Dual Receptor Agonist Research Articles

Effect of survodutide, a glucagon and GLP-1 receptor dual agonist, on weight loss: a meta-analysis of randomized controlled trials

BackgroundConsidering the increasing prevalence of obesity/overweight, its treatment or prevention with new interventions can greatly help health and reduce its adverse effects in people. One of these new interventions is investigating the effect of Survodutide as a dual agonist of glucagon and GLP-1 receptors, which seems to be able to influence weight loss processes in different ways. In this study, we investigated the effect of injectable Survodutide on weight loss.MethodsIn order to identify all randomized controlled trials that investigated the effects of Survodutide on factores related to obesity, a systematic search was conducted in the original databases using predefined keywords until August 2024. The pooled weighted mean difference and 95% confidence intervals were computed using the random-effects model.ResultsThe Findings from 18 treatment arms with 1029 participants indicated significant reductions in weight (WMD: -8.33 kg; 95% CI: -10.80, -5.86; I2 = 99.6%), body mass index (BMI) (WMD:-4.03 kg/m2; 95% CI: -4.86, -3.20; I2 = 72.7%), and waist circumferences (WC) (WMD: -6.33 cm; 95% CI: -8.85 to -3.81; I2 = 99.5%) following the Survodutide injection compared to the control group. Subgroup analysis reveals that longer interventions (more than 16 weeks) and higher doses (more than 2 mg/week) of Survodutide are associated with more significant reductions in weight and WC. These results were also observed in the meta-regression analysis.ConclusionsThe results of this meta-analysis show that Survodutide is effective in reducing weight, BMI and waist circumference, especially with longer interventions and higher doses.

Survodutide for treatment of obesity: rationale and design of two randomized phase 3 clinical trials (SYNCHRONIZE™-1 and -2).

The objective of this study was to describe the rationale and design of two multinational phase 3 clinical trials of survodutide, an investigational glucagon and glucagon-like peptide-1 receptor dual agonist for the treatment of obesity with or without type 2 diabetes (T2D; SYNCHRONIZE-1 and -2). In these ongoing double-blind trials, participants were randomized to once-weekly subcutaneous injections of survodutide or placebo added to lifestyle modification. Survodutide doses are uptitrated to 3.6 or 6.0 mg, and dose flexibility is permitted. Participants (n = 726) in SYNCHRONIZE-1 (NCT06066515) have a baseline BMI ≥ 30 kg/m2 or ≥27 kg/m2 with at least one obesity-related complication but without T2D; participants (n = 755) in SYNCHRONIZE-2 (NCT06066528) have a baseline BMI ≥ 27 kg/m2 and T2D. The primary endpoints are percentage change in body weight and proportion of participants achieving ≥5% body weight reduction from baseline to week 76. Secondary endpoints include change in systolic blood pressure and measures of glycemia. A SYNCHRONIZE-1 substudy is evaluating changes in body composition and liver fat content using magnetic resonance imaging. These trials are designed to provide robust evaluation of the efficacy, safety, and tolerability of survodutide for the treatment of obesity in the presence or absence of T2D.

Role of Dual GIP and GLP-1 Receptor Agonist, Tirzepatide in the Management of Weight Loss; A Systematic Review.

The eventuality of tirzepatide, a binary GIP and GLP- 1 receptor agonist, as a treatment for rotundity and metabolic diseases is addressed in this comprehensive review. A definition of tirzepatide is that it is an implicit intervention for rotundity, given its effectualness per the cure-dependent effect. Beyond the beneficial effects on body weight loss, tirzepatide also brings about an improvement in lipid biographies and insulin perceptivity, in harmony with binary receptor activation. Assaying data from seven phases 3 trials, it's constantly shown that tirizepatide reduces body weight in a significant and clinically meaningful way for a variety of party biographies and lengths of time. The drug's effect was supported by its favorable safety profile, which shows low prevalence rates of common adverse goods. Its efficacy in the management of type 2 diabetes is supported by relative evaluations, underscoring the inevitability of its breakthrough as a therapeutic volition. Treatment individualization is key, as evidenced by the tailor-made response proposed by group analysis based on birth BMI. The efficacy, safety, and demand for personalized treatment plans of tirzepatide are each supported in recommendations for clinical practice. Tirzepatide's eventuality as a long-term strategy for habitual rotundity is corroborated by long-term follow-up studies that show sustained weight loss. Indeed with these encouraging results, further study and clinical experience are demanded to completely comprehend the safety, optimal integration, and long-term effectiveness of tirzepatide in a multiplicity of patient populations.

Survodutide, a glucagon receptor/GLP-1 receptor (GCGR/GLP-1R) dual agonist, improves cardiometabolic parameters in adults with obesity: analysis of a placebo-controlled, randomised phase 2 trial

Abstract Background Obesity increases the risk of cardiovascular (CV) disease and contributes to CV risk factors, such as hypertension (HTN) and dyslipidaemia. Survodutide is a GCGR/GLP-1R dual agonist in clinical development for obesity. In a phase 2 clinical trial in individuals with obesity without diabetes, survodutide elicited up to 18.7% mean reduction in body weight after 46 weeks (primary endpoint) according to actual treatment.1 Purpose We explored the effect of survodutide on cardiometabolic parameters in this trial cohort. Methods 387 people aged ≥18 to <75 years with body mass index (BMI) ≥27 kg/m2 without diabetes were randomised 1:1:1:1:1 to once-weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or placebo (PBO) for 46 weeks (wk), comprising an initial 20-wk escalation period when the dose could be adjusted for gastrointestinal (GI) tolerability, followed by a 26-wk maintenance period. We evaluated changes from baseline (BL) to wk 46 in waist circumference; lipid parameters (triglyceride [TG], high-density lipoprotein [HDL], very low-density lipoprotein [VLDL], low-density lipoprotein [LDL], total cholesterol [TC], and non-HDL cholesterol [non-HDL-C]); and blood pressure (BP) by presence/absence of HTN before and at screening. Data were analysed descriptively for all participants receiving ≥1 dose of study drug with data for ≥1 efficacy endpoint, i.e. full analysis set (FAS), according to doses received during the maintenance period (actual treatment) and according to doses assigned at randomization (planned treatment) using on-treatment data. Results In the FAS (n=384), BL demographic and clinical characteristics were similar across treatment groups: overall mean age 49.1 years, BMI 37.1 kg/m2, 262 (68.2%) female, 301 (78.4%) White, 40 (10.4%) Asian, and 37 (9.6%) Black. Before and at screening, 133 (34.6%) participants had hypertension and 108 (28.1%) had dyslipidaemia. Waist circumference was reduced in all survodutide doses vs PBO; the largest mean reduction was 16.6 cm (4.8 mg group; actual treatment). Survodutide was associated with reductions of up to 10.2 mmHg in SBP and 4.8 mmHg in DBP from BL to wk 46 by actual treatment; similar reductions were observed for planned treatment, and reductions were comparable with/without HTN before and at screening (Figure 1). A marked decrease in mean TG was observed in all survodutide groups by planned treatment (Figure 2). Mean HDL was relatively unchanged over the period. Small decreases occurred in mean VLDL (all survodutide doses) and mean LDL (2.4 and 3.6 mg doses). Mean TC and non-HDL-C decreased in 0.6, 2.4, and 3.6 mg groups. Conclusion In people living with obesity, the GCGR/GLP-1R dual agonist survodutide was associated with clinically meaningful reductions in waist circumference, BP (with/out HTN before and at screening), and TG.

Comparison of cardiovascular outcomes in patients with diabetes treated with tirzepatide versus semaglutide: a multi-institutional analysis

Abstract Introduction Glucagon-like-peptide-1 (GLP-1) receptor agonists have been demonstrated to have cardiovascular benefits in patients with diabetes. Two of the most prescribed medications in this class are tirzepatide and semaglutide. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist. Tirzepatide and semaglutide have previously been directly compared to assess efficacy in glycemic control as the primary endpoint. However, there is limited data directly comparing cardiovascular outcomes between the two medications in patients with diabetes. This retrospective cohort study compares the incidence of major adverse cardiovascular events (MACE) in patients with diabetes treated with tirzepatide or semaglutide. Purpose The purpose of this study is to identify differences in cardiovascular outcomes between patients with diabetes treated with tirzepatide as compared to semaglutide. Materials and Methods The TriNetX research network was used for this study. Two patient cohorts were generated using International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts of patients had a history of diabetes (E08-E13) and no prior history of cerebral vascular accident (I63) or myocardial infarction (I21). One cohort received semaglutide and the other tirzepatide. Each cohort was prohibited from receiving the other agent. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm resulting in 36,212 patients in each arm. They were then evaluated for the 3-year outcomes of major adverse cardiovascular events (myocardial infarction, cerebral vascular accident, and death). Results Tirzepatide was associated with statistically significantly fewer MACE outcomes compared to semaglutide for each of the individual endpoints as well as the overall composite endpoint over the 3 year follow up period. Table 1. MACE events for semaglutide and tirzepatide. Table 2. Relative risks for semaglutide MACE endpoints compared to tirzepatide. Conclusions In this retrospective cohort study, tirzepatide was associated with a lower incidence of major adverse cardiovascular events compared to semaglutide in patients with diabetes. These findings suggest that tirzepatide offers superior cardiovascular protection for primary prevention compared to semaglutide and warrant further investigation in future studies and clinical trials.Table 1Table 2

Characterizing body composition modifying effects of a glucagon-like peptide 1 receptor-based agonist: A meta-analysis.

Diabetes is an independent risk factor for muscle mass loss, with possible mechanisms including impaired insulin signalling and chronic inflammation. The use of a glucagon-like peptide 1 (GLP-1) receptor-based agonist could lead to weight reduction, which might result from the loss of both fat and skeletal muscle. However, the body composition-modifying effects of GLP-1 receptor-based agonists have not been systematically characterized. PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to October 2023. Randomized controlled trials of GLP-1 receptor agonist or glucose-dependent insulinotropic polypeptide/GLP-1 receptor dual agonist, which reported the changes of body composition, were included. The results were computed as weighted mean differences (WMDs) and 95% confidence intervals (CIs) in a random-effects model. In all, 19 randomized controlled trials were included. When compared with controls, substantial reductions in fat body mass were observed in patients using GLP-1 receptor-based agonist treatment (WMD = -2.25 kg, 95% CI -3.40 to -1.10 kg), with decrease in areas of both subcutaneous fat (WMD = -38.35 cm2, 95% CI, -54.75 to -21.95 cm2) and visceral fat (WMD = -14.61 cm2, 95% CI, -23.77 to -5.44 cm2). Moreover, greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users compared with non-users (WMD = -1.02 kg, 95% CI, -1.46 to -0.57 kg), while the changes in lean mass percentage were comparable between GLP-1 receptor-based agonist users and non-users. Compared with the controls, GLP-1 receptor-based agonist users experienced greater reductions in fat body mass, with body shaping effects in terms of both subcutaneous fat mass and visceral fat mass. Although greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users, the changes in lean mass percentage were comparable between the users and non-users.

Estimating the lives that could be saved by expanded access to weight-loss drugs

Obesity is a major public health crisis in the United States (US) affecting 42% of the population, exacerbating a spectrum of other diseases and contributing significantly to morbidity and mortality overall. Recent advances in pharmaceutical interventions, particularly glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, liraglutide) and dual gastric inhibitory polypeptide and GLP-1 receptor agonists (e.g., tirzepatide), have shown remarkable efficacy in weight-loss. However, limited access to these medications due to high costs and insurance coverage issues restricts their utility in mitigating the obesity epidemic. We quantify the annual mortality burden directly attributable to limited access to these medications in the US. By integrating hazard ratios of mortality across body mass index categories with current obesity prevalence data, combined with healthcare access, willingness to take the medication, and observed adherence to and efficacy of the medications, we estimate the impact of making these medications accessible to all those eligible. Specifically, we project that with expanded access, over 42,000 deaths could be averted annually, including more than 11,000 deaths among people with type 2 diabetes. These findings underscore the urgent need to address barriers to access and highlight the transformative public health impact that could be achieved by expanding access to these novel treatments.

6926 Subgroup Analysis by Gender and Body Mass Index (BMI) in People Living With Overweight/Obesity in the Survodutide, a Glucagon/GLP-1 Receptor Dual Agonist, Phase II Trial

Abstract Disclosure: C.W. Le Roux: Consulting Fee; Self; Boehringer Ingelheim, Novo Nordisk, GI Dynamics, Herbalife, Johnson & Johnson, Eli Lilly, Keyron. O. Steen: Consulting Fee; Self; Eli Lilly & Company, Novo Nordisk, Sanofi. Grant Recipient; Self; Alnylam, Anji, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Janssen, Genzyme Corporation, Medacorp, Novo Nordisk, Medicago, Moderna, Novavax, Pfizer, Sanofi, Zucara Therapeutics, Gilead, ViaCyte, CRISPR Therapeutics, Kowa. Speaker; Self; Amgen Inc, AstraZeneca, Bausch Health, Janssen, LMC, Novo Nordisk. K.J. Lucas: None. E. Startseva: Employee; Self; Boehringer Ingelheim. A. Unseld: Employee; Self; Boehringer Ingelheim. A.M. Hennige: Employee; Self; Boehringer Ingelheim. Aim: To explore the effect of gender and BMI on weight loss and adverse events with survodutide in people living with overweight/obesity. Methods: In this double-blind, placebo (PBO)-controlled Phase II trial (NCT04667377), 387 adults with BMI ≥27 kg/m2 without diabetes were randomized 1:1:1:1:1 to weekly subcutaneous survodutide (0.6, 2.4, 3.6, 4.8 mg) or PBO over 46 weeks. Percentage change in body weight (primary endpoint), absolute change in body weight and waist circumference (secondary endpoints), and adverse events (AEs) were assessed in subgroups based on gender and BMI at baseline (BL). Data were analyzed descriptively for all participants who received ≥1 dose of study drug and had data for ≥1 efficacy endpoint (full analysis set [FAS]; planned treatment: n=384). Results: Of 384 participants, 68.2% (262) were female. At BL, 9.9% (38), 30.5% (117), 31.8% (122), and 27.9% (107) had a BMI of <30, 30-<35, 35-<40, and ≥40 kg/m2, respectively. Demographics and clinical characteristics at BL were similar between males and females and across BMI subgroups. At Week 46, mean percentage change in body weight from BL with survodutide 4.8 mg vs PBO was -11.9% vs -3.3% in males and -17.0% vs -3.2% in females, and -19.1% vs -1.7%, -15.8% vs -3.1%, -15.4% vs -5.8%, and -13.4% vs -0.8% across BL BMI categories. Mean absolute body weight loss from BL (survodutide 4.8 mg vs PBO) was -15.9 vs -4.2 kg in males and -22.0 vs -3.0 kg in females. Reductions in absolute body weight with survodutide 4.8 mg vs PBO were similar across BMI subgroups: -21.3 vs 1.4 kg, -16.2 vs -3.3 kg, -22.2 vs -7.5 kg, and -19.9 vs -1.6 kg. Mean absolute change in waist circumference from BL (survodutide 4.8 mg vs PBO) was -12.8 vs -1.7 cm in males and -17.9 vs -4.9 cm in females, and -8.4 vs -2.6 cm, -14.3 vs -6.4 cm, -17.5 vs -5.0 cm, and -17.2 vs 3.3 cm across BL BMI categories. A higher proportion of participants lost ≥15% of BL body weight with survodutide 4.8 mg vs PBO: 31.8% vs 9.5% in males and 66.7% vs 3.0% in females, and 75.0% vs 14.3%, 57.9% vs 4.5%, 52.0% vs 6.7%, and 50.0% vs 0.0% across BL BMI categories; respectively. All survodutide doses (pooled) were tolerated as expected across gender and BL BMI subgroups. In males vs females, respectively, rates of any AE (87.9% vs 92.4%), serious AEs (4.0% vs 4.3%), and discontinuations due to AEs (25.3% and 24.3%) were comparable. Gastrointestinal (GI) AEs with all survodutide doses were experienced by fewer males (65.7%) than females (79.5%); mild to moderate nausea was the most frequently reported GI AE in both subgroups. Conclusion: After 46 weeks of survodutide treatment, females appeared to lose more body weight and waist circumference than males. Participants with a lower vs higher BL BMI generally lost more proportional body weight, with an opposite trend observed for waist circumference. Presentation: 6/2/2024

7018 Improved Tolerability After Transitioning from Glucagon-like Peptide-1 Receptor Agonists to Tirzepatide

Abstract Disclosure: S. Hudson: None. J. Aurora: None. F. Erenler: None. Background: Tirzepatide is a dual incretin targeting glucagon-like peptide-1 receptor agonist (GLP-1RA) and glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA) with potent reductions in HbA1c and weight, especially compared to semaglutide, a GLP-1RA (1). Gastrointestinal (GI)-related events are commonly associated with incretins. As an imbalanced dual agonist, tirzepatide has a stronger affinity for GIP compared to GLP-1 receptors (2). This stronger affinity for GIP receptors may be related to the improved tolerability of tirzepatide, as GIP is not as associated with GI effects as compared to GLP-1 (2). There is a reported dose-dependent increase in GI events and treatment discontinuation with tirzepatide compared to semaglutide in RCTs, although this has not been corroborated in real-world data (1). Additionally, there is no literature evaluating GI tolerability when switching from GLP-1 receptor agonists to tirzepatide. We present a case series to highlight improved tolerability and sustained clinical outcomes observed in patients transitioning from GLP-1RA to tirzepatide, who previously had GI intolerances. Clinical Case A retrospective review was conducted of five patients who started on GLP-1RA for either T2DM (n=3) or obesity (n=2) but stopped due to GI-related events. All patients were female with a mean age of 57 years. On average, patients with T2DM had a 23-year duration of diabetes, HbA1c 8.4%, weight 78.4 kg, and BMI 29.5 kg/m2 prior to starting tirzepatide. For patients without T2DM, the average weight was 75.9 kg and BMI 30.0 kg/m2 prior to starting tirzepatide. Before switching to tirzepatide, three patients were on maximally tolerated dulaglutide and two patients were on semaglutide. Patients were initially transitioned to tirzepatide 2.5 mg (n=2), 5 mg (n=2), and 7.5 mg (n=1). All patients tolerated tirzepatide with no GI-related events after an average of 6 months of treatment. Of the three patients with T2DM, they saw an additional average HbA1c reduction of 1.1% and an average weight loss of 3%. For patients who transitioned to tirzepatide for weight loss, they saw an additional average weight loss of 9%. Clinical Implications Tirzepatide may offer improved tolerability in patients who are intolerant of GLP-1RA drugs, while yielding further glycemic lowering and weight loss. Given tirzepatide’s stronger affinity to GIP than GLP-1 receptors, this may explain improved GI tolerability as seen in our case series. Further research is needed to evaluate tolerability improvement with tirzepatide using real-world data and larger sample sizes.

Review of current and new drugs for the treatment of metabolic-associated fatty liver disease.

In the past 3 decades, metabolic-associated fatty liver disease (MAFLD) has emerged as a widespread liver condition, with its global prevalence on the rise. It ranks as a leading contributor to hepatocellular carcinoma (HCC) and necessitates liver transplantation. Under the multiple parallel hits model, the pathogenesis of MAFLD stems from various liver stressors, notably nutrient overload and sedentary lifestyles. While medical management for MAFLD is well-established, encompassing non-pharmaceutical and pharmaceutical interventions, determining the most effective pharmaceutical therapy has remained elusive. This review discusses diabetic medications for MAFLD treatment, emphasizing recent studies and emerging drugs while reviewing other nondiabetic agents. Emerging evidence suggests that combination therapies hold promise for resolving MAFLD and metabolic steatohepatitis (MASH) while managing side effects. Ongoing trials play a pivotal role in elucidating the effects of mono, dual, and triple receptor agonists in individuals with MASH. With the rising burden of MAFLD/MASH and its severe consequences, the need for effective treatments is more pressing than ever. This review provides a comprehensive overview of the current landscape of pharmaceutical interventions for MAFLD and MASH, shedding light on the potential of newer drugs especially diabetic medications and the importance of ongoing research in this field.

Survodutide for the Treatment of Obesity: Rationale and Design of the SYNCHRONIZE Cardiovascular Outcomes Trial.

Dual agonism of glucagon and glucagon-like peptide-1 (GLP-1) receptors may be more effective than GLP-1 receptor agonism alone in reducing body weight, but the cardiovascular (CV) effects are unknown. The authors describe the rationale and design of SYNCHRONIZE-CVOT, a phase 3, randomized, double-blind, parallel-group, event-driven, CV safety study of survodutide, a dual glucagon and GLP-1 receptor agonist, administered subcutaneously once weekly compared with placebo in adults with a body mass index≥27kg/m2 and established CV disease or chronic kidney disease, and/or at least 2 weight-related complications or risk factors for CV disease. The primary endpoint of SYNCHRONIZE-CVOT is time to first occurrence of the composite adjudicated endpoint of 5-point major adverse CV events. This global CV outcomes trial is currently enrolling, with a target recruitment of 4,935 participants. SYNCHRONIZE-CVOT is the first trial that will determine the CV safety and efficacy of survodutide in people with obesity and increased CV risk. (A Study to TesttheEffect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity [SYNCHRONIZE-CVOT]; NCT06077864).

Glucagon-like peptide-1 receptor agonist-based agents and weight loss composition: Filling the gaps.

Excess adiposity is at the root of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as first-line treatments for T2D based on significant weight loss results. The composition of weight loss using most diets consists of <25% fat-free mass (FFM) loss, with the remainder from fat stores. Higher amounts of weight loss (achieved with metabolic bariatric surgery) result in greater reductions in FFM. Our aim was to assess the impact that GLP-1RA-based treatments have on FFM. We analysed studies that reported changes in FFM with the following agents: exenatide, liraglutide, semaglutide, and the dual incretin receptor agonist tirzepatide. We performed an analysis of various weight loss interventions to provide a reference for expected changes in FFM. We evaluated studies using dual-energy X-ray absorptiometry (DXA) for measuring FFM (a crude surrogate for skeletal muscle). In evaluating the composition of weight loss, the percentage lost as fat-free mass (%FFML) was equal to ΔFFM/total weight change. The %FFML using GLP-1RA-based agents was between 20% and 40%. In the 28 clinical trials evaluated, the proportion of FFM loss was highly variable, but the majority reported %FFML exceeding 25%. Our review was limited to small substudies and the use of DXA, which does not measure skeletal muscle mass directly. Since FFM contains a variable amount of muscle (approximately 55%), this indirect measure may explain the heterogeneity in the data. Assessing quantity and quality of skeletal muscle using advanced imaging (magnetic resonance imaging) with functional testing will help fill the gaps in our current understanding.

Seven glucagon-like peptide-1 receptor agonists and polyagonists for weight loss in patients with obesity or overweight: an updated systematic review and network meta-analysis of randomized controlled trials

PurposeThis study aimed to provide evidence-based support and a reference for the efficacy and safety of seven glucagon-like peptide-1 (GLP-1) receptor agonists and polyagonists for weight loss in patients with obesity or overweight through a network meta-analysis. MethodsRelevant randomized controlled trials (RCTs) with an intervention duration of at least 16 weeks assessing seven GLP-1 receptor agonists and polyagonists (mazdutide, 6 or 4.5 mg; retatrutide, 12 or 8 mg; tirzepatide, 15 or 10 mg; liraglutide, 3.0 mg; semaglutide, 2.4 mg; orforglipron, 45 or 36 mg; and beinaglutide, 0.2 mg) in patient with obesity or overweight was searched using three databases (Cochrane Library, PubMed, and Embase) from creation to August 30, 2024. The primary outcome was the percentage change in body weight from baseline. Secondary outcomes included changes in waist circumference, hemoglobin A1c, and fasting plasma glucose level from baseline; adverse events, serious adverse events, adverse event withdrawal, and hypoglycemic events. We conducted a frequentist random-effects network meta-analysis to analyze the data extracted from the RCTs using Stata 16.1 software. ResultsTwenty-seven RCTs of seven GLP-1 receptor agonists and polyagonists and 15,584 patients were included in the network meta-analysis. In terms of efficacy, compared with placebo, retatrutide 12 mg (−22.10 % in body weight and − 17.00 cm in waist circumference), retatrutide 8 mg (−20.70 % and − 15.90 cm), and tirzepatide 15 mg (−16.53 % and − 13.23 cm) were the three most efficacious treatments for reducing body weight and waist circumference. However, these treatments were less effective in patients with type 2 diabetes mellitus (T2DM). In addition, patients with a high body mass index (BMI) or longer treatment cycles exhibited significantly greater weight loss than those with a low BMI or shorter treatment cycles. In terms of safety, patients without T2DM had a higher incidence of adverse events than those with T2DM. None of the interventions increased the incidence of serious adverse or hypoglycemic events (˂54 mg/dL). There was no significant difference in the incidence of adverse event withdrawal for all interventions in head-to-head comparisons. In addition, disparities in race, BMI, and treatment cycles did not significantly increase the incidence of adverse events. Finally, the sensitivity and publication bias analyses indicated that the basic analysis results were reliable. ConclusionRetatrutide (both doses) and tirzepatide exhibited superior efficacy compared to other GLP-1 receptor agonists and polyagonists in reducing body weight and waist circumference. Patients without T2DM, those with a high BMI, and individuals undergoing longer treatment cycles demonstrated significantly greater weight loss and reductions in waist circumference. Dual or triple receptor agonists (GLP-1 plus glucose-dependent insulinotropic polypeptide and/or Glucagon receptor) are more effective for weight loss than GLP-1 receptor agonists.

Tirzepatide administration improves cognitive impairment in HFD mice by regulating the SIRT3-NLRP3 axis.

High-fat diet (HFD) currently is reported that in connection with cognitive impairment. Tirzepatide is a novel dual receptor agonist for glycemic control. But whether Tirzepatide exerts a protective effect in HFD-related cognitive impairment remains to be explore. During the study, the cognitive dysfunction mice model induced by HFD were established. The expressions synapse-associated protein and other target proteins were detected. The oxidative stress parameters, levels of inflammatory cytokine were also detected. Our findings proved that Tirzepatide administration attenuates high fat diet-related cognitive impairment. Tirzepatide administration suppresses microglia activation, alleviates oxidative stress as well as suppressed the expression of NLRP3 in HFD mice by up-regulating SIRT3 expression. In conclusion, Tirzepatide attenuates HFD-induced cognitive impairment through reducing oxidative stress and neuroinflammation via SIRT3-NLRP3 signaling. This study suggest that Tirzepatide has neuroprotective effects in HFD-related cognitive dysfunction mice model, which provides a promising treatment of HFD-related cognitive impairment.

216 - Subgroup analysis by gender and body mass index (BMI) in people living with overweight/obesity in the survodutide, a glucagon/GLP-1 receptor dual agonist, phase II trial

216 - Subgroup analysis by gender and body mass index (BMI) in people living with overweight/obesity in the survodutide, a glucagon/GLP-1 receptor dual agonist, phase II trial

241 - Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial

241 - Glucagon and GLP-1 receptor dual agonist survodutide improved liver histology in people with MASH and fibrosis: Results from a randomized, double-blind, placebo-controlled phase 2 trial

Tirzepatide's innovative applications in the management of type 2 diabetes and its future prospects in cardiovascular health.

Tirzepatide, a novel GLP-1/GIP dual receptor agonist, shows significant advantages in glycemic management and weight control. By summarizing the results of the SURMOUNT and SURPASS clinical trials, we evaluate the efficacy and safety of tirzepatide in reducing blood glucose and weight. These trials indicate that tirzepatide significantly lowers HbA1c levels (with a maximum reduction of 2.24%) and promotes weight loss (up to 11.2kg) with good tolerability. However, there are still some challenges in its clinical application, including high treatment costs and gastrointestinal discomfort. Additionally, the safety and efficacy of tirzepatide in special populations, such as patients with renal impairment, require further investigation. Future large-scale clinical trials, such as SURPASS-CVOT and SUMMIT, are expected to further verify the long-term benefits of tirzepatide in cardiovascular health management, providing stronger evidence for its comprehensive treatment of diabetes and its complications.

Molecular Mechanisms behind Obesity and Their Potential Exploitation in Current and Future Therapy.

Obesity is a chronic disease caused primarily by the imbalance between the amount of calories supplied to the body and energy expenditure. Not only does it deteriorate the quality of life, but most importantly it increases the risk of cardiovascular diseases and the development of type 2 diabetes mellitus, leading to reduced life expectancy. In this review, we would like to present the molecular pathomechanisms underlying obesity, which constitute the target points for the action of anti-obesity medications. These include the central nervous system, brain-gut-microbiome axis, gastrointestinal motility, and energy expenditure. A significant part of this article is dedicated to incretin-based drugs such as GLP-1 receptor agonists (e.g., liraglutide and semaglutide), as well as the brand new dual GLP-1 and GIP receptor agonist tirzepatide, all of which have become "block-buster" drugs due to their effectiveness in reducing body weight and beneficial effects on the patient's metabolic profile. Finally, this review article highlights newly designed molecules with the potential for future obesity management that are the subject of ongoing clinical trials.

The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity: A Meta-Analysis

ObjectiveRecent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on asthma, which is often comorbid with type 2 diabetes mellitus (T2DM) and obesity. Therefore, we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1 (GLP-1) receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity. MethodsPubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov were systematically searched from inception to July 2023. Randomized controlled trials (RCTs) of GLP-1 receptor-based agonists (GLP-1RA, GLP-1 based dual and triple receptor agonist) with reports of asthma events were included. Outcomes were computed as risk ratios (RR) using a fixedeffects model. ResultsOverall, 39 RCTs with a total of 85,755 participants were included. Compared to non-GLP-1 receptor-based agonist users, a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments, although the difference was not statistically significant [RR = 0.91, 95% confidence interval (CI): 0.68 to 1.24]. Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users (RR = 0.65, 95% CI: 0.43 to 0.99, P = 0.043). We also performed sensitivity analyses for participant characteristics, study design, drug structure, duration of action, and drug subtypes. However, no significant associations were observed. ConclusionCompared with non-users, a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments. Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

Effects of Lipoproteins on Metabolic Health.

Lipids are primarily transported in the bloodstream by lipoproteins, which are macromolecules of lipids and conjugated proteins also known as apolipoproteins. The processes of lipoprotein assembly, secretion, transportation, modification, and clearance are crucial components of maintaining a healthy lipid metabolism. Disruption in any of these steps results in pathophysiological abnormalities such as dyslipidemia, obesity, insulin resistance, inflammation, atherosclerosis, peripheral artery disease, and cardiovascular diseases. By studying these genetic mutations, researchers can gain valuable insights into the underlying mechanisms that govern the relationship between protein structure and its physiological role. These lipoproteins, including HDL, LDL, lipoprotein(a), and VLDL, mainly serve the purpose of transporting lipids between tissues and organs. However, studies have provided evidence that apo(a) also possesses protective properties against pathogens. In the future, the field of study will be significantly influenced by the integration of recombinant DNA technology and human site-specific mutagenesis for treating hereditary disorders. Several medications are available for the treatment of dyslipoproteinemia. These include statins, fibrates, ezetimibe, niacin, PCSK9 inhibitors, evinacumab, DPP 4 inhibitors, glucagon-like peptide-1 receptor agonists GLP1RAs, GLP-1, and GIP dual receptor agonists, in addition to SGLT2 inhibitors. This current review article exhibits, for the first time, a comprehensive reflection of the available body of publications concerning the impact of lipoproteins on metabolic well-being across various pathological states.