Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists: Exploring Their Impact on Diabetes, Obesity, and Cardiovascular Health Through a Comprehensive Literature Review.

Glucagon-like peptide-1 receptor agonists (GLP-1-RAs) are a novel class of medications promising for treating type 2 diabetes mellitus (T2DM) and obesity-related conditions such as cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). This comprehensive literature review examines available research on these medications, focusing on their mechanisms of action, clinical effectiveness, safety profiles, and socioeconomic implications. A comprehensive search was performed using the PubMed, EMBASE, and Cochrane Library databases. Although initially developed for glucose management, these drugs have also demonstrated efficacy in promoting weight loss and reducing the risk of CVD. GLP-1-RAs function similarly to naturally occurring incretins. They stimulate insulin secretion in response to glucose levels, inhibit glucagon release, delay stomach emptying, and generate a sense of fullness via brain pathways. Head-to-head clinical studies have indicated that GLP-1-RAs outperform conventional antidiabetic medicines in terms of glycemic management and weight reduction. According to cardiovascular outcome studies, various drugs in this category have been found to reduce the frequency of severe adverse cardiovascular events. A common side effect is gastrointestinal toxicity, which can be mitigated by gradually increasing the dose. Personalized treatment is likely because the effectiveness, safety, and dose regimens of currently available GLP-1-RAs differ. GLP-1-RAs are a superior choice for patients with T2DM, especially those who already have CVD or require weight-control support. The high cost of these drugs creates hurdles to access and fair healthcare. Current research mainly focuses on increasing therapeutic uses and producing orally delivered medicines with greater potency and bioavailability. Integrating GLP-1-RAs into clinical practice can enhance patient outcomes and reduce the community burden of cardiometabolic disease.

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 ß 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.

Semaglutide and blood pressure: an individual patient data meta-analysis.

BACKGROUND AND AIMS: Randomized clinical trials (RCTs) assessing semaglutide reported reductions of systolic blood pressure (SBP) in trial populations with baseline blood pressure in the normotensive range. This study aimed to determine whether this SBP reduction is greater in hypertensive groups. METHODS: Individual patient data (IPD) from three RCTs examining the effect of semaglutide 2.4 mg on body weight over 68 weeks were included. Trial participants were categorized according to a hypertension diagnosis, treatment or baseline measurement (HTN), baseline SBP > 130 mmHg (HTN130) or >140 mmHg (HTN140), and those with apparent resistant hypertension (RH). The primary analysis compared the in-trial change in SBP in the semaglutide and placebo arms. Alterations of anti-hypertensive medications were quantified by treatment intensity score and compared between arms. These analyses were performed using analysis of covariance. RESULTS: Overall, 3136 participants were included. The difference in SBP change between the treatment (n = 2109) and placebo (n = 1027) groups was -4.95 mmHg [95% confidence interval (CI) -5.86 to -4.05] overall. This difference was -4.78 mmHg (95% CI -5.97 to -3.59) for HTN, -4.93 mmHg (95% CI -6.75 to -3.11) for HTN130, -4.09 mmHg (95% CI -7.12 to -1.06) for HTN140, and -3.16 mmHg (95% CI -8.69-2.37) for RH. Reduction in SBP was mediated substantially by weight loss. The anti-hypertensive treatment intensity score decreased for those on semaglutide compared to placebo (-0.51; 95% CI -0.71 to -0.32). CONCLUSIONS: This IPD analysis of three large RCTs found blood pressure reductions with semaglutide in participants with hypertension that were similar to those seen in all trial participants. This finding may in part be due to concurrent reductions to anti-hypertensive medications. These results suggest that semaglutide is a useful adjunctive treatment for patients with hypertension and obesity.

Effects of Semaglutide on Heart Failure Outcomes in Diabetes and Chronic Kidney Disease in the FLOW Trial.

BACKGROUND: People with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m2, kidney replacement therapy, and kidney or CV death) by 24%. OBJECTIVES: This prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population. METHODS: Participants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee. RESULTS: A total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment. CONCLUSIONS: Semaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153).

Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program.

BACKGROUND: Inflammation is thought to be an important mechanism for the development and progression of obesity-related heart failure with preserved ejection fraction (HFpEF). In the STEP-HFpEF Program, once-weekly 2.4 mg semaglutide improved heart failure-related symptoms, physical limitations, and exercise function, reduced the levels of C-reactive protein (CRP), a biomarker of inflammation, and reduced body weight in participants with obesity-related HFpEF. However, neither the prevalence nor the clinical characteristics of patients who have various magnitudes of inflammation in the context of obesity-related HFpEF have been well described. Furthermore, whether the beneficial effects of semaglutide on the various HF efficacy endpoints in the STEP-HFpEF Program are modified by the baseline levels of inflammation has not been fully established. Finally, the relationship between weight reduction and changes in CRP across the STEP-HFpEF Program have not been fully defined. OBJECTIVES: This study sought to: 1) evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF that have various levels of inflammation in the STEP-HFpEF Program; 2) determine if the effects of weekly semaglutide 2.4 mg vs placebo across all key outcomes are influenced by baseline levels of inflammation assessed by CRP levels; and 3) determine the relationship between change in CRP and weight loss in the STEP-HFpEF Program. METHODS: This was a secondary analysis of pooled data from 2 international, double-blind, placebo-controlled, randomized trials (STEP-HFpEF and STEP-HFpEF DM). The outcomes were change in the dual primary endpoints (health status [measured by the Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS)] and body weight) from baseline to 52 weeks according to baseline CRP levels. Additional efficacy endpoints included change in 6-minute walk distance (6MWD), a hierarchical composite endpoint that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6MWD, and levels of CRP in semaglutide- vs placebo-treated patients. Patients were stratified into 3 categories based on baseline CRP levels (<2, ≥2 to <10, and ≥10 mg/L). RESULTS: In total, 1,145 patients were randomized, of which 71% of patients had evidence of inflammation (CRP ≥2 mg/L). At baseline, those with higher levels of inflammation were younger, were more likely to be female, and had higher body mass index, worse health status (KCCQ-CSS), and shorter 6MWD. Semaglutide vs placebo led to reductions in HF-related symptoms and physical limitations as well as body weight, and to improvements in 6MWD and the hierarchical composite endpoint that were consistent across baseline CRP categories (all P interaction nonsignificant). Semaglutide also reduced CRP to a greater extent than placebo regardless of baseline CRP levels (P interaction = 0.32). Change in CRP from baseline to 52 weeks was similar regardless of the magnitude of weight loss (P interaction = 0.91). CONCLUSIONS: Inflammation is highly prevalent in obesity-related HFpEF. Semaglutide consistently improved HF-related symptoms, physical limitations, and exercise function, and reduced body weight across the categories of baseline CRP. Semaglutide also reduced inflammation, regardless of either baseline CRP or magnitude of weight loss during the trials. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511]; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP HFpEF DM; NCT04916470]).

Incretin hormone agonists: Current and emerging pharmacotherapy for obesity management.

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management.

Incidence of new onset type 2 diabetes in adults living with obesity treated with tirzepatide or semaglutide: real world evidence from an international retrospective cohort study.

Background: Tirzepatide, a novel dual agonist of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), has demonstrated greater magnitude of weight loss compared to semaglutide in a phase 3 clinical trial. However, the effect of tirzepatide on incidence of type 2 diabetes (T2D) in individuals with overweight and obesity, and the effect on major adverse cardiovascular outcomes in individuals with pre-existing T2D, remains unknown. Methods: We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (TriNetX LLC, Cambridge, MA, USA) a global federated database. The data used in this study was collected on 5th June 2024. Two cohorts of individuals were generated: 1) without pre-existing T2D and, 2) with T2D. We adopted an active comparator new user design on new initiations of either tirzepatide or semaglutide therapy. Analysis began from the index event which was defined as individuals on respective therapy for 6 months only. Analysis of outcomes was conducted off-drug, in individuals without a pre-existing history of the disease of interest. Individuals were followed up for 12 months post the index event. Primary outcome for cohort 1 was incidence of T2D, and for cohort 2 was composite: all-cause mortality, cerebral infarction, acute coronary syndrome, and heart failure. Secondary outcomes for cohort 1 were change in HbA1c and body weight and for cohort 2: incidence of micro- and macrovascular complications, suicidal ideation and/or attempt, and all-cause mortality. We propensity score matched (1:1) for potential confounders: baseline demographics, socioeconomic circumstances, HbA1c, weight, relevant co-morbidities, and anti-obesity, hypoglycaemic and cardioprotective agents. Findings: The study population without T2D consisted of 13,846 individuals, equally split between tirzepatide and semaglutide users. Tirzepatide was associated with both lower risk for incident T2D (HR 0.73, 95% CI 0.58-0.92, p < 0.001) and greater weight loss (-7.7 kg, [95% CI -6.8, -8.5 kg], p < 0.001), compared to semaglutide (-4.8 kg, [95% CI -3.9, -5.6 kg], p < 0.001). In individuals with pre-existing T2D (n = 8446), tirzepatide was associated with lower risk of the composite outcome (HR 0.54, 95% CI 0.38-0.76, p < 0.001), cerebral infarction (HR 0.45, 95% CI 0.24-0.84, p = 0.010) and all-cause mortality (HR 0.33, 95% CI 0.15-0.73, p = 0.004) compared to semaglutide. Interpretation: Tirzepatide is associated with significantly reduced risk of developing T2D and major adverse cardiovascular events in individuals living with obesity and T2D respectively. Randomised controlled trials investigating the utility of dual incretin agonists in the primary prevention of T2D and cardiovascular disease in higher risk populations are now required. Funding: Nil.

The cost-effectiveness analysis of semaglutide for the treatment of adult and adolescent patients with overweight and obesity: a systematic review.

PURPOSE: The present study aimed to systematically collect and synthesize available cost-effectiveness studies of semaglutide in patients with obesity or overweight in comparison with other interventions. METHODS: We comprehensively searched multiple electronic databases to identify relevant literature. Studies were selected based on inclusion and exclusion criteria. The quality of studies was appraised using the "Consolidated Health Economic Evaluation Reporting Standards" (CHEERS) tool. This study is conducted and reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS: Out of a total of 252 items, after review, 32 articles were fully reviewed, and, finally, 7 studies met inclusion and exclusion criteria. The discount rate was in the range of 1.5-3.5%. Studies included showed semaglutide offered more QALYs than anti-obesity drugs but because of higher cost, in some cases, ICER exceeds the willingness to pay threshold. Results show that semaglutide creates higher total cost compared to conventional interventions in patients with class I, II, and III obesities. Results show that in patients with class I obesity (BMI 33) lifestyle intervention (LI), endoscopic sleeve gastroplasty (ESG), Sleeve gastrectomy (SG), and semaglutide create $124,195; $126,732; $139,971; and $370,776, respectively. CONCLUSION: The current systematic review showed that semaglutide provides more QALYs and creates more costs in comparison with phentermine-topiramate, phentermine, and naltrexone-bupropion. Semaglutide may be cost-effective with substantial cost reduction. Semaglutide appears to be cost-effective versus diet and exercise (D&E) and liraglutide but it was not cost-effective versus sleeve gastrectomy, endoscopic sleeve gastroplasty, and gastric bypass.

The crucial role of beta-catenin in the osteoprotective effect of semaglutide in an ovariectomized rat model of osteoporosis.

Postmenopausal osteoporosis is a common chronic medical illness resulting from an imbalance between bone resorption and bone formation along with microarchitecture degeneration attributed to estrogen deficiency and often accompanied by other medical conditions such as weight gain, depression, and insomnia. Semaglutide (SEM) is a recently introduced GLP-1 receptor agonist (GLP-1RA) for the treatment of obesity and type 2 diabetes mellitus by mitigating insulin resistance. It has been discovered that the beneficial effects of GLP-1 are associated with alterations in lipolysis, adipogenesis, and anti-inflammatory processes. GLP-1 analogs transmit signals directly to adipose tissue. Mesenchymal stem cells (MSCs) are multidisciplinary cells that originate from bone marrow, migrate to injury sites, and promote bone regeneration. MSCs can differentiate into osteoblasts, adipose cells, and cartilage cells. Our aim is to investigate the role of semaglutide on bone formation and the Wnt signaling pathway. Osteoporosis was induced in female rats by ovariectomy, and the ovariectomized rats were treated with alendronate as standard treatment with a dose of 3 mg/kg orally and semaglutide with two doses (150 mcg/kg and 300 mcg/kg) S.C. for 10 successive weeks. Semaglutide ameliorates bone detrimental changes induced by ovariectomy. It improves bone microarchitecture and preserves bone mineral content. Semaglutide ameliorates ovariectomy-induced osteoporosis and increases the expression of ß-catenin, leading to increased bone formation and halted receptor activator of nuclear factor kappa-Β ligand (RANKL's) activation. Semaglutide can be used as a potential prophylactic and therapeutic drug against osteoporosis, possibly by activating Wnt signaling and decreasing bone resorption.

Semaglutide use in people with obesity and type 2 diabetes from real-world utilization data: An analysis of the All of US Program.

AIM: To analyse data from the All of Us Research Program to evaluate the real-world application and long-term effectiveness of semaglutide in treating type 2 diabetes and obesity patients in a large population. MATERIALS AND METHODS: We identified patients prescribed semaglutide and analysed differences in route of administration and the time on semaglutide. For individuals diagnosed with obesity, we measured changes in body mass index (BMI) and weight from baseline, while measured changes in HbA1c for those patients with type 2 diabetes. We also examined the occurrence of newly diagnosed common adverse events from taking semaglutide. RESULTS: For 3739 semaglutide patients, those on injectable semaglutide (3364 patients) averaged 301.54 days on the medication, with 20.36% having no end date, while those on oral semaglutide (435 patients) averaged 172.48 days, with 24.60% having no end date. We found average decreases of 1.54 kg/m2 in BMI, 4.65 kg in weight and 0.75% in HbA1c for semaglutide users. The decreases were larger in participants taking injectable formulation, probably because of higher starting values. Over time, improvements in these outcomes diminished, but the values remained significantly lower than baseline levels. Approximately only 1.0% of patients reported newly diagnosed common adverse events. CONCLUSIONS: Consistent with clinical trial findings, this real-world data analysis showed that semaglutide was well tolerated and that, for a large population, it effectively reduced BMI, body weight and HbA1c, albeit to smaller magnitudes than observed in clinical trials. These findings provide valuable insights into real-world experience and the long-term effectiveness of semaglutide.

The Antiobesity Effect and Safety of GLP-1 Receptor Agonist in Overweight/Obese Adolescents Without Diabetes Mellitus: A Systematic Review and Meta-Analysis.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), particularly semaglutide, have become the leading anti-obesity drugs for adults, and a similar trend may follow in adolescents with its recent approval for this age group. However, there is a lack of comparative analysis on the weight loss effects and safety of GLP-1 RAs in obese or overweight pediatric and adolescent populations, especially those who are non-diabetic. This systematic review and meta-analysis aim to provide current evidence on the efficacy and safety of GLP-1 RAs as an anti-obesity treatment in obese or overweight non-diabetic pediatric and adolescent populations. METHOD:  We searched electronic databases from inception until January 2024 for randomized controlled trials (RCTs) that analyzed the weight loss effect of GLP-1 receptor agonists in adolescents with obesity or overweight without diabetes mellitus. Search results were screened, and eligible studies were included to perform a systematic review and meta-analysis using the Review Manager (RevMan) computer program Version 5.4.1 (The Cochrane Collaboration, 2020) with a random-effects model. The primary efficacy outcomes were changes in body weight, BMI, and BMI Z-score, while the secondary outcomes were the incidence of gastrointestinal adverse events, treatment discontinuation rate due to adverse events, and incidence of serious adverse events. The mean difference, odds ratio, and 95% confidence interval (CI) were used to present the meta-analysis results. Publication bias was visualized using a funnel plot. The quality of the studies was analyzed using Cochrane's Risk of Bias tool (RoB2). RESULTS: A total of seven RCTs with 576 adolescent participants were included in the analysis. GLP-1 RAs significantly achieved greater weight loss than placebo, with a mean difference of -4.98 kg (-8.49, -1.46), I² = 99%, p = 0.006. Subgroup analysis showed that semaglutide had the most pronounced anti-obesity effect (mean difference of -17.70 kg (-18.89, -16.51), p < 0.00001), compared to liraglutide (mean difference of -2.26 kg (-5.17, 0.65), I² = 99%, p = 0.13) and exenatide (mean difference of -3.17 kg (-4.45, -1.90), I² = 0%, p < 0.0001). Similar results were obtained for other efficacy parameters such as BMI and BMI z-score. However, GLP-1 RA was associated with more gastrointestinal adverse events (such as nausea and vomiting) than placebo (3.06 (2.12, 4.42), I² = 0%, p < 0.00001), with incidence comparable among all GLP-1 RAs in the subgroup analysis. The overall risk of bias among included studies was either of 'some concern' or 'high risk.' CONCLUSIONS: Our meta-analysis demonstrated that GLP-1 RAs had a superior anti-obesity effect compared to placebo or lifestyle modification in obese or overweight non-diabetic adolescents, particularly semaglutide, which had a more pronounced anti-obesity effect than liraglutide and exenatide, with tolerable gastrointestinal adverse effects.

Adherence and treatment discontinuation of oral semaglutide and once-weekly semaglutide injection at 12 month follow-up: Japanese real-world data.

Adherence and treatment continuation rates of the glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide for both oral (O-SEMA) and subcutaneous injection (SEMA-SC) remain unknown in real-world clinical practice. This retrospective observational study compared the 12 month adherence and treatment discontinuation of O-SEMA and once-weekly SEMA-SC in patients with type 2 diabetes using a real-world claims database. SEMA-SC initiators were 1:1 propensity score-matched to O-SEMA initiators. Non-adherence was defined as <0.8 of the proportion of days covered. SEMA-SC had a significantly higher odds ratio (OR) for non-adherence than O-SEMA (OR: 1.39). The hazard ratio for treatment discontinuation, using O-SEMA as the reference, was 1.45 for SEMA-SC, although the discontinuation rate of O-SEMA was higher during the early stage. O-SEMA initiators showed significantly higher adherence and greater persistence in therapy than SEMA-SC initiators at 12 months, which could lead to earlier initiation of GLP-1RA treatment.

Sodium glycocholate liposome encapsulated semaglutide increases oral bioavailability by promoting intestinal absorption.

The aim of this study was to prepare sodium glycocholate liposomes (SGC-Lip) encapsulating semaglutide (Sml) to improve oral bioavailability and better exert hypoglycemic effect. In this paper, SGC-Lip was prepared by reverse-phase evaporation method with particle size around 140 nm, potential around -27 mV, rounded morphology and better stability. The hypoglycemic and intestinal uptake effects of SGC-Lip and cholesterol-containing liposomes (CH-Lip) were comparatively investigated in rats, and the oral safety of SGC-Lip was examined by cytotoxicity assay. The results indicate that SGC-Lip can achieve a hypoglycemic effect of 40% of the initial value within 12 hours, and the AAC0-12h is approximately six times that of CH-Lip without sodium glycocholate. The results of the cytotoxicity tests indicate that SGC-Lip has good oral safety. SGC-Lip enhances the absorption of semaglutide in the small intestinal villi via an apical sodium-dependent bile acid transporter (ASBT)-mediated pathway with the highest penetration at the ileal site. In summary, the oral bioavailability of semaglutide can be improved by encapsulating semaglutide in SGC-Lip and utilizing the stabilizing and permeation-promoting effects of SGC on liposomes.

Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program.

BACKGROUND: Obesity is a key factor in the development and progression of both heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF). In the STEP-HFpEF Program (comprising the STEP-HFpEF [Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity] and STEP-HFpEF DM [Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes] trials), once-weekly semaglutide 2.4 mg improved HF-related symptoms, physical limitations, and exercise function and reduced body weight in patients with obesity-related HFpEF. Whether the effects of semaglutide in this patient group differ in participants with and without AF (and across various AF types) has not been fully examined. OBJECTIVES: The goals of this study were: 1) to evaluate baseline characteristics and clinical features of patients with obesity-related HFpEF with and without a history of AF; and 2) to determine if the efficacy of semaglutide across all key trial outcomes are influenced by baseline history of AF (and AF types) in the STEP-HFpEF Program. METHODS: This was a secondary analysis of pooled data from the STEP-HFpEF and STEP-HFpEF DM trials. Patients with heart failure, left ventricular ejection fraction ≥45%, body mass index ≥30 kg/m2, and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) <90 points were randomized 1:1 to receive once-weekly semaglutide 2.4 mg or matching placebo for 52 weeks. Dual primary endpoints (change in KCCQ-CSS and percent change in body weight), confirmatory secondary endpoints (change in 6-minute walk distance; hierarchical composite endpoint comprising all-cause death, HF events, thresholds of change in KCCQ-CSS, and 6-minute walk distance; and C-reactive protein [CRP]), and exploratory endpoint (change in N-terminal pro-B-type natriuretic peptide [NT-proBNP]) were examined according to investigator-reported history of AF (yes/no). Responder analyses examined the proportions of patients who experienced a ≥5-, ≥10, ≥15, and ≥20-point improvement in KCCQ-CSS per history of AF. RESULTS: Of the 1,145 participants, 518 (45%) had a history of AF (40% paroxysmal, 24% persistent AF, and 35% permanent AF) and 627 (55%) did not. Participants with (vs without) AF were older, more often male, had higher NT-proBNP levels, included a higher proportion of those with NYHA functional class III symptoms, and used more antithrombotic therapies, beta-blockers, and diuretics. Semaglutide led to larger improvements in KCCQ-CSS (11.5 points [95% CI: 8.3-14.8] vs 4.3 points [95% CI: 1.3-7.2]; P interaction = 0.001) and the hierarchal composite endpoint (win ratio of 2.25 [95% CI: 1.79-2.83] vs 1.30 [95% CI: 1.06-1.59]; P interaction < 0.001) in participants with AF vs without AF, respectively. The proportions of patients receiving semaglutide vs those receiving placebo experiencing ≥5-, ≥10-, ≥15-, and ≥20-point improvement in KCCQ-CSS were also higher in those with (vs without) AF (all P interaction values <0.05). Semaglutide consistently reduced CRP, NT-proBNP, and body weight regardless of AF status (all P interaction values not significant). There were fewer serious adverse events and serious cardiac disorders in participants treated with semaglutide vs placebo irrespective of AF history. CONCLUSIONS: In the STEP-HFpEF Program, AF was observed in nearly one-half of patients with obesity-related HFpEF and was associated with several features of more advanced HF. Treatment with semaglutide led to significant improvements in HF-related symptoms, physical limitations, and exercise function, as well as reductions in weight, CRP, and NT-proBNP in people with and without AF and across AF types. The magnitude of semaglutide-mediated improvements in HF-related symptoms and physical limitations was more pronounced in those with AF vs without AF at baseline.(Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM; NCT04916470]).

Efficacy and Safety in a Real-World Study of the New Oral Formulation of Semaglutide in Patients with Chronic Kidney Disease and Type 2 Diabetes Mellitus.

Background/Objectives: GLP-1 receptor agonists (GLP-1RAs) have emerged as fundamental components in the treatment of type 2 diabetic patients (T2DM) with chronic kidney disease (CKD). The oral formulation represents a novel therapeutic tool but may affect drug efficacy. This study sought to compare the effectiveness of subcutaneous versus oral semaglutide formulations in patients with CKD. Methods: A retrospective study in a real-world setting compared type 2 diabetes and chronic kidney disease patients, initiating oral semaglutide treatment to a historically matched control group treated with subcutaneous semaglutide. The matching considered factors such as estimated glomerular filtration rate (eGFR), age, and sex. Results: Nineteen patients were included in both groups, with a mean age of 68.0. Seventy-two percent were males with a CKD-EPI eGFR of 49.9 mL/min/1.73 m2 and a median urine albumin-to-creatinine ratio of 12.7 mg/g. Of the study participants, 94% and 79% of patients were on the maximum semaglutide sbc vs. oral dose, while 5.3% and 15.8% were on the sbc vs. oral low dose. Oral semaglutide significantly reduced HbA1C and BMI, identical to the control group (-0.9 and -1.4, p > 0.05). Renal function parameters and blood pressure remained stable throughout the follow-up in both groups. The main side effect was digestive intolerance (affecting three patients in the oral group and two patients in the subcutaneous group, p = 0.6), although the treatment abandonment percentage was similar. Conclusions: The oral formulation of semaglutide demonstrated equivalent effectiveness in glucose control and body weight management in patients with T2DM and CKD, even with a higher proportion of patients receiving low to medium doses. Gastrointestinal side effects were comparable between both oral and subcutaneous formulations.

Glucagon-like Receptor-1 agonists for obesity: Weight loss outcomes, tolerability, side effects, and risks.

Background: This review investigates the side effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide, semaglutide, and tirzepatide, medications known for their efficacy in promoting weight loss among individuals with obesity. The rationale is rooted in understanding the balance between their therapeutic benefits and associated risks. Methods: This was a comprehensive clinical review, including systematic reviews, meta-analyses, randomized controlled trials (RCTs), and cohort studies. Data were extracted from databases such as PubMed, Scopus, Embase, MEDLINE, and Google Scholar, focusing on the tolerability, severity, and risks of these medications. Results: GLP-1RAs demonstrated significant weight loss outcomes. In clinical trials, liraglutide showed a placebo-corrected weight loss of around 5 %, semaglutide 12 %, and tirzepatide 18 %. Common side effects were predominantly gastrointestinal, including nausea, diarrhea, constipation, and vomiting. Rare serious adverse events included gallbladder disorders and acute pancreatitis. In, addition, multiple studies identify new risks associated with GLP-1RAs including increased aspiration risk during anesthesia due to delayed gastric emptying and challenges with bowel preparation for colonoscopies. Conclusion: While GLP-1RAs are effective in managing obesity, their use is associated with gastrointestinal side effects and rare but serious adverse events. The findings underscore the importance of individualized dosing and thorough patient assessment. Continuous research and vigilant monitoring are essential to optimize their safe use. Further studies are needed to refine guidelines, particularly regarding new concerns such as delayed gastric emptying and its implications for anesthesia.

Mechanisms of Non-alcoholic Fatty Liver Disease and Beneficial Effects of Semaglutide: A Review.

Non-alcoholic fatty liver disease stands as the predominant cause of chronic liver disease, with its prevalence and morbidity expected to escalate significantly, leading to substantial healthcare costs and diminished health-related quality of life. It comprises a range of disease manifestations that commence with basic steatosis, involving the accumulation of lipids in hepatocytes, a distinctive histological feature. If left untreated, it often advances to non-alcoholic steatohepatitis, marked by inflammatory and/or fibrotic hepatic changes, leading to the eventual development of non-alcoholic fatty liver disease-related cirrhosis and hepatocellular carcinoma. Because of the liver's vital role in body metabolism, non-alcoholic fatty liver disease is considered both a consequence and a contributor to the metabolic abnormalities observed in the metabolic syndrome. As of date, there are no authorized pharmacological agents for non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Semaglutide, with its glycemic and weight loss advantages, could potentially offer benefits for individuals with non-alcoholic fatty liver disease. This review aims to investigate the impact of semaglutide on non-alcoholic fatty liver disease.

Semaglutide-associated kidney injury.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are multipurpose agents effective in improving glycemic control in patients with type 2 diabetes while also achieving weight loss and risk reduction of major cardiovascular (CV) events and chronic kidney disease progression. With their increased utility in diabetes, obesity, CV health and renal protection, the use of GLP-1RAs has increased. However, with this increased use, there have also been increased reports of associated kidney adverse events, including case reports of acute interstitial nephritis (AIN) associated with GLP-1RA use. We report the data from the Food and Drug Administration adverse event reporting system (FAERS) in relation to GLP-1RA use and adverse kidney events, with acute kidney injury being the most common. In addition, we report two cases of semaglutide-associated biopsy-proven AIN and one with associated podocytopathy. To our knowledge, this is the first case of biopsy-proven AIN with podocytopathy associated with semaglutide use. Both patients experienced complete remission shortly after discontinuing semaglutide and undergoing immunosuppressive therapy. Further analysis of the FAERS database revealed 17 cases of proteinuria and 1 case of glomerulonephritis associated with semaglutide in the FAERS database, however no further information was available. While further research is needed to establish causality, this case series adds to the growing body of literature that semaglutide is associated with AIN and adds a new association, semaglutide with AIN and podocytopathies. While the overall clinical and mortality benefits of GLP-1RAs may outweigh the rarer risks, prescribers need to be aware of these associations, particularly as the use of GLP-1RAs continues to expand.