeQur Corporation, Intarcia Therapeutics, Inc., Servier. M. Hompesch: Other Relationship; Self; Hanmi Pharmaceutical. C.H. Sorli: Employee; Self; Sanofi.

Research paper thumbnail of Severe insulin resistance treated with insulin lispro