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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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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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Dapagliflozin once-daily and exenatide once-weekly dual therapy: A 24-week randomized, placebo-controlled, phase II study examining effects on body weight and prediabetes in obese adults without diabetes.
Lundkvist, P, Sjöström, CD, Amini, S, Pereira, MJ, Johnsson, E, Eriksson, JW
Diabetes, obesity & metabolism. 2017;(1):49-60
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AIMS: To explore the effects of dual therapy with dapagliflozin and exenatide on body weight, body composition, glycaemic variables and systolic blood pressure (SBP) in obese adults without diabetes. MATERIALS AND METHODS In this single-centre, double-blind trial, we randomized 50 obese adults without diabetes (aged 18-70 years; body mass index 30-45 kg/m2 ) to oral dapagliflozin 10 mg once daily plus subcutaneous long-acting exenatide 2 mg once weekly or placebo. MRI was used to assess change in body composition. Participants were instructed to follow a balanced diet and exercise moderately. RESULTS Of 25 dapagliflozin/exenatide- and 25 placebo-treated participants, 23 (92.0%) and 20 (80.0%) completed 24 weeks of treatment, respectively. At baseline, the mean participant age was 52 years, 61% were female, the mean body weight was 104.6 kg, and 73.5% of participants had prediabetes (impaired fasting glucose or impaired glucose tolerance). After 24 weeks, for dapagliflozin/exenatide versus placebo: the difference in body weight change was -4.13 kg (95% confidence interval -6.44, -1.81; P < .001), which was mostly attributable to adipose tissue reduction without lean tissue change; 36.0% versus 4.2% of participants achieved ≥5% body weight loss, respectively; and prediabetes was less frequent with active treatment (34.8% vs 85.0%, respectively; P < .01). The difference in SBP change for dapagliflozin/exenatide versus placebo was -6.7 mm Hg. As expected, nausea and injection-site reactions were more frequent with dapagliflozin/exenatide than with placebo. Only two and three participants, respectively, discontinued because of adverse events. CONCLUSIONS Compared with placebo, dapagliflozin/exenatide dual therapy reduced body weight, frequency of prediabetes and SBP over 24 weeks and was well tolerated in obese adults without diabetes.
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Exenatide exerts direct protective effects on endothelial cells through the AMPK/Akt/eNOS pathway in a GLP-1 receptor-dependent manner.
Wei, R, Ma, S, Wang, C, Ke, J, Yang, J, Li, W, Liu, Y, Hou, W, Feng, X, Wang, G, et al
American journal of physiology. Endocrinology and metabolism. 2016;(11):E947-57
Abstract
Glucagon-like peptide-1 (GLP-1) may have direct favorable effects on cardiovascular system. The aim of this study was to investigate the effects of the GLP-1 analog exenatide on improving coronary endothelial function in patients with type 2 diabetes and to investigate the underlying mechanisms. The newly diagnosed type 2 diabetic subjects were enrolled and given either lifestyle intervention or lifestyle intervention plus exenatide treatment. After 12-wk treatment, coronary flow velocity reserve (CFVR), an important indicator of coronary endothelial function, was improved significantly, and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were remarkably decreased in the exenatide treatment group compared with the baseline and the control group. Notably, CFVR was correlated inversely with hemoglobin A1c (Hb A1c) and positively with high-density lipoprotein cholesterol (HDL-C). In human umbilical vein endothelial cells, exendin-4 (a form of exenatide) significantly increased NO production, endothelial NO synthase (eNOS) phosphorylation, and GTP cyclohydrolase 1 (GTPCH1) level in a dose-dependent manner. The GLP-1 receptor (GLP-1R) antagonist exendin (9-39) or GLP-1R siRNA, adenylyl cyclase inhibitor SQ-22536, AMPK inhibitor compound C, and PI3K inhibitor LY-294002 abolished the effects of exendin-4. Furthermore, exendin-4 reversed homocysteine-induced endothelial dysfunction by decreasing sICAM-1 and reactive oxygen species (ROS) levels and upregulating NO production and eNOS phosphorylation. Likewise, exendin (9-39) diminished the protective effects of exendin-4 on the homocysteine-induced endothelial dysfunction. In conclusion, exenatide significantly improves coronary endothelial function in patients with newly diagnosed type 2 diabetes. The effect may be mediated through activation of AMPK/PI3K-Akt/eNOS pathway via a GLP-1R/cAMP-dependent mechanism.
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Exenatide Treatment Causes Suppression of Serum Ghrelin Levels following Mixed Meal Test in Obese Diabetic Women.
Topyildiz, F, Kiyici, S, Gul, Z, Sigirli, D, Guclu, M, Kisakol, G, Cavun, S
Journal of diabetes research. 2016;:1309502
Abstract
AIM: To investigate the effect of exenatide treatment on serum ghrelin levels in obese female patients with type 2 diabetes mellitus. METHODS Fourteen female patients with type 2 diabetes mellitus being treated with metformin and exenatide were enrolled. A mixed meal test was applied to the patients while continuing with their daily medications. Blood samples were taken before and at 60, 120, and 180 minutes following mixed meal test to measure serum total ghrelin, glucose, and insulin levels. The following week, exenatide treatment of the patients was paused for 24 hours and the same experimental procedures were repeated. RESULTS Serum ghrelin levels were suppressed significantly at 180 minutes with exenatide treatment compared with baseline (294.4 ± 57.5 versus 234.5 ± 59.4 pg/mL) (p < 0.001). Serum ghrelin levels at 180 minutes were statistically different when percentage change in serum ghrelin levels after mixed meal tests with and without exenatide usage were compared (p = 0.001). Estimated total area under the curve values for serum ghrelin concentrations was also significantly lower with exenatide compared with omitted treatment (p = 0.035). CONCLUSION These results suggest that the effect of exenatide on weight loss may be related with the suppression of serum ghrelin levels, which is an orexigenic peptide.
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A direct comparison of long- and short-acting GLP-1 receptor agonists (taspoglutide once weekly and exenatide twice daily) on postprandial metabolism after 24 weeks of treatment.
Gastaldelli, A, Balas, B, Ratner, R, Rosenstock, J, Charbonnel, B, Bolli, GB, Boldrin, M, Balena, R
Diabetes, obesity & metabolism. 2014;(2):170-8
Abstract
AIMS: T-emerge 2 was a randomized, open-label, 24-week trial comparing subcutaneous taspoglutide 10 mg weekly (Taspo10), taspoglutide 20 mg weekly (Taspo20; titrated after 4 weeks of Taspo10), with exenatide 10 mcg BID (Exe; after 4 weeks of Exe 5 mcg) in patients inadequately controlled on metformin, a thiazolidinedione, or both. T-emerge 2 showed that once-weekly Taspo provided better glycaemic control than Exe. This report focuses on a subset of T-emerge 2 participants undergoing a standardized liquid meal comparing Taspo to Exe, which has been previously shown to lower postprandial glucose. METHODS Meal tolerance tests (MTT) were performed at baseline and at week 24 in a subset of Taspo10, Taspo20 and Exe patients (n = 42, 39 and 67, respectively). Blood samples for glucose, insulin, glucagon and C-peptide were obtained before and after (30, 60, 90, 120 and 180 min) ingestion of a standardized liquid meal. RESULTS The 2-h postprandial, mean 0-3 h and iAUC0-3 h glucose during the MTT was reduced to a similar extent in all groups and the time profile of the postprandial glucose showed a similar pattern. Taspo10 and Taspo20, but not Exe, significantly increased insulin from baseline (both mean and iAUC0-3 h). Although changes from baseline in C-peptide were not significant within any treatment group, the mean change from baseline (both mean 0-3 h and iAUC0-3 h) was significantly increased in Taspo10 vs. Exe. Mean glucagon showed significant decreases in all groups. CONCLUSION Taspoglutide and Exe improved postprandial glucose tolerance to a similar extent but possibly with different intimate mechanisms.
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Comparative efficacy of exenatide versus insulin glargine on glycemic control in type 2 diabetes mellitus patients inadequately treated with metformin monotherapy.
Karagianni, P, Polyzos, SA, Kartali, N, Zografou, I, Sambanis, C
Advances in medical sciences. 2013;(1):38-43
Abstract
PURPOSE Comparative efficacy of exenatide versus insulin glargine primarily on glucemic control, and secondarily on body mass index (BMI), lipid profile and blood pressure, in type 2 diabetes mellitus (T2DM) patients suboptimally treated with metformin monotherapy. MATERIAL/METHODS Forty-seven inadequately treated T2DM patients on metformin assigned to exenatide (n=18) or insulin glargine (n=29) for 26 weeks. Glycosylated hemoglobin (HbA1c), serum lipids, BMI, systolic and diastolic blood pressure, and adverse events, including episodes of hypoglycemia and gastrointestinal symptoms, were recorded. RESULTS Either treatment had a similar favorable mean reduction in HbA1c. However, more patients in exenatide group achieved HbA1c ≤ 7% at the 26th week compared with insulin glargine group (p=0.036). Insulin glargine group had significantly more episodes of hypoglycemia compared with exenatide group (p=0.039). Gastrointestinal adverse events were non-significantly higher in the exenatide group. A significantly greater BMI reduction was observed in exenatide group, whereas ΒΜΙ was not altered in insulin glargine group. Total and LDL cholesterol (p=0.012), and triglycerides (p=0.016) significantly decreased, whereas HDL cholesterol increased (p=0.021) in the exenatide group, whereas only total cholesterol decreased in insulin glargine group. Changes in systolic and diastolic blood pressure were insignificant in both groups. CONCLUSIONS Exenatide provided similar reduction in HbA1c, but fewer episodes of hypoglycemia, compared with insulin glargine. Exenatide had also a favorable effect on weight loss, although more gastrointestinal adverse events. Exenatide may provide a justified alternative in second line treatment of T2DM, but more trials are required to elucidate its long-term safety and cost-effectiveness.
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Treatment of patients with type 2 diabetes with exenatide once weekly versus oral glucose-lowering medications or insulin glargine: achievement of glycemic and cardiovascular goals.
Meloni, AR, DeYoung, MB, Han, J, Best, JH, Grimm, M
Cardiovascular diabetology. 2013;:48
Abstract
BACKGROUND Diabetes is associated with a higher risk for adverse cardiovascular outcomes. To improve the health outcomes of patients with type 2 diabetes (T2DM), the American Diabetes Association (ADA) recommended target goals for the improvement of glycemic control and the reduction of cardiovascular risk factors associated with the disease. This retrospective analysis calculated the absolute benefit increase (ABI) of using exenatide once weekly (QW), a glucagon-like peptide-1 (GLP-1) receptor agonist, vs an oral glucose-lowering medication or insulin glargine to achieve ADA-recommended goals. The number needed to treat (NNT) to achieve these goals was also calculated and provides a useful clinical metric for comparing potential therapies from different drug classes. METHODS Patient data from three double-blind or open label, 26-week, randomized, controlled trials were retrospectively analyzed separately. ABI and NNT were calculated by comparing the percentage of patients treated with exenatide QW (N = 641) vs metformin (N = 246), sitagliptin (N = 329), pioglitazone (N = 328), or insulin glargine (N = 223), who achieved a single glycemic, weight, blood pressure, or lipid goal or a composite of these recommended goals, during the DURATION-2, -3, and -4 clinical trials. RESULTS Significant ABIs favoring exenatide QW over all four glucose-lowering medications were observed for at least one HbA1c glycemic goal. NNTs of 4 and 5 were calculated when exenatide QW was compared to sitagliptin for attaining HbA1c goals of <7.0% and ≤6.5%, respectively. Additionally, significantly more patients using exenatide QW compared to sitagliptin, pioglitazone, or insulin glargine attained the composite goal of HbA1c <7% or ≤6.5%, without weight gain or hypoglycemia. Exenatide QW was also favored over sitagliptin and insulin glargine for the achievement of the composite goals of HbA1c <7% (or ≤6.5%), systolic blood pressure <130 mm Hg, and low-density lipoprotein <2.59 mmol/L. For most goals, exenatide QW and metformin had similar effects in treatment naïve patients. CONCLUSIONS This analysis assessed the between-therapy differences in achieving therapeutic goals with therapies commonly used for glycemic control in patients with T2DM. In clinical trials, exenatide QW assisted more patients in reaching the majority of ADA-recommended therapeutic goals than treatment with sitagliptin, pioglitazone, or insulin glargine. TRIAL REGISTRATION NCT00637273, NCT00641056, NCT00676338.
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[Exenatide stimulated solute-free water excretion by human kidney].
Shakhmatova, EI, Shutskaia, ZhV, Vladimirova, ME, Gorelov, AI, Gorbunov, AI, Natochin, IuV
Rossiiskii fiziologicheskii zhurnal imeni I.M. Sechenova. 2012;(8):1021-9
Abstract
Exenatide effect was studied in 55 human including 38 patients with type 2 diabetes mellitus without signs of diabetic nephropathy and primary renal diseases. Preliminary study with water load in volume from 0.5 to 1% b.w. showed that water load equal to 0.7% b.w. caused significant increase in urine excretion. The rise of diuresis after 10 microg Byetta (exenatide) injection and simultaneous water load of 0.7% of b.w. depended on increase in solute-free water clearance. Thus, exenatide (mimetic of GLP-1) action let us to consider its possible role as component of osmoregulation system in human. This peptide provides high efficiency of renal function in osmotic homeostasis.
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[The influence of 6-months treatment with exenatide on type 2 diabetes mellitus compensation, anthropometric and biochemical parameters].
Roubícek, T, Mráz, M, Bártlová, M, Kaválková, P, Haluzíková, D, Trachta, P, Housová, J, Matoulek, M, Svacina, S, Haluzík, M
Vnitrni lekarstvi. 2010;(1):15-20
Abstract
OBJECTIVES Exenatide, a synthetic GLP-1 analogue, is a new antidiabetic agent from the group ofincretine mimetics coming into the daily clinical practice. In our study we evaluated the effect of 6-months treatment with exenatide on diabetes compensation, anthropometric and biochemical parameters in the patients with poorly controlled type 2 diabetes mellitus and obesity. METHOD We included 18 patients with poorly controlled diabetes (mean HbA1c 8.5 +/- 0.3%) treated with diet and peroral antidiabetic agents (4 patients were treated with insulin in the past). Exenatide was administered via subcutaneous injection twice daily for 6 months. Patients were examined after 1 month, when the dose ofexenatide was increased from 5 microg twice daily to 10 microg twice daily and after 3 and 6 months. We evaluated the diabetes compensation, biochemical parameters, body weight changes and side effects ofexenatide. RESULTS 6-months exenatide treatment significant decreased body weight (baseline vs 6 month treatment 107.3 +/- 4.4 kg vs 103.7 +/- 4.6 kg, p = 0.02), BMI (36.7 +/- 1.2 kg/m2 vs 35.3 +/- 1.3 kg/m2, p = 0.01) a HbA1c (8.5 +/- 0.3% vs 7.4 +/- 0.4%, p = 0.04) and increased HDL-cholesterol (0.92 +/- 0.1 mmol/l vs 0.98 +/- 0.1 mmol/l, p = 0.02). Fasting glycemia tended to decline at the end of the study, but the difference did not reach the statistical significance. The area under the curve of glycemia levels after the standardized breakfast in the subgroup of 8 patients after the 6-months exenatide treatment was significantly lower when compared to baseline values (2,908 +/- 148 vs 2,093 +/- 194, p = 0.03). Concentrations of total and LDL-cholesterol and triglycerides did not change significantly. The most frequent side effects of exenatide treatments were transient anorexia and nausea (38.5%), dyspepsia and functional gastrointestinal discomfort (38.5%) and various neuropsychical symptoms (nervosity and insomnia - 30.8%). Most of the side effects disappeared during the treatment, none of these side effects was a reason for discontinuation of a treatment. 3 minor hypoglycemic episodes occured in patients simultaneously treated with derivates of sulfonylurea, but no serious hypoglycemia occured during the entire study. CONCLUSION Exenatide treatment in obese patients with poor diabetes control was accompanied by statistically significant decrease of body weight, improvement of diabetes control and increase in HDL-cholesterol.