exenatide and Obesity--Morbid

This study sought to evaluate the effect of 52 weeks of exenatide extended release (XR) on the maintenance of meal replacement therapy (MRT)-induced BMI reduction in adolescents with severe obesity.. In this randomized, double-blind, placebo-controlled trial, 100 participants aged 12 to 18 years with BMI ≥ 1.2 × 95th percentile were enrolled in a short-term MRT run-in phase. Those who achieved ≥5% BMI reduction during the run-in were then randomized to 52 weeks of exenatide XR 2.0 mg or placebo weekly. Both groups also received lifestyle therapy. The prespecified primary end point was mean percent change in BMI from randomization (post run-in) to 52 weeks in the intention-to-treat population.. A total of 100 participants were enrolled, and 66 (mean age 16 = [SD 1.5] years; 47% female) achieved ≥5% BMI reduction with MRT and were randomized (33 to exenatide XR and 33 to placebo). From randomization (post run-in) to 52 weeks, mean BMI increased 4.6% and 10.1% in the exenatide XR and placebo groups, respectively. The placebo-subtracted exenatide XR treatment effect was -4.1% (95% CI: -8.6% to 0.5%, p = 0.078).. Although not achieving statistical significance, exenatide XR, compared with placebo, may partly mitigate the propensity toward BMI rebound in adolescents who achieved initial weight loss with dietary intervention.

Topics: Adolescent; Double-Blind Method; Exenatide; Female; Humans; Hypoglycemic Agents; Male; Obesity, Morbid; Treatment Outcome; Weight Loss

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.. 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).. 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).. 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.

Topics: Adipose Tissue; Adult; Blood Glucose; Exenatide; Fasting; Female; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Lipolysis; Liver; Male; Middle Aged; Obesity, Morbid; Peptides; Postprandial Period; Venoms

In two previous, separate clinical trials, we demonstrated significant reductions in body mass index (BMI) with exenatide in adolescents with severe obesity. In the present study, we pooled data from these near identical trials to evaluate factors that may predict BMI reduction at 3 months. Data from 32 patients (mean age 14.3 ± 2.2 years; 69% female; mean BMI 39.8 ± 5.8 kg m(-2)) were included. Exenatide treatment consisted of 5 mcg twice daily for 1 month, followed by an increase to 10 mcg twice daily for 2 additional months. Predictor variables included baseline BMI, BMI percent change at 1 month, incidence of nausea or vomiting and baseline appetite and satiety measures. Treatment effects of percent change in BMI from baseline were estimated within predictor subgroups using generalized estimating equations with exchangeable working correlation and robust variance estimation for confidence intervals and P-values to account for paired observations. The pooled data treatment effect on absolute BMI at 3 months was -3.42% (95% confidence interval: -5.41%, -1.42%) compared to placebo. Within treated participants, appetite at baseline (treatment effect in high [-4.28%] vs. low [1.02%], P = 0.028) and sex (treatment effect in female [-4.78%] vs. male [0.76%], P = 0.007) were significant predictors of change in BMI at 3 months. Baseline BMI, BMI percent change at 1 month, age, incidence of nausea, vomiting, or other gastrointestinal symptoms and satiety scores did not predict 3-month responses. Sex and measures of appetite may serve as useful predictors of glucagon-like peptide-1 receptor agonist treatment response among adolescents with severe obesity.

Topics: Adolescent; Body Mass Index; Child; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Male; Obesity, Morbid; Peptides; Treatment Outcome; Venoms; Weight Loss; Young Adult

Bariatric surgery constitutes the most effective treatment for severely obese type 2 diabetic patients. Exenatide is a glucagon-like peptide 1 receptor agonist that can improve glycemic control and cause weight loss in patients with type 2 diabetes. Clinical experience with exenatide in obese patients with type 2 diabetes waiting for bariatric surgery has not been reported. The aim of the study was to evaluate, in clinical practice, weight and metabolic effects of exenatide (after 3 and 6 months) in patients with type 2 diabetes and obesity waiting for bariatric surgery.. A total of 100 diabetic adult subjects with a BMI ≥ 35 kg/m(2) were included. Primary endpoints were changes in weight and HbA1c after 6 months of treatment. Secondary endpoints were changes from baseline of a variety of clinical measures (triglycerides levels, blood pressure, and waist circumference). Data were analyzed at 3 and 6 months of follow-up.. Treatment for 6 months with exenatide decreased significantly body weight (-12.5 kg) and waist circumference (-13 cm). Twenty percent of patients reduced their BMI under 35 kg/m(2) and significantly improved their metabolic profile (HbA1c <7 %). Significant and maintained decreases in HbA1c of 1 % were observed in the 3 and 6 months cohorts. Triglycerides levels and blood pressure also decreased from baseline to the end of the study. Treatment was discontinued in 19 % of patients mainly due to drug inefficacy (6 %) or adverse events (4 %).. Exenatide twice daily (BID) leads to early, robust, and significant weight loss in a subset of patients with diabetes and severe obesity before bariatric surgery. Clinical trials are needed to confirm the benefits of GLP-1 agonists in type 2 diabetic obese patients or high-risk super-obese patients waiting for bariatric surgery.

Topics: Adult; Bariatric Surgery; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Male; Middle Aged; Obesity, Morbid; Peptides; Prospective Studies; Treatment Outcome; Venoms; Waist Circumference; Weight Loss

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9-16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m(2)) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (-1.7 kg/m(2), 95% confidence interval (CI) (-3.0, -0.4), P = 0.01), body weight (-3.9 kg, 95% CI (-7.11, -0.69), P = 0.02), and fasting insulin (-7.5 mU/l, 95% CI (-13.71, -1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and β-cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

Topics: Adolescent; Blood Pressure; Body Mass Index; Body Weight; Cardiovascular Diseases; Child; Cross-Over Studies; Diabetes Mellitus, Type 2; Exenatide; Female; Glucose Tolerance Test; Humans; Injections, Subcutaneous; Male; Minnesota; Obesity, Morbid; Peptides; Pilot Projects; Risk Factors; Risk Reduction Behavior; Time Factors; Treatment Outcome; Venoms; Weight Loss

Glucagon-like peptide-1 (GLP-1) analogues improve glycaemic control in type 2 diabetic (T2D) patients and cause weight loss in obese subjects by as yet unknown mechanisms. We recently demonstrated that the GLP-1 receptor, which is present in adipocytes and the stromal vascular fraction of human adipose tissue (AT), is up-regulated in AT of insulin-resistant morbidly obese subjects compared with healthy lean subjects. The aim of this study was to explore the effects of in vitro and in vivo administration of GLP-1 and its analogues on AT and adipocyte functions from T2D morbidly obese subjects.. We analysed the effects of GLP-1 on human AT and isolated adipocytes in vitro and the effects of GLP-1 mimetics on AT of morbidly obese T2D subjects in vivo.. GLP-1 down-regulated the expression of lipogenic genes when administered during in vitro differentiation of human adipocytes from morbidly obese patients. GLP-1 also decreased the expression of adipogenic/lipogenic genes in AT explants and mature adipocytes, while increasing that of lipolytic markers and adiponectin. In 3T3-L1 adipocytes, GLP-1 decreased free cytosolic Ca2+ concentration ([Ca2+]i). GLP-1-induced responses were only partially blocked by GLP-1 receptor antagonist exendin (9–39). Moreover, administration of exenatide or liraglutide reduced adipogenic and inflammatory marker mRNA in AT of T2D obese subjects.. Our data suggest that the beneficial effects of GLP-1 are associated with changes in the adipogenic potential and ability of AT to expand, via activation of the canonical GLP-1 receptor and an additional, as yet unknown, receptor.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Cell Differentiation; Diabetes Mellitus, Type 2; Exenatide; Gene Expression; Genetic Markers; Glucagon-Like Peptide 1; Humans; Mice; Obesity, Morbid; Peptides; Pilot Projects; Prospective Studies; Venoms

Glucagon-like peptide-1 receptor agonists, a new class of anti-diabetic drugs, are widely used in the treatment of type 2 diabetes. However, the effect of glucagon-like peptide-1 receptor agonists on the treatment of preoperative weight loss in obese type 2 diabetic patients has not been reported.. A 38-year-old Taiwanese woman presented to our hospital with morbid obesity and type 2 diabetes mellitus. Bariatric surgery was recommended by a general surgery specialist. Weight loss before surgery was recommended to reduce the frequency of surgical complications. In addition to diet control with lifestyle modifications, pharmacological treatment with metformin and glucagon-like peptide-1 receptor agonists was administered. Fourteen months of treatment reduced her hemoglobin A1c level from 7.4 to 5.5% and reduced her body weight by 21.2 kg.. One year of diet control with lifestyle modifications and pharmacological treatment with glucagon-like peptide-1 receptor agonists and metformin markedly decreased hemoglobin A1c levels and resulted in effective and substantial weight loss in a morbidly obese patient with dysregulated diabetes during the preoperative period.

Topics: Adult; Bariatric Surgery; Combined Modality Therapy; Diabetes Mellitus, Type 2; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Metformin; Obesity, Morbid; Peptides; Preoperative Care; Receptors, Glucagon; Venoms; Weight Loss

Gastric bypass surgery and exenatide therapy represent two relatively new methods in treating morbid obesity and type 2 diabetes, although there are many differences between them. With the data supported from our hospital, we just want to investigate the differences between bypass surgery and exenatide injection and want to answer the question: Which one is the best? And Why?. Data from January 2009 to January 2010 were summarized for comparison at Shengjing hospital, including weight loss, plasma glucose and insulin changes, glycosylated hemoglobin, and the subjective scores of patients themselves. Plasma lipoprotein and serum ions were measured to evaluate the nutrition status.. Patients in the GB group received more weight loss and better glucose control compared with the EX group. At 6 months, feeding insulin level in the GB group was 18.1 ± 3.2 mU/L, which was much lower than that in the EX group (64.5 ± 13.2 mU/L, P < 0.01). The Hb1AC level in the GR group was 6.08 ± 0.56 %, much lower than that in the EX group (7.19 ± 0.72 %, P < 0.01). We did not find any statistical differences in lipoprotein, plasma ions, and subjective scores between the GB and EX groups.. Gastric bypass surgery is better in weight control and in the remission of insulin resistance compared with exenatide therapy. Both methods were safe and have no nutritional disorder in early stage, although the transferring in the GB group was higher than the EX group. The subjective scores from both groups declared that both methods could be accepted by patients.

Topics: Adult; Blood Glucose; Body Weight; Diabetes Mellitus, Type 2; Eating; Exenatide; Fasting; Female; Gastric Bypass; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Lipoproteins; Male; Middle Aged; Obesity, Morbid; Peptides; Remission Induction; Treatment Outcome; Venoms; Weight Loss

A role of GLP-1 (glucagon-like peptide-1) in the recovery of the metabolic conditions of morbidly obese patients after bariatric surgery has been proposed. Exendin 4 (Ex-4) and exendin 9 (Ex-9) both have GLP-1-like effects upon glucose metabolism in human myocytes. We investigated in normal human adipocytes the effect of GLP-1, Ex-4 and Ex-9, compared with insulin upon the activity of PI3K, PKB, MAPKs and p70s6 kinases, and the participation of these enzymes in their action upon 2-deoxy-D-glucose transport by using potential inhibitors. The study was extended to morbidly obese patients. In normal subjects, GLP-1, Ex-4 and insulin, but not Ex-9, increased glucose uptake. In addition, GLP-1 and Ex-4 stimulated PI3K and MAPKs, similar to insulin, but not PKB. Ex-9 only enhanced PI3K, while none affected p70s6k. Inhibition of both PI3K and MAPKs blocked the stimulatory action of GLP-1, Ex-4 and insulin upon glucose transport. In obese patients, basal PI3K, PKB and MAPK activity was, as a rule, lower than that in normal subjects, while cells maintained their normal incremental response to GLP-1, Ex-4 or insulin; Ex-9 induced a clear stimulation of p42 MAPK. In summary, in normal human adipocytes, GLP-1 and Ex-4 have a protein kinase-dependent increasing effect upon glucose transport, which is impaired in obese patients. The participation of GLP-1 in the normalization of the metabolic conditions of the obese may occur through its effects on lipid metabolism or through effects upon glucose transport and/or metabolism in the liver and muscle, which in human obesity remain to be investigated.

Topics: Adipocytes; Adult; Biological Transport; Cells, Cultured; Deoxyglucose; Exenatide; Female; Glucagon-Like Peptide 1; Glucose; Humans; Male; Middle Aged; Obesity, Morbid; Peptide Fragments; Peptides; Phosphotransferases; Venoms