Effects Of Exenatide Research Articles

Effect of exenatide twice daily and dapagliflozin, alone and in combination, on markers of kidney function in obese patients with type 2 diabetes: A prespecified secondary analysis of a randomized controlled clinical trial.

AimsTo evaluate the effects of separate and combined use of the sodium‐glucose cotransporter‐2 (SGLT2) inhibitor dapagliflozin and the glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) exenatide on measures of kidney function.MethodsIn this prespecified secondary analysis of the DECREASE trial, we enrolled 66 obese patients with type 2 diabetes in a 16‐week randomized double‐blind placebo‐controlled clinical trial to investigate the effects of dapagliflozin and exenatide twice daily, alone or in combination, versus placebo on 24‐hour urinary albumin:creatinine ratio (UACR), creatinine and cystatin C‐estimated glomerular filtration rate (GFR) and kidney injury molecule‐1:creatinine ratio (KIM‐1:Cr).ResultsAt week 16, the mean UACR change from baseline was −39.6% (95% confidence interval [CI] −58.6, −11.9; P = 0.001) in the combined exenatide‐dapagliflozin group, −18.1% (95% CI −43.1, 18.0; P = 0.278) in the dapagliflozin group, −15.6% (95% CI −41.4, 21.6; P = 0.357) in the exenatide group and − 11.0% (95% CI −39.8, 31.5; P = 0.552) in the placebo group. Compared to placebo, UACR difference at week 16 in the exenatide‐dapagliflozin group was −32.2% (95% CI −60.7, 16.9; P = 0.159). Effects were similar in 37 participants who were using angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers at baseline. Compared to placebo, in the exenatide‐dapagliflozin group, an acute dip in estimated GFR was observed with creatinine‐estimated GFR (−4.0 mL/min/1.73 m2 [95% CI −9.3, 1.2]; P = 0.129) and cystatin C‐estimated GFR (−10.4 mL/min/1.73 m2 [95% CI −14.9, −5.8]; P < 0.001). The mean KIM‐1:Cr difference in the combined treatment arm versus placebo was −43.8% (95% CI −73.5, 18.9; P = 0.129).ConclusionThis prespecified secondary analysis suggests that combined therapy with exenatide and dapagliflozin may have synergistic effects on markers of kidney function compared to either therapy alone or placebo in obese patients with type 2 diabetes.

Exenatide regulates inflammation and the production of reactive oxygen species via inhibition of S1PR2 synthesis.

Microvascular dysfunction is one of the most serious complications of diabetic retinopathy (DR). As a novel treatment drug for type 2 diabetes, exenatide possesses protective properties against retinal neurodegeneration. Sphingosine-1-phosphate receptor 2 (S1PR2) could regulate blood glucose in diabetes, and inhibition of S1PR2 is involved in the treatment of diabetes. However, the mechanism of exenatide in human retinal vascular endothelial cells (hRVECs) has not been fully defined. We tested the hypothesis that S1PR2 plays a vital role in high glucose (HG)-induced hRVECs, and that exenatide could ameliorate HG-induced hRVEC injury by regulating S1PR2 production. The hRVECs underwent HG-stimulation. Quantitative real-time polymerase chain reaction (RT-qPCR) and western blot were performed to examine the expression of S1PR2. Oxidative stress levels, inflammatory markers and cell apoptosis were detected using reactive oxygen species (ROS) staining, enzyme-linked immunosorbent assay (ELISA) kits and TUNEL staining. High glucose increased the level of S1PR2 in hRVECs and reduced the expression of glucagon-like peptide-1 receptor (GLP1R) compared to the control group. Exenatide decreased the level of S1PR2 induced by HG. Sphingosine-1 blocked the effects of exenatide, alleviating the ROS and cell apoptosis induced by HG. JTE-013 treatment protected hRVECs from injury by HG. The inhibitory effects of exenatide on S1PR2 expression lessened HG-induced hRVEC injury. The results demonstrate a possible mechanism of exenatide mediated inhibition of S1PR2 synthesis, and support S1PR2 as a novel target for treating DR.

Exenatide Attenuates Non-Alcoholic Steatohepatitis by Inhibiting the Pyroptosis Signaling Pathway.

Background/AimsExenatide is a glucagon-like polypeptide-1 analog, whose main clinical use is to treat type 2 diabetes. However, the mechanism of exenatide in mitigating non-alcoholic steatohepatitis (NASH) remains unclear. This study aimed to investigate the in vitro and in vivo effect of exenatide on NASH.MethodsLeptin receptor-deficient C57BL/KsJ- db/db male mice were fed with methionine-choline-deficient (MCD) diet for 4 weeks to induce NASH, while oleic acid/LPS-treated HepG2 cells were used as an in vitro cell model. Exenatide (20 µg/kg/day, subcutaneous) and specific exenatide inhibitors (20 µg/kg/day, intraperitoneal) were used to determine the effects of exenatide on NASH.ResultsExenatide treatment inhibited the pyroptosis signaling pathway to attenuate NASH.ConclusionTo the best of our knowledge, this report provides the first evidence showing that exenatide attenuated NASH by inhibiting the pyroptosis signaling pathway. Exenatide thus has important pathophysiological functions in NASH and may represent a useful new therapeutic target.

Exenatide promotes cholesterol efflux in pancreatic tissue of obese diabetic rats

To study the effect of exenatide on the expression of ABCA1 and cholesterol metabolism in the pancreas of obese diabetic rats. Twenty-four normal male SD rats and 18 obese diabetic rats (induced by high-fat feeding and STZ injection) were both divided equally into 2 groups for injections of saline or exenatide. After treatment for a week, the expression of ABCA1, cholesterol metabolism, and islet function of the rats were examined using real-time PCR, Western blotting, oil red O staining, cholesterol content determination, and HE staining. The expressions of ABCA1 at both mRNA and protein levels in pancreatic tissue were significantly lower in obese diabetic rats than in normal SD rats. The obese diabetic rats showed obvious lipid deposition and increased cholesterol content in the pancreatic tissue with significantly reduced islet volume and structural changes (P < 0.05); exenatide treatment of the diabetic rats significantly up-regulated ABCA1 expression, reduced lipid deposition and cholesterol content in pancreatic tissue, and increased number and volume of the islets, which presented with more orderly alignment (P < 0.05). Obese diabetic rats have lowered ABCA1 expression, cholesterol efflux block, and cholesterol accumulation in the pancreatic tissue. Exenatide can up-regulate ABCA1 expression and promote cholesterol efflux to reduce cholesterol content in the pancreatic tissue and improve islet function in obese diabetic rats.

Integrated expression profiles of mRNA and miRNA in a gerbil model of fatty liver fibrosis treated with exenatide

The morbidity of nonalcoholic fatty liver disease (NAFLD) has increased consistently in recent years. Exenatide could reverse liver fibrosis and lower the occurrence of fatty liver. The aim of the study was to identify and characterize mRNA and miRNA expression to elucidate the mechanism of exenatide in the gerbil model. Gerbils were fed a high-fat diet for 8 weeks to induce a fibrosis model; then, the gerbil models were treated with exenatide for 4 weeks. The total RNA extracted from the liver tissue samples was used to prepare the library and sequence on a HiSeq 2000. Bioinformatic methods were employed to analyze the sequence data to identify the mRNAs and miRNAs and to acquire the miRNA-mRNA regulatory network. By RNA-seq, 2344 differentially expressed genes (DEGs) and 72 miRNAs were found in the model group. Compared with the model group, 591 DEGs and 19 miRNAs were found in the quercetin group, whereas 876 DEGs and 18 miRNAs were found in the treatment group. The miRNA-mRNA regulatory network was constructed in a gerbil model. Immunohistochemistry and RNA sequencing confirmed that the therapeutic effect of exenatide may be derived from extrahepatic signal transduction. The key differential genes are CYP3A, CYP4A11, ACAA1, ACSM, PHX1, MAO, FMO, UGT, ACOX2, ABAT, PIK3C and PLCG1. The key miRNAs are miR-15a, miR-27b, miR-532-3P, miR-627, miR-3596, miR-142-3P, Let-7e-5p, miR-214-5, miR-101-3p, miR-378d. New miRNAs, such as novel_127, novel_143, novel_15, novel_204 are associated with liver fibrosis, while novel_127, novel_15, and novel_54 are associated with reverse treated with exenatide. Our research represents the first description of mRNA/miRNA profiles in a gerbil model of fatty liver fibrosis treated with exenatide, which may provide insights into the pathogenesis or treatment of the metabolic syndrome.

Neutral effect of exenatide on serum testosterone in men with type 2 diabetes mellitus: A prospective cohort.

Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. Uncover the effects of Glucagon-Like Peptide-1 receptor agonist (GLP-1 RA) therapy on serum testosterone. Prospective cohort study of men starting GLP-1 RA therapy for type 2 diabetes mellitus. 51 men lost 2.27kg (p=0.00162) and their HbA1c values improved by 0.7% (p=0.000503) after 6months of GLP-1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone <320ng/dL (238.5±56.5ng/dL to 272.2±82.3ng/dL) compared to higher values (438±98.2ng/dL to 412±141.2ng/dL) (p=0.0172);free testosterone increased if the baseline total testosterone was <320ng/dL (55.2±12.8pg/mL to 57.2±17.6pg/mL) and decreased if >320ng/dL (74.7±16.3pg/mL to 64.2±17.7pg/mL) (p=0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6±123.9ng/dL to 394.4±136.5ng/dL) compared to men with HbA1c changes <1% (331.8±128.6ng/dL to 316.1±126.2ng/dL) (p=0.0413). GLP-1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits.

The glucagon-like peptide-1 (GLP-1) analog exenatide ameliorates intrauterine adhesions in mice

ObjectiveThe purpose of the experiments in this study was to explore the effect of exenatide on intrauterine adhesions (IUAs) and to elucidate its mechanism to provide new ideas for the clinical treatment of IUAs. MethodsIn this study, an animal model of IUAs was established by double stimulation using mechanical curettage and inflammation. After modeling, the treatment group was injected subcutaneously with three doses of exenatide for two weeks. The model group was injected with sterile ultrapure water, and the sham operation group was treated the same as the normal group, except for the observation of abdominal wound changes. Two weeks later, all mice were sacrificed by cervical dysfunction. The obtained mouse uterine tissue was used for subsequent experimental detection, using HE and Masson staining for histomorphological and pathological analysis; qRT-PCR for the detection of TGF-β1, α-SMA, and MMP-9 gene expression in uterine tissue; and western blotting analysis of TGF-β1, α-SMA, and collagen 1 protein expression to verify whether exenatide has a therapeutic effect on IUAs in mice. ResultsIn the high-dose exenatide treatment group, the endometrial glands significantly increased in size, and the deposition area of collagen fibers in the endometrial tissue was significantly reduced. We observed that the mRNA expression of TGF-β1 and α-SMA in the endometrial tissue of IUAs mice in this group was significantly reduced, while the expression of MMP-9 was significantly increased. In addition, we found that the protein expression of TGF-β1, α-SMA, and collagen 1 remarkably decreased after treatment with exenatide. ConclusionExenatide may reduce the deposition of collagen fibers in the uterus of IUAs mice and promote the proliferation of endometrial glands in mice.

Non-targeted metabolomic analysis predicts the therapeutic effects of exenatide on endothelial injury in patients with type 2 diabetes.

We aimed to investigate whether treatment with exenatide could ameliorate endothelial injury in patients with type 2 diabetes mellitus (T2DM), and to identify biomarkers for predicting amelioration of the endothelial injury induced by the treatment. Ninety-three patients with T2DM were recruited and treated with exenatide for 16 weeks. Enzyme-linked immunosorbent assays were performed at baseline and after the treatment to measure serum levels of endothelial injury markers, including soluble thrombomodulin (sTM). Patients were categorized as responders (n = 47) or non-responders (n = 46) based on median changes in their sTM levels. Serum levels of metabolites at baseline were measured with non-targeted liquid chromatography-mass spectrometry. The results obtained were evaluated with multivariate analysis. Treatment with exenatide for 16 weeks resulted in reduced body weight and improved levels of fasting plasma glucose, 2-hour postprandial plasma glucose, and HbA1c in patients with T2DM (all P < 0.05). Compared with baseline, serum levels of endothelial injury markers including sTM were significantly lowered after the treatment. Metabolites presented at significantly different levels in responders versus non-responders were considered as biomarkers for a therapeutic response of sTM to the exenatide treatment. Among those identified, 4-hydroxyproline and 12-oxo-9(Z)-dodecenoic acid were found to correlate most closely with the exenatide-induced endothelial protection response. The specificity and sensitivity of the multi-metabolite signature model contained higher 4-hydroxyproline and lower 12-oxo-9(Z)-dodecenoic acid were 53.3% and 92.3%, respectively, and the area under receiver operating characteristic curve was 69.2% (P < 0.001). Treatment with exenatide for 16 weeks ameliorates endothelial injury in patients with T2DM. Endothelial protection benefit from exenatide treatment was effectively predicted by the specific metabolomic combination of higher 4-hydroxyproline and lower 12-oxo-9(Z)-dodecenoic acid.

Effects of exenatide on microvascular reactivity in patients with type 2 diabetes and coronary artery disease: A randomized controlled study.

We studied the effect of the GLP-1RA exenatide on skin microvascular function in patients with T2DM and CAD. Thirty-five patients with T2DM, CAD, and HbA1C 42-86mmol/mol were randomized to treatment with exenatide or conventional non-GLP-1-based therapy for 12weeks. Skin microvascular function was examined in the forearm by LDF and iontophoretic application of acetyl choline and SNP, and by PORH at baseline and after 12weeks. Blood samples for fasting plasma glucose, HbA1C, and lipid profile were collected. At 12weeks, patients on exenatide showed reductions in HbA1C (from 63.5±13 to 60.7±14mmol/mol, p=.065), body weight (from 92.6±16 to 89±16kg, p<.001), and systolic blood pressure (from 141±13 to 134±16mmHg, p<.05) as compared to the conventionally treated group. There were no significant changes in skin microvascular function between or within the two groups at follow-up. Three months' daily treatment with the GLP-1RA exenatide in T2DM patients with CAD showed no significant effects on skin microvascular function or blood glucose control, while this study confirms a reduction in body weight and blood pressure by exenatide, as compared to conventional antidiabetic drug treatment.

Exenatide improves random-pattern skin flap survival via TFE3 mediated autophagy augment.

Random-pattern skin flaps are widely applied to rebuild and restore soft-tissue damage in reconstructive surgery; however, ischemia and subsequent ischemia-reperfusion injury lead to flap necrosis and are major complications. Exenatide, a glucagon-like peptide-1 analog, exerts therapeutic benefits for diabetic wounds, cardiac injury, and nonalcoholic fatty liver disease. Furthermore, Exenatide is a known activator of autophagy, which is a complex process of subcellular degradation that may enhance the viability of random skin flaps. In this study, we explored whether exenatide can improve skin flap survival. Our results showed that exenatide augments autophagy, increases flap viability, enhances angiogenesis, reduces oxidative stress, and alleviates pyroptosis. Coadministration of exenatide with 3-methyladenine and chloroquine, potent inhibitors of autophagy, reversed the beneficial effects, suggesting that the therapeutic benefits of exenatide for skin flaps are due largely to autophagy activation. Mechanistically, we identified that exenatide enhanced activation and nuclear translocation of TFE3, which leads to autophagy activation. Furthermore, we found that exenatide activates the AMPK-SKP2-CARM1 and AMPK-mTOR signaling pathways, which likely lead to exenatide's effects on activating TFE3. Overall, our findings suggest that exenatide may be a potent therapy to prevent flap necrosis, and we also reveal novel mechanistic insight into exenatide's effect on flap survival.

Once-Weekly Exenatide Effects on eGFR Slope and Urine Albumin-to-Creatinine Ratio (UACR) as a Function of Baseline UACR: An EXSCEL Post Hoc Analysis

Once-Weekly Exenatide Effects on eGFR Slope and Urine Albumin-to-Creatinine Ratio (UACR) as a Function of Baseline UACR: An EXSCEL Post Hoc Analysis

Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease

Background: Cardiovascular outcomes in clinical trials with type 2 diabetes mellitus (T2DM) patients have shown that glucagon-like peptide-1 receptor agonist can have a beneficial effect on the kidney. This trial aimed to assess the effects of exenatide on renal outcomes in patients with T2DM and diabetic kidney disease (DKD). Methods: We performed a randomized parallel study encompassing 4 general hospitals. T2DM patients with an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m² and macroalbuminuria, defined as 24-h urinary albumin excretion rate (UAER) >0.3 g/24 h were randomized 1:1 to receive exenatide twice daily plus insulin glargine (intervention group) or insulin lispro plus glargine (control group) for 24 weeks. The primary outcome was the UAER percentage change from the baseline after 24 weeks of intervention. The rates of hypoglycemia, adverse events (AEs), and change in eGFR during the follow-up were measured as safety outcomes. Results: Between March 2016 and April 2019, 92 patients were randomized and took at least 1 dose of the study drug. The mean age of the participants was 56 years. At baseline, the median UAER was 1,512.0 mg/24 h and mean eGFR was 70.4 mL/min/1.73 m². After 24 weeks of treatment, the UAER percentage change was significantly lower in the intervention group than in the control group (p = 0.0255). Moreover, the body weight declined by 1.3 kg in the intervention group (the difference between the 2 groups was 2.7 kg, p = 0.0001). Compared to the control group, a lower frequency of hypoglycemia and more gastrointestinal AEs were observed in the intervention group. Conclusion: Exenatide plus insulin glargine treatment for 24 weeks resulted in a reduction of albuminuria in T2DM patients with DKD.

Exenatide, a GLP-1 analog, has healing effects on LPS-induced autism model: Inflammation, oxidative stress, gliosis, cerebral GABA, and serotonin interactions.

Previous studies have established anti-inflammatory, antioxidant, and neuroprotective effects of Exenatide in the central nervous system. Since these mechanisms are thought to have important roles in the pathophysiology of autism, we hypothesized that Exenatide may have healing effects in autism. We tested this hypothesis by examining the effects of Exenatide in an experimental autism model created by lipopolysaccharide (LPS) exposure in the womb, with behavioral tests, histopathological examinations, and biochemical measurements. The autism model was created by administration of LPS (i.p) to pregnant rats on the 10th day of their pregnancy at a dose of 100µg/kg. On postnatal 21st day, a total of four groups were formed from offspring with regard to sex distribution and treatment. After a 45-day treatment, behavioral analysis tests were performed on rats. Subsequently, the rats were sacrificed and biochemical analysis [superoxide dismutase, tumor necrotizing factor alpha, nerve growth factor, 5-hydroxyindoleacetic acid, and glutamic acid decarboxylase-67] and histopathological analysis were performed. On the 10th day of the intrauterine period, LPS exposure was found to disrupt behavioral findings, increase inflammation and hippocampal gliosis, and decrease 5-HIAA, GAD-67, and NGF, especially in male rats. However, among the rats exposed to LPS in the intrauterine period, recipients of Exenatide demonstrated significant amelioration of findings. Exenatide therapy shows positive effects on behavioral disorders in an LPS-induced autism model. This agent probably exerts its effects by suppressing inflammation and oxidative stress and reducing hippocampal gliosis. In addition, Exenatide has also been shown to positively affect cerebral serotonergic and GABAergic effects.

GLP-1 receptor agonists for Parkinson's disease.

Parkinson's disease (PD) is a progressive disorder characterised by both motor and non-motor problems. Glucagon-like peptide-1 (GLP-1) receptor agonists, licensed for treatment of type 2 diabetes, work by stimulating GLP-1 receptors in the pancreas, which triggers the release of insulin. GLP-1 receptors have been found in the brain. Insulin signalling in the brain plays a key role in neuronal metabolism and repair and in synaptic efficacy, but insulin signalling is desensitised in the brain of people with PD. Researchers are exploring the neuroprotective effects of GLP-1 receptor agonists in neurodegenerative disorders such as PD. To evaluate the effectiveness and safety of GLP-1 receptor agonists for Parkinson's disease. We searched the Cochrane Movement Disorders Group trials register; the Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; and Ovid MEDLINE and Embase. We also searched clinical trials registries, and we handsearched conference abstracts. The most recent search was run on 25 June 2020. We included randomised controlled trials (RCTs) of adults with PD that compared GLP-1 receptor agonists with conventional PD treatment, placebo, or no treatment. Two review authors independently assessed studies for inclusion, extracted data, and assessed risk of bias. We rated the quality of evidence using GRADE. We resolved discrepancies between the two data extractors by consultation with a third review author. Through our searches, we retrieved 99 unique records, of which two met our inclusion criteria. One double-blind study of exenatide versus placebo randomised 62 participants, who self-administered exenatide or placebo for 48 weeks and were followed up at 60 weeks after a 12-week washout. One single-blind study of exenatide versus no additional treatment randomised 45 participants; participants in the intervention group self-administered exenatide for 12 months, and all participants were followed up at 14 months and 24 months following absence of exenatide for 2 months and 12 months, respectively. These trials had low risk of bias, except risk of performance bias was high for Aviles-Olmos 2013. Exenatide versus placebo Primary outcomes We found low-certainty evidence suggesting that exenatide improves motor impairment as assessed by the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III in the off-medication state (mean difference (MD) -3.10, 95% confidence interval (CI) -6.11 to -0.09). The difference in scores was slightly greater when scores were adjusted for baseline severity of the condition (as reported by study authors) (MD -3.5, 95% CI -6.7 to -0.3), exceeding the minimum clinically important difference (MCID). We found low-certainty evidence suggesting that exenatide has little or no effect on health-related quality of life (HRQoL) as assessed by the Parkinson's Disease Questionnaire (PDQ)-39 Summary Index (SI) (MD -1.80, 95% CI -6.95 to 3.35), the EuroQol scale measuring health status in five dimensions (EQ5D) (MD 0.07, 95% CI -0.03 to 0.16), or the EQ5D visual analogue scale (VAS) (MD 5.00, 95% CI -3.42 to 13.42). Eight serious adverse events (SAEs) were recorded, but all were considered unrelated to the intervention. Low-certainty evidence suggests that exenatide has little or no effect on weight loss (risk ratio (RR) 1.25, 95% CI 0.89 to 1.76). Exenatide versus no treatment Primary outcomes at 14 months We found very low-certainty evidence suggesting that exenatide improves motor impairment as assessed by MDS-UPDRS Part III off medication (MD -4.50, 95% CI -8.64 to -0.36), exceeding the MCID. We are uncertain whether exenatide improves HRQoL as assessed by the PDQ-39 SI (MD 3.50, 95% CI -2.75 to 9.75; very low-quality evidence). We found very low-certainty evidence suggesting that exenatide has little or no effect on the number of SAEs (RR 1.60, 95% 0.40 to 6.32). We found very low-certainty evidence suggesting that exenatide may lead to weight loss (MD -2.40 kg, 95% CI -4.56 to -0.24). Primary outcomes at 24 months We found evidence as reported by study authors to suggest that exenatide improves motor impairment as measured by MDS-UPDRS Part III off medication (MD 5.6 points, 95% CI 2.2 to 9.0). Exenatide may not improve HRQoL as assessed by the PDQ-39 SI (P = 0.682) and may not result in weight loss (MD 0.1 kg, 95% CI 3.0 to 2.8). Low- or very low-certainty evidence suggests that exenatide may improve motor impairment for people with PD. The difference in motor impairment observed between groups may persist for some time following cessation of exenatide. This raises the possibility that exenatide may have a disease-modifying effect. SAEs were unlikely to be related to treatment. The effectiveness of exenatide for improving HRQoL, non-motor outcomes, ADLs, and psychological outcomes is unclear. Ongoing studies are assessing other GLP-1 receptor agonists.

The effect of exenatide on fasting bile acids in newly diagnosed type 2 diabetes mellitus patients, a pilot study

BackgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) demonstrated good glycemic efficacy in patients with type 2 diabetes mellitus (T2DM) recent years, whereas studies on GLP-1 RAs’ biliary effects were limited. Therefore, we aimed to assess the effect of exenatide on bile acids (BAs) and investigate the role of BAs in the glycemic control effect of exenatide.MethodsThirty-eight newly diagnosed T2DM participants without glucose-lowering drugs intake were recruited. Plasma total bile acids in fasting state (FTBAs) and other parameters were tested at baseline. Then exenatide were applied to the T2DM participants for 12 weeks. FTBAs and glycemic parameters were measured again after exenatide treatment, and correlation analysis between changes of FTBAs and glycemic parameters were conducted to investigate the role of BAs in the glycemic control effect of exenatide.ResultsThe baseline FTBAs level of T2DM patients had no significance (3.84 ± 2.06 vs. 3.87 ± 2.89, P = 0.954) compared with healthy subjects. After 12-week exenatide treatment for the T2DM patients, FTBAs were decreased from 3.84 ± 2.06 μmol/L to 3.06 ± 1.27 μmol/L (P < 0.01). The correlation analysis showed that changes of FTBAs was positively correlated with changes of FPG (r = 0.355, P < 0.05).ConclusionsOur results demonstrated a decreased FTBAs level after exenatide treatment for 12 weeks, without the interference of metformin and other glucose-lowering drugs. The reduction of FTBAs might not exert a positive role in the glycemic control effect of exenatide.Trial registrationTrial registration number: NCT04303819. Registered in March 11, 2020 - Retrospectively registered.

958-P: Once-Weekly Exenatide Effects on EGFR Slope and UACR as a Function of Baseline UACR: An EXSCEL Trial Post Hoc Analysis

GLP-1 RA effects on major kidney outcome in unselected T2D patients at high cardiovascular (CV) risk are modest or neutral. However, GLP-1 RA may provide renal benefit in those at high risk of worsening kidney disease. We examined once-weekly exenatide (EQW) effects on eGFR slope and UACR change, as a function of baseline UACR, in a subset of EXSCEL participants. Of 14752 EXSCEL participants, eGFR slope was assessed in those with baseline UACR and ≥1 post-baseline eGFR (n=3503 [23.7%]) via mixed model repeated measures (MMRM) analysis (median follow-up 3.3 years). UACR percent change from baseline to first post-baseline measurement (median time 8.9 months) was assessed in those with baseline and ≥1 follow-up UACR (n=2828 [19.2%]) via ANCOVA of log-transformed UACR, with baseline UACR as a covariate. Participants with baseline UACR measurements were generally similar to the overall EXSCEL population, and balanced across treatment arms. EQW improved eGFR slope in those with baseline UACR&amp;gt;100mg/g and UACR&amp;gt;200mg/g, but not at lower UACR thresholds. No difference in EQW effect on eGFR was observed as a function of baseline eGFR, CV disease history, RAAS inhibitor use, or SBP. UACR improvement was similar across UACR categories. This EXSCEL post-hoc analysis suggests that EQW reduces UACR, with improvement in eGFR slope specifically in participants with elevated baseline UACR. Disclosure L.E. Clegg: Employee; Self; AstraZeneca. A. van der Aart: None. R.C. Penland: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. D.W. Boulton: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca, Bristol-Myers Squibb. C. Sjöström: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. R.J. Mentz: Consultant; Self; Amgen, AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Merck &amp; Co., Inc., Novartis Pharmaceuticals Corporation, Sanofi. Research Support; Self; GlaxoSmithKline plc. R.R. Holman: Advisory Panel; Self; Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp &amp; Dohme Corp. H.L. Heerspink: Consultant; Self; AbbVie Inc., AstraZeneca, Boehringer Ingelheim International GmbH, CSL Behring, Gilead Sciences, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., Mitsubishi Tanabe Pharma Corporation, Mundipharma International, Retrophin, Inc. Funding AstraZeneca

26-LB: Exenatide and Renal Outcomes in Patients with Type 2 Diabetes and Diabetic Kidney Disease: A Multicenter, Randomized, Parallel Study

Aim: This trial aimed to assess the effects of exenatide, a GLP-1RA, on renal outcomes in patients with T2DM and DKD. Methods: We performed a randomized, parallel study conducted in 4 general hospitals. T2DM patients with an eGFR≥30mL/min/1.73m2 and macroalbuminuria, defined as 24h-urinary albumin-creatinine ratio (UAER) &amp;gt;0.3g/24h, were randomized 1:1 to receive exenatide twice daily plus glargine or lispro insulin plus glargine for 24 weeks. The primary outcome was percentage change in 24h-UAER after 24 weeks of intervention comparing to baseline measurement. The secondary outcomes included the percentage change in urinary ACR, change in 24h-UAER, ACR, HbA1c, FPG, body weight and blood pressure. The safety outcomes include rates of hypoglycemia, adverse events and change in eGFR during the follow up. Results: Between March 2016 and April 2019, 92 patients were randomized and took at least one dose of study drug. The mean age of the participants was 56 years. At baseline, the median 24h-UAER was 1512.0 mg/24h (IQR 782.5-2818.0), and mean eGFR was 70.4 mL/min/1.73 m2 (SD 23.4). After 24 weeks, exenatide reduced the percentage change of the 24h-UAER (difference between groups was 29.7%, p=0.0255), the percentage change of ACR (difference between groups was 28.4%, p=0.0395) and the absolute change of ACR (difference between groups was 607.8 mg/g, p=0.0209) but had no significant difference on the absolute change of 24h-UAER than the control group. Meanwhile, the body weight declined by 1.3kg with exenatide (difference between groups was 2.7kg, p=0.0001). There was no difference between two groups on the change in HbA1c, FPG, blood pressure or eGFR. Comparing to the control group, lower frequency of hypoglycemia as well as more gastrointestinal adverse events were in intervention group. Conclusions: Exenatide twice daily plus glargine for 24 weeks resulted in significant reduction of albuminuria in T2DM patients with DKD. Disclosure X. Wang: None. Q. Zhang: None. M. Guan: None. S. Sheng: None. W. Mo: None. M. Zou: None. J. Li: None. J. Bi: None. X. Tang: None. J. He: None. G. Xu: None. P. Li: None. H. Zhang: None. Y. Xue: None.

Effect of treatment with exenatide and pioglitazone or basal-bolus insulin on diabetic neuropathy: a substudy of the Qatar Study

IntroductionTo assess the effect of exenatide and pioglitazone or basal-bolus insulin on diabetic peripheral neuropathy (DPN) in patients with poorly controlled type 2 diabetes (T2D).Research design and methodsThis is a...

Exenatide once weekly decreases urinary albumin excretion in patients with type 2 diabetes and elevated albuminuria: Pooled analysis of randomized active controlled clinical trials.

AimsTo examine the albuminuria‐lowering effect of exenatide once weekly (EQW) compared with active glucose‐lowering comparators in patients with type 2 diabetes and elevated urinary albumin‐to‐creatinine ratio (uACR).MethodsSix randomized double‐blind and open‐label phase III studies were pooled in a post hoc, exploratory analysis to evaluate the efficacy and safety of EQW versus non‐glucagon‐like peptide‐1 receptor agonist comparators in patients with type 2 diabetes and baseline uACR ≥30 mg/g. Treatment groups were EQW versus all comparators pooled. Efficacy outcomes were percent change from baseline to week 26/28 in uACR and absolute change in glycated haemoglobin (HbA1c), systolic blood pressure (SBP), body weight and estimated glomerular filtration rate (eGFR).ResultsBaseline characteristics were generally similar between the two treatment groups (EQW: N = 194, all comparators: N = 274). Relative to the comparator group, EQW changed albuminuria by −26.2% (95% confidence interval [CI] −39.5 to −10). Similar improvements were observed with EQW versus oral glucose‐lowering drugs (−29.6% [95% CI −47.6 to −5.3) or insulin (−23.8% [95% CI −41.8 to −0.2]). The effect of EQW on uACR was independent of baseline renin‐angiotensin system inhibitor usage. Adjusted mean decreases in HbA1c, SBP and body weight were more pronounced in the EQW versus the comparator group. Adjustment for changes in HbA1c, eGFR and SBP did not substantially affect the uACR‐lowering effect of EQW. When also adjusting for changes in body weight, the uACR‐lowering effect was reduced to (−13.0% [95% CI −29.9 to 7.8]).ConclusionExenatide once weekly reduced uACR in patients with type 2 diabetes and elevated albuminuria compared to commonly used glucose‐lowering drugs.

Effects of Exenatide and Humalog Mix25 on Fat Distribution, Insulin Sensitivity, and β-Cell Function in Normal BMI Patients with Type 2 Diabetes and Visceral Adiposity.

In China, most normal BMI (body mass index of ≥18.5 to <25 kg/m2) adults with type 2 diabetes (T2DM) exhibit visceral adiposity. This study compared the effects of exenatide and humalog Mix25 on normal BMI patients with T2DM and visceral adiposity. A total of 95 patients were randomized to receive either exenatide or humalog Mix25 treatment for 24 weeks. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were quantified by magnetic resonance imaging (MRI) and liver fat content (LFC) by liver proton magnetic resonance spectroscopy (1H MRS). Each patient's weight, waist circumference, BMI, blood glucose, insulin sensitivity, pancreatic β-cell function, and fibroblast growth factor 21 (FGF-21) levels were measured. Data from 81 patients who completed the study (40 and 41 in the exenatide and humalog Mix25 groups, respectively) were analysed. The change in 2 h plasma blood glucose was greater in the exenatide group (P = 0.039). HOMA-IR and MBCI improved significantly after exenatide therapy (P < 0.01, P = 0.045). VAT and LFC decreased in both groups (P < 0.01 for all) but to a greater extent in the exenatide group, while SAT only decreased with exenatide therapy (P < 0.01). FGF-21 levels declined more in the exenatide group (P < 0.01), but were positively correlated with VAT in the entire cohort before (r = 0.244, P = 0.043) and after (r = 0.290, P = 0.016) the intervention. The effects of exenatide on glycaemic metabolism, insulin resistance, pancreatic β-cell function, and fat deposition support its administration to normal BMI patients with T2DM and visceral adiposity.