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The effects of add-on exenatide to insulin on glycemic variability and hypoglycemia in patients with type 1 diabetes mellitus.
Jiang, LL, Wang, SQ, Ding, B, Zhu, J, Jing, T, Ye, L, Lee, KO, Wu, JD, Ma, JH
Journal of endocrinological investigation. 2018;(5):539-547
Abstract
OBJECTIVE To investigate the effect of add-on exenatide to insulin on glycemic excursion and the counter-regulatory hormone in response to hypoglycemia in patients with type 1 diabetes mellitus (T1DM). METHODS 30 patients with T1DM were recruited and randomly assigned to exenatide + insulin-treated group (group 1, n = 15) or insulin-only-treated group (group 2, n = 15) for 4 weeks. All patients had continuous glucose monitor system (CGMS) applied at before (week-0) and after (week-4) treatment to evaluate the glycemic variability. All patients had an arginine-stimulated test at before and after treatment. Six patients from each group also had hypoglycemic clamp test to assess counter-regulatory hormone level. RESULTS Patients in the exenatide group had significant reductions in body weight, body mass index (BMI), total insulin dose, bolus insulin dose, fructosamine, and glycemic excursion after 4 weeks' treatment. Compared with patients in group 2, the mean amplitude of glycemic excursion (MAGE) and coefficient of variation (CV) of exenatide group decreased significantly. Similarly, a significant decrease of glucagon (GLC) in the arginine-stimulated test was found in group 1. No significant changes of GLC, growth hormone (GH), cortisol (COR), epinephrine (E), and norepinephrine (NE) were found in both groups during hypoglycemia clamp test. However, patients who had residual islet function in group 1 showed an upward trend of basic C-peptide (C-P) and GLC during the hypoglycemia period. CONCLUSION Although exenatide could inhibit glucagon secretion during euglycemia or hyperglycemia in patients with T1DM, it has no effect on GLC and counter-regulatory hormones during hypoglycemia clamp in patients with no functional residual islet test.
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2.
Real-world clinical outcomes and predictors of glycaemic and weight response to exenatide once weekly in patients with type 2 diabetes: The CIBELES project.
Gorgojo-Martínez, JJ, Gargallo-Fernández, MA, Brito-Sanfiel, M, Lisbona-Catalán, A
International journal of clinical practice. 2018;(3):e13055
Abstract
AIMS: To evaluate in a real-world setting the effectiveness of exenatide once-weekly (ExQW) in patients with T2D and to determine predictors of glycaemic and weight response to this drug at 6 months. METHODS Observational, retrospective, multicenter study in adult patients with T2D and BMI ≥30 kg/m2 from 4 tertiary Spanish hospitals who started ExQW therapy at least 6 months before the inclusion and had not achieved adequate glycaemic control on oral therapies or other GLP-1 receptor agonists. Glycaemic response was defined as an A1C reduction ≥1.0% and weight response as a weight loss ≥3% 6 months after ExQW. The best predictive models of glycaemic and weight response were estimated by binary logistic regression. RESULTS One hundred and forty eight patients were included, mean age 58.0 years, A1C 7.7%, weight 105.9 kg and BMI 38.4 kg/m2 . A1C (-1.1%), weight (-3.9 kg), systolic blood pressure (-4.0 mm Hg), diastolic blood pressure (-2.9 mm Hg), LDL-cholesterol (-14.2 mg/dL) and triglycerides (-31.0 mg/dL) significantly decreased 6 months after ExQW. 41.5% of patients had an A1C reduction ≥1.0% and 53.1% lost ≥3% of baseline weight. Glycaemic and weight reductions were sustained in patients completing 1 and 2 years of follow-up. The best predictive model of glycaemic response only included higher A1C levels (OR 3.9), whereas higher BMI (OR 1.1) and prior DPP-4i therapy (OR 3.1) were associated to weight response in the multivariate analysis. CONCLUSIONS In a real-world setting, ExQW significantly decreased A1C, weight, blood pressure and lipids at 6 months. Our study identified higher baseline A1C as the sole independent predictor of glycaemic response to ExQW and higher BMI and previous DDP4i treatment as predictive factors of meaningful weight response.
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3.
Clinical Impact of ITCA 650, a Novel Drug-Device GLP-1 Receptor Agonist, in Uncontrolled Type 2 Diabetes and Very High Baseline HbA1c: The FREEDOM-1 HBL (High Baseline) Study.
Henry, RR, Rosenstock, J, Denham, DS, Prabhakar, P, Kjems, L, Baron, MA
Diabetes care. 2018;(3):613-619
Abstract
OBJECTIVE ITCA 650 is a subdermal osmotic mini-pump that continuously delivers exenatide subcutaneously for 3-6 months. The efficacy, safety, and tolerability of ITCA 650 added to diet and exercise alone or combined with metformin, sulfonylurea, or thiazolidinedione monotherapy or a combination of these drugs was evaluated in poorly controlled patients with type 2 diabetes (T2D) who were ineligible for participation in a placebo-controlled study (FREEDOM-1) because of severe hyperglycemia (HbA1c >10% [86 mmol/mol]). RESEARCH DESIGN AND METHODS This 39-week, open-label, phase 3 trial enrolled patients aged 18-80 years with HbA1c >10% to ≤12% (86-108 mmol/mol) and BMI 25-45 kg/m2. Patients received ITCA 650 20 μg/day for 13 weeks, then 60 μg/day for 26 weeks. The primary end point was change in HbA1c at week 39. RESULTS Sixty patients were enrolled. At baseline, mean HbA1c was 10.8% (94.7 mmol/mol) and mean (± SD) duration of diabetes was 8.6 (± 5.3) years. At week 39, there was a mean reduction in HbA1c of -2.8% (-30.3 mmol/mol; P < 0.001 vs. baseline) and in body weight of -1.2 kg (P = 0.105), and 25% of patients achieved HbA1c <7% (53 mmol/mol). A reduction in HbA1c of ≥1% (≥10.9 mmol/mol) occurred in 90% of patients. The most common adverse events were nausea, vomiting, diarrhea, and headache. Gastrointestinal adverse events were generally transient and subsided over time; only 4 patients (6.7%) discontinued for gastrointestinal events. CONCLUSIONS Treatment with ITCA 650, the first injection-free glucagon-like peptide 1 receptor agonist, resulted in significant improvements in glycemic control in poorly controlled long-standing T2D patients with a high baseline HbA1c >10%.
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Insulin secretion predicts the response to therapy with exenatide plus pioglitazone, but not to basal/bolus insulin in poorly controlled T2DM patients: Results from the Qatar study.
Abdul-Ghani, M, Migahid, O, Megahed, A, Singh, R, Kamal, D, DeFronzo, RA, Jayyousi, A
Diabetes, obesity & metabolism. 2018;(4):1075-1079
Abstract
The present study aims to identify predictors for response to combination therapy with pioglitazone plus exenatide vs basal/bolus insulin therapy in T2DM patients who are poorly controlled with maximum/near-maximum doses of metformin plus a sulfonylurea. Participants in the Qatar study received a 75-g OGTT with measurement of plasma glucose, insulin and C-peptide concentration at baseline and were then randomized to receive either treatment with pioglitazone plus exenatide or basal/bolus insulin therapy for one year. Insulin secretion measured with plasma C-peptide concentration during the OGTT was the strongest predictor of response to combination therapy (HbA1c ≤ 7.0%) with pioglitazone plus exenatide. A 54% increase in 2-hour plasma C-peptide concentration above the fasting level identified subjects who achieved the glycaemic goal (HbA1c < 7.0%) with 82% sensitivity and 79% specificity. Only baseline HbA1c was a predictor of response to basal/bolus insulin therapy. Thus, the increment in 2-hour plasma C-peptide concentration above the fasting level provides a useful tool to identify poorly controlled T2DM patients who can achieve glycaemic control without insulin therapy, and thereby, can be used to individualize antihyperglycaemic therapy in poorly controlled T2DM patients.
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The Role of the Pharmacist in Managing Type 2 Diabetes with Glucagon-Like Peptide-1 Receptor Agonists as Add-On Therapy.
Meece, J
Advances in therapy. 2017;(3):638-657
Abstract
UNLABELLED The prevalence and associated clinical burden of type 2 diabetes (T2D) is increasing in the USA and other countries. As a consequence, the role of the pharmacist in managing T2D is expanding, and it is becoming increasingly important for pharmacists to have a complete understanding of the disease course and treatment options. Pharmacists have a key role in the use of injectable therapies, including incretin-based treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This article discusses the role of the pharmacist in the management of patients with T2D, particularly with respect to the use of GLP-1RAs to achieve glycemic control. GLP-1RAs are a class of injectable agents used as an adjunct to diet and exercise to improve glycemic control in adults with T2D. GLP-1RAs have been shown to lower glucose levels, slow gastric emptying, enhance satiety, and reduce body weight without increasing the risk of hypoglycemia. GLP-1RAs currently approved in the USA include exenatide twice daily, liraglutide once daily, and albiglutide, dulaglutide, and exenatide once weekly. Pharmacists can work with physicians to help identify patients for whom GLP-1RA therapy is appropriate. In addition, pharmacists can educate patients regarding medication storage, preparation, and injection techniques, glycated hemoglobin (HbA1c) targets, pre- and post-meal blood glucose goals, adverse events and management strategies, and the long-term benefits of reducing HbA1c. As members of the diabetes care team, pharmacists play an important role in improving patient outcomes. FUNDING AstraZeneca.
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Pharmacokinetics and Preliminary Pharmacodynamics of Single- and Multiple-dose Lyophilized Recombinant Glucagon-like Peptide-1 Receptor Agonist (rE-4) in Chinese Patients with Type 2 Diabetes Mellitus.
Wang, Y, Xu, B, Zhu, L, Lou, K, Chen, Y, Zhao, X, Wang, Q, Xu, L, Guo, X, Ji, L, et al
Clinical drug investigation. 2017;(12):1107-1115
Abstract
BACKGROUND AND OBJECTIVES Recombinant glucagon-like peptide-1 receptor agonist (rE-4) is a glucagon-like peptide-1 receptor agonist, which has the same amino acid sequence to exenatide, except for the C-terminal deamidated. This study assessed the pharmacokinetics and preliminary pharmacodynamics of rE-4, following single and multiple subcutaneous injections in Chinese patients with type 2 diabetes mellitus (T2DM). DESIGN AND METHODS In the randomized, open-label study, Chinese patients with T2DM (n = 36) were randomly assigned to three groups of rE-4 (n = 12), rE-4 with metformin (n = 12) and exenatide (n = 12, as the control group) for 12 weeks. rE-4 and exenatide were administered by subcutaneous injection in the abdomen, and metformin was given by oral administration. Patients received rE-4 or exenatide 5 μg twice a day for the first 4 weeks and adjusted the dose of rE-4 or exenatide to 10 μg twice a day at day 29 for the following 8 weeks, if their glycated albumin (GA) values were still greater than 17%. We evaluated pharmacokinetic parameters of rE-4 and exenatide, fasting plasma glucose (FPG), 2-h postprandial blood glucose (PG2 h), glycosylated hemoglobin (HbA1c) and body weight at designated time points. RESULTS Thirty-six patients were enrolled, and 29 subjects finished the study. rE-4 was absorbed quickly with a median peak-reaching time (t max) of 0.8-1.5 h and eliminated rapidly with a median terminal half-life (t 1/2z) of 1.6-1.9 h. The exposure of rE-4 increased in an approximately dose-proportional method without accumulation. rE-4 10 μg twice a day could reduce FPG (~2.29 mmol/L), PG2 h (~6.00 mmol/L), HbA1c (~1.19%) and body weight (~0.48 kg) from baseline to 12 weeks, with no statistical significance compared with exenatide (FPG: ~1.88 mmol/L; PG2 h: ~6.66 mmol/L; HbA1c: ~1.13%; body weight: ~0.47 kg) and rE-4 with metformin (FPG: ~2.33 mmol/L; PG2 h: ~6.51 mmol/L; HbA1c: ~0.84%; body weight: ~1.16 kg) (p > 0.05). CONCLUSIONS rE-4 twice a day has a pharmacokinetic profile similar to exenatide and rE-4 with metformin after single and multiple doses in Chinese patients with T2DM. Also, rE-4 could improve glycemic control effectively. CLINICALTRIALS. GOV IDENTIFIER NCT01342042.
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A meta-analysis comparing clinical effects of short- or long-acting GLP-1 receptor agonists versus insulin treatment from head-to-head studies in type 2 diabetic patients.
Abd El Aziz, MS, Kahle, M, Meier, JJ, Nauck, MA
Diabetes, obesity & metabolism. 2017;(2):216-227
Abstract
AIMS: To study differences in clinical outcomes between initiating glucagon-like peptide-1 receptor agonist (GLP-1 RAs) vs insulin treatment in patients with type 2 diabetes treated with oral glucose-lowering medications (OGLM). METHODS Prospective, randomized trials comparing GLP-1 RA and insulin treatment head-to-head as add-on to OGLM were identified (PubMed). Differences from baseline values were compared for HbA1c, fasting plasma glucose, bodyweight, blood pressure, heartrate and lipoproteins. Proportions of patients reporting hypoglycaemic episodes were compared. RESULTS Of 712 publications identified, 23 describing 19 clinical trials were included in the meta-analysis. Compared to insulin, GLP-1 RAs reduced HbA1c more effectively (Δ -.12%, P < .0001). Basal insulin was more effective in reducing fasting plasma glucose (Δ -1.8 mmol/L, P < .0001). GLP-1 RAs reduced bodyweight more effectively (Δ -3.71 kg; P < .0001). The proportion of patients experiencing hypoglycaemic episodes was 34% lower with GLP-1 RAs ( P < .0001), with a similar trend for severe hypoglycaemia. Systolic blood pressure was lower and heartrate was higher with GLP-1 RAs ( P < .0001). Triglycerides and LDL cholesterol were significantly lower with GLP-1 RAs. Long-acting GLP-1 RAs were better than short-acting GLP-1 RAs in reducing HbA1c and fasting glucose, but were similar regarding bodyweight. CONCLUSIONS Slightly better glycaemic control can be achieved by adding GLP-1 RAs to OGLM as compared to insulin treatment, with added benefits regarding bodyweight, hypoglycaemia, blood pressure and lipoproteins. These differences are in contrast to the fact that insulin is prescribed far more often than GLP-1 RAs.
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Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R).
Koole, C, Reynolds, CA, Mobarec, JC, Hick, C, Sexton, PM, Sakmar, TP
The Journal of biological chemistry. 2017;(17):7131-7144
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) is a key therapeutic target in the management of type II diabetes mellitus, with actions including regulation of insulin biosynthesis and secretion, promotion of satiety, and preservation of β-cell mass. Like most class B G protein-coupled receptors (GPCRs), there is limited knowledge linking biological activity of the GLP-1R with the molecular structure of an intact, full-length, and functional receptor·ligand complex. In this study, we have utilized genetic code expansion to site-specifically incorporate the photoactive amino acid p-azido-l-phenylalanine (azF) into N-terminal residues of a full-length functional human GLP-1R in mammalian cells. UV-mediated photolysis of azF was then carried out to induce targeted photocross-linking to determine the proximity of the azido group in the mutant receptor with the peptide exendin-4. Cross-linking data were compared directly with the crystal structure of the isolated N-terminal extracellular domain of the GLP-1R in complex with exendin(9-39), revealing both similarities as well as distinct differences in the mode of interaction. Generation of a molecular model to accommodate the photocross-linking constraints highlights the potential influence of environmental conditions on the conformation of the receptor·peptide complex, including folding dynamics of the peptide and formation of dimeric and higher order oligomeric receptor multimers. These data demonstrate that crystal structures of isolated receptor regions may not give a complete reflection of peptide/receptor interactions and should be combined with additional experimental constraints to reveal peptide/receptor interactions occurring in the dynamic, native, and full-length receptor state.
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Clinical Effectiveness of Intravenous Exenatide Infusion in Perioperative Glycemic Control after Coronary Artery Bypass Graft Surgery: A Phase II/III Randomized Trial.
Besch, G, Perrotti, A, Mauny, F, Puyraveau, M, Baltres, M, Flicoteaux, G, Salomon du Mont, L, Barrucand, B, Samain, E, Chocron, S, et al
Anesthesiology. 2017;(5):775-787
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Abstract
BACKGROUND We aimed to assess the clinical effectiveness of intravenous exenatide compared to insulin in perioperative blood glucose control in coronary artery bypass grafting surgery patients. METHODS Patients more than 18 yr old admitted for elective coronary artery bypass grafting were included in a phase II/III nonblinded randomized superiority trial. Current insulin use and creatinine clearance of less than 60 ml/min were exclusion criteria. Two groups were compared: the exenatide group, receiving exenatide (1-h bolus of 0.05 µg/min followed by a constant infusion of 0.025 µg/min), and the control group, receiving insulin therapy. The blood glucose target range was 100 to 139 mg/dl. The primary outcome was the proportion of patients who spent at least 50% of the study period within the target range. The consumption of insulin (Cinsulin) and the time to start insulin (Tinsulin) were compared between the two groups. RESULTS In total, 53 and 51 patients were included and analyzed in the exenatide and control groups, respectively (age: 70 ± 9 vs. 68 ± 11 yr; diabetes mellitus: 12 [23%] vs. 10 [20%]). The primary outcome was observed in 38 (72%) patients in the exenatide group and in 41 (80%) patients in the control group (odds ratio [95% CI] = 0.85 [0.34 to 2.11]; P = 0.30). Cinsulin was significantly lower (60 [40 to 80] vs. 92 [63 to 121] U, P < 0.001), and Tinsulin was significantly longer (12 [7 to 16] vs. 7 [5 to 10] h, P = 0.02) in the exenatide group. CONCLUSIONS Exenatide alone at the dose used was not enough to achieve adequate blood glucose control in coronary artery bypass grafting patients, but it reduces overall consumption of insulin and increases the time to initiation of insulin.
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Effect of exenatide on postprandial glucose fluxes, lipolysis, and ß-cell function in non-diabetic, morbidly obese patients.
Camastra, S, Astiarraga, B, Tura, A, Frascerra, S, Ciociaro, D, Mari, A, Gastaldelli, A, Ferrannini, E
Diabetes, obesity & metabolism. 2017;(3):412-420
Abstract
AIMS: To investigate the effect of exenatide on glucose disposal, insulin secretion, ß-cell function, lipolysis and hormone concentrations in non-diabetic, morbidly obese subjects under physiological conditions. MATERIALS AND METHODS Patients were assigned to exenatide 10 µg twice daily (EXE, n = 15) or control (CT, n = 15) for 3 months. Patients received a meal test/tracer study (MTT) to measure endogenous glucose production (EGP), rate of oral glucose appearance (RaO), insulin secretion rate (ISR), ß-cell function, hepatic insulin resistance (HIR) and adipose tissue insulin resistance (AT-IR) and insulin sensitivity (IS). RESULTS Post treatment, the EXE group showed a significant reduction in body weight ( P < .001). The postmeal time-course of glucose, insulin and ISR showed a lower peak between 60 and 180 minutes in phase with a reduction in RaO ( P < .01). After an initial similar suppression, EGP resumed at higher rates between 60 and 180 minutes ( P = .02) in EXE vs CT, while total RaO and EGP were similar throughout the MTT. In EXE, the postmeal glucagon, GLP1 and GIP responses were reduced ( P < .05). Fasting and postprandial lipolysis and ß-cell function were unaltered by active treatment. HIR, AT-IR and IS were all improved after exenatide treatment ( P < .05). CONCLUSIONS In morbidly obese non-diabetic subjects, exenatide causes weight loss, decreased postprandial glycaemia and glucagon response without changes in ß-cell function. These effects are consequent upon delayed oral glucose appearance in the circulation. Exenatide treatment is also associated with an improvement in hepatic, adipose tissue and whole-body IS with no influence on postprandial lipolysis.