Once-weekly (QW), subcutaneous efpeglenatide (efpeg) is a long-acting GLP-1 RA being developed to improve glycemic control in T2D. In the 20-week BALANCE 205 study (NCT02075281), all doses of efpeg led to significant reductions in body weight (BW) vs. placebo (PBO) in patients with obesity without diabetes (p<0.0001; primary endpoint). This exploratory analysis investigated the effects of efpeg on glycemic, BW, BMI, waist circumference (WC) and cholesterol parameters in patients from BALANCE with prediabetes (HbA1c 5.7−6.4% or FPG 100−125 mg/dL) at baseline (n=140/295). At study end, percentages of patients with normoglycemia (i.e., no longer prediabetic) were higher with efpeg (4 mg QW, 64.3%; 6 mg QW, 46.2%; 6 mg once every 2 weeks [Q2W], 40.6%; 8 mg Q2W, 41.7%; pooled efpeg, 48.2%) than with PBO (10.0%; Table). All efpeg doses led to significant reductions vs. PBO in BW and HbA1c (p<0.0001 for all comparisons; −6.6 kg and −0.4%, respectively for pooled group), BMI, total cholesterol, FPG and WC (p<0.05 for all), except the 4 mg QW dose for WC. Adverse events (AEs) mirrored those known for GLP-1 RAs, with higher rates of gastrointestinal AEs vs. PBO, with no incidences of severe hypoglycemia. In conclusion, treatment with efpeg led to significant improvements vs. PBO in HbA1c, BW, BMI, FPG, WC and cholesterol, and greater proportions of patients achieving normoglycemia, in patients with obesity and prediabetes. Disclosure R.E. Pratley: Consultant; Self; Sanofi US. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Janssen Global Services, LLC., Janssen Research & Development, Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk Inc., Pfizer Inc., Sanofi, Takeda Development Center Americas, Inc. S. Jacob: Advisory Panel; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novartis AG, Novo Nordisk A/S, Roche Diabetes Care, Sanofi. J. Kang: Employee; Self; Hanmi Pharm. Co., Ltd. M.E. Trautmann: Consultant; Self; CeQur Corporation, Hanmi Pharm. Co., Ltd., Intarcia Therapeutics, Inc., Oramed Pharmaceuticals, ProSciento, Servier. Stock/Shareholder; Self; Lilly Diabetes. M. Hompesch: Stock/Shareholder; Self; ProSciento. O. Han: None. J.A. Stewart: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. I. Ogbaa: Stock/Shareholder; Self; Lexicon Pharmaceuticals, Inc. Other Relationship; Self; Sanofi. C.H. Sorli: Employee; Self; Sanofi. K. Yoon: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc. Speaker's Bureau; Self; Takeda Pharmaceutical Company Limited. Funding Hanmi Pharmaceutical, Co., Ltd.; Sanofi

As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, 40-60% are unable to achieve or maintain their target HbA(1c) goals. For these people, treatment intensification options are relatively limited and include the addition of short-acting prandial insulin or a glucagon-like peptide-1 receptor agonist. Glucagon-like peptide-1 receptor agonists vary in their effects, with short- and long-acting agents having a greater impact on postprandial and fasting hyperglycaemia, respectively. Studies comparing treatment intensification options have found both glucagon-like peptide-1 receptor agonists and prandial insulin to be effective in reducing HbA(1c) concentrations; however, recipients of glucagon-like peptide-1 receptor agonists lost weight and had a greater frequency of gastrointestinal adverse events, whereas those receiving prandial insulin gained weight and had a greater incidence of hypoglycaemia. In addition to the separate administration of a glucagon-like peptide-1 receptor agonist and basal insulin, fixed-ratio combinations of a glucagon-like peptide-1 receptor agonist and basal insulin offer a single administration for both treatments but have less flexibility in dose titration than treatment with their individual components. For individuals who require treatment intensification beyond basal insulin, use of these various options allows physicians to target the individual needs of their patients for the achievement of optimal long-term glycaemic control.

Aims: To evaluate the 3-year efficacy and safety of exenatide once weekly (QW) for type 2 diabetes (T2D) in a large clinical population.Methods: This post hoc analysis of three DURATION studies examined pooled efficacy and adverse events with exenatide QW from the 2.5- to 3-year completer populations; insulin glargine (glargine) was a reference (DURATION-3). Patients randomized to exenatide QW during the controlled study periods continued controlled treatment (DURATION-3) or single-arm treatment (DURATION-1; DURATION-2) with exenatide QW for the study duration.Results: In the exenatide QW group (N = 329), reductions from baseline in HbA(1c), fasting glucose, and body weight were maintained from weeks 4 to 156 (HbA1c: 1.1 +/- 1.3%; fasting glucose: -1.7 +/- 2.7 mmol/L; body weight: -2.4 +/- 5.6 kg; P < 0.05). Glycemic efficacy with exenatide QW and glargine was similar (HbA(1c) reduction: 0.8 +/- 1.0%; N = 158); body weight increased with glargine (+2.0 +/- 4.9 kg). Variable reductions in systolic blood pressure and low-density lipoprotein cholesterol occurred with exenatide QW. At week 156, 483% and 30.7% of exenatide QW recipients achieved HbA(1c) goals of < 7.0% and <= 6.5%, respectively. No new safety or tolerability issues were identified.Conclusions: Exenatide QW improved glycemic outcomes and was well tolerated in patients with T2D for up to 156 weeks. (C) 2017 The Authors. Published by Elsevier Inc.

Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time‐course and cross‐reactivity of anti‐exenatide antibodies and potential effects on efficacy and safety.Methods: Data from intent‐to‐treat patients in 12 controlled (n = 2225,12–52weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice‐daily (BID) trials and 4 controlled (n = 653,24–30weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52weeks) were analysed.Results: Mean titres peaked early (6–22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody‐positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody‐positive (45.0% low/11.8% higher titre) at 24–30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment‐emergent anti‐exenatide antibodies from a subset of patients tested did not cross‐react with human GLP‐1 or glucagon. Other than injection‐site reactions, adverse event rates in antibody‐positive and antibody‐negative patients were similar. Efficacy was robust in both antibody‐negative and antibody‐positive patients (mean HbA1c change: −1.0 and −0.9%, respectively, exenatide BID; −1.6% and −1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody‐negative and low‐titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres.Conclusions: Low‐titre anti‐exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher‐titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection‐site reactions, anti‐exenatide antibodies did not impact the safety of exenatide.

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.

Aim: Exenatide, an incretin mimetic for the adjunct treatment of type 2 diabetes (DM2), reduced A1C and weight in 30‐week placebo‐controlled trials. This analysis examined the effects of exenatide on glycaemic control and weight over an 82‐week period in patients with DM2 unable to achieve adequate glycaemic control with sulphonylurea (SU) and/or metformin (MET).Methods: This interim analysis is of 314 patients who received exenatide in the 30‐week placebo‐controlled trials and subsequently in 52 weeks of open‐label uncontrolled extension studies for 82 weeks of exenatide in total. Patients continued their SU and/or MET regimens throughout.Results: Patients completed 82 weeks of exenatide treatment [n = 314, 63% M, age 56 ± 10 years, weight 99 ± 21 kg, body mass index 34 ± 6 kg/m2, A1C 8.3 ± 1.0% (mean ± SD)]. Reduction in A1C from baseline to week 30 [−0.9 ± 0.1% (mean ± SE)] was sustained to week 82 (−1.1 ± 0.1%), with 48% of patients achieving A1C ≤ 7% at week 82. At week 30, exenatide reduced body weight (a secondary endpoint) from baseline (−2.1 ± 0.2 kg), with progressive reduction at week 82 (−4.4 ± 0.3 kg). Similar results were observed for the intent‐to‐treat population (n = 551), with reductions in A1C and weight at week 82 of −0.8 ± 0.1% and −3.5 ± 0.2 kg respectively. The 82‐week completer cohort showed statistically significant improvement in some cardiovascular risk factors. The most frequent adverse events were generally mild‐to‐moderate nausea and hypoglycaemia.Conclusion: In summary, 82 weeks of adjunctive exenatide treatment in patients with DM2 treated with SU and/or MET resulted in sustained reduction in A1C and progressive reduction in weight, as well as improvement in some cardiovascular risk factors.

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.

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.

One hundred and fifteen gastroenteropancreatic (GEP) patients with malignant endocrine tumours entered a prospective multicentre trial (12 patients with gastrinoma, 53 with carcinoid syndrome, 45 with nonfunctioning tumours and 5 with other endocrine GEP tumours) to determine the efficacy of 200 micrograms Sandostatin t.i.d. in the control of tumour growth. This interim report describes the results in 85 patients. Thirty-four patients died, 14 before and 20 after the first follow-up investigation, indicating a 'negative' selection of patients included in the trial and suggesting that Sandostatin is unable to prevent disease progression when it is far advanced. In the evaluation of 68 patients followed up for at least 3 months, partial regression was observed in 4.4%, stable disease in 50% and tumour progression in 45%. An initially favourable response occurred frequently, however, it was followed by a decrease in response, from 54.4% at 3 months to 38% at 12 months, for the whole group of patients. Proven inhibition of tumour growth was mirrored by suppression of serum and urine hormone parameters. It is concluded that Sandostatin exerts a beneficial effect on tumour growth in patients with metastatic endocrine GEP tumours. This beneficial effect decreases with time and is as yet unpredictable in the individual patient.

Receptor scintigraphy with 111In-pentetreotide is a complementary imaging technique with a sensitivity of 88% for the localization of the primary tumor and its metastases in patients presenting with the clinical and biochemical symptoms of an endocrine tumor of the gastrointestinal tract or the pancreas. As a whole-body scintigraphic technique it covers all body regions and is also able to reveal small tumors which can only be detected with difficulty or not at all by the usual imaging methods. In 104 patients with GEP tumors or after operative removal of such tumors, receptor scintigraphy proved to be superior to ultrasound and computed tomography in 34%, equal in 52% and inferior in 14% of the cases.

Receptor scintigraphy with 111In-pentetreotide is a simple method with a sensitivity of 86% for the localization of the primary tumor and its metastases in patients presenting with the clinical and biochemical symptoms of an endocrine tumor of the gastrointestinal tract or the pancreas. As a whole-body scintigraphic technique it covers all body regions and is also able to reveal small tumors which either cannot be detected or can only be detected with difficulty by the usual imaging methods. In 85 patients with GEP tumors or after operative removal of such tumors, receptor scintigraphy proved to be superior to ultrasound and computed tomography in 34%, equal in 52%, and inferior in 14% of the cases.