Incretin Mimetics Research Articles

755-P: A Phase 2 Evaluation of a Novel GLP-1 Analog Ecnoglutide (XW003) for Glycemic Control in Adults with Type 2 Diabetes

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a Phase 2 randomized, double-blind, placebo-controlled study of ecnoglutide, which enrolled 145 adults at over 20 hospital-based sites in China. Eligible participants had T2DM that was inadequately controlled by lifestyle or a single oral hypoglycemic agent. Participants were randomized to receive 0.4, 0.8, or 1.2 mg ecnoglutide or placebo as once weekly injections for 20 weeks, including dose escalation. Change in mean HbA1c, body weight, and BMI, as well as safety and tolerability were evaluated. At baseline, participants had mean HbA1c of 8.55 ± 0.707 % and BMI of 26.27 ± 3.308 kg/m2. At the end of treatment, participants receiving ecnoglutide achieved significant HbA1c reductions of 1.81% to 2.39% from baseline (P<0.0001 for all cohorts vs placebo). At end of treatment, up to 67% of participants in the ecnoglutide cohorts achieved HbA1c levels ≤6.5% and up to 33% had body weight reductions ≥5% from baseline (Figure). Ecnoglutide was generally safe and well tolerated. There were no treatment-related ≥Grade 3 AEs and no treatment-related SAEs. The proportion of participants reporting any AE ranged from 72.2 to 78.4% for ecnoglutide and 58.3 % for placebo. The most frequently reported AEs were gastrointestinal, including diarrhea and nausea. Disclosure D.Zhu: None. S.Xu: Employee; Sciwind. M.K.Junaidi: None. H.H.Qin: Employee; Sciwind Biosciences, Sichuan Anerobic Biotech. Q.Zheng: Employee; Sciwind Biosciences. J.Ning: None. Z.Zhu: Employee; Sciwind Biosciences. G.Mengying: None. Y.Bu: Employee; Sciwind Biosciences. C.Jones: Employee; Sciwind Biosciences. M.Fenaux: Employee; Sciwind Biosciences, Stock/Shareholder; Terns Pharmaceuticals. Funding Sciwind Biosciences

79-LB: An Open-Label, Active-Controlled Phase 2 Evaluation of Novel GLP-1 Analog Ecnoglutide in Adults with Obesity

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes mellitus (T2DM) and obesity. We conducted a multi-center, open-label, active-controlled Phase 2b study in adults with a body mass index (BMI) ≥30 to ≤40 kg/m2. The trial was conducted at nine sites in Australia and New Zealand, with 206 participants enrolled. Participants were randomized to receive target doses of ecnoglutide at 1.2, 1.8, or 2.4 mg as once weekly SC injections or liraglutide (Saxenda®) at 3.0 mg as once daily injections for 26 weeks. Doses were increased by titration for up to 14 weeks before reaching the target dose. Safety and tolerability were assessed, along with efficacy parameters including change in body weight. At baseline, participants had a mean body weight of 100.67 ± 13.54 kg and BMI of 35.29 ± 2.76 kg/m2. After 26 weeks of dosing, participants receiving 1.2, 1.8, or 2.4 mg ecnoglutide weekly achieved a least square mean (LSM) body weight reduction from baseline of -11.5%, -11.2%, and -14.7%, respectively, compared to -8.8% for those receiving 3.0 mg liraglutide daily injections. Participants receiving 2.4 mg ecnoglutide showed significantly more pronounced body weight reduction compared to liraglutide (LSM difference -5.9, 95% confidence interval -10.4, -1.5; p<0.001). Overall, treatment with ecnoglutide was safe and well tolerated. Treatment emergent AEs were reported in 93.5% of participants in the ecnoglutide groups and 98.0% in the liraglutide group. Gastrointestinal disorders were reported in 81.9% of ecnoglutide-treated participants and 80.4% of those receiving liraglutide, most of which were mild to moderate and most occurred during the dose escalation period. Two SAEs related to the study drug were reported. Both were cases of acute cholecystitis, one in a participant receiving 1.2 mg ecnoglutide and one in the liraglutide group. Disclosure Z. Zhu: Employee; Sciwind Biosciences. M. K. Junaidi: None. Y. Li: Employee; Sciwind Biosciences. Q. Zheng: Employee; Sciwind Biosciences. E. Adegbite: Employee; Sciwind Biosciences. S. Ross: None. L. Telusca: None. C. L. Jones: Employee; Sciwind Biosciences. M. Fenaux: Employee; Sciwind Biosciences, Stock/Shareholder; Terns Pharmaceuticals. S. Xu: Employee; Sciwind. Funding Sciwind Biosciences Co., Ltd.

13-LB: Treatment Patterns of Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease in Colombia

Aim: Describe treatment patterns of patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) in outpatient setting from Colombia. Methods: We conducted a cross-sectional study characterizing treatment patterns of T2DM and CKD using the Audifarma S.A. drug dispensing database and included all patients with both diagnoses using ICD-10 codes and at least one disease-related prescription from April 1st 2019 to March 31st 2020. Sociodemographic variables, comorbidities, treatment received and combinations were evaluated. Drugs were classified as those for management of T2DM (oral antidiabetic agents, insulins, SGLT2i, GLP-1 analogs (GLP1a), dipeptidyl peptidase-4 inhibitors (DPP4i)), and others including renin angiotensin aldosterone system blockers (angiotensin converting enzyme inhibitors-ACEI, angiotensin receptor antagonists-ARBs) and mineralocorticoid receptor antagonists (MRAs). A descriptive analysis with frequencies and proportions, means and standard deviation was carried out. Results: Of a total of 194,023 patients with a primary diagnosis of T2DM, it was possible to identify that 14,722 (7.5%) had concomitant CKD, during the observation period. A total of 7513 (51%) were men, and the mean age was 74.7±10.9 years. The main comorbidities were hypertension (n=10665; 72.4%) and hypothyroidism (n=1138; 7.7%). The most used drugs were metformin (n=9901; 67.3%) alone or associated with some other antidiabetic, followed by 52.2% used DPP4i (n=7691), 17.0% an SGLT2i (n=2500), and 5.2% GLP-1a (n=766). Additionally, 67.2% (n=9895) of patients were under treatment with ARBs, 15.8% (n=2325) with ACEIs and 10.9% (n=1598) with MRAs. Conclusions: This contemporary study from Colombia further highlights the complexity and heterogeneity of treating patients with T2DM and CKD, which could be improved if the beneficial properties of newer agents that have shown positive anti-hyperglycemic and renal outcomes were implemented in the local treatment strategy. Disclosure M. Machado: Research Support; Bayer Inc., Pfizer Inc. A. Gaviria-mendoza: Employee; Audifarma S. A, Research Support; Bayer Inc., Pfizer Inc. J. S. Franco: Employee; Bayer Inc. M. D. R. Forero: Employee; Bayer Inc. D. Vizcaya: Employee; Bayer Inc. L. F. Valladales restrepo: Research Support; Bayer Inc., Pfizer Inc. J. E. Machado-alba: None. Funding Bayer AG

756-P: A Phase 1c Evaluation of a Novel GLP-1 Analog Ecnoglutide (XW003) for Weight Loss in Adults with Overweight and Obesity

Ecnoglutide (XW003) is a novel, long-acting GLP-1 analog being developed for the treatment of type 2 diabetes and obesity. We conducted a Phase 1c randomized, double-blind, placebo-controlled study of ecnoglutide, which enrolled 60 nondiabetic adults with BMI 24-35 kg/m2. The study was conducted in China. PK, change in mean body weight and BMI, safety, and tolerability were evaluated. Participants received 1.8 or 2.4 mg ecnoglutide or placebo as once weekly injections for 14 weeks, including dose escalation. This core treatment was followed by an open-label extension of the ecnoglutide groups, for a total duration of 26 weeks. At baseline, participants had a mean body weight of 84.61 ± 10.44 kg and BMI of 29.53 ± 1.73 kg/m2. After 14 weeks of core treatment, mean weight reduction from baseline was -8.29 ± 0.52 kg in the 1.8 mg ecnoglutide group and -7.24 ± 0.56 kg in the 2.4 mg group, compared to -0.61 ± 0.82 kg for placebo (P<0.0001 vs placebo for both doses). At Week 14, the proportion of participants achieving ≥5% weight loss from baseline was 87.5% (95% CI, 67.6 to 97.3) and 70.0% (95% CI, 45.7 to 88.1) for 1.8 and 2.4 mg ecnoglutide, respectively, and 22.2% (95% CI, 2.8 to 60.0) for placebo. Continued weight reduction was observed until the end of study at Week 26, with a mean percent change from baseline of -15.0% (95%CI, -16.8 to -13.2) and -13.2% (95% CI, -15.3 to -11.1) for 1.8 and 2.4 mg ecnoglutide, respectively. At Week 26, ≥5% weight loss was observed for 94.7% (95% CI, 74.0 to 99.9) of participants in the 1.8 mg group and 100.0% (95% CI, 75.3 to 100.0) in the 2.4 mg group. At steady state, ecnoglutide showed a mean Cmax of 310 - 468 ng/mL, Tmax of 26 - 29 h, and half-life of 139 - 162 h. Overall, ecnoglutide was safe and well tolerated. The proportion of participants reporting any AE was similar between cohorts (95.2 to 100% for ecnoglutide vs 90% for placebo). The most frequent AEs were gastrointestinal, including diarrhea and vomiting. No drug-related SAE or drug-related AEs ≥Grade 3 were reported. Disclosure G. Wang: None. W. Hu: None. H.H. Qin: Employee; Sciwind Biosciences, Sichuan Anerobic Biotech. Q. Zheng: Employee; Sciwind Biosciences. J. Ning: None. G. Mengying: None. Y. Bu: Employee; Sciwind Biosciences. C. Jones: Employee; Sciwind Biosciences. M. Fenaux: Employee; Sciwind Biosciences. Stock/Shareholder; Terns Pharmaceuticals. S. Xu: Employee; Sciwind. M.K. Junaidi: None. Funding Sciwind Biosciences

87-OR: Engineered Vasculature Induces Functional Maturation of Pluripotent Stem Cell–Derived Islet Organoids

Blood vessels play a critical role in islet health and function. Native islets are richly vascularized and their interaction with blood vessels is important for β-cell function. Therefore, vasculature ought to be an integral component of a model for studying human islet physiology and diabetes pathobiology. Here, we develop a vascularized islet organoid model by integrating hPSC-derived islets (SC-islets) with human endothelial cells (ECs) and fibroblasts (FBs). To analyze β-cell function, we generated an hPSC line carrying GCaMP6f, a Ca2+ reporter, as Ca2+ oscillation can be used as a proxy for insulin secretion. Comparing β-cell Ca2+ responses of non-vascularized and vascularized SC-islets revealed more frequent and stronger Ca2+ influx in response to high glucose and the GLP-1 analogue in vascularized SC-islets. To identify vasculature-derived signals beneficial to β-cell function, we performed cell-cell interaction network analyses based on single-cell transcriptomic data from SC-islets, ECs, and FBs. Among the top candidates were integrin receptors that interact with extracellular matrix proteins. Consistent with these predictions, a higher number of β-cells were in contact with EC-derived basement membrane proteins (e.g., laminin α1, collagen IV) and exhibited activation of integrin β1. The analysis also revealed BMP4-BMPR2 as a potential crosstalk between ECs and β-cells. Indeed, BMP4 addition augmented Ca2+ response and insulin secretion of β-cells under glucose stimulation. Finally, to develop a system mimicking in vivo physiology, we integrated SC-islets into a microfluidic platform where the organoids are supported by a network of perfused microvessels. Our newly-established model of vascularized SC-islet organoids will enable further studies of crosstalk between β-cells and vasculature under conditions mimicking the native islet microenvironment. The model will serve as a platform to study disease mechanisms of diabetes and test therapeutics. Disclosure K.Nguyen-ngoc: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (UG3DK1226390); JDRF (3-PDF-2017-386-A-N, 3-PDF-2020-932-A-N)

#5867 EFFECT OF SGLT2I ON URIC ACID AND GLUCOSE URINARY FRACTIONAL EXCRETION IN PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES MELLITUS

Abstract Background and Aims Sodium-glucose cotranspoter type 2 inhibitors (SGLT2i) have demonstrated broad benefits beyond glycemic control, including hypouricemic effects. However, this fact has not been completely validated in chronic kidney disease (CKD). The mechanism by which SGLT2i produces an increase in uric acid elimination is not fully understood and appears to be mediated in part by increased glucose in the renal tubule, which would compete in reabsorption with uric acid through GLUTb transporter. The aim of this study is to analyse the effect of SGLT2i on uric acid and glucose urinary fractional excretion (FE) in type 2 diabetes mellitus (T2DM) + CKD patients. Method Retrospective observational single-center study conducted between January18 and December 22 in T2DM-CKD patients on SGLT2i. Subjects on renal replacement therapy, treatment with GLP1 analogues and those for whom we did not have uricosuria prior to the start of iSGLT2 were excluded. Urinary uric acid and glucose FE were analysed at baseline and during follow-up of up to 24 months, with 3, 6 and 12 months cut-offs. Data are described as mean and standard deviation (SD). Statistical analysis was performed using STATA v14 with statistics for paired samples. Results 82 patients were included in the study, with a mean follow-up of 1.2 years. During follow-up, 23 patients left the study (arGLP1 initiation (n = 9), adverse reactions (n = 4), exitus (n = 2) and loss to follow-up (n = 8). 78.1% were male, mean age 72.7 years (SD 8.5), and main co-morbidities were: obesity 76.8%, arterial hypertension 95%, hyperuricemia 75.6% and congestive heart failure 25.6%. Distribution according SGLT2i drug was: 65.6% dapagliflozin, 25% canagliflozin and 9.4% empagliflozin. eGFR decreased immediately after initiation of SGLT2i with ulterior stabilization as described elsewhere (Table 1). We observed a significant increase on urinary uric acid FE that remain stable along the follow-up: basal 7.4%, 3 months 9.4% (p < 0.001). However, serum uric acid levels did not show significant differences along the study. Urinary glucose FE increase remained stable along the whole observation period in spite of no significant differences from a clinical point of view on % of glycosylated haemoglobin (Table 1). Conclusion Despite decreased GFR, T2DM-CKD patients exhibited significant urinary uric acid and glucose FE increase after starting SGLT2i. This increase remained stable for at least 2 years. However, we did not observe significant reductions on uricemia in these patients, implying that increase on urinary uric acid excretion is not enough in this setting to obtain significant modifications on uricemia.

The effect of exenatide (a GLP-1 analogue) and sitagliptin (a DPP-4 inhibitor) on asymmetric dimethylarginine (ADMA) metabolism and selected biomarkers of cardiac fibrosis in rats with fructose-induced metabolic syndrome

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, is a risk factor for endothelial dysfunction, a common pathophysiological denominator for both atherogenesis and cardiac fibrosis.We aimed to investigate whether the cardioprotective and antifibrotic effects of incretin drugs, exenatide and sitagliptin, may be associated with their ability to affect circulating and cardiac ADMA metabolism.Normal and fructose-fed rats were treated with sitagliptin (5.0/10 mg/kg) or exenatide (5/10 µg/kg) for 4 weeks. The following methods were used: LC-MS/MS, ELISA, Real-Time-PCR, colorimetry, IHC and H&E staining, PCA and OPLS-DA projections.Eight-week fructose feeding resulted in an increase in plasma ADMA and a decrease in NO concentration. Exenatide administration into fructose-fed rats reduced the plasma ADMA level and increased NO level. In the heart of these animals exenatide administration increased NO and PRMT1 level, reduced TGF-ß1, α-SMA levels and COL1A1 expression. In the exenatide treated rats renal DDAH activity positively correlated with plasma NO level and negatively with plasma ADMA level and cardiac α-SMA concentration. Sitagliptin treatment of fructose-fed rats increased plasma NO concentration, reduced circulating SDMA level, increased renal DDAH activity and reduced myocardial DDAH activity. Both drugs attenuated the myocardial immunoexpression of Smad2/3/P and perivascular fibrosis.In the metabolic syndrome condition both sitagliptin and exenatide positively modulated cardiac fibrotic remodeling and circulating level of endogenous NOS inhibitors but had no effects on ADMA levels in the myocardium.

Obesity-related hypertension: Implications for advanced nursing practice.

Obesity increases the risk of hypertension and other cardiometabolic comorbidities. Lifestyle modifications are usually recommended, though lasting effects on weight and BP reduction are limited. Weight-loss medications, especially incretin mimetics, are effective for short- and long-term treatment. Metabolic surgery provides cure of obesity-related hypertension in some patients. NPs are well positioned to manage obesity-related hypertension to improve clinical outcomes of affected individuals.

TYPE 2 DIABETES IN YOUNG ADULTS: PREVALENCE AND RISK FACTOR CONTROL IN A TERTIARY DIABETES CENTRE

Objective: The prevalence of type 2 diabetes (T2DM) is increasing in younger adults. Diagnosis at young age translates into increased lifetime complications risk and number of years of life lost. Despite this, clinical guidelines advocate risk-factor management based on 10-year rather than lifetime risk, and there are no specific treatment targets for young adults as this group is under-represented in outcome studies. We reviewed prescribing; risk-factor management; glycaemic control; and follow-up arrangements in people with T2DM aged 18-30 living in North-East Glasgow. Design and method: We used the Scottish Care Information – Diabetes Collaboration (Sci-Diabetes) registry to identify all individuals with T2DM aged 18-30 years and collected data from online medical records. Results: We identified a cohort of 74 (70% female) individuals. Mean age at diagnosis was 23 years. Social deprivation was high (mean SIMD 1.7). Mean HbA1c was 60.4 (range 32 – 119) mmol/mol with 35 (47%) requiring more than 1 glucose-lowering medication and 7 were (9%) insulin-treated. Mean BMI was 35kg/m2 and 55 (74%) individuals were clinically obese. Dietetic review was documented in 30 (45%), GLP-1 analogues were prescribed to 18 (24%). Blood pressure (mean 125/82; range 100-168/60-101) mmHg was above target in 16 (22%) individuals. Only 8 (10%) and 4 (5%) people were on anti-hypertensive and lipid-lowering drugs respectively. Pregnancy advice had been given in 39 (75%) of female patients. Seventeen (22%) individuals were lost to follow-up. Conclusions: Follow-up and risk-factor control are inconsistent in this high-risk group. Service innovation is urgently required to ensure young adults with T2DM are offered appropriate and accessible follow-up in order to minimise cardiovascular risk in later life.

EPS4.07 Management of cystic fibrosis diabetes (CFD): a new era

Introduction: CFD affects up to 50% of adults. Guidelines recommend insulin therapy to primarily treat associated insulin insufficiency. Historically people with CFD have also benefited from anabolic properties of insulin. Improved nutritional status and increasing population-age observed since highly effective CF-modulators (HEMT) now prompts consideration of SGLT2 inhibitors and GLP-1 analogues as appropriate for an ageing cohort of clinically stable adults with CFD due to additional extra-glycaemic benefits.

A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese nonhuman primate model.

Growth Differentiation Factor-15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half-life is ~3 h and activates the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half-life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long-acting GLP-1 analog dulaglutide. Mechanism-based longitudinal exposure-response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure-dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose-proportional pharmacokinetics (terminal half-life ~8 days) and treatment caused exposure-dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9-12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure-dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long-acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.

Blood pH Analysis in Combination with Molecular Medical Tools in Relation to COVID-19 Symptoms.

The global outbreak of SARS-CoV-2/COVID-19 provided the stage to accumulate an enormous biomedical data set and an opportunity as well as a challenge to test new concepts and strategies to combat the pandemic. New research and molecular medical protocols may be deployed in different scientific fields, e.g., glycobiology, nanopharmacology, or nanomedicine. We correlated clinical biomedical data derived from patients in intensive care units with structural biology and biophysical data from NMR and/or CAMM (computer-aided molecular modeling). Consequently, new diagnostic and therapeutic approaches against SARS-CoV-2 were evaluated. Specifically, we tested the suitability of incretin mimetics with one or two pH-sensitive amino acid residues as potential drugs to prevent or cure long-COVID symptoms. Blood pH values in correlation with temperature alterations in patient bodies were of clinical importance. The effects of biophysical parameters such as temperature and pH value variation in relation to physical-chemical membrane properties (e.g., glycosylation state, affinity of certain amino acid sequences to sialic acids as well as other carbohydrate residues and lipid structures) provided helpful hints in identifying a potential Achilles heel against long COVID. In silico CAMM methods and in vitro NMR experiments (including 31P NMR measurements) were applied to analyze the structural behavior of incretin mimetics and SARS-CoV fusion peptides interacting with dodecylphosphocholine (DPC) micelles. These supramolecular complexes were analyzed under physiological conditions by 1H and 31P NMR techniques. We were able to observe characteristic interaction states of incretin mimetics, SARS-CoV fusion peptides and DPC membranes. Novel interaction profiles (indicated, e.g., by 31P NMR signal splitting) were detected. Furthermore, we evaluated GM1 gangliosides and sialic acid-coated silica nanoparticles in complex with DPC micelles in order to create a simple virus host cell membrane model. This is a first step in exploring the structure-function relationship between the SARS-CoV-2 spike protein and incretin mimetics with conserved pH-sensitive histidine residues in their carbohydrate recognition domains as found in galectins. The applied methods were effective in identifying peptide sequences as well as certain carbohydrate moieties with the potential to protect the blood-brain barrier (BBB). These clinically relevant observations on low blood pH values in fatal COVID-19 cases open routes for new therapeutic approaches, especially against long-COVID symptoms.

Sustained release of GLP-1 analog from γ-PGA-PAE copolymers for management of type 2 diabetes.

GLP-1 has been clinically exploited for treating type 2 diabetes, while its short circulation half-life requires multiple daily injections to maintain effective glycemic control, thus limiting its widespread application. Here we developed a drug delivery system based on self-assembling polymer-amino acid conjugates (γ-PGA-PAE) to provide sustained release of GLP-1 analog (DLG3312). The DLG3312 loaded γ-PGA based nanoparticles (DLG3312@NPs) exhibited a spherical shape with a good monodispersity under transmission electron microscope (TEM) observation. The DLG3312 encapsulation was optimized, and the loading efficiency was as high as 78.4±2.2%. The transformation of DLG3312@NPs to network structures was observed upon treatment with the fresh serum, resulting in a sustained drug release. The in vivo long-term hypoglycemic assays indicated that DLG3312@NPs significantly reduced blood glucose and glycosylated hemoglobin level. Furthermore, DLG3312@NPs extended the efficacy of DLG3312, leading to a decrease in the dosing schedule that from once a day to once every other day. This approach combined the molecular and materials engineering strategies that offered a unique solution to maximize the availability of anti-diabetic drug and minimize its burdens to type 2 diabetic patients.

Treatment of short bowel syndrome: Breaking the therapeutic ceiling?

Short bowel syndrome (SBS) is the most common cause of chronic intestinal failure, requiring home parenteral support (intravenous fluid, parenteral nutrition, or parenteral nutrition with intravenous fluid) to compensate for severe malabsorption. The loss of mucosal absorptive area after extensive intestinal resection is accompanied by an accelerated transit and hypersecretion. Changes in physiology and clinical outcomes differ between patients with SBS with or without the distal ileum and/or colon-in-continuity. This narrative review summarizes the treatments used in SBS, with a focus on novel approaches with intestinotrophic agents. During the early postoperative years, spontaneous adaptation occurs and can be induced or accelerated with conventional therapies, which include dietary and fluid modifications and antidiarrheal and antisecretory drugs. Based on the proadaptive role of enterohormones (eg, glucagon-like peptide [GLP]-2), analogues have been developed to allow enhanced or hyperadaptation after a period of stabilization. Teduglutide is the first GLP-2 analogue developed and commercialized with proadaptive effects resulting in reduced parenteral support needs; however, the potential for weaning of parenteral support is variable. Whether early treatment with enterohormones or accelerated hyperadaptation would further improve absorption and outcomes remains to be shown. Longer-acting GLP-2 analogues are currently being investigated. Encouraging reports with GLP-1 agonists require confirmation in randomized trials, and dual GLP-1 and GLP-2 analogues have yet to be clinically investigated. Future studies will prove whether the timing and/or combinations of different enterohormones will be able to break the ceiling of intestinal rehabilitation in SBS.

Major evidence of the GLP-1 analog (liraglutide) in the treatment of obesity: a systematic review

Introduction: Obesity is a chronic disease that affects a significant portion of the population. In Brazil, in the surveillance survey of risk and protective factors for diseases, more than half of the Brazilian population, 55.7% are overweight. Objective: A systematic review of the literature was carried out with the primary objective of verifying the effectiveness of weight loss of liraglutide in obesity, the secondary objective is the evaluation and clinical benefits secondary to the medication. Methods: The systematic review rules of the PRISMA Platform were followed. The research was carried out from September to October 2022 in Scopus, PubMed, Science Direct, Scielo, and Google Scholar databases. The quality of the studies was based on the GRADE instrument and the risk of bias was analyzed according to the Cochrane instrument. Results: A total of 84 articles were found, 52 articles were evaluated and 20 were included in this systematic review. Considering the Cochrane tool for risk of bias, the overall assessment resulted in 8 studies with a high risk of bias and 19 studies that did not meet GRADE. Most studies showed homogeneity in their results, with X2 =96.9% >50%. In this context of a serious disease with a high prevalence in the population, a literature review was carried out to verify the effectiveness of weight loss of liraglutide 3.0mg in obesity. A total of 781 works were found, of which all titles and abstracts were individually evaluated and sixteen related to the clinical question and PICOS were selected. Primary studies show the superiority of liraglutide over placebo and orlistat in weight loss and improvements in clinical outcomes. Conclusion: Liraglutide 3.0mg proved to be a safe and effective option in the treatment of obesity.

Centrally administered GLP-1 analogue improves intestinal barrier function through the brain orexin and the vagal pathway in rats

Leaky gut, an altered intestinal barrier function, has been described in many diseases such as irritable bowel syndrome (IBS). We have recently demonstrated that orexin in the brain blocked leaky gut in rats, suggesting that the brain plays a role in regulation of intestinal barrier function. In the present study, we tried to clarify whether GLP-1 acts centrally in the brain to regulate intestinal barrier function and its mechanism. Colonic permeability was estimated in vivo by quantifying the absorbed Evans blue in colonic tissue in rats. Intracisternal injection of GLP-1 analogue, liraglutide dose-dependently abolished increased colonic permeability in response to lipopolysaccharide. Either atropine or surgical vagotomy blocked the central GLP-1-induced improvement of colonic hyperpermeability. Intracisternal GLP-1 receptor antagonist, exendin (9–39) prevented the central GLP-1-induced blockade of colonic hyperpermeability. In addition, intracisternal injection of orexin receptor antagonist, SB-334867 blocked the GLP-1-induced improvement of intestinal barrier function. On the other hand, subcutaneous liraglutide also improved leaky gut but larger doses of liraglutide were needed to block it. In addition, neither atropine nor vagotomy blocked subcutaneous liraglutide-induced improvement of leaky gut, suggesting that central or peripheral GLP-1 system works separately to improve leaky gut in a vagal-dependent or independent manner, respectively. These results suggest that GLP-1 acts centrally in the brain to reduce colonic hyperpermeability. Brain orexin signaling and the vagal cholinergic pathway play a vital role in the process. We would therefore suggest that activation of central GLP-1 signaling may be useful for leaky gut-related diseases such as IBS.

Clinical pathways in the management of the obese: Pre- and postoperative aspects.

Bariatric surgery (BS) leads to substantial weight loss accompanied by reversal of several obesity-related co-morbidities and reduced mortality. However, surgery is associated with risks and its nearly irreversible characteristic requires a clearly established pre- and postoperative clinical pathway. In France, this pathway relies on recommendations made by the High Authority of Health (Haute Autorité de santé (HAS)) in 2009; an update is awaited in 2023. BS should be proposed only after failure of well-conducted medical treatment and is intended for patients whose body mass index (BMI) is ≥40kg/m2 or for those with BMI ≥35kg/m2 who also have co-morbidities amenable to improvement, and in whom there are no contra-indications, particularly, those related to general anesthesia or psychological factors. The success and safety of surgical management requires preparation of the patient with regard to dietetic and nutritional counseling, and physical activity. The possibility of complications must be recognized and communicated, including, in view of the large variability of outcomes between individuals, the risk of failure and regain of weight. Prior to the operation, patients should be informed of and accept the program of postoperative clinical and laboratory follow-up, as well as the need for lifelong supplementation in micronutrients and the financial implications including what patients may have to pay out of their own pocket. Surgical management of obesity cannot replace the multidisciplinary medical management of severe obesity. The results obtained by BS are sustainable only if the patient adheres to the proposed modalities. New drugs such a GLP-1 analogues have opened encouraging perspectives as possible alternatives to BS in certain indications.

Novel LC-MS/MS analysis of the GLP-1 analog semaglutide with its application to pharmacokinetics and brain distribution studies in rats

Semaglutide, one of the most potent glucagon-like peptide (GLP)-1 analogs, has widely been used to treat type II diabetes mellitus and obesity. Recent studies have shown that semaglutide also works on the brain, suggesting its potential utility for various diseases, including Parkinson’s disease and Alzheimer’s disease. This study aimed to develop a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of semaglutide in both plasma and brain to characterize the pharmacokinetics and brain distribution in rats. Semaglutide was extracted by simple protein precipitation with methanol from plasma and by solid phase extraction from brain tissue. Liraglutide was used as an internal standard. Gradient elution profiles with mobile phases comprising 0.1 % formic acid in water and acetonitrile were used for chromatographic separation. The lower limit of quantification (LLOQ) of the LC-MS/MS assay was 0.5 ng/mL for both rat plasma and brain. Intra- and inter-day accuracy ranged 89.20–109.50 % in the plasma and 92.00–105.00 % in the brain. Precision was within 8.92 % in the plasma and 7.94 % in the brain. Sprague-Dawley rats were given semaglutide by intravenous (IV, 0.02 mg/kg) and subcutaneous (SC, 0.1 and 0.2 mg/kg) injection. Plasma concentrations of semaglutide showed a multi-exponential decline with an average half-life of 7.22–9.26 hr in rats. The subcutaneous bioavailability of semaglutide was 76.65–82.85 %. The brain tissue to plasma partition coefficient (Kp) value of semaglutide was estimated as <0.01. Among the different regions of the brain, semaglutide concentrations were significantly higher in the hypothalamus. The analytical method and pharmacokinetic information may be helpful toward a better understanding of the effect of semaglutide in the brain and further development of GLP-1 analogs for various brain diseases.

Glucagon-Like Peptide-1 Protects Against Atrial Fibrillation and Atrial Remodeling in Type 2 Diabetic Mice

Atrial fibrillation (AF) is highly prevalent in type 2 diabetes where it increases morbidity and mortality. Glucagon-like peptide (GLP)-1 receptor agonists are used in the treatment of type 2 diabetes (T2DM), but their effects on AF in T2DM are poorly understood. The present study demonstrates type 2 diabetic db/db mice are highly susceptible to AF in association with atrial electrical and structural remodeling. GLP-1, as well as the long-acting GLP-1 analogue liraglutide, reduced AF and prevented atrial remodeling in db/db mice. These data suggest that GLP-1 and related analogues could protect against AF in patients with T2DM.

The Efficacy of GLP-1 Analogues on Appetite Parameters, Gastric Emptying, Food Preference and Taste Among Adults with Obesity: Systematic Review of Randomized Controlled Trials.

Obesity is an epidemiological issue that negatively affects public health and has led to a high global burden on the healthcare system. Several approaches to control and overcome the obesity crisis have been established. However, Nobel discoverers found that glucagon-like peptide-1 analogues (GLP-1 analogues) positively regulate appetite and food intake, eventually leading to weight loss. The present systematic review aims to summarize the currently available evidence of the impact of GLP-1 analogues on appetite, gastric emptying, taste sensitivity, and food preferences among adults with obesity without other chronic diseases. A systematic literature search was conducted from October 2021 to December 2021 from three electronic databases (PubMed, Scopus, and ScienceDirect), including only randomized clinical trials (RCTs). Studies were based on the use of GLP-1 analogues, of any dosage and duration among adults with obesity without other medical diseases; studies measured appetite, gastric emptying, food preferences, and taste as a primary or secondary outcome. The risk of publication bias in each study was assessed independently using the updated Cochrane risk-of-bias tool (RoB2). Twelve studies met the inclusion criteria with a total sample size of 445 participants. All the included studies measured at least one or more of the primary outcomes. The promising effect was evidenced by most studies showing appetite suppression, delayed gastric emptying, and changes in taste and food preferences. GLP-1 analogues are effective obesity management therapy that could decrease food intake and eventually reduce weight by suppressing appetite, reducing hunger, decreasing gastric emptying, and altering food preferences and taste. However, high-quality, long-term, large sample size studies are crucial to examine the efficacy and effective dose of GLP-1 analogues intervention.