Peptide-1 Receptor Agonists Research Articles

ODP222 Liragluitde Increased IL-1RA Concentrations in Obese Type 2 Diabetes: A Small Randomized Controlled Trial

Abstract Background Therapy with exenatide, exendin-4-based glucagon liked peptide-1 receptor agonist (GLP-1 RA) increased plasma interleukin-1 receptor antagonist (IL-1RA), an endogenous anti-inflammatory protein which protected pancreatic ß cells independent of glycemic and weight controlled. We hypothesized that liraglutide, long-acting GLP-1 analogue might contribute to a potential protective effect on ß cells in diabetes. Methods Twenty-four obese patients with type 2 diabetes receiving oral hypoglycemic agents with insulin therapy, except pioglitazone or incretin-based therapy, were randomly assigned to receive either maximum tolerate dose of liraglutide (n=12) or standard therapy (n=12) for twelve weeks. Results Among 24 participants who completed over 12 weeks of this study, median change was +258.7% (78.7, 656.6) and +101. 0% (-3.3, 189.4) of IL-1RA; P<0. 04, and -1.2% (-1.7, -0.8) and -0.4% (-1. 0, 0.3) of A1c; P<0. 03 in liraglutide and standard group, respectively. Percent changes of fasting plasma glucose, body weight, neck circumference and body mass index were all not statistically significant, when comparing between group. Pearson correlation between percent change of IL-1RA and percent change of A1c response to therapy were also not statistically significant. Conclusion Liraglutide might have anti-inflammatory effect independent of the glycemic control during initial short-term duration. Keywords: Liraglutide, Interleukin-1 receptor antagonist, obese type 2 diabetes. Presentation: No date and time listed

RF04 | PSUN295 Evolution of Monomeric Multi-Agonists of GLP-1 and NPY Receptors

Abstract Current treatments for type 2 diabetes (T2D) and obesity do not reliably achieve long-term weight-loss and up to 50% of patients experience nausea and vomiting. Thus, there is a critical need for obesity medications that provide glycemic control with enhanced hypophagic response without nausea/emesis. Based on rational design and in silico modelling of the glucagon-like peptide 1-receptor agonist (GLP1RA) exendin-4 (Ex4) and the neuropeptide Y2 receptor (Y2R) agonist peptide YY (PYY) 3-36, we have developed and screeened several new monomeric chimeric peptides that display dual agonism of the anorectic Y2R and the glucoregulatory GLP1R. In addition, we explored a third agonistic behavior at the neuropeptide Y1 receptor (Y1R), which potentially relates to pancreatic beta-cell protection. Our current lead, GEP44, binds the Y2R, Y1R, and GLP1R. We tested effects of daily injections of these chimeric peptides in adult Sprague-Dawley rats on food intake (FI), body weight (BW) changes, blood glucose levels and an indicator of nausea (kaolin intake). GEP44 produced profound reduction in FI (2-d average GEP44 at 20 nmol/kg FI -71%; Ex-4 20 nmol/kg FI -40%). Anorectic doses of GEP44 did not trigger a pica response assessed by kaolin consumption in treated rats, while in Ex-4 treated rats, kaolin consumption accounted for 28% of total daily solid intake, indicating a clear nausea response. In addition, we assayed for emetic response in the musk shrew, with little to no such emesis displayed (n=8) for GEP44 (1/8), but emesis noted across all animals tested for Ex4. During 11 d of treatment with GEP44, FI was consistently reduced resulting in a significantly stronger reduction of BW compared to Ex4 at the end of treatment (GEP44 -7.6%, Ex4 -3.7%, p<0.05). Furthermore, 5-day injections of GEP44 showed greater reduction of glucose levels than for Ex4 in diet induced obese rats receiving ip glucose. In conclusion, simultaneously targeting serial anorectic pathways with single molecule chimeric peptides can address multiple coexisting conditions to more efficaciously reduce FI, BW and blood glucose levels, devoid of side-effects to improve patient patient and quality of life. Presentation: Saturday, June 11, 2022 1:00 p.m. - 1:05 p.m., Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

LBODP046 Reduction In "Cardiovascular Death Or Hospitalisation For Heart Failure" With Sglt-2is Is Dependent On Weight Reduction: A Meta-regression Analysis

Abstract Aims The modern management of type 2 diabetes (T2D) has shifted focus from a "glucocentric" approach to one that focuses on outcomes reduction. As a result, the aim of management is skewed toward specific molecules like sodium glucose co-transporter 2 inhibitors (SGLT-2is) and glucagon-like peptide receptor agonists (GLP1-RAs) associated with microvascular and macrovascular benefits. The aim of this meta-regression analysis is to assess whether these molecule specific results are dependent or independent of associated metabolic benefits. Methods A web-based search identified five citations for the analysis. The meta-analysis was conducted on a pooled population of 46,969 patients with 26,765 patients in the SGLT-2is arm and 20,204 participants in the placebo arm. A two-step approach to analysis was planned. The first step included a meta-analysis of the cardiovascular death or hospitalization due to heart failure (CV death or hHF) end point using the random effects model to identify significant heterogeneity of the effect size. If identified, the second step would involve conducting a meta-regression analysis using three moderators (HbA1c, weight, and systolic blood pressure) to identify the co-variate explaining this heterogeneity. Results The pooled effect size of the CV death or hHF endpoint was associated with significant heterogeneity (Q: 8. 06, df: 4, I2: 50.44, p=0. 09). The model using HbA1c difference (p=0.17) between the two groups or difference in SBP (p=0.86) did not explain the variance in the observed effect size. However, the difference in weight between the SGLT-2is and placebo group correlated significantly with the variance in CV death or hHF effect size (95% CI 0. 05-0.32, p=<0. 01). The relationship between weight differential and CV death of hHF reduction is given by the formula, Y=-0.5441+0.1883*Weight difference. Conclusion The reduction in CV death or hHF with SGLT-2is is not an exclusive molecule-specific effect but dependent on weight reduction. Presentation: No date and time listed

The Biocomplex Assembled from Antigen Peptide and Toll-like Receptor Agonist Improved the Immunity against Pancreatic Adenocarcinoma In Vivo.

One of the biggest challenges in cancer immunotherapy is generating robust cancer-specific immunity. This work describes using a biocomplex assembled from a toll-like receptor agonist CpG oligodeoxynucleotide 1826 (CpG) and a pancreatic cancer antigen peptide mesothelin for tuning pancreatic tumor immunity. This biocomplex was assembled via electrostatic interactions and characterized in size, morphology, zeta potential, and cargo loading. The effect of biocomplex on cell viability and activation of DCs and macrophages were measured by flow cytometry. The production of cytokines (GM-CSF, TNF, and IL-6) was evaluated by using ELISA kits. The effect of biocomplex on tumor cell proliferation was also evaluated by in vivo tumor model. We can modulate the surface charge of the biocomplex by simply varying the ratios of the two components. In cell models, this biocomplex did not impact cell viability in the antigen-presenting cell (i.e., dendritic cell and macrophage)-directed immunity. Moreover, this biocomplex regulated the secretion of tumor-related cytokines (i.e., GM-CSF, TNF, and IL-6) and promoted the activation of immune cell surface markers (i.e., CD80+, CD86+, and CD40+). In the mouse model, the biocomplex inhibited the tumor burden effectively and promoted the production of effector cytokines. The present studies showed that the biocomplex with antigen peptide and toll-like receptor agonist was able to potentiate the antitumor immunity in vivo. This study will help understanding of immunity in pancreatic cancer and developing new immune therapeutic strategies for pancreatic adenocarcinoma.

Effectiveness and Tolerability of Once-Weekly GLP-1 Receptor Agonists in Clinical Practice: A Focus on Switching Between Once-Weekly Molecules in Type 2 Diabetes.

AimsThis study aims to evaluate the effectiveness and tolerability of once-weekly glucagon-like peptide receptor agonists (OW GLP-1RAs) and to assess the clinical benefits of switching from one GLP-1RA to another (switchers) in a routine clinical setting.Materials and MethodsThis is a retrospective, real-world cohort study, based on electronic medical records utilized in one Italian diabetes clinic. Estimated mean changes in HbA1c and body weight after 6 and 12 months from the first prescription of a long-acting GLP1-RA were evaluated using longitudinal linear mixed models for repeated measures. The effectiveness of the three long-acting GLP1-RAs was compared separately in the GLP1-RA naive and switchers cohorts, after propensity score adjustment.ResultsInitiating a long-acting GLP1-RA was associated with statistically significant improvements in HbA1c (−1%) and body weight (−2.6 kg) after 6 months, and benefits were maintained after 12 months. In GLP1-RA naive cohort, semaglutide showed the largest effect on HbA1c (−1.55%; 95%CI, −1.77;−1.34) and body weight (−3.76 kg; 95%CI, −5.05;−2.47) at 6 months, maintained at 12 months (−1.55%; 95%CI, −1.82;−1.28 and −6.29 kg; 95%CI, −7.94;−4.63). In the switchers’ cohort, statistically significant reductions at 6 months in HbA1c and body weight were documented with semaglutide and dulaglutide only, with semaglutide associated with the most marked reduction (−0.84%; 95%CI, −1.03;−0.65 and −3.43 kg; 95%, −4.67;−2.19). Dropout rates were 9.2%, 28.5%, and 41.7% in semaglutide, dulaglutide, and exenatide groups, respectively.ConclusionsThe effectiveness and tolerability of the OW GLP-1RAs in the real world were documented. Semaglutide was associated with the highest response without impact on safety. Clinical improvements were obtained even in switchers, especially in those switching to semaglutide.

Tirzepatide, a New Era of Dual-Targeted Treatment for Diabetes and Obesity: A Mini-Review.

The prevalence of obesity and diabetes is an increasing global problem, especially in developed countries, and is referred to as the twin epidemics. As such, advanced treatment approaches are needed. Tirzepatide, known as a ‘twincretin’, is a ‘first-in-class’ and the only dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonist, that can significantly reduce glycemic levels and improve insulin sensitivity, as well as reducing body weight by more than 20% and improving lipid metabolism. This novel anti-diabetic drug is a synthetic peptide analog of the human GIP hormone with a C20 fatty-diacid portion attached which, via acylation technology, can bind to albumin in order to provide a dose of the drug, by means of subcutaneous injection, once a week, which is appropriate to its a half-life of about five days. Tirzepatide, developed by Eli Lilly, was approved, under the brand name Mounjaro, by the United States Food and Drug Administration in May 2022. This started the ‘twincretin’ era of enormously important and appealing dual therapeutic options for diabetes and obesity, as well as advanced management of closely related cardiometabolic settings, which constitute the leading cause of morbidity, disability, and mortality worldwide. Herein, we present the key characteristics of tirzepatide in terms of synthesis, structure, and activity, bearing in mind its advantages and shortcomings. Furthermore, we briefly trace the evolution of this kind of medical agent and discuss the development of clinical studies.

Cleavage-Responsive Biofactory T Cells Suppress Infectious Diseases-Associated Hypercytokinemia.

Severe infectious diseases, such as coronavirus disease 2019 (COVID‐19), can induce hypercytokinemia and multiple organ failure. In spite of the growing demand for peptide therapeutics against infectious diseases, current small molecule‐based strategies still require frequent administration due to limited half‐life and enzymatic digestion in blood. To overcome this challenge, a strategy to continuously express multi‐level therapeutic peptide drugs on the surface of immune cells, is established. Here, chimeric T cells stably expressing therapeutic peptides are presented for treatment of severe infectious diseases. Using lentiviral system, T cells are engineered to express multi‐level therapeutic peptides with matrix metallopeptidases‐ (MMP‐) and tumor necrosis factor alpha converting enzyme‐ (TACE‐) responsive cleavage sites on the surface. The enzymatic cleavage releases γ‐carboxyglutamic acid of protein C (PC‐Gla) domain and thrombin receptor agonist peptide (TRAP), which activate endothelial protein C receptor (EPCR) and protease‐activated receptor‐1 (PAR‐1), respectively. These chimeric T cells prevent vascular damage in tissue‐engineered blood vessel and suppress hypercytokinemia and lung tissue damages in vivo, demonstrating promise for use of engineered T cells against sepsis and other infectious‐related diseases.

Pyridazinones and Structurally Related Derivatives with Anti-Inflammatory Activity.

Persistent inflammation contributes to a number of diseases; therefore, control of the inflammatory response is an important therapeutic goal. In an effort to identify novel anti-inflammatory compounds, we screened a library of pyridazinones and structurally related derivatives that were used previously to identify N-formyl peptide receptor (FPR) agonists. Screening of the compounds for their ability to inhibit lipopolysaccharide (LPS)-induced nuclear factor κB (NF-κB) transcriptional activity in human THP1-Blue monocytic cells identified 48 compounds with anti-inflammatory activity. Interestingly, 34 compounds were FPR agonists, whereas 14 inhibitors of LPS-induced NF-κB activity were not FPR agonists, indicating that they inhibited different signaling pathways. Further analysis of the most potent inhibitors showed that they also inhibited LPS-induced production of interleukin 6 (IL-6) by human MonoMac-6 monocytic cells, again verifying their anti-inflammatory properties. Structure–activity relationship (SAR) classification models based on atom pair descriptors and physicochemical ADME parameters were developed to achieve better insight into the relationships between chemical structures of the compounds and their biological activities, and we found that there was little correlation between FPR agonist activity and inhibition of LPS-induced NF-κB activity. Indeed, Cmpd43, a well-known pyrazolone-based FPR agonist, as well as FPR1 and FPR2 peptide agonists had no effect on the LPS-induced NF-κB activity in THP1-Blue cells. Thus, some FPR agonists reported to have anti-inflammatory activity may actually mediate their effects through FPR-independent pathways, as it is suggested by our results with this series of compounds. This could explain how treatment with some agonists known to be inflammatory (i.e., FPR1 agonists) could result in anti-inflammatory effects. Further research is clearly needed to define the molecular targets of pyridazinones and structurally related compounds with anti-inflammatory activity and to define their relationships (if any) to FPR signaling events.

235-LB: YH34160, a Novel Long-Acting GDF15 Fusion Protein, Exerts Potent and Sustained Body Weight Loss in Rodent Obesity Models

Growth differentiation factor 15 (GDF15) is a multifunctional protein associated with energy homeostasis and body weight regulation. GDF15 has emerged as an attractive therapeutic target to treat obesity-related metabolic disorders. GDF15 reduces food intake with a unique mode of action via its receptor GDNF family receptor α-like (GFRAL) and the co-receptor RET. YH34160 is an engineered GDF15 variant-Fc fusion protein to have extended half-life and potent functional activity by enhancing binding affinity to GDF15 receptors (GFRAL/RET) . Based on rodent and monkey pharmacokinetic (PK) data, YH34160 is expected to have an optimal PK profile for once-weekly dosing in humans. In efficacy studies using obese mouse models, YH34160 demonstrated a potent and sustained weight-lowering effect. After a single subcutaneous injection in diet-induced obese (DIO) mice, YH34160-treated groups showed sustained and dose-dependent body weight (BW) reduction compared to long-acting glucagon like peptide-1 receptor agonist (GLP-1RA) . Following a 6-week multiple-dose study in DIO mice, YH34160-treated groups exhibited a greater and more prolonged BW loss compared to the group of GLP-1RA. Marked BW reduction and improved lipid profile by YH34160 were also proved in leptin-deficient (ob/ob) mice compared to GLP-1RA. In addition, YH34160 caused significantly better anti-obesity effects, and a much more improved metabolic profile than that of albumin-GDF15, and dual GLP-1/Glucagon receptor agonist. Interestingly, YH34160 in combination with GLP-1RA or dual GLP-1/glucose-dependent insulinotropic polypeptide receptor agonist (GIPRA) achieved more potent and greater BW loss compared to each mono-treated group. Overall, these findings indicate that YH34160 would be a promising therapeutic candidate, as well as in combination with GLP-1-based therapeutics, for the treatment of obesity and obesity-related comorbidities. Disclosure S. Lim: None. D. Kim: None. J. Yang: None. M. Ju: None. S. Kim: None. B. Sim: None. J. Kim: None. S. Oh: Employee; Yuhan, Stock/Shareholder; Yuhan.

934-P: Real-World Evidence of Glucose Lowering Drug Use, Glycemic Outcomes, and Severe Hypoglycemia in Hong Kong: Eighteen-Year Trends in 0.9 Million Adults with Diabetes

Introduction: Improvements in glycemic outcomes have stalled since 20in some international surveys. We examined the latest trends in drug use and glycemic outcomes following recent introduction of newer classes of glucose lowering drugs (GLDs) in a territory-wide analysis. Methods: Using data from the Hong Kong Diabetes Surveillance Database, we estimated age-specific trends in the proportion of patients reaching different glycemic targets, and rates of severe hypoglycemia (SH) in 963,612 patients between 2002-2019. We assessed patterns of GLDs use by age, sex, presence of atherosclerotic cardiovascular disease (ASCVD) and estimated glomerular filtration rate (eGFR) . Results: HbA1c improved most markedly between 2007-2014 but plateaued since 2014, with 53.1% patients achieving HbA1c <7% in 2019. The 20-44 age group had the highest proportion with HbA1c ≥9% (22.1% in 2002 and 16.8% in 2019) compared with the ≥75 age-group (14.9% in 2002 and 5.5% in 2019) . SH rates declined between 2002-20 and further in 2010-2014. Between 2002-2019, metformin use increased steadily from 41.1% to 58.7%, sulfonylurea use decreased from 52.2% to 31.1% while insulin use remained static. Use of dipeptidyl-peptidase 4 inhibitors (DPP4i) experienced rapid growth between 2007-20equally in all age groups, with a slower rise between 2011-2019. DPP4i remains the most widely prescribed newer oral GLDs (14.3%) compared with sodium glucose co-transporter 2 inhibitors (SGLT2is) (4.2%) and glucagon like peptide-1 receptor agonists (GLP1-RAs) (0.6%) in 2019. Compared with over 75s, higher proportions of the 20-44 age-group were treated with SGLT2is (6.4% versus 1.7%) and GLP-1RAs (1.5% versus 0.1%) and thiazolidinediones (8.1% versus 3.4%) in 2019, irrespective of ASCVD status. Conclusions: Following rapid improvement in 2007-2014, glycemic control and SH rates had plateaued despite the increasing use of SGLT2is and GLP-1RA in Hong Kong. Disclosure A.Yang: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp & Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. H.Wu: None. E.S.H.Lau: None. X.Zhang: None. M.Shi: None. B.Fan: None. A.P.Kong: Advisory Panel; Abbott, Kyowa Kirin Co., Ltd., Other Relationship; AstraZeneca, Novo Nordisk, Research Support; Boehringer Ingelheim, Speaker's Bureau; AstraZeneca, Bayer, Eli Lilly and Company, Sanofi, Stock/Shareholder; Aptorum Group Limited. A.Luk: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc.

728-P: Glycemic Variability of Tirzepatide vs. Insulin Degludec in People with Type 2 Diabetes Using Continuous Glucose Monitoring (SURPASS-3 CGM)

Tirzepatide (TZP) is a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist in development for T2D. In a continuous glucose monitoring (CGM) sub-study of SURPASS-3 (NCT03882970) , participants with T2D on metformin with or without SGLT-2 inhibitors spent up to 91% of time in range (71-180 mg/dL) for TZP (5, 10, 15 mg) vs. 75% for insulin degludec (IDeg) (p<0.001) and within-day coefficient of variation was 16% vs. 24% for TZP vs. IDeg (p<0.001) . Reported here are additional pre-specified glycemic variability (GV) measures at 52 weeks for the sub-study (N=243; mean age of participants, 57 years; T2D duration, 8.8 years; baseline HbA1c, 8.14%) . The between-day GV measured as the mean of daily differences was significantly less for TZP vs. IDeg (TZP 5-15 mg; p<0.001) . The frequency and severity of hypoglycemic events measured by the low blood glucose (BG) index were significantly lower at all doses of TZP vs. IDeg (mg: p<0.05; 5, 15 mg: p<0.001) , as were hyperglycemic events measured by the high BG index compared to IDeg (5 mg: p<0.05; 10, 15 mg: p<0.001) . The BG risk index was significantly less at all doses of TZP (5 mg: p<0.05; 10, 15 mg: p<0.001) (Table) . TZP showed clinically meaningful and significant reductions in the risk of hyperglycemia and hypoglycemia in comparison to IDeg in people with T2D. Disclosure R.M.Bergenstal: Advisory Panel; Hygieia, Medtronic, Roche Diabetes Care, Zealand Pharma A/S, Consultant; Abbott Diabetes, Ascensia Diabetes Care, Bigfoot Biomedical, Inc., CeQur SA, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, Onduo LLC, Sanofi, United HealthCare Services, Inc., Research Support; Abbott Diabetes, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Medtronic, Novo Nordisk, Sanofi. A.Bartee: None. M.Zeytinoglu: Employee; Eli Lilly and Company. R.Bray: Employee; Eli Lilly and Company. S.Allen: None. K.Brown: Employee; Eli Lilly and Company.

339-OR: Oral Small-Molecule GLP-1R Agonist Danuglipron Robustly Reduces Plasma Glucose and Body Weight after Eight Weeks in Japanese Adults with Type 2 Diabetes Mellitus

Danuglipron is an oral small molecule glucagon-like peptide-1 receptor (GLP-1R) agonist shown to reduce plasma glucose and body weight after 28 days of treatment in adults with type 2 diabetes mellitus (T2DM) . This randomized, double-blind (sponsor-open) , placebo-controlled, Phase 1 study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of danuglipron in Japanese patients with T2DM. A total of 37 patients with T2DM inadequately controlled on diet and exercise alone were randomized to twice-daily (BID) oral doses of placebo or multiple, ascending doses of danuglipron titrated to 40 mg, 80 mg, and 120 mg for 8 weeks. Multiple, oral doses of danuglipron were generally safe in Japanese participants with T2DM and resulted in approximate dose-proportional increases in exposure and significant reductions in fasting plasma glucose (FPG) , 24-hour mean daily glucose (MDG) , glycated hemoglobin (HbA1c) , and body weight (Table) . Most adverse events (AEs) were mild or moderate, with AEs of nausea, vomiting, abdominal discomfort, diarrhea, and headache reported most frequently. There were no deaths and no serious AEs related to dosing of danuglipron. No clinically significant adverse trends in labs, electrocardiogram, or vital sign abnormalities were apparent. Disclosure R.Ono: Employee; Pfizer Japan Inc. K.Furihata: Other Relationship; Eli Lilly and Company, Pfizer Japan Inc. Y.Ichikawa: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Japan Inc. Y.Nakazuru: Employee; Pfizer Japan Inc., Stock/Shareholder; Pfizer Inc. A.Bergman: Employee; Pfizer Inc., Stock/Shareholder; Pfizer Inc. D.N.Gorman: Employee; Pfizer Inc. A.R.Saxena: Employee; Pfizer Inc. Funding Sponsored by Pfizer Inc.

723-P: The Dual Glucagon and Glucagon-Like Peptide-1 Receptor (GCGR/GLP-1R) Agonist BI 4569Reduces Body Weight in Diet-Induced Obese Mice Based on Food Intake Reduction and an Increase in Energy Expenditure

BI 4569 is a synthetic peptide optimized to simultaneously engage the GCGR and GLP-1R. BI 4569 contains a fatty acid-based half-life extension that supports once-weekly subcutaneous injection in humans, and is currently in clinical investigation in patients with obesity or NASH. BI 4569 activates the human GCGR and GLP-1R in 100% human plasma with a potency (EC50) of 6.3 nM and 1 nM, respectively. BI 4569 potently increases glucose-stimulated insulin secretion from mouse islets (EC50 5.7 nM) and insulin secretion from perifused human islets. On single injection in lean mice, BI 4569 dose-dependently reduced food intake (FI) , gastric emptying (GE) and improved oral glucose tolerance (oGTT) with an ED50 of 90, 41, and 2.1 nmol/kg, respectively. Based on dose-dependent changes in liver NNMT mRNA and plasma amino acids, BI 4569 engages the GCGR, unlike semaglutide. Receptor-specificity of target engagement was further shown in GLP-1R knockout mice (FI, GE, oGTT) . The bodyweight-lowering efficacy of BI 4569 (3, 10, 20, 30 nmol/kg) was compared with semaglutide (20, 100 nmol/kg) in diet-induced obese mice. After 4 weeks of daily dosing, BI 4569 showed a superior bodyweight-lowering efficacy (32% at 30 nmol/kg, p≤0.0vs. vehicle) compared with a maximally effective dose of semaglutide (27% at 100 nmol/kg; p≤0.0vs. vehicle) . This greater bodyweight-lowering efficacy of BI 4569 was associated with changes in GCGR target engagement biomarkers, such as liver lipids, NNMT mRNA, plasma glucagon, FGF21, and cholesterol. Mechanistically, the superior bodyweight-lowering efficacy of BI 4569 was attributed to an increase in energy expenditure (measured at and 20 nmol/kg) . In summary, the preclinical characterization of the novel dual GCGR/GLP-1R agonist BI 4569 provides strong evidence for its clinical benefit in patients with obesity and associated comorbidities. Disclosure T. Zimmermann: Employee; Boehringer Ingelheim Pharma GmbH&Co.KG. L. Thomas: Employee; Boehringer Ingelheim International GmbH. T. Baader-Pagler: Employee; Boehringer Ingelheim International GmbH. P. Haebel: Employee; Boehringer Ingelheim International GmbH. H. Neubauer: Employee; Boehringer Ingelheim International GmbH. E. Simon: Employee; Boehringer Ingelheim Pharma GmbH&Co KG. W. Reindl: Employee; Boehringer Ingelheim International GmbH. B. Bajrami: None. W. Rist: Employee; Boehringer Ingelheim International GmbH. I. Uphues: Employee; Boehringer Ingelheim International GmbH. R. Augustin: None.

1433-P: Comparative Weight Loss with GLP-1 Receptor Agonists vs. Bariatric Surgery in Obesity: A Systematic Review and Pair-Wise Meta-analysis

Background: One in three adults suffers from obesity.1 Glucagon-like peptide-1 (GLP-1) receptor agonists have been associated with 15-20% weight loss, a range previously only achieved with bariatric surgery.2,3,4 This systematic review and meta-analysis compares weight loss between GLP-1 receptor agonists and bariatric surgery. Methods: MEDLINE, Medline-in-Process, Medline EPUBS Ahead of Print, EMBASE Classic + EMBASE (OvidSP) ; and Cochrane (Wiley) databases were searched from inception to April 21, 2021. We included randomized controlled trials (RCTs) and observational studies. Two independent reviewers extracted data, reported risk of bias, and graded certainty of evidence. Risk of bias was reported using Risk of Bias 2 (RoB 2) tool for RCTs and Risk of Bias in Non-randomized Studies- of Interventions (ROBINS-I) tool for observational studies. Data were pooled separately for RCTs and observational studies using random effects models. Change in weight, body mass index (BMI) , and glycated hemoglobin (HbA1C) were summarized. Results: Seven included studies encompassed 11patients. Among RCTs, mean difference in weight between bariatric surgery and GLP-1 receptor agonist was −22.68 (95% CI: −31.41, −13.96) , mean difference in BMI was −8.18 (95% CI: −11.59, −4.77) , and mean difference in HbA1C was −1.28 (95% CI: −1.94, −0.61) . Among observational studies, mean difference in weight was −16.56 (95% CI: −36.53, 3.42) and mean change in BMI was −10.60 (95% CI:−17.22, −3.98) . These effects all favoured bariatric surgery. Conclusion: In adults with obesity, bariatric surgery still confers highest reductions in weight and BMI compared to GLP-1 receptor agonists, but similar effects in glycemic control. Word count: 248 Disclosure P. Palcu: None. Funding Clinician Investigator Program, University of Toronto

Non-inferiority and clinical superiority of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors: Systematic analysis of cardiorenal outcome trials in type 2 diabetes.

AimsMost trials leading to the approval of glucagon‐like peptide receptor agonists (GLP‐1RAs) and sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) were primarily designed to confirm their non‐inferiority to placebo (commonly using an upper 95% confidence limit threshold of 1.3) and, if confirmed, superiority (threshold 1): this asymmetry of margins (1 vs. 1.3) favours the active intervention. We aimed to quantify the probability of clinical superiority of the active treatment by applying the same threshold used to claim non‐inferiority.Materials and MethodsWe searched PubMed and Cochrane CENTRAL for cardiorenal outcome trials in subjects with type 2 diabetes published before 5 December 2021, to reconstruct from Kaplan‐Meier plots individual‐level data for the primary outcome or all‐cause mortality. We calculated Bayesian posterior densities to obtain the probability for a treatment effect (hazard ratio) <0.769, which is symmetric to the 1.3 threshold (i.e. its reciprocal 1/1.3), emulating a scenario where the active treatment is placebo and placebo is the active treatment.ResultsWe extracted data from 27 Kaplan‐Meier plots (18 for the primary outcome, nine for mortality). Probabilities of clinical superiority to placebo varied significantly: for GLP‐1RAs, from a minimum of 0% to a maximum of 69% for the primary outcome and from 0% to 8% for mortality; corresponding estimates for SGLT2is were 0% to 96% and 0% to 93%. Probabilities were on average greater for SGLT2is, particularly in trials investigating kidney or heart failure outcomes.ConclusionsThe probability of clinical superiority to placebo varies widely across trials previously reported as showing superiority of GLP‐1RAs or SGLT2is compared with placebo. These results showed within‐ and between‐class differences, highlight the drawbacks of a binary interpretation of the results, particularly in the context of the current designs of non‐inferiority trials, and have implications for decision makers and future clinical recommendations.

Current and Future Therapeutic Optionsin Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation.

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Is liraglutide the solution for weight loss in women with polycystic ovarian syndrome?

Madam, Liraglutide is an acylated glucagon-like peptide-1 (GLP-1) receptor agonist that helps patients suffering from diabetes mellitus type 2 in control their blood glucose level day through its meal induced insulin secretion, so-called incretin effect. The pharmacokinetic properties of liraglutide enable it to control 24-hour glycaemia(1). It is also found to decrease the risk of stroke and cardiovascular events among patients with type 2 diabetes. It has gained a lot of popularity as it is potent and can be taken in combination with almost any other diabetic medication. However, the use of this drug is not just limited to the treatment of diabetes mellitus. Several recent studies have shown that this drug could treat obese women suffering from polycystic ovarian syndrome (PCOS). A randomized controlled trial published in 2015 in Hormones (Athens) compared the effect of liraglutide and metformin on weight loss in women with PCOS(2). Twenty-eight individuals participated in this study and were randomly categorized into patients receiving liraglutide (n=14) or patients receiving metformin (n=14). The study highlighted that the short-term use of liraglutide significantly reduced the weight in newly diagnosed PCOS womenThe aforementioned is not the only study that supports this result. A 2018 meta-analysis published in Obesity Reviews compared liraglutide, metformin and orlistat in reducing the weight in obese women suffering from PCOS(3). Data from 23 randomized controlled trials, consisting of 941 women, were evaluated, and the results showed that liraglutide whether used alone or in combination with metformin, helped reduce weight. PCOS is one of the most prevalent endocrinology disorders in South Asia, including Pakistan. It leads to several health risks and is found to affect the quality of life. Most women with PCOS show signs of metabolic syndrome, including obesity, hypertension, dyslipidaemia, and insulin resistance(4). Obesity along with insulin resistance is found to increase risk of hyperandrogenism. This leads to a chain of circumstances that promotes development of PCOS(5). Lifestyle changes and dietary modifications should be the first- line treatment for women with PCOS. But if lifestyle intervention is not effective in reducing weight, then the more aggressive treatment, use of liraglutide, should be considered after consultation with the health care professional. Continuous...

Long-term treatment with glucagon-like peptide-1 (GLP-1) receptor agonists: a real-life study

Long-term treatment with glucagon-like peptide-1 (GLP-1) receptor agonists: a real-life study

Comprehensive Review and Updates on Holistic Approach Towards Non-Alcoholic Fatty Liver Disease Management with Cardiovascular Disease.

The global prevalence of non-alcoholic fatty liver disease (NAFLD) presents an unmet need in treating these, often asymptomatic, individuals. In this review, we summarised NAFLD management and described recent developments in non-alcoholic steatohepatitis (NASH) therapeutics that can shape the future of NAFLD. A multi-disciplinary effort in promoting sustainable lifestyle measures is paramount, with the goal of either limiting energy surplus alone or in combination with targeting downstream pathways of inflammation and fibrosis. Several antidiabetic medications like PPAR-γ agonist and glucagon-like peptide receptor agonists have beneficial effects on the metabolic profile as well as NASH histology. Vitamin E has shown promise in specific groups of patients with the haptoglobin2 allele protein. Newer drugs have demonstrated promising results in NASH resolution and fibrosis improvement such as obeticholic acid, resmetirom, aramchol, efruxifermin, aldafermin and lanifibranor. Apart from discussing the results of late stage clinical trials and the possible challenges in managing these patients with limited approved therapies, we also discussed the specific management of comorbidities (diabetes, hypertension, hyperlipidaemia, cardiovascular diseases) in NAFLD patients. Treatment strategy needs to target improvements in liver-related outcomes and cardiometabolic profile.

Plasma proteomics reveals an improved cardio-metabolic profile in patients with type 2 diabetes post-liraglutide treatment.

BackgroundDiabetes mellitus is a chronic multisystem disease with a high global prevalence, including in Saudi Arabia. The Glucagon-like Peptide (GLP-1) receptor agonist liraglutide is known to lower glucose levels, reduce weight and improve cardiovascular outcome. However, mechanisms underlying the benefits of liraglutide treatment in patients with type 2 diabetes mellitus (T2DM) remain unclear.MethodsIn the present study, a 2D-DIGE MALDI-TOF mass spectrometric approach combined with bioinformatics and network pathway analysis explore the plasma proteomic profile. The study involved 20 patients with T2DM with mean age of 54.4 ± 9.5 years and Hemoglobin A1c (HbA1c) between 8% and 11% (inclusive).ResultsA statistically significant change (p < .006) was observed in HbA1c with no significant changes in body weight, renal function, or markers of dyslipidemia post-treatment with liraglutide. 2 D-DIGE gel analysis identified significant changes (⩾1.5-fold change, Analysis of variance (ANOVA), p ⩽ 0.05) in 72 proteins, (62 down and 10 up) in liraglutide pre-treatment compared to the post-treatment state. Proteins identified in our study were found to regulate metabolic processes including acute phase response proteins, enzymes, apolipoproteins with involvement of the inflammatory signaling pathways, NF-κB, AKT, and p38 MAPKConclusionLiraglutide treatment decreased levels of acute phase response that to reduce the systemic chronic inflammatory state and oxidative stress, and eventually improve the cardio-metabolic profile in these patients.