Causal relationship between novel antidiabetic drugs and ischemic stroke: a drug-targeted Mendelian randomization study.

Background: The escalating global economic burden of ischemic stroke poses a significant public health challenge amid global aging trends. The broad therapeutic efficacy of new antidiabetic drugs may offer new options in the prevention and treatment of ischemic stroke. Consistent conclusions regarding the relationship between novel antidiabetic agents and the risk of ischemic stroke remain elusive, and the causal relationship deserves further investigation. Materials and methods: Three novel antidiabetic drug targets were selected, and cis-expression quantitative trait loci (cis-eQTL) were screened as instrumental variables. Genetic association data for ischemic stroke were obtained from the Genome-wide Association Study (GWAS) database. Mendelian randomization (MR) analysis, facilitated by R software, calculated MR estimates for each single nucleotide polymorphism (SNP), and meta-analysis was performed using five methods. To ensure robustness, sensitivity analyses, heterogeneity analyses, horizontal pleiotropy analyses, and co-localization analyses were conducted for significant MR associations. Results: Three eQTLs for antidiabetic drug genes served as instrumental variables, utilizing a GWAS dataset comprising 34,217 cases and 406,111 controls for ischemic stroke. Genetic variants in glucagon-like peptide-1 receptor agonists (GLP-1 RA) targets exhibited a positive correlation with ischemic stroke risk (OR 1.06, 95% CI 1.04-1.08, P = 0.000), while genetic variation in dipeptidyl peptidase 4 inhibitors (DPP-4i) targets showed a negative association with ischemic stroke risk (OR 0.93, 95% CI 0.89-0.97, P = 0.003). Sensitivity analyses supported robust conclusions, revealing no heterogeneity or horizontal pleiotropy. Conclusion: This study found that GLP-1 RA and DPP-4i were associated with an increased risk of ischemic stroke by MR analysis. Although sensitivity analyses provide support for this result, it contradicts previous knowledge. Therefore, the results of this study still need to treated with caution. Updated and more in-depth GWAS data and high-quality real-world data are expected to validate the results.

Efficacy of Different Doses and Forms of the GLP-1 Receptor Agonist Semaglutide in Weight Reduction Among Non-diabetic Obese or Overweight Populations.

Disorders linked to increased body weight are on the rise and obesity is a global epidemic associated with a rising risk for developing comorbidities, such as hypertension or type 2 diabetes. There is a significant need to develop a multimodal approach targeting obesity within clinical medicine. Pharmacological options to produce weight loss have been a popular research area and the novel glucagon-like Peptide-1 receptor agonists (GLP-1 RA) are highly effective glycemic control agents that have shown a substantial weight loss effect. This systematic review explores the efficacy of semaglutide, a GLP-1 RA agent, in a non-diabetic population, looking at endpoints of changes in weight and waist circumference and the percentage of patients achieving a clinically effective weight loss of at least 5%. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A comprehensive search was undertaken to find applicable papers using three databases, including PubMed, PubMed Central, and Cochrane Library. The included articles were narrowed down from an initial pool of 423 papers using filters, automation tools, inclusion/exclusion criteria, and quality appraisal tools. In this systematic review, we have analyzed 10 high-quality studies published in the last five years, including nine randomized control trials (RCTs) and a retrospective cohort study. The aim was to combine the results of these studies, encompassing 6623 participants, to showcase the effectiveness of GLP-1 RAs in the non-diabetic obese or overweight population. The consolidated data from the literature in this systematic review endorses the use of semaglutide as a highly efficient weight-reducing agent, contributing positive insight to both clinicians and researchers in the field of obesity treatment.

Cardiovascular outcomes with exenatide in type 2 diabetes according to ejection fraction: The EXSCEL trial.

AIMS: Glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events (MACE) and cardiovascular mortality in people with type 2 diabetes (T2D). However, previous studies suggest the effects on heart failure outcomes vary according to left ventricular ejection fraction (LVEF). We aimed to evaluate the effects of exenatide on cardiovascular events according to LVEF in people with T2D. METHODS AND RESULTS: Post-hoc analysis of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial evaluating the effects of once-weekly exenatide (EQW) versus placebo on cardiovascular outcomes according to baseline LVEF (<40% or ≥40%). Outcomes were also evaluated according to New York Heart Association (NYHA) class and obesity. The main outcome was hospitalization for heart failure (HHF). A treatment-by-LVEF interaction was used. In EXSCEL (n = 14 752), 4749 participants had LVEF available at baseline; 455 (10%) with LVEF <40%, 4294 (90%) with LVEF ≥40%. LVEF modified the EQW effect on hHF: hazard ratio (HR) = 1.52 (95% confidence interval [CI] = 0.95-2.43) in participants with LVEF < 40% and HR = 0.74 (95% CI = 0.55-1.01) in those with LVEF ≥ 40% (p-interaction = 0.012). No significant treatment-by-LVEF interactions (p-interaction >0.10) were observed for MACE, cardiovascular death or all-cause mortality. The risk of HHF was also modified by baseline NYHA class (HR 0.91, 95% CI 0.65-1.27 for NYHA class I/II; HR 1.84, 95% CI 0.95-3.59 for NYHA class III/IV; p-interaction = 0.062), mostly driven by the LVEF <40% subgroup. Obesity did not modify the effects of EQW on HHF. CONCLUSIONS: The EQW effect on HHF was influenced by LVEF, with a potentially decreased risk in participants with LVEF ≥40% and increased risk in those with LVEF <40%. The risk of HHF was particularly high in participants with LVEF <40% and NYHA class III/IV. LVEF did not modify the effect of EQW on atherosclerotic outcomes.

Clinical Consequences of Delayed Gastric Emptying With GLP-1 Receptor Agonists and Tirzepatide.

CONTEXT: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are established therapeutics for type 2 diabetes and obesity. Among other mechanisms, they slow gastric emptying and motility of the small intestine. This helps limiting postprandial glycemic excursions and reducing chylomicron formation and triglyceride absorption. Conversely, motility effects may have detrimental consequences, e.g., retained gastric contents at endoscopy or general anesthesia, potentially complicated by pulmonary aspiration, or bowel obstruction. EVIDENCE ACQUISITION: We searched the PubMed database for studies involving GLP-1RA therapy and adverse gastrointestinal/biliary events. EVIDENCE SYNTHESIS: Retained gastric contents at the time of upper gastrointestinal endoscopy are found more frequently with GLP-1 RAs, but rarely are associated with pulmonary aspiration. Well-justified recommendations for the peri-procedural management of GLP-1RAs (e.g., whether to withhold these medications, and for how long) are compromised by limited evidence. Important aspects to be considered are (a) their long half-lives, (b) the capacity of GLP-1 receptor agonism to slow gastric emptying even at physiological GLP-1 concentrations, (c) tachyphylaxis observed with prolonged treatment, and (d) the limited effect on gastric emptying in individuals with slow gastric emptying before initiating treatment. Little information is available on the influence of diabetes mellitus itself (i.e., in the absence of GLP-1 RA treatment) on retained gastric contents and pulmonary aspiration. CONCLUSIONS: Prolonged fasting periods regarding solid meal components, point-of-care ultrasound examination for retained gastric content, and the use of prokinetic medications like erythromycin may prove helpful, and are an important area needing further study to increase patient safety for those treated with GLP-1 RAs.

Patients experience with preoperative use of anti-obesity medications and associations with bariatric surgery expectations.

BACKGROUND: Few studies have investigated the use of anti-obesity medications (AOMs) before bariatric surgery and how prior use impacts patients' goals and expectations for surgery. OBJECTIVES: This study investigated associations between patients' experiences with AOMs and weight loss expectations before bariatric surgery. SETTINGS: Single tertiary university hospital. METHODS: Patients were electronically surveyed with a 31-item questionnaire via email or the patient portal with a primary predictor variable of AOMs presurgery. Outcomes included degree of weight loss and weight regain and motivation for seeking surgery. RESULTS: A total of 346 persons were invited to complete the survey; 112 surveys (32.4%) were completed, with 7 excluded because of not answering the AOM question. 73% reported AOM use. Among those who took AOMs before seeking bariatric surgery, average weight loss was 13 kg (SD 10) corresponding to a 4.4-kg/m2 decrease in BMI. Of past AOM recipients, 87% reported weight regain on stopping AOMs. Average weight regain was 18 kg (SD 13; 126% increase). Patients reported improved longevity and quality of life as motivation for seeking surgery, with AOM use history having no effect. Subjects reported an average weight loss goal of 65.8 kg (39% of baseline weight) from bariatric surgery. CONCLUSIONS: AOMs were commonly used in those seeking bariatric surgery, but motivation for surgery did not differ by AOM use history. Motivations were most often related to goals for better overall health.

A randomized, double-blind, placebo-controlled trial of weight loss using liraglutide 3.0 mg for weight recurrence after Roux-en-Y gastric bypass.

BACKGROUND: Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB) remains the gold standard for treating obesity. Most people regain weight from postsurgery nadir. OBJECTIVES: Liraglutide 3.0 mg is approved for weight management. This study will examine the effects on liraglutide 3.0 mg on weight regain post-RYGB. SETTING: University Hospital, United States. METHODS: A 56-week, double-blind, placebo-controlled study was conducted in 132 subjects, who achieved ≥25% total body weight loss (TBWL) status-post-RYGB and regained ≥10% TBWL after reaching nadir weight (NW). Subjects 18-120 months post-RYGB were randomized to receive liraglutide 3.0 mg/d (n = 89) or placebo (n = 43) with lifestyle counseling regularly for 56 weeks. The co-primary endpoints were the proportion of subjects losing at least 5%, 10%, and 15% TBWL and achieving weight lower than their NW. RESULTS: 53.4% of the placebo group and 65% of the liraglutide group completed the trial due to Severe acute respiratory syndrome coronavirus 2 pandemic. The change in %TBWL from baseline to 56-weeks was -8.8 (8.5, -29.2 to 9.7) and 1.1 (3.5, -7.9 to 5.99) in the liraglutide and placebo groups, respectively. 76% and 17% of subjects achieved ≥5% TBWL at 56 weeks in the liraglutide and placebo groups, respectively; 51% and 26.0% of the liraglutide group achieved ≥10% and ≥15% TBWL, respectively. None of the placebo group lost ≥10% TBWL. Twenty-one percent of subjects receiving liraglutide surpassed postoperative NW. No subjects on placebo met this goal. Nonserious adverse events occurred in 41.6% of subjects on liraglutide. Serious adverse events (SAE) occurred less often on liraglutide. CONCLUSIONS: Liraglutide was significantly more effective than placebo in treating weight regain that occurs post-RYGB without increased SAE.

Effect of the glucagon-like peptide-1 receptor agonists on diabetic peripheral neuropathy: A meta-analysis.

Previous researches found that glucagon-like peptide 1 receptor agonists (GLP-1RA) offer benefits beyond their anti-diabetic properties, including weight loss and cardiovascular disease prevention. However, the effects of GLP-1RA on diabetic peripheral neuropathy (DPN) remain unclear. This meta-analysis aims to assess the potential benefits of GLP-1RA treatment in DPN patients by evaluating peripheral neural function. Following the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a meta-analysis of the clinical trials investigating the impact of GLP-1RA treatment on peripheral neural function in patients with DPN. Outcomes were measured using electrophysiological tests, including nerve conduction velocity (NCV) and action potential amplitude. Our meta-analysis included six studies with 271 participants. Following GLP-1RA treatment, NCV significantly improved compared to the control group (MD 1.74; 95% CI 1.16 to 2.33; p < 0.001) and before treatment (MD 2.16; 95% CI 1.04 to 3.27; p < 0.001). Despite the improvement in NCV, blood glucose levels did not change significantly (MD -0.20 95% CI -0.87 to 0.46, p = 0.55) indicating that GLP-1RA enhances NCV through mechanisms other than glucose lowering. Nonetheless, as a result of the limited population studied, further research is needed to strengthen the reliability of these findings.

Semaglutide Treatment Effects on Liver Fat Content in Obese Subjects with Metabolic-Associated Steatotic Liver Disease (MASLD).

Background: Metabolic-dysfunction-associated steatotic liver disease (MASLD) represents a major clinical complication of obesity. Methods: In this study, we used magnetic resonance (MR) methods to determine the effect of obesity treatment with semaglutide, a GLP-1 receptor agonist, on the liver fat content and selected metabolic variables. We investigated whether treatment would affect the acute response of liver fat to glucose and fructose administration and whether it would affect the fatty acid profile of VLDL-triglycerides. Sixteen obese non-diabetic men underwent a 16-week dietary intervention and 16-week treatment with subcutaneous semaglutide in a crossover design without a washout period. The order of the interventions was randomized. Results: After treatment, body weight of the subjects decreased by 5% and liver fat by a third, whereas dietary intervention had no impact on these parameters. The decrease in liver fat with semaglutide did not correlate with changes in body weight and other measures of adiposity and was unrelated to improved insulin sensitivity. Conclusions: The proportion of palmitic and palmitoleic acids in VLDL-triglycerides decreased after treatment, suggesting that the beneficial effects of semaglutide on liver fat are mediated by the suppression of de novo lipogenesis.

Anti-Hyperglycemic Medication Management in the Perioperative Setting: A Review and Illustrative Case of an Adverse Effect of GLP-1 Receptor Agonist.

A host of anti-hyperglycemic agents are currently available and widely prescribed for diabetes and weight loss management. In patients undergoing surgery, use of these agents poses a clinical challenge to surgeons, anesthesiologists, and other perioperative care providers with regard to optimal timing of discontinuation and resumption of use, as well as possible effects of these agents on physiology and risk of postoperative complications. Here, we provide a comprehensive review of anti-hyperglycemic medications' effects on physiology, risks/benefits, and best practice management in the perioperative setting. Additionally, we report an illustrative case of small bowel obstruction in a patient taking semaglutide for 6 months prior to an otherwise uncomplicated laparoscopic hysterectomy and bilateral salpingo-oophorectomy. This review is meant to serve not as a replacement of, but rather as a consolidated complement to, various society guidelines regarding perioperative anti-hyperglycemic agent management.

Impact of ADA Guidelines and Medication Shortage on GLP-1 Receptor Agonists Prescribing Trends in the UK: A Time-Series Analysis with Country-Specific Insights.

Background: Several GLP-1 receptor agonists (GLP-1 RAs) are used to treat type 2 diabetes (T2DM). Their cardio- and renal-protective effects and their association with substantial weight loss have been evident and progressively expanded their role in the American Diabetes Association (ADA) guidelines, which are endorsed by the European Association for the Study of Diabetes (EASD). The increased demand led to a global shortage. Methods: We utilized a repeated cross-sectional design, drawing data from national prescribing databases, to analyze six GLP-1 RAs: Dulaglutide, Exenatide, Liraglutide, Lixisenatide, Semaglutide, and Tirzepatide. AutoRegressive Integrated Moving Average (ARIMA) models with exogenous variables were applied to assess the trends over time and in different regions. Results: The prescription rates significantly differ between regions. Wales shows the highest prescribing rate for most GLP-1 RAs. The ARIMA models indicated a significant increase in their prescribing rates after the release of the 2022 ADA guidelines (e.g., Dulaglutide: Post-ADA effect of 15.22, 95% CI: [12.97, 17.47]). Following the GLP-1 RA shortages in July 2023, the prescribing rates, particularly for Semaglutide, increased (Shortage effect: 74.36, 95% CI: [71.92, 76.80]). Model diagnostics, including the Akaike Information Criterion (AIC) and Durbin-Watson statistics, confirmed the robustness of these trends. Conclusions: Informed decisions should be made by considering the prescribing trends before and after important events such as the issuing of new guidelines or safety alerts.

Glucose-Lowering Drugs and Primary Prevention of Chronic Kidney Disease in Type 2 Diabetes Patients: A Real-World Primary Care Study.

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: We used the Spanish primary care database BIFAP to perform a retrospective cohort study with a nested case-control analysis to assess the incidence, risk factors, and the effect of glucose-lowering drugs (GLDs) on the primary prevention of CKD. Results: From a cohort of 515,701 T2DM subjects (2.75 million person-years), we found 89,075 incident CKD cases, yielding an overall incidence rate (95%CI) of 324.3 (322.1-326.5) per 10,000 person-years. In the nested case-control analysis, gout, hyperuricemia, and hyperkalemia were the factors showing the highest AORs. Long-term users (≥3 years) of GLP1-RAs and SGLT-2i, compared to other GLDs, showed a decreased risk for CKD (AOR = 0.85; 95%CI: 0.73-0.99 and AOR = 0.89; 95%CI: 0.74-1.08, respectively), and for incident CKD at KDIGO stages G3-G5 (AOR = 0.72; 95%CI: 0.56-0.94 and AOR = 0.64; 95%CI: 0.46-0.91, respectively). Conclusions: In a real-world primary care setting, the long-term use of GLP-1RAs and SGLT-2i, but not other GLDs, appeared to decrease the risk of incident CKD in T2DM, supporting a role in primary prevention of CKD.

Trends in Presentation and Management of Endogenous Hyperinsulinaemic Hypoglycaemia Over the Last Three Decades at a Tertiary Care Centre (1992-2022).

Introduction: Endogenous hyperinsulinaemic hypoglycaemia (EHH) is characterized by inappropriate insulin secretion from pancreatic beta cells despite low blood glucose concentrations. We aimed to evaluate the secular changes in presentation and management of EHH due to insulinoma/non-insulinoma pancreatogenous hypoglycaemia syndrome (NIPHS) at our centre. Methods: This was a single-centre ambispective study (2014-2022). The clinical, biochemical, hormonal and radiological parameters (n = 63) collected as part of this study were compared with our earlier studies (1992-2005, n = 31; and 2006-2013, n = 35) and with other centres across the world. Results: A total of 63 patients (39 males) with a preoperative diagnosis of EHH (insulinoma, n = 58; and NIPHS, n = 5) and a mean age of 40.7 years were studied. The mean lag time from the onset of symptoms to diagnosis decreased from 4.6 years during the first study period to 1.9 years during this study period. However, the majority presented with fasting hypoglycaemia of 98.4%, and both fasting and postprandial hypoglycaemia of 32%. Exclusive postprandial hypoglycaemia was present in 1.7% of insulinoma. A histopathological diagnosis of insulinoma was made in 52 patients and nesidioblastosis in two patients. Intraoperative ultrasonography (IOUS) and intraoperative palpation (IOP) yielded 100% sensitivity, while endoscopic ultrasonography (EUS) and 68Ga-DOTA-Exendin-4 positron emission tomography/computed tomography (PET/CT) yielded sensitivity of 86% and 85%, respectively, for localizing insulinoma. Resolution of hypoglycaemia was noted in 53 of 57 (93%) patients who underwent surgery with a preoperative diagnosis of insulinoma. Conclusion: We observed a trend towards earlier diagnosis of EHH, increased patient numbers and availability of nuclear imaging techniques for preoperative localization in the last decade compared to earlier.

Exploring omics signature in the cardiovascular response to semaglutide: Mechanistic insights and clinical implications.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is a widely used drug for the treatment of type 2 diabetes that offers significant cardiovascular benefits. RESULTS: This review systematically examines the proteomic and metabolomic indicators associated with the cardiovascular effects of semaglutide. A comprehensive literature search was conducted to identify relevant studies. The review utilizes advanced analytical technologies such as mass spectrometry and nuclear magnetic resonance (NMR) to investigate the molecular mechanisms underlying the effects of semaglutide on insulin secretion, weight control, anti-inflammatory activities and lipid metabolism. These "omics" approaches offer critical insights into metabolic changes associated with cardiovascular health. However, challenges remain such as individual variability in expression, the need for comprehensive validation and the integration of these data with clinical parameters. These issues need to be addressed through further research to refine these indicators and increase their clinical utility. CONCLUSION: Future integration of proteomic and metabolomic data with artificial intelligence (AI) promises to improve prediction and monitoring of cardiovascular outcomes and may enable more accurate and effective management of cardiovascular health in patients with type 2 diabetes. This review highlights the transformative potential of integrating proteomics, metabolomics and AI to advance cardiovascular medicine and improve patient outcomes.

Perioperative Considerations for Patients on GLP1 Agonists.

GlP-1 receptor agonists are a class of medications that are becoming increasingly popular. Large trials have shown that their use provides reliable weight loss in obese patients and improved glycemic control in diabetic patients. Its use also has broader implications for overall metabolic health and has been shown to improve cardiovascular outcomes in high-risk populations. Glucagon-like peptide 1 receptors cause multiple effects in the body through stimulation of receptors expressed in a broad range of tissues including the pancreas, liver, gastrointestinal tract, kidneys, heart, endothelium, muscle, and brain. For the anesthesia professionals the effects of these medications on gastric emptying is important.

The potential adverse effects of hypodermic glucagon-like peptide -1 receptor agonist on patients with type 2 diabetes: A population-based study.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a class of injectable antidiabetic drugs, have shown significant efficacies in improving glycemic and weight control in patients with type 2 diabetes (T2D). However, the long-term safety of GLP-1 RAs remains insufficiently studied. This study aimed to provide real-world evidence on potential adverse outcomes associated with GLP-1 RAs use in T2D patients without major chronic diseases including impaired cardiac or renal function. METHODS: We conducted a retrospective cohort study involving 7746 T2D patients on GLP-1 RAs in Shenzhen, China. They were compared with 124 371 metformin-only users and 36 146 insulin-only users, forming two therapy control groups. GLP-1 RAs users were also further 1:2 paired with the control groups. Competing risk survival analyses were conducted to assess the incidence risks, presenting subdistributional hazard ratios (sHRs) with 95% confidence intervals (CIs) for various adverse outcomes associated with GLP-1 RAs use. RESULTS: Compared with metformin-only users, GLP-1 RAs use was associated with increased risks of various adverse outcomes (sHRs with 95% CIs), including pancreatitis (2.01, 1.24-3.24), acute nephritis (3.20, 2.17-4.70), kidney failure (3.73, 2.74-5.08), thyroid cancer (2.25, 1.23-4.10), and thyroid dysfunction (1.27, 1.00-1.63), respectively; Similar results were also found when compared with insulin-only users. Importantly, long-term (≥12 months) GLP-1 RAs use may further elevate the incidence risks of pancreatitis, acute nephritis, thyroid cancer, and thyroid dysfunction. CONCLUSION: Compared with traditional T2D treatments, GLP-1 RAs use may be associated with increased risks of various adverse outcomes in a Chinese population. Cautions were strongly warranted in the use of GLP-1 RAs. Further validation is crucial across diverse populations.

Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates.

Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC50 value of 6.9 µM, the IC50 of SAL0112 on hERG was greater than 100 µM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (P > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies.

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 ≥27 kg/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 Test the Effect of Survodutide [BI 456906] on Cardiovascular Safety in People With Overweight or Obesity [SYNCHRONIZE-CVOT]; NCT06077864).

Weight Loss Therapies and Hypertension Benefits.

Obesity and hypertension have become an international health issue, with detrimental consequences on patients. Obesity and hypertension share common pathophysiological mechanisms, such as overactivity of the renin-angiotensin-aldosterone and the sympathetic nervous systems, insulin resistance, and disruption of the leptin pathway. Approved therapies for obesity and overweight include phentermine/topiramate, orlistat, naltrexone/bupropion, the glucagon-like peptide-1 receptor agonists liraglutide and semaglutide, tirzepatide, and bariatric surgery. This review gives the clinical data in a thorough manner and explains in detail how each of the previously mentioned therapies affects blood pressure levels.