Effects Of Exenatide Research Articles

Effects of exenatide once weekly plus dapagliflozin, exenatide once weekly alone, or dapagliflozin alone added to metformin monotherapy in subgroups of patients with type 2 diabetes in the DURATION-8 randomized controlled trial.

This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n = 231), exenatide once weekly alone (n = 230), or dapagliflozin alone (n = 233) differed in key patient subpopulations of the DURATION‐8 trial. Potential treatment‐by‐subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28 weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least‐squares mean reductions ranged from −8.4 to −26.1 mmol/mol (−0.77% to −2.39%) for HbA1c and from −2.07 to −4.55 kg for body weight. Potential treatment‐by‐subgroup interactions (P < .10) were found for HbA1c change by age (P = .016) and eGFR (P = .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ≥65 years (n = 74 vs n = 499 for patients aged <65 years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ≥90 vs ≥60 to <90 mL/min/1.73 m2 (least‐squares mean reductions of −23.6 vs −19.0 mmol/mol [−2.16% vs −1.74%], −17.3 vs −12.0 mmol/mol [−1.58% vs −1.10%], and −17.7 vs −16.9 mmol/mol [−1.62% vs −1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment‐by‐subgroup interaction was observed for change in body weight by sex (P = .099), with greater weight loss for women vs men across all treatments (range −2.56 to −3.98 kg vs −0.56 to −2.99 kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

T160. TREATMENT OF CLOZAPINE-ASSOCIATED OBESITY AND DIABETES WITH EXENATIDE (CODEX) IN ADULTS WITH SCHIZOPHRENIA: A RANDOMISED CONTROLLED TRIAL

BackgroundClozapine is the most effective anti-psychotic for treatment refractory schizophrenia, but causes significant metabolic disturbances including obesity and type 2 diabetes. The metabolic adverse reactions may be mediated in part by clozapine induced dysregulation of Glucagon-like-peptide-1 (GLP-1). GLP-1 is an intestinal epithelial derived peptide, released with ingestion of food, that triggers satiety, reduces glucagon production, promotes insulin production and slows gut motility. Clozapine has been shown to interfere with GLP-1 function in animal models, leading to metabolic dyregulation including obesity and preference for high calorie meals. Administration of exogenous GLP-1 agonists such as exenatide to animals have been shown to counter this effect of clozapine. Exenatide subcutaneous weekly injections may assist obese people on clozapine lose weight.MethodsThis randomised, controlled, open-label, pilot trial aimed to evaluate the effect of exenatide on weight loss among clozapine-treated obese adults who have schizophrenia, with or without stable diabetes. Twenty-eight out-patients were randomised to once weekly extended release sub-cutaneous exenatide or treatment as usual for 24 weeks. This trial examined the safety, tolerability and acceptability of exenatide among obese people with schizophrenia on clozapine, with an evaluation of change in weight, glycaemic control, psychosis severity and metabolic parameters.ResultsAll 28 participants completed the study. (Exenatide=14 (3 T2DM), control=14 (2 T2DM)). Six people on exenatide achieved >5% weight loss, compared to only 1 control (p=0.029). Mean weight loss was greater for exenatide than control at week 24 (-5.29kg vs -1.12kg, p=0.015) as were. BMI (-1.78 vs -0.39 p=0.019), fasting glucose (-0.34 vs 0.39, p=0.036) and HbA1c (-0.21 vs 0.03, p=0.004). There was no significant difference for other metabolic syndrome components. There were higher rates of transient nausea (n=8), vomiting (n=7) and diarrhoea (n=7) in the exenatide group.DiscussionExenatide is a promising therapeutic agent for glycaemic control and weight loss in clozapine-treated people with obesity. These results suggest good tolerability and a consistent and favourable pattern of weight loss effects with exenatide. GLP-1 agonists could assist in reducing the cardio-metabolic associated morbidity and mortality secondary to clozapine.

Exenatide has a pronounced effect on energy intake but not energy expenditure in non-diabetic subjects with obesity: A randomized, double-blind, placebo-controlled trial

AimsExenatide is a glucagon-like peptide 1 (GLP-1) mimetic which induces weight loss predominantly, it is presumed, via decreased food intake. However, circulating GLP-1 is also a determinant of energy expenditure. We sought to quantify the effect of exenatide on energy expenditure (EE) and energy intake. Materials and MethodsIn this single-center, randomized double-blind placebo controlled trial, we randomized 80 healthy, non-diabetic volunteers with obesity (46 women, age: 34.4 ± 8.7 y, body fat by DXA: 44.2 ± 7.8%) to subcutaneous exenatide 10 μg twice daily or placebo. Subjects were admitted to our clinical research unit for measurement of 24 h-EE in a whole-room indirect calorimeter and ad libitum food intake using an automated vending machine paradigm before and after randomization. Furthermore, energy expenditure and ad libitum food intake measures were repeated at 24-week after readmission for 7-day inpatient stay. Body weight was obtained weekly for up to 5 weeks and was recorded at each monthly follow up visit up to 24 weeks. ResultsPrior to randomization, participants over ate during the 3-day vending machine period in the whole study group (114.6 ± 35.2%), expressed as percentage of weight maintaining energy needs (WMEN) with those who were eventually randomized to exenatide overeating more (121.6 ± 37.7%) compared to placebo group (107.6 ± 31.5%). In the exenatide group, ad libitum absolute energy intake decreased by 1016.1 ± 724.5 kcal/day (95% CI: −1250.9 to −781.2) versus a 245.1 ± 710.5 kcal/day (95% CI: −475.4 to −14.7) decrease in placebo (Δ = −624.8 Kcal/day, p < 0.0001) whereas the reduction in ad libitum caloric intake relative to WMEN was a more modest 366.8 ± 752.1 kcal/day (95% CI: −614.0 to −119.6) decrease compared to 8.0 ± 860.1 kcal/day (95% CI: −286.8 to 270.8) reduction in placebo (Δ = −382.3 Kcal/day, p = 0.03). The decrease was uniform across all macronutrients groups.No differences in 24hEE or substrate oxidation rates were found. In the exenatide group, body weight decreased more over the 5 weeks (β = −0.039 kg/week, p = 0.02) and was lower compared to placebo at the end of fifth week (−1.48 ± 0.77 kg; 95% CI: −3.02 to 0.05, p = 0.06).At the 24-week follow up, there was no difference in energy intake between exenatide group and placebo group and the treatment group decreased 24-h EE more compared to placebo (β = −160.6 Kcal/day, 95% CI: −307.6 to 13.6, p = 0.03) compared to their pre-randomization measurement. However, this reduction was not present after adjustment for changes in FM and FFM (β = −87 kcal/day, p = 0.14). No difference was observed in body weight (Δ = −1.72 kg, 95% CI: −5.77 to 2.30, p = 0.39) in exenatide versus placebo over 24 weeks. ConclusionCompared with placebo, exenatide decreased early ad libitum energy intake but did not change 24 h-EE. However, the reduction was more modest in relative versus absolute terms (i.e. below that needed for WMEN). Thus, although rate of weight change was greater in the exenatide treated subjects at 5 weeks, the absolute difference in weight was not significant. These findings indicate that although exenatide reduces food intake, it may be more beneficial in blunting overeating and thus may serve to more prevent weight regain following initial weight loss.

Don't Play with Your Nodule: Case Report of Tachycardia and Other Adverse Reactions from Manipulation of an Exenatide Injection Site Nodule

BackgroundType II diabetes mellitus (DM) is an increasingly prevalent cause of morbidity and mortality among U.S. adults, with increasing prevalence in emergency department (ED) visits. Multiple medications, such as exenatide, a glucagon-like peptide-1 agonist, have been developed in the past decade to combat this growing problem. This medication is well documented to cause gastrointestinal upset and skin nodules at the injection site. However, currently no documented cases exist regarding manipulation of injection nodules causing increased absorption or reports demonstrating an increase in adverse drug reactions. Case ReportWe report an interesting case of an adult male patient who likely experienced increased systemic absorption of exenatide by manipulating an injection nodule, which ultimately resulted in nausea, retching, diarrhea, and a tachycardic heart rate of 130–140 beats/min. These symptoms are known side effects of exenatide. Why Should an Emergency Physician Be Aware of This?Given the high frequency of DM patients presenting to the ED, emergency physicians should be familiar with diabetic maintenance medications and their adverse reactions. Treating these side effects and properly educating patients can alleviate discomfort, prevent future adverse reactions, and decrease return visits to the ED.

The Glucagon-Like Peptide-1 Analog Exenatide Increases Blood Glucose Clearance, Lactate Clearance, and Heart Rate in Comatose Patients After Out-of-Hospital Cardiac Arrest.

To investigate the effects of the glucagon-like peptide-1 analog exenatide on blood glucose, lactate clearance, and hemodynamic variables in comatose, resuscitated out-of-hospital cardiac arrest patients. Predefined post hoc analyzes from a double-blind, randomized clinical trial. The ICU of a tertiary heart center. Consecutive sample of adult, comatose patients undergoing targeted temperature management after out-of-hospital cardiac arrest from a presumed cardiac cause, irrespective of the initial cardiac rhythm. Patients were randomized 1:1 to receive 6 hours and 15 minutes of infusion of either 17.4 μg of the glucagon-like peptide-1 analog exenatide (Byetta; Lilly) or placebo within 4 hours from sustained return of spontaneous circulation. The effects of exenatide were examined on the following prespecified covariates within the first 6 hours from study drug initiation: lactate level, blood glucose level, heart rate, mean arterial pressure, and combined dosage of norepinephrine and dopamine. The population consisted of 106 patients receiving either exenatide or placebo. During the first 6 hours from study drug initiation, the levels of blood glucose and lactate decreased 17% (95% CI, 8.9-25%; p = 0.0004) and 21% (95% CI, 6.0-33%; p = 0.02) faster in patients receiving exenatide versus placebo, respectively. Exenatide increased heart rate by approximately 10 beats per minute compared to placebo (p < 0.0001). There was no effect of exenatide on other hemodynamic variables. In comatose out-of-hospital cardiac arrest patients, infusion with exenatide lowered blood glucose and resulted in increased clearance of lactate as well as increased heart rate. The clinical importance of these physiologic effects remains to be investigated.

Real-world clinical outcomes and predictors of glycaemic and weight response to exenatide once weekly in patients with type 2 diabetes: The CIBELES project.

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 6months. Observational, retrospective, multicenter study in adult patients with T2D and BMI ≥30kg/m2 from 4 tertiary Spanish hospitals who started ExQW therapy at least 6months 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% 6months after ExQW. The best predictive models of glycaemic and weight response were estimated by binary logistic regression. One hundred and forty eight patients were included, mean age 58.0years, A1C 7.7%, weight 105.9kg and BMI 38.4kg/m2 . A1C (-1.1%), weight (-3.9kg), systolic blood pressure (-4.0mm Hg), diastolic blood pressure (-2.9mm Hg), LDL-cholesterol (-14.2mg/dL) and triglycerides (-31.0mg/dL) significantly decreased 6months 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 2years 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. In a real-world setting, ExQW significantly decreased A1C, weight, blood pressure and lipids at 6months. 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.

Exenatide Increases IL-1RA Concentration and Induces Nrf-2‒Keap-1‒Regulated Antioxidant Enzymes: Relevance to β-Cell Function.

We previously demonstrated the anti-inflammatory and antioxidant effects of exenatide. We now hypothesized that exenatide also increases the plasma concentration of interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein, and modulates the nuclear factor erythroid 2‒related factor‒Kelchlike ECH-associated protein 1‒antioxidant response element (Nrf-2‒Keap-1‒ARE) system to induce key antioxidant enzymes to suppress inflammatory and oxidative stress. Twenty-four patients with obesity and type 2 diabetes receiving combined oral and insulin therapy were randomly assigned to receive either exenatide 10 μg or placebo twice a day for 12 weeks. Exenatide increased IL-1RA concentration by 61% (from 318 ± 53 to 456 ± 88 pg/mL; P < 0.05). Exenatide treatment also suppressed Keap-1 protein (P < 0.05) and increased messenger RNA expression of NQO-1, glutathione S-transferase PI, heme oxygenase-1, and p21 and increased NAD(P)H dehydrogenase [quinone] 1 protein (P < 0.05) in mononuclear cells. Because IL-1RA protects, maintains, and stimulates β-cell function in humans and Nrf-2‒Keap-1‒ARE protects β cells in animals with experimental diabetes, these actions of exenatide may contribute to a potential protective effect on β cells in diabetes.

Marked Improvement in Glycemic Control with Exenatide on Addition to Metformin, Sulfonylurea and Insulin Glargine in Type 2 Diabetes Mellitus, a Real World Experience

Background: The major effect of Exenatide is attributed to lowering of post-prandial glycemia, whereas insulin glargine mainly improves fasting glycemia [FPG]. Objective: Therefore, we assessed effect of Exenatide administration at 6 months and for at 1 year on glycemic control, lipids, body weight [BW], daily insulin dose and hypoglycemic events. Methods: Records of 164 subjects, 126 men and 38 women administered Exenatide between January 2011 and December 2013 are included in this report. Exenatide was initiated at 5 mcg subcutaneously twice daily [BID] in obese subjects, BMI > 30 kg/m2, with C-peptide > 1 ng/d, and HbA1c 7.5% - 9.5%, while receiving daily metformin 2000 mg, Sulfonylurea Glimepiride 8 mg and insulin Glargine [GLAR]. Exclusion criteria were creatinine > 1.5 mg/dL and liver enzymes > 2.5 times upper limit of normal. Indices of glycemic control include fasting plasma glucose levels and HbA1c. Lipids include serum concentrations of total, LDL and HDL cholesterol. Other endpoints are body weight, daily insulin dose and number of hypoglycemic events per patient during 4 weeks prior to initiation of Exenatide, at 6 months and 1 year of therapy. Results: In 37 subjects, Exenatide was discontinued within 1 - 3 weeks; 29 due to onset of nausea and vomiting. Seven of these also complained of abdominal pain and in these, serum amylase and lipase were elevated indicating presence of acute pancreatitis. One subject discontinued because of chest pain. Fasting plasma Glucose remained unchanged following Exenatide administration. However, HbA1c declined significantly denoting improvement in overall glycemic control without significant changes in body weight, daily insulin dose and hypoglycemic events. Lipid panel improved as well. Conclusion: Exenatide may be an appropriate adjuvant option in obese subjects with Type 2 diabetes mellitus with lack of desirable glycemic control while receiving therapy with Metformin, Glimepiride, and insulin Glargine. Moreover, improvement in glycemic control is likely to be secondary to lowering of post prandial hyperglycemia induced by Exenatide.

Exenatide with Metformin Ameliorated Visceral Adiposity and Insulin Resistance

Background To study the effectiveness of exenatide with metformin and sequential treatment with exenatide and glargine added to metformin and their influence on insulin sensitivity and adipose distribution. Methods 20 newly diagnosed obese type 2 diabetic patients were enrolled, and 2-month washout treatment of metformin, 6-month exenatide treatment, and 6-month glargine treatment were administrated sequentially accompanied with previous metformin. Glucolipid metabolic parameters were compared among groups. Adipose distribution was quantified with computerized tomography according to anatomy, dividing into visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), adding up to total adipose tissue (TAT). Results The 6-month exenatide treatment dramatically ameliorated the glucose and lipid profile, improved insulin sensitivity, and mainly decreased VAT and also the ratio of VAT/SAT (RVS). The following 6-month glargine treatment increased VAT. The whole 12-month sequential treatment with exenatide and glargine added to metformin basically improved the insulin sensitivity and glucolipid control though VAT rebounded at the end, however without deteriorating the other parameters. Conclusion Exenatide is an ideal treatment for obese type 2 diabetic patients in the aspect of adipose tissue distribution. Sequential treatment of exenatide and glargine could be an alternative for low-income patients who cannot afford GLP-1 agonist for long time. This trial is registered with ChiCTR-OOC-17013679.

Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB signal pathways mediate exenatide-stimulated expression of M2 microglial markers

GLP-1 receptor agonists, exenatide and GLP-1, promoted M2 type polarization in monocytes/macrophages and microglial cells. This study explored the signal basis underlying exenatide-stimulated expression of M2 microglia-specific genes, including the cytoplasmic marker Arg 1, surface marker CD206, and secretion protein marker IL-4. Treatment with exenatide in cultured primary microglial cells concentration dependently stimulated the expression of Arg 1, CD206 and IL-4, but did not significantly alter LPS-stimulated expression of TNF-α, IL-1β and IL-6. The stimulatory effects of exenatide were completely prevented by the GLP-1 receptor antagonist exendin(9–39), but not altered by application of LPS. Furthermore, the adenylyl cyclase inhibitor DDA, PKA inhibitor H89 and CREB inhibitor KG501 completely blocked exenatide-induced overexpression of Arg 1, CD206 and IL-4. In addition, exenatide-stimulated expression of Arg 1 and CD206 was totally blocked by the p38 MAPK inhibitor SB203580 and gene silencer siRNA/p38β (but not siRNA/p38α), whereas the expressed IL-4 was not significantly altered by the p38 inhibitor or other MAPK subtype inhibitors. These findings revealed that both classic Gs-cAMP/PKA/CREB and alternative Gs-cAMP/PKA/p38β/CREB mediated GLP-1 receptor agonism-induced overexpression of M2 microglial biomarkers.

Cardioprotection by exenatide: A novel mechanism via improving mitochondrial function involving the GLP-1 receptor/cAMP/PKA pathway.

Accumulating evidence suggests that glucagon-like peptide-1 (GLP-1) and its analogues exert cardioprotective effects via modulating cardiomyocyte metabolism. Mitochondria play a pivotal role in the regulation of cell metabolism. It was hypothesized that treatment with exenatide, a GLP-1 analogue, may exert cardioprotective effects by improving mitochondrial function in an invitro model of hypoxia/reoxygenation(H/R). H9c2 cells were employed to establish an invitro model of H/R. Exenatide was added to the cells for 30min prior to exposure to hypoxia. The GLP-1 receptor antagonist exendin‑(9‑39), the cyclic adenosine monophosphate (cAMP) inhibitor Rp-cAMPS and the protein kinaseA (PKA) inhibitor H-89 were added to the cells for 10min prior to treatment with exenatide. The release of lactate dehydrogenase(LDH) and creatine kinase-MB (CK-MB) and cardiomyocyte apoptosis were evaluated. The characteristics of mitochondrial morphology and functions, including ATP synthesis, membrane potential (ΔΨm), mitochondrial permeability transition pore (mPTP), mitochondrial ATPase activity and oxidative stress, were determined. the mitochondrial uncoupling protein-3(UCP-3) and nuclear respiratory factor-1(Nrf-1) were also investigated by western blot analysis. Exenatide pretreatment significantly decreased LDH and CK-MB release and cardiomyocyte apoptosis in H9c2 cells subjected to H/R. More importantly, to the best of our knowledge, this is the first report of exenatide pretreatment decreasing mitochondrial abnormalities and reducing oxidative stress, while enhancing ATP synthesis, mitochondrial ATPase activity and ΔΨm in H9c2 cells subjected to H/R. Exenatide pretreatment also decreased mitochondrial calcium overload and inhibited the opening of mPTP in H9c2 cells subjected to H/R. Furthermore, exenatide pretreatment upregulated UCP-3 and Nrf-1 expression in H9c2cells subjected to H/R. However, the abovementioned observed effects of exenatide were all abolished when exenatide was co-administered with exendin‑(9‑39), Rp-cAMPS and̸or H-89. Therefore, the GLP-1 analogue exenatide was found to exert cardioprotective effects in an in vitro model of H/R, and this cardioprotection may be attributed to the improvement of mitochondrial function. These effects are most likely associated with the activation of the GLP-1 receptor/cAMP/PKA signaling pathway.

Exenatide treatment causes suppression of serum fasting ghrelin levels in patients with type 2 diabetes mellitus.

AimIn the present study, we investigated the long-term effects of exenatide treatment on serum fasting ghrelin levels in patients with type 2 diabetes mellitus.MethodsType 2 diabetic patients, who were using metformin with and without the other antihyperglycemic drugs on a stable dose for at least 3 months, were enrolled in the study. BMI>35 kg/m2 and HbA1c>7.0% were the additional inclusion criteria. Oral antihyperglycemic drugs, other than metformin, were stopped, and metformin treatment was continued at 2000 mg per day. Exenatide treatment was initiated at 5 µg per dose subcutaneously (sc) twice daily, and after one month, the dose of exenatide was increased to 10 µg twice daily. Changes in anthropometric variables, glycemic control, lipid parameters and total ghrelin levels were evaluated at baseline and following 12 weeks of treatment.ResultsThirty-eight patients (male/female = 7/31) entered the study. The mean age of patients was 50.5 ± 8.8 years with a mean diabetes duration of 8.5 ± 4.9 years. The mean BMI was 41.6 ± 6.3 kg/m2 and the mean HbA1c of patients was 8.9 ± 1.4%. The mean change in the weight of patients was −5.6 kg and the percentage change in weight was −5.2 ± 3.7% following 12 weeks of treatment. BMI, fasting plasma glucose and HbA1c levels of patients were decreased significantly (P < 0.001 and P < 0.001; respectively), while there was no change in lipid parameters. Serum fasting ghrelin levels were significantly suppressed following 12 weeks of exenatide treatment compared with baseline values (328.4 ± 166.8 vs 245.3 ± 164.8 pg/mL) (P = 0.024).ConclusionThese results suggest that the effects of exenatide on weight loss may be related with the suppression of serum fasting ghrelin levels, which is an orexigenic peptide.

Exenatide Improves Bone Quality in a Murine Model of Genetically Inherited Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is associated with skeletal complications, including an increased risk of fractures. Reduced blood supply and bone strength may contribute to this skeletal fragility. We hypothesized that long-term administration of Exenatide, a glucagon-like peptide-1 receptor agonist, would improve bone architecture and strength of T2DM mice by increasing blood flow to bone, thereby stimulating bone formation. In this study, we used a model of obesity and severe T2DM, the leptin receptor-deficient db/db mouse to assess alterations in bone quality and hindlimb blood flow and to examine the beneficial effects of 4 weeks administration of Exenatide. As expected, diabetic mice showed marked alterations in bone structure, remodeling and strength, and basal vascular tone compared with lean mice. Exenatide treatment improved trabecular bone mass and architecture by increasing bone formation rate, but only in diabetic mice. Although there was no effect on hindlimb perfusion at the end of this treatment, Exenatide administration acutely increased tibial blood flow. While Exenatide treatment did not restore the impaired bone strength, intrinsic properties of the matrix, such as collagen maturity, were improved. The effects of Exenatide on in vitro bone formation were further investigated in primary osteoblasts cultured under high-glucose conditions, showing that Exenatide reversed the impairment in bone formation induced by glucose. In conclusion, Exenatide improves trabecular bone mass by increasing bone formation and could protect against the development of skeletal complications associated with T2DM.

The effect of the GLP-1 analogue Exenatide on functional connectivity within an NTS-based network in women with and without obesity.

SummaryObjectiveThe differential effect of GLP‐1 agonist Exenatide on functional connectivity of the nucleus tractus solitaries (NTS), a key region associated with homeostasis, and on appetite‐related behaviours was investigated in women with normal weight compared with women with obesity.MethodsFollowing an 8‐h fast, 19 female subjects (11 lean, 8 obese) participated in a 2‐d double blind crossover study. Subjects underwent functional magnetic resonance imaging at fast and 30‐min post subcutaneous injection of 5 μg of Exenatide or placebo. Functional connectivity was examined with the NTS. Drug‐induced functional connectivity changes within and between groups and correlations with appetite measures were examined in a region of interest approach focusing on the thalamus and hypothalamus.ResultsWomen with obesity reported less hunger after drug injection. Exenatide administration increased functional connectivity of the left NTS with the left thalamus and hypothalamus in the obese group only and increased the correlation between NTS functional connectivity and hunger scores in all subjects, but more so in the obese.ConclusionsObesity can impact the effects of Exenatide on brain connectivity, specifically in the NTS and is linked to changes in appetite control. This has implications for the use of GLP‐1 analogues in therapeutic interventions.

Inconclusive effects of once‐weekly exenatide on cardiovascular outcomes in type 2 diabetes

Inconclusive effects of once‐weekly exenatide on cardiovascular outcomes in type 2 diabetes

Exenatide Inhibits the KCa3.1 Channels of Aortic Vascular Smooth Muscle in Diabetic Rats.

KCa3.1 ion channels play an important role during atherosclerosis. We aimed to investigate the effect of exenatide on KCa3.1 expression in aortic vascular smooth muscle cells (VSMCs) of diabetic rats. Sprague-Dawley rats were randomly divided into normal control (NC), diabetes model (DM), and exenatide treatment (ET) groups. Hematoxylin and eosin and α-actin immunohistochemical staining were used to detect changes in rat aortic vascular smooth muscle. Quantitative RT-PCR and Western blot analysis were used to detect changes in KCa3.1 mRNA and protein levels, respectively. Aortic tissue staining in the DM group revealed an absence of smooth or integrated endothelium, increased smooth muscle cell proliferation in the media, smooth muscle hyperplasia, disorganized smooth muscle cells, and an increased number of collagen fibers, relative to the NC and ET groups. KCa3.1 mRNA expression was higher in the DM group than in the NC and ET groups. Similarly, the KCa3.1 protein level was higher in the DM group than in the NC and ET groups. The KCa3.1 protein level did not significantly differ between the ET and NC groups. Exenatide could inhibit the expression of the KCa3.1 channel in VSMCs of diabetic rats.

Effects of exenatide twice daily, exenatide once weekly or insulin in patients with type 2 diabetes and baseline HbA1c ≥10.0%: Two pooled analyses including 20 randomised controlled trials.

Patients with advanced type 2 diabetes (T2D) and high glycated haemoglobin (HbA1c) values can be difficult to treat because of their severe metabolic disease. This pooled analysis examined the treatment effects of exenatide twice daily (BID), exenatide once weekly (QW) and insulin in patients with high baseline HbA1c (≥10.0%). This post hoc analysis used pooled data from 12 and 8 randomised controlled trials of exenatide BID and exenatide QW, respectively. Patients with T2D who completed at least 24weeks of treatment with exenatide BID, exenatide QW or insulin (insulin glargine, insulin detemir or insulin aspart) were categorised by baseline HbA1c. Patients with HbA1c ≥10.0% were included in the analysis. Both exenatide and insulin reduced HbA1c (mean±SE reduction: -2.0%±0.2% [exenatide] and -2.1%±0.2% [insulin] in the exenatide BID studies, and -2.6%±0.1% [exenatide] and -2.1%±0.2% [insulin] in the exenatide QW studies; all P<.001). Body weight decreased with exenatide and increased with insulin. Systolic blood pressure decreased with exenatide QW. Insulin dose increased over the course of treatment. The most common adverse events with exenatide were gastrointestinal. Insulin was associated with some hypoglycaemia risk. Hypoglycaemia events occurred infrequently with exenatide when given without sulphonylureas. For patients with high HbA1c, treatment with exenatide or insulin both improved glycaemic control. Given the associated weight loss and low risk of hypoglycaemia, exenatide may be a suitable alternative to treatment with insulin in certain patients with T2D and high HbA1c.

Glucagon-like peptide-1 analogues exenatide and liraglutide exert inhibitory effect on the early phase of liver regeneration after partial hepatectomy in rats.

Glucagon-like peptide-1 (GLP-1) is an incretin known for proliferative and antiapoptotic effects on various tissues. Exenatide and Liraglutide are GLP-1 analogues used in clinical practice as antidiabetic drugs. Since GLP-1 and its analogues exert significant effect on liver metabolism and since changes in intermediary metabolism play an important role in the process of liver regeneration, we decided to determine the effect of Exenatide and Liraglutide on the early phase of liver regeneration and selected metabolic parameters in a model of 2/3 partial hepatectomy (PHx) in rats. Animals were submitted either to PHx or laparotomy and received 3 doses of either GLP-1 analogues (Exenatide - 42 microg/kg b.w., Liraglutide - 0.75 mg/kg b.w.) or saline intraperitoneally. We analyzed body and liver weight, liver bromodeoxyuridine incorporation, liver content of DNA, triacylglycerols and cholesterol and biochemical serum parameters. Bromodeoxyuridine labeling was significantly lower in hepatectomized rats receiving either type of GLP-1 analogues when compared to hepatectomized controls. This effect was more pronounced in the Liraglutide group compared to Exenatide (p<0.001). In addition, liver DNA content was lower in hepatectomized rats receiving Liraglutide than in hepatectomized control rats (p<0.001). In conclusion, GLP-1 analogues Exenatide and Liraglutide significantly inhibited an early phase of liver regeneration after PHx in rats. This inhibitory effect was more pronounced in rats receiving Liraglutide.

Tolerability and Effectiveness of Exenatide Once Weekly Relative to Basal Insulin Among Type 2 Diabetes Patients of Different Races in Routine Care.

IntroductionAnalyses of efficacy and tolerability of pharmacologic interventions are based on clinical trials that often include predominately white populations, in part because of challenges associated with recruitment and retention of racial/ethnically diverse study populations. Using real-world electronic health record (EHR) data, we sought to evaluate the tolerability and effectiveness of exenatide once weekly (EQW), overall and relative to basal insulin (BI), according to race.MethodsPatients with type 2 diabetes initiating EQW or BI between 2012 and 2015 were selected from the Optum EHR Research Database, a system pooling data from dozens of hospitals throughout the US. Measures of HbA1c, weight, and body mass index (BMI) were summarized at initiation and quarterly in the first year afterwards. Occurrences of gastrointestinal (GI) symptoms and hypoglycemia were identified by diagnostic codes and clinical notes, and incidence rates (IR) and relative rates (RR) were calculated.ResultsOverall, 4907 white patients (mean age = 57 years) and 454 African American patients (mean age = 53 years) were included. The percent change in HbA1c from initiation through 9–12 months was similar for white and African American patients [EQW-White: −6.89 (95% CI: −8.29, −5.50), EQW-African American: −5.99 (95% CI: −10.33, −1.65), BI-White: −4.68 (95% CI: −5.51, −3.86), BI-African American: −3.11 (95% CI: −5.37, −0.85)]. For EQW, percent change in weight was −1.73 (95% CI: −2.45, −1.02) for white patients and −1.11 (95% CI: −3.02, −0.81) for African American patients. No weight loss was observed among BI initiators. Relative to BI initiators, EQW initiators had lower rates of hypoglycemia [White RR: 0.82 (95% CI: 0.66, 1.01), African American RR: 0.59 (95% CI: 0.26, 1.34)]. GI symptoms were increased in white EQW initiators.ConclusionsTreatment with EQW, relative to BI, was associated with larger reductions in HbA1c and weight and reduced risk of hypoglycemia, effects that were not different for white and African American patients.FundingAstraZeneca, Gothenburg, Sweden