Subcutaneous Semaglutide Research Articles

REAL life study of subcutaneous SEMaglutide in patients with type 2 diabetes in SPain: Ambispective, multicenter clinical study. Results in the GLP1-experienced cohort

ObjectiveTo evaluate the efficacy of switching to once-weekly subcutaneous semaglutide in patients with type 2 diabetes mellitus (T2DM) who were previously treated with other glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in a real-world setting in Spain. MethodsThe REAL Life study of SEMaglutide in Patients with Type 2 diabetes in Spain (REALSEM-SP) was conducted in four endocrinology departments in Madrid, Spain. Adult patients with T2DM who were prescribed once-weekly (OW) subcutaneous semaglutide and had been previously treated with other GLP-1 RAs were included. Baseline characteristics, including demographic, anthropometric, and laboratory variables, were recorded at baseline and at 6 ± 3 and 12 ± 3 months of follow-up. The primary outcome was the change in HbA1c at 12 ± 3 months of follow-up, with secondary outcomes including changes in weight, BMI, and other glycemic parameters. ResultsA total of 267 patients were included in the analysis, with a mean age of 61.6 years and a mean T2DM duration of 11.3 years. The majority of patients had grade 1 or 2 obesity at baseline. Switching to OW-semaglutide was associated with a significant reduction in HbA1c from baseline to 13 months (−0.35 % ± 0.81). Patients who reached the 1.0 mg OW-dose showed a significant reduction in HbA1c compared to those on the ≤0.5 mg OW-dose. Significant reductions in weight, BMI, and fasting plasma glucose were also observed. Adverse events were mostly gastrointestinal and led to treatment withdrawal in few cases. ConclusionSwitching to OW-subcutaneous semaglutide in patients with T2DM previously treated with other GLP-1 RAs was associated to improvements in glycemic control and weight management in a real-world setting in Spain. These findings support the use of OW-semaglutide as an effective option for patients with T2DM who require additional glycemic control and weight management.

Time-Efficacy Relationship of Semaglutide in the Treatment of Type 2 Diabetes Mellitus: A Model-Based Meta-Analysis.

Our objective was to quantify the efficacy of subcutaneous once-weekly semaglutide in treating type 2 diabetes mellitus (T2DM) over time. Based on a literature search of the PubMed, Embase, Cochrane, and Web of Science databases, a modified maximum effect (Emax) model including rebound effects was built using model-based meta-analysis with change from baseline in glycated hemoglobin as the efficacy endpoint. This was combined with the covariate model to form a final model, and then theoretical values of Emax and time to reach 50% of Emax (ET50) were obtained for each dose. Model fit and prediction were assessed using goodness-of-fit plots and visual prediction checking. Emax and ET50 were influenced by the proportion of males and the baseline values, respectively. There was no evidence of a placebo effect with semaglutide. The efficacy of other doses became more significant over time, and a rebound effect was observed after maximum efficacy, at a rate of 0.018. Simulation of the typical efficacy at the different doses yielded a maximum efficacy of -1.58% with 0.5 mg and a maximum efficacy of -1.87% with 1 mg. In addition, the six simulated doses (0, 0.1, 0.2, 0.5, 1, and 2 mg) showed a dose-dependent relationship between dose and efficacy except for 0.4 mg and 0.8 mg. A higher dose would result in greater efficacy and a faster onset of action. The efficacy of semaglutide in glucose control was investigated using the model-based meta-analysis method, which yields new insights into the treatment of T2DM with semaglutide.

De-intensification of basal-bolus therapy by replacing prandial insulin with once-weekly subcutaneous semaglutide in individuals with well-controlled type 2 diabetes: A single-centre, open-label randomised trial (TRANSITION-T2D).

The study aims to examine the outcome of replacement of prandial insulin with once-weekly subcutaneous semaglutide in people with type 2 diabetes reasonably controlled on multiple daily insulin injections (MDI). This single-centre, randomised, open-label trial enrolled a statistically predetermined sample of 60 adults with HbA1c ≤7.5% (58 mmol/mol) receiving MDI, with a total daily dose (TDD) ≤120 units/day. Participants were assigned 2:1 to subcutaneous semaglutide 1.0 mg plus insulin degludec, or to continue MDI. The primary outcome was percentage of subjects maintaining HbA1c ≤7.5% (58 mmol/mol) at Week 26. At Week 26, 90% of semaglutide and 75% of MDI subjects maintained HbA1c ≤7.5% (≤58 mmol/mol) (p = 0.18). Mean changes (95% CI) in HbA1c, weight and percentage body weight for semaglutide versus MDI, respectively, were -0.5% (-0.7, -0.3) versus 0.0% (-0.3, 0.3; p = 0.009); -8.9 kg (-9.9, -7.8) versus 1.5 kg (-0.1, 3.1; p < 0.001); and -8.6% (-9.6, -7.6) versus 1.4% (0.0, 2.8; p < 0.001). Insulin TDD decreased 56.0% (-62.3, -49.7) with semaglutide and increased 6.7% (-2.5, 16.0) with MDI (p < 0.001). Among semaglutide subjects, 58% reduced insulin TDD > 50%, 97.5% stopped prandial insulin and 45% lost >10% body weight. Participant treatment satisfaction scores trended higher with semaglutide. Hypoglycaemia frequency was similar between groups. In people with type 2 diabetes well controlled (HbA1c ≤7.5% [≤58 mmol/mol]) on MDI ≤120 units/day, replacing multiple daily injections of prandial insulin with once-weekly subcutaneous semaglutide can maintain and even improve HbA1c, lower body weight and lessen the burden of management.

Cardiovascular, Metabolic, and Safety Outcomes with Semaglutide by Baseline Age: Post Hoc Analysis of SUSTAIN6 and PIONEER6.

The high risk of cardiovascular events in people with type2 diabetes increases with age. The cardiovascular effects of once-weekly subcutaneous and once-daily oral semaglutide versus placebo in people with type2 diabetes at high cardiovascular risk were investigated in the SUSTAIN6 and PIONEER6 cardiovascular outcomes trials, respectively. It is unknown whether the effects of semaglutide are age dependent. This post hoc analysis evaluated cardiovascular, metabolic, and safety outcomes with semaglutide versus placebo in age subgroups (≤ 60; > 60 to ≤ 65; > 65 to ≤ 70; and > 70years) pooled from SUSTAIN6 and PIONEER6. Major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke), changes from baseline in glycated hemoglobinA1c (HbA1c) and body weight, and adverse events were analyzed. Semaglutide reduced major adverse cardiovascular events and its components versus placebo across age subgroups (most hazard ratios < 1.0; pinteraction > 0.05). The treatment difference in HbA1c reduction was greater in those aged ≤ 60years than in older subgroups (pinteraction = 0.01). Reductions in body weight with semaglutide versus placebo were consistent across agesubgroups (pinteraction = 0.124). Serious adverse events or severe hypoglycemic episodes did not differ between semaglutide and placebo across age subgroups. Semaglutide consistently reduced major adverse cardiovascular events and body weight versus placebo across age subgroups; its safety profile did not differ with age. These results suggest that relaxing HbA1c targets based solely on age may not always be required for people with type2 diabetes. SUSTAIN6 (NCT01720446) and PIONEER6 (NCT02692716) are registered at ClinicalTrials.gov.

Benchmarking the medication efficiency and technological progress of diabetes drugs

BackgroundDiabetes poses a serious global challenge, given its increasing prevalence, detrimental effects on public health, and substantial economic burden. Since 1950s, tens of drugs have been approved by the United States (US) Food and Drug Administration (FDA). In the past decade, the medical community and regulatory agencies have moved away from the glucose-centric paradigm and increasingly call for a holistic approach to assess different treatments’ benefits and harms.ObjectiveThis study aimed to assess the medication efficiency and technological progress of Type 2 Diabetes (T2D) drugs, by considering their physiological outcomes, including both benefits (i.e., glucose lowering and weight loss) and adverse effects (mortality), relative to dosing frequency.MethodsTo derive medication efficiency, this study utilized data from the US FDA and prominent meta-analyses. Given that both the benefits and adverse effects of medications are multidimensional, this study employed a nonparametric frontier method, the data envelopment analysis (DEA) model, to integrate these factors into a measure of medication efficiency. Physiological outcomes could assume both positive and negative values. Adverse effects were regarded undesirable outputs. The DEA model was built under the framework of directional distance function and was able to handle negative and undesirable values which naturally arose in the case of T2D medications.ResultsThe paper presented a ranking of 20 T2D drugs in terms of medication efficiency. Three of them were able to attain the highest medication efficiency, all of which were in the GLP-1 class, including oral Semaglutide, subcutaneous Semaglutide and Dulaglutide. However, the other two GLP-1 drugs, Lixisenatide and Liraglutide, were less efficient. The average medication efficiency of drugs approved post-2010 was significantly higher than pre-2010 drugs. High dose frequency, low HbA1c reduction and insignificant weight loss were the main driving factors behind inefficiencies. Overall, medication efficiency provided an alternative perspective on treatment effectiveness other than conventional measures such as cost-effectiveness.

Dosing Patterns of Dulaglutide and Semaglutide in Patients with Type2 Diabetes Mellitus in France and Italy: A Retrospective Cohort Study.

Type2 diabetes mellitus (T2DM) is a complex metabolic disease with several treatment options. Some glucagon-like peptide1 receptor agonists (GLP-1 RAs) approved by the European Medicines Agency include dulaglutide, subcutaneous (s.c.) semaglutide, and oral semaglutide. This study examines dulaglutide and semaglutide dosing patterns for T2DM in France and Italy. IQVIA Longitudinal Prescription Data identified adults with T2DM prescribed dulaglutide or semaglutide between August 1, 2020 and December 31, 2022. Cohort1 (incident) and cohort2 (prevalent) users were followed for 12months. In France and Italy, 255,571 and 350,853 patients, respectively, received at least one study GLP-1 RA. Most dulaglutide-naïve patients in France (62%) and approximately half in Italy (49%) started on 1.5mg and remained on this dose for up to 12months (France: 66% cohort1, 88% cohort2; Italy: 73% cohort1, 87% cohort2). In cohort1, s.c. semaglutide users mostly started on 0.25mg (France, 78%; Italy, 61%). At 12months, s.c. semaglutide 1.0mg was most prescribed (France: 58% cohort1, 75% cohort2; Italy: 59% cohort2), with cohort1 in Italy mostly receiving 0.5mg (57%). Most oral semaglutide users in Italy started on 3.0mg (78% cohort1; 68% cohort2), which was increased to 7.0mg (62% cohort1) and 14.0mg (48% cohort2) at 12months. GLP-1 RA dosing patterns, although similar between France and Italy, were heterogeneous over time. As oral semaglutide and higher dulaglutide doses are recent to the market, additional real-world evidence is required to evaluate utilization patterns. Graphical abstract available for this article.

Once-Weekly Semaglutide in Persons with Obesity and Knee Osteoarthritis

BackgroundWeight reduction has been shown to alleviate symptoms of osteoarthritis of the knee, including pain. The effect of glucagon-like peptide-1 receptor agonists on outcomes in knee osteoarthritis among persons with obesity has not been well studied.MethodsWe conducted a 68-week, double-blind, randomized, placebo-controlled trial at 61 sites in 11 countries. Participants with obesity (a body-mass index [BMI; the weight in kilograms divided by the square of the height in meters] of ≥30) and a clinical and radiologic diagnosis of moderate knee osteoarthritis with at least moderate pain were randomly assigned, in a 2:1 ratio, to receive once-weekly subcutaneous semaglutide (2.4 mg) or placebo, in addition to counseling on physical activity and a reduced-calorie diet. The primary end points were the percentage change in body weight and the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score (on a scale of 0 to 100, with higher scores reflecting worse outcomes) from baseline to week 68. A key confirmatory secondary end point was the physical-function score on the 36-Item Short Form Health Survey (SF-36), version 2 (on a scale of 0 to 100, with higher scores indicating greater well-being).ResultsA total of 407 participants were enrolled. The mean age was 56 years, the mean BMI 40.3, and the mean WOMAC pain score 70.9. A total of 81.6% of the participants were women. The mean change in body weight from baseline to week 68 was −13.7% with semaglutide and −3.2% with placebo (P<0.001). The mean change in the WOMAC pain score at week 68 was −41.7 points with semaglutide and −27.5 points with placebo (P<0.001). Participants in the semaglutide group had a greater improvement in SF-36 physical-function score than those in the placebo group (mean change, 12.0 points vs. 6.5 points; P<0.001). The incidence of serious adverse events was similar in the two groups. Adverse events that led to permanent discontinuation of the trial regimen occurred in 6.7% of the participants in the semaglutide group and in 3.0% in the placebo group, with gastrointestinal disorders being the most common reason for discontinuation.ConclusionsAmong participants with obesity and knee osteoarthritis with moderate-to-severe pain, treatment with once-weekly injectable semaglutide resulted in significantly greater reductions in body weight and pain related to knee osteoarthritis than placebo. (Funded by Novo Nordisk; STEP 9 ClinicalTrials.gov number, NCT05064735.)

Exploratory mediation analysis of the effect of semaglutide on cardiovascular outcomes in people with overweight or obesity in the SELECT randomised trial

Abstract Background Glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to reduce major adverse cardiovascular (CV) events (MACE) in people with diabetes. The SELECT trial investigated weekly subcutaneous semaglutide 2.4 mg versus placebo in people with pre-existing CV disease and body mass index ≥27kg/m², but without diabetes at randomisation. Over a mean duration of follow-up of 39.8 months, risk of MACE was lower in patients treated with semaglutide vs placebo (6.5% vs 8.0%, hazard ratio, 0.80; 95% CI, 0.72, 0.90; P&amp;lt;0.001). There were improvements in several CV risk factors; however, mechanisms underlying the MACE reduction are unclear. Purpose This prespecified analysis explored whether the effects on measured CV risk factors may mediate the 20% reduction in MACE in SELECT. Methods CV risk factors measured during the trial and included as potential mediators in the analysis were: body weight, waist circumference, high-sensitivity C-reactive protein (hsCRP), glycated haemoglobin (HbA1c), lipids, blood pressure, estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR). Mediation analyses were performed using the Vansteelandt repeated regression approach. First, the observed difference in MACE-free survival between semaglutide and placebo at 36 months was estimated as the total effect. The direct effect of semaglutide was then estimated as the difference in MACE-free survival, had the semaglutide arm experienced the values of the mediator observed in the placebo arm during follow-up. The % mediation was then calculated as 100 × (1 – [direct effect] / [total effect]). A reversed counterfactual approach estimating the direct effect as the difference between arms in MACE-free survival, had the placebo arm experienced the mediator values observed in the semaglutide arm, was also conducted. A large disparity between the % mediation from the two approaches can indicate potential treatment–mediator interaction or hidden confounding. Results Statistically significant (P&amp;lt;0.05) improvements in all potential mediators were observed with semaglutide. Table 1 shows the estimated mediation of each potential mediator when evaluated separately. Point estimates for the % mediation were largest for waist circumference (64.0%), hsCRP (42.1%), HbA1c (29.0%) and body weight (19.5%), but with wide 95% CIs. For waist circumference, the estimated mediation was markedly lower using the reversed counterfactual approach, suggesting potential hidden confounding or treatment–mediator interaction (Figure 1). In a multivariable analysis, the estimated joint mediation was 31.4% (−30.1%, 143.6%). Conclusions The results suggest that neither change in body weight nor other measured CV risk factors fully explain the effect of semaglutide on MACE in SELECT. Substantial unmeasured pleiotropic effects of semaglutide on MACE not mediated through these risk factors remain possible.

Semaglutide and atrial fibrillation: a systematic review and meta-analysis of randomized clinical trials

Abstract Introduction Semaglutide is a glucagon-like peptide-1 receptor agonist that has been highly recommended for glycemic controland weight reduction. Obesity can also increase the risk of developing atrial fibrillation (AF). Aims To assess the association of semaglutide with cardiac arrhythmias, primarily AF. Methods We performed a systematic searched Pubmed, Embase and Cochrane database, between November and December 2023, to identify semaglutide’s randomized controlled trials (RCTs) with or without diabetic patients that reported new-onset cardiac arrythmias. A Mantel-Haenszel method and a random-effects model was used to calculate the odds ratio (OR) and 95% confidence interval (CI). Results 16 RCTs were included, 6 with oral semaglutide and 11 with subcutaneous semaglutide. A total of 19892 patients were included, providing 137 new-onset AF. Our meta-analysis revealed a lower incidence of new-onset AF in semaglutide patients (pooled odds ratio [OR], 0.54; 95% confidence interval [CI] 0.39, 0.77, P &amp;lt; 0.01; I2 = 0%). Sub-analysis of oral and subcutaneous showed similar significant reduction (pooled OR 0.44; 95% CI [0.22, 0.87], P = 0.02, I2 = 0% and pooled OR 0.59; 95% CI [0.39, 0.88], P &amp;lt; 0.01, I2 = 0%, respectively). Significant reduction was also observed, regardless diabetic status. However, semaglutide revealed similar atrial flutter incidence (pooled OR 0.78; 95% CI [0.30, 2.05], P = 0.62, I2 = 0%), ventricular arrhythmias (pooled OR 1.68; 95% CI [0.77, 3.6], P = 0.19, I2 = 0%) and sudden cardiac death (pooled OR 1.68; 95% CI [0.77, 3.66], P = 0.19, I2 = 0%). Conclusion Our study suggests that in patients with or without diabetes, semaglutide reduces the risk of new-onset atrial fibrillation. This analysis provides an additionalcardiovascular benefit of this drug besides the major adverse cardiovascular events.

Baseline patient reported outcomes in patients with peripheral artery disease and type 2 diabetes from STRIDE: a phase 3, 52-week, randomised, double-blind, placebo-controlled trial

Abstract Introduction Lower extremity peripheral artery disease (PAD) is caused by atherosclerotic steno-occlusive arterial lesions in the lower extremities and can lead to intermittent claudication, severe functional impairment and reduced health-related quality of life (HRQoL). People living with type 2 diabetes (T2D) are at higher risk of developing PAD than those without T2D. The most common clinical manifestation of PAD, functional impairment, can be stratified based on severity using Fontaine classification (stages I-IV). There are a limited number of therapies approved for the management of PAD related functional impairment and no glucose-lowering medication has been shown to improve functional capacity in people with PAD and T2D. STRIDE is a phase 3 clinical trial investigating once-weekly subcutaneous (s.c.) semaglutide treatment in people with PAD (Fontaine IIa claudication) and T2D. Purpose To report the patient-reported outcomes (PROs) at baseline from STRIDE and elucidate the impact that PAD has on the functional capacity and HRQoL in this early-stage symptomatic PAD population with T2D. Methods STRIDE enrolled 792 participants with PAD (Fontaine IIa claudication) and T2D who were randomised to receive either 1 mg once-weekly s.c. semaglutide or placebo for 52 weeks. The primary outcome of STRIDE is the change in maximum walking distance at week 52 on a constant load treadmill. Baseline PRO assessments included two Patient Global Impression of Severity (PGI-S) questions and three patient-reported questionnaires: the six items version of the Vascular Quality of Life questionnaire (VascuQoL-6), the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Short Form 36 (SF-36). Results Baseline responses to both PGI-S questions showed that two thirds of patients reported a moderate-to-severe limitation in their ability to walk (64.9%) and reported that the impact of poor blood circulation in their legs on their HRQoL was also moderate-to-severe (62.5%) (Figure 1A and B). The baseline VascuQoL-6 median score was 15 (score range: 6-24, with a low score indicating more severe impact) and details of impact on the six domains are presented in Table 1. Baseline responses to the WIQ indicated that 20.1% of participants found the degree of difficulty to walk 200 meters either ‘much difficulty’ or were ‘unable to do so’ and 21.8% reported the same when climbing 2 flights of stairs. The secondary supportive outcome assessed in the SF-36 questionnaire was the domain physical functioning where a median baseline value of 38.09 was observed (score range: 19.03-57.60, with a low score indicating more impact). Conclusion Participants in STRIDE, characterized as having early-stage symptomatic PAD, have reported moderate-to-high impact on their physical functioning and HRQoL at baseline. These findings highlight the need for better therapies that improve the functional capacity and HRQoL in people with PAD and T2D.

Comparative analysis of semaglutide induced adverse reactions: Insights from FAERS database and social media reviews with a focus on oral vs subcutaneous administration.

Compared to alternative weight-loss strategies and medications, semaglutide stands out for its convenience and efficacy, resulting in a significant increase in prescriptions and raising public safety concerns. Furthermore, the safety profiles of its oral and subcutaneous formulations require further examination. Our goal is to investigate the potential safety risks associated with semaglutide by analyzing data from the FAERS database and social media. Additionally, we aim to compare the adverse drug reaction (ADR) signals between the oral and subcutaneous administration routes of semaglutide. We collected semaglutide-related reports from the FAERS database spanning Q1 2018 to Q2 2023, and patient reviews on WebMD and AskaPatient up to 20 July 2023. Following data extraction and cleansing, we conducted descriptive analyses of demographic characteristics. Subsequently, we calculated adverse drug reaction (ADR) signals using the reporting odds ratio (ROR). We identified 19,289 and 422 semaglutide-related adverse drug events (ADEs) reported in the FAERS database and online patient reviews, respectively. Gastrointestinal disorders emerged as the most commonly reported System Organ Class (SOC) in both datasets. Predominant Preferred Terms (PTs) included nausea, vomiting, and diarrhea. Serious outcomes constituted 3.07% and 2.25% of all cases for oral and subcutaneous semaglutide, respectively. At the SOC level, gastrointestinal disorders accounted for 30.19% of total ADEs in oral semaglutide, slightly surpassing the 27.76% in subcutaneous semaglutide. The median onset for gastrointestinal PTs was 4 days in both oral (Q1: 1, Q3: 32) and subcutaneous (Q1: 1, Q3: 35) formulations. Noteworthy, new serious adverse event (AE) signals were identified, including hemorrhagic diarrhea (ROR: 3.69), hepatic pain (ROR: 4.20), abnormal hormone levels (ROR: 6.51), and pancreatic failure (ROR: 36.34) in subcutaneous semaglutide, and Dupuytren's contracture (ROR: 46.85) in oral semaglutide. Our study delineates the safety profile of semaglutide using data from the FAERS database and social media. And identified novel ADR signals specific to oral and subcutaneous forms of semaglutide.

Relationship between residual gastric content and peri-operative semaglutide use assessed by gastric ultrasound: a prospective observational study.

Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist known to delay gastric emptying. Despite a growing body of evidence, its peri-operative safety profile remains uncertain, particularly with regard to the risk of increased residual gastric content and aspiration of gastric contents during anaesthesia. We hypothesised that semaglutide interruption of ≤ 10 days before elective surgical procedures is insufficient to reduce or normalise the residual gastric content, despite fasting intervals that comply with current guidelines. In this prospective observational study, we recruited patients who received pre-operative once-weekly subcutaneous semaglutide within 10 days of the procedure (semaglutide group) and control patients who had not been exposed to semaglutide (non-semaglutide group). On the day of surgery, all patients underwent pre-operative point-of-care gastric ultrasound to evaluate their residual gastric content. Increased residual gastric content was defined as any solid content or > 1.5 ml.kg-1 of clear fluids as assessed by gastric ultrasound. We recruited 220 patients, 107 in the semaglutide group and 113 in the non-semaglutide group. Increased residual gastric content was found in 43/107 patients (40%) in the semaglutide group and 3/113 (3%) in the non-semaglutide group (p < 0.001). In propensity-weighted analysis, semaglutide use (OR 36.97, 95%CI 16.54-99.32), age (OR 0.95, 95%CI 0.93-0.98) and male sex (OR 2.28, 95%CI 1.29-4.06) were significantly associated with increased residual gastric content. There were no cases of pulmonary aspiration of gastric contents. Pre-operative semaglutide use within 10 days of elective surgical procedures was independently associated with increased risk of residual gastric content on pre-operative gastric ultrasound assessment.

Design and Baseline Characteristics of the STRIDE Trial: evaluating Semaglutide in People with Symptomatic Peripheral Artery Disease and Type 2 Diabetes.

People with lower extremity peripheral artery disease (PAD) suffer from a high burden of symptoms and significant functional impairment. There are few therapies that improve function and reduce symptoms in this population. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to improve glycemic control, reduce body weight and reduce the risk of major adverse cardiovascular events, in people with atherosclerotic cardiovascular disease and type 2 diabetes (T2D). STRIDE (NCT04560998) is a randomized, placebo-controlled, double-blind phase 3b trial evaluating 1mg once-weekly subcutaneous semaglutide (GLP-1 RA) vs. placebo, in people with symptomatic PAD (Fontaine IIa claudication) and T2D. Eligible participants were≥18 years, had hemodynamically stable PAD, had no planned intervention, and were not receiving a GLP-1 RA. The primary endpoint is change in maximum walking distance on a constant-load treadmill (CLT). Secondary endpoints include quality of life and cardiometabolic assessments. A total of 792 participants were randomized in 20 countries. Participants' median age was 68 and they had T2D for a median of 12 years. Risk factors included 25.6% current smokers, 87.9% with hypertension, and 42.7% with coronary heart disease. The mean BMI was 29.6kg/m2 and mean HbA1C was 7.3%. Participants exhibited baseline functional impairment with a median maximum walking distance of 186 meters on a CLT. STRIDE has enrolled participants with symptomatic PAD and T2D, frequent risk factors and comorbidities, and functional impairment. The trial will provide evidence for the functional outcomes with semaglutide in people with PAD and T2D.

Semaglutide 2.4 mg in Participants With Metabolic Dysfunction-Associated Steatohepatitis: Baseline Characteristics and Design of the Phase 3 ESSENCE Trial.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated potential beneficial effects in metabolic dysfunction-associated steatohepatitis (MASH). To describe the trial design and baseline characteristics of the 'Effect of Semaglutide in Subjects with Non-cirrhotic Non-alcoholic Steatohepatitis' (ESSENCE) trial (NCT04822181). ESSENCE is a two-part, phase 3, randomised, multicentre trial evaluating the effect of subcutaneous semaglutide 2.4 mg in participants with biopsy-proven MASH and fibrosis stage 2 or 3. The primary objective of Part 1 is to demonstrate that semaglutide improves liver histology compared with placebo. The two primary endpoints are: resolution of steatohepatitis and no worsening of liver fibrosis, and improvement in liver fibrosis and no worsening of steatohepatitis. The Part 2 objective is based on clinical outcomes. The current work reports baseline characteristics of the first 800 randomised participants which includes demographics, laboratory parameters, liver histology, non-invasive tests and presence of metabolic dysfunction-associated steatotic liver disease (MASLD) cardiometabolic criteria. Of 800 participants, 250 (31.3%) had fibrosis stage 2 and 550 (68.8%) had fibrosis stage 3. In the overall population, mean (standard deviation [SD]) age was 56 (11.6) years, 57.1% were female, mean (SD) body mass index was 34.6 (7.2) kg/m2, 55.5% had type 2 diabetes and > 99% had at least one MASLD cardiometabolic criterion according to the published definition. The ESSENCE baseline population includes participants with clinically significant fibrosis stages 2 and 3. Although MASLD cardiometabolic criteria were not a requirement for study enrolment, almost all participants (> 99%) had at least one MASLD cardiometabolic criterion. NCT04822181.

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.

Bioengineered Nanomedicines Targeting the Intestinal Fc Receptor Achieve the Improved Glucoregulatory Effect of Semaglutide in a Type 2 Diabetic Mice Model.

The oral administration of the glucagon-like peptide-1 analogue, semaglutide, remains a hurdle due to its limited bioavailability. Herein, neonatal Fc receptor (FcRn)-targeted nanoparticles (NPs) were designed to enhance the oral delivery of semaglutide. The nanocarriers were covalently linked to the FcRn-binding peptide FcBP or the affibody molecule ZFcRn that specifically binds to the human FcRn (hFcRn) in a pH-dependent manner. These FcRn-targeted ligands were selected over the endogenous ligands of the receptor (albumin and IgG) due to their smaller size and simpler structure, which could facilitate the transport of functionalized NPs through the tissues. The capacity of FcRn-targeted semaglutide-NPs in controlling the blood glucose levels was evaluated in an hFcRn transgenic mice model, where type 2 diabetes mellitus (T2DM) was induced via intraperitoneal injection of nicotinamide followed by streptozotocin. The encapsulation of semaglutide into FcRn-targeted NPs was translated in an improved glucoregulatory effect in T2DM-induced mice when compared to the oral free semaglutide or nontargeted NP groups, after daily oral administrations for 7 days. Notably, a similar glucose-lowering response was observed between both FcRn-targeted NPs and the subcutaneous semaglutide groups. An increase in insulin pancreatic content and a recovery in β cell mass were visualized in the mice treated with FcRn-targeted semaglutide-NPs. The biodistribution of fluorescently labeled NPs through the gastrointestinal tract demonstrated that the nanosystems targeting the hFcRn are retained longer in the ileum and colorectum, where the expression of FcRn is more prevalent, than nontargeted NPs. Therefore, FcRn-targeted nanocarriers proved to be an effective platform for improving the pharmacological effect of semaglutide in a T2DM-induced mice model.

S2087 Efficacy and Safety of Subcutaneous Semaglutide and Tirzepatide Injections in Elderly vs Younger Obese: A Case-Control Study

S2087 Efficacy and Safety of Subcutaneous Semaglutide and Tirzepatide Injections in Elderly vs Younger Obese: A Case-Control Study

The blood pressure-lowering property of subcutaneous semaglutide: a systematic review, meta-analysis, and meta-regression.

Semaglutide is a glucagon-like peptide (GLP1) receptor agonist with unprecedented weight-lowering and anti-hyperglycemic properties. Recent clinical trials reported that subcutaneous semaglutide can modulate blood pressure; however, its effect on blood pressure widely varied in different studies and different subgroups of patients. PubMed, Web of Science, Scopus, and the Cochrane Library were systematically searched from the inception to July 18, 2024. Due to high heterogeneity, a random-effects model was adopted to pool data. Twenty clinical trials with 15,312 participants in the placebo group and 18,231 participants in the semaglutide group were included in this study. Subcutaneous semaglutide significantly decreased both systolic (WMD - 3.71 mmHg, 95% CI (-4.29, -3.13), I2: 50.2%) and diastolic (WMD - 1.10 mmHg, 95% CI (-1.58, -0.63), I2: 69.7%) blood pressure. Subgroup analyses indicated that the blood pressure-lowering property of subcutaneous semaglutide was greater among patients without diabetes, with lower baseline hemoglobin A1c (HbA1c), baseline body mass index (BMI) greater than 35kg/m2, dose of semaglutide more than 1mg/week, baseline systolic blood pressure equal or less than 130 mmHg, weight loss greater than 10kg, and BMI reduction greater than 3kg/m2. In addition, a treatment length of 50 to 100 weeks was associated with greater blood pressure-lowering effects in subgroup analysis. After adjusting for other factors, meta-regression revealed that placebo-adjusted weight change was independently correlated with the effect of semaglutide on systolic and diastolic blood pressure. Subcutaneous semaglutide can significantly decrease systolic and diastolic blood pressure, particularly in selected groups of patients.

Psychiatric Safety of Semaglutide for Weight Management in People Without Known Major Psychopathology

Obesity is associated with numerous psychosocial complications, making psychiatric safety a consideration for treating people with obesity. Few studies have investigated the psychiatric safety of newly available antiobesity medications. To evaluate the psychiatric safety of subcutaneous semaglutide, 2.4 mg, once weekly in people without known major psychopathology. This post hoc analysis of pooled data from the randomized, double-blind, placebo-controlled, multicenter phase 3a STEP 1, 2, and 3 trials (68 weeks; 2018-2020) and phase 3b STEP 5 trial (104 weeks; 2018-2021) included adults with overweight or obesity; STEP 2 participants also had type 2 diabetes. Trial designs have been published previously. Semaglutide, 2.4 mg, vs placebo. Depressive symptoms and suicidal ideation/behavior were assessed using the Patient Health Questionnaire (PHQ-9) and Columbia-Suicide Severity Rating Scale, respectively. Psychiatric and nervous system disorder adverse events were investigated. This analysis included 3377 participants in the STEP 1, 2, and 3 trials (2360 women [69.6%]; mean [SD] age, 49 [13] years) and 304 participants in STEP 5 (236 women [77.6%]; mean [SD] age, 47 [11] years). In the STEP 1, 2, and 3 trials, mean (SD) baseline PHQ-9 scores for the semaglutide, 2.4 mg, and placebo groups were 2.0 (2.3) and 1.8 (2.3), respectively, indicating no/minimal symptoms of depression. PHQ-9 scores at week 68 were 2.0 (2.9) and 2.4 (3.3), respectively; the estimated treatment difference (95% CI) between groups was -0.56 (-0.81 to -0.32) (P < .001). Participants treated with semaglutide vs placebo were less likely to shift (from baseline to week 68) to a more severe category of PHQ-9 depression (odds ratio, 0.63; 95% CI, 0.50-0.79; P < .001). Based on the Columbia-Suicide Severity Rating Scale, 1% or fewer of participants reported suicidal ideation/behavior during treatment, with no differences between semaglutide, 2.4 mg, and placebo. Psychiatric disorder adverse events were generally balanced between groups. Similar results were observed in STEP 5. The results of this post hoc analysis suggest that treatment with semaglutide, 2.4 mg, did not increase the risk of developing symptoms of depression or suicidal ideation/behavior vs placebo and was associated with a small but statistically significant reduction in depressive symptoms (not considered clinically meaningful). People with obesity should be monitored for mental health concerns so they can receive appropriate support and care. ClinicalTrials.gov Identifiers: STEP 1 (NCT03548935), 2 (NCT03552757), 3 (NCT03611582), and 5 (NCT03693430).

Effect of Subcutaneous Semaglutide on Diabetic Retinopathy among Adults with Type 2 Diabetes in Saudi Arabia. A Systematic Review

Diabetic Retinopathy (DR) is one of the leading causes of progressive and irreversible vision loss. The relationship between metabolic control and progression of DR is observed in previous landmark randomized clinical studies. Moreover, a potential association between DR progression and glucagon-like peptide1 receptor agonists (GLP1-RA) is reported in diabetes literature. Objectives: To explore the effect of semaglutide treatment on diabetic retinopathy progression in adults with type 2 diabetes (T2DM) among the Middle East and North Africa (MENA) area. Methods: This is a systematic review of randomized clinical trials, we searched electronic databases including Google Scholars, PubMed, Science Direct, Cochrane, ClinicalTrials.gov, and The Medical Subject Heading (MeSH) terms using the PRISMA flow chart based on our inclusion criteria and used PROSPERO for searching for registered systematic reviews in MENA area. Results: Among 12 studies 11,854 patients were included in the mean follow-up period which was 52.5 weeks on semaglutide therapy with non-significant association with a pooled effect size for retinopathy incidence of 1.12 (95% CI: 1.00, 1.12). Conclusion: The current literature revealed that semaglutide has an uncertain effect on diabetic retinopathy progression. A need for larger randomized clinical trials in MENA area to expose the definitive effect.