Search Results (516)

Background and Aim: Type 2 diabetes (T2D) continues to pose a significant public health challenge worldwide. Among therapeutic options, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have proven effective in optimizing glycemic control and improving cardiometabolic profiles. Semaglutide, now available in an oral formulation, represents a modern strategy to improve patient adherence while supporting glucose and weight regulation. This study primarily investigated the effects of oral semaglutide on key metabolic indicators and secondary endpoints included cardiovascular risk markers (blood pressure and lipid profile) and patient-reported quality of life (QoL). Study Design and Methods: A longitudinal, prospective observational study was conducted involving patients with T2D across two Italian healthcare facilities. Participants were assessed at baseline (T0) and at three subsequent intervals—6 months (T1), 12 months (T2), and 18 months (T3)—following the initiation of oral semaglutide use. Key Findings: Out of 116 participants enrolled, 97 had complete and analyzable data. Across the 18-month follow-up, significant improvements were observed in glycemic parameters, with a notable reduction in HbA1c levels (T0 vs. T3, p = 0.0028; p ≤ 0.05, statistically significant). Self-reported outcomes showed enhanced quality of life, especially in treatment satisfaction and perceived flexibility (T0 vs. T3, p < 0.001). Conclusions: Daily administration of 14 mg oral semaglutide in individuals with T2D resulted in substantial benefits in glycemic regulation, weight reduction, cardiovascular risk management, and overall patient satisfaction. These findings reinforce its potential role as a sustainable and effective option in long-term diabetes care from both a clinical and public health perspective. Full article

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome with increasing prevalence and substantial morbidity and mortality. Recent advances in pharmacotherapy have transformed its management. This review summarizes current evidence supporting the use of sodium–glucose cotransporter 2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, alongside selected use of angiotensin receptor–neprilysin inhibitors. Emphasis is placed on early initiation of disease-modifying therapies, phenotypic tailoring, and comorbidity-targeted strategies, especially in obese and diabetic patients. Together, these approaches define a new era of guideline-directed, personalized care for patients with HFpEF. Full article

The glucagon-like peptide-1 receptor (GLP-1R), which belongs to the class B1 G protein-coupled receptor (GPCR) family, is an important target for treatment of metabolic disorders, including type 2 diabetes and obesity. The growing interest in GLP-1R-based therapies is driven by the development of various functional agonists as well as the huge commercial market. Thus, understanding the structural details of ligand-induced signaling are important for developing improved GLP-1R drugs. Here, we investigated the conformational dynamics of the receptor in complex with a selection of prototypical functional agonists, including CHU-128 (small molecule-biased), danuglipron (small molecule balanced), and Peptide 19 (peptide balanced), which exhibit unique, distinct binding modes and induced helix packing. Furthermore, our all-atom molecular dynamics (MD) simulations revealed atomic feature how different those ligands led to signaling pathway preference. Our findings offer valuable insights into the mechanistic principle of GLP-1R activation, which are helpful for the rational design of next-generation GLP-1R drug molecules. Full article

Background and Objectives: Obesity and type 2 diabetes (T2D) are closely linked and associated with a higher risk of complications. This study aims to evaluate the effectiveness of once-weekly semaglutide in achieving a composite endpoint of A1C and weight reduction. Materials and Methods: This retrospective cohort study assessed the effectiveness of semaglutide in obese patients with T2D at a tertiary care hospital in Saudi Arabia. This study included patients who received semaglutide treatment for 12 months, and the endpoint was reducing A1C by ≥ 1% and body weight by ≥ 5% after 12 months of starting semaglutide. Secondary endpoints include predictors of achieving the composite endpoint and the effect on the lipid profile. Results: The present study enrolled 459 participants, with dyslipidemia and hypertension being the most common comorbidities. After 12 months of treatment with semaglutide, 42% of the patients achieved the composite endpoint. Semaglutide significantly reduced weight, BMI, A1C, FBG, total cholesterol, LDL, and triglycerides. The subgroup analysis showed that patients who achieved the composite endpoint were younger and had significantly lower use of insulin. Females in the study had significantly higher BMI, A1C, and HDL levels and lower levels of triglycerides compared to males. Multivariate analysis revealed that baseline BMI (aOR = 0.953; 95% CI: 0.915 to 0.992; p = 0.02), baseline A1C (aOR = 1.213; 95% CI: 1.062 to 1.385; p = 0.004), and receiving insulin (aOR = 0.02; 95% CI: 0.001 to 0.343; p = 0.007) were significant predictors of composite endpoint achievement. Conclusions: Semaglutide is a valuable option for the treatment of obese patients with T2D. This study found that semaglutide is effective in reducing weight and A1C and improving the lipid profile. The predictors of achievement of the composite endpoint were lower baseline BMI, higher baseline A1C, and insulin non-use. Full article

Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children and young adults, but no effective disease-modifying therapies are currently available. Here, we identify glucagon-like peptide-1 (GLP-1) signaling as a novel therapeutic target for NPH through a systematic drug repurposing screen in zebrafish. By simultaneously depleting nphp1 and nphp4, we developed a robust zebrafish model that reproduces key features of human NPH, including glomerular cyst formation. Our screen revealed that dipeptidyl peptidase-4 (DPP4) inhibitors (Omarigliptin and Linagliptin) and GLP-1 receptor agonists (Semaglutide) significantly reduce cystogenesis in a dose-dependent manner. Genetic analysis demonstrated that GLP-1 receptor signaling is important for maintaining pronephros integrity, with gcgra and gcgrb (GLP-1 receptor genes) playing a particularly important role. Transcriptomic profiling identified adenosine receptor A2ab (adora2ab) as a key downstream effector of GLP-1 signaling, which regulates ciliary morphology and prevents cyst formation. Notably, nphp1/nphp4 double mutant zebrafish exhibited the upregulation of gcgra as a compensatory mechanism, which might explain their resistance to cystogenesis. This compensation was disrupted by the targeted depletion of GLP-1 receptors or the inhibition of adenylate cyclase, resulting in enhanced cyst formation, specifically in the mutant background. Our findings establish a signaling cascade from GLP-1 receptors to adora2ab in terms of regulating ciliary organization and preventing cystogenesis, offering new therapeutic opportunities for NPH through the repurposing of FDA-approved medications with established safety profiles. Full article

Background: Chronic Kidney Disease (CKD) is a major global health issue, with diabetes being its primary cause and cardiovascular disease contributing significantly to patient mortality. Recently, two classes of medications—sodium–glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—have shown promise in protecting both kidney and heart health beyond their effects on blood sugar control. Methods: We conducted a narrative review summarizing the findings of different clinical trials and mechanistic studies evaluating the effect of SGLT2i and GLP-1 RAs on kidney function, cardiovascular outcomes, and overall disease progression in patients with CKD and DKD. Results: SGLT2i significantly mitigate kidney injury by restoring tubuloglomerular feedback, reducing intraglomerular hypertension, and attenuating inflammation, fibrosis, and oxidative stress. GLP-1 RAs complement these effects by enhancing endothelial function, promoting weight and blood pressure control, and exerting direct anti-inflammatory and anti-fibrotic actions on renal tissues. Landmark trials—CREDENCE, DAPA-CKD, and EMPA-KIDNEY—demonstrate that SGLT2i reduce the risk of kidney failure and renal or cardiovascular death by 25–40% in both diabetic and non-diabetic CKD populations. Likewise, trials such as LEADER, SUSTAIN, and AWARD-7 confirm that GLP-1 RAs slow renal function decline and improve cardiovascular outcomes. Early evidence suggests that using both drugs together may offer even greater benefits through multiple mechanisms. Conclusions: SGLT2i and GLP-1 RAs have redefined the therapeutic landscape of CKD by offering organ-protective benefits that extend beyond glycemic control. Whether used individually or in combination, these agents represent a paradigm shift toward integrated cardiorenal-metabolic care. A deeper understanding of their mechanisms and clinical utility in both diabetic and non-diabetic populations can inform evidence-based strategies to slow disease progression, reduce cardiovascular risk, and improve long-term patient outcomes in CKD. Full article

Obesity is a growing global health concern with widespread impacts on physical, psychological, and social well-being. Clinically, it is a major driver of type 2 diabetes (T2D), cardiovascular disease (CVD), non-alcoholic fatty liver disease (NAFLD), and cancer, reducing life expectancy by 5–20 years and imposing a staggering economic burden of USD 2 trillion annually (2.8% of global GDP). Despite its significant health and socioeconomic impact, earlier obesity medications, such as fenfluramine, sibutramine, and orlistat, fell short of expectations due to limited effectiveness, serious side effects including valvular heart disease and gastrointestinal issues, and high rates of treatment discontinuation. The advent of glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, tirzepatide) has revolutionized obesity management. These agents demonstrate unprecedented efficacy, achieving 15–25% mean weight loss in clinical trials, alongside reducing major adverse cardiovascular events by 20% and T2D incidence by 72%. Emerging therapies, including oral GLP-1 agonists and triple-receptor agonists (e.g., retatrutide), promise enhanced tolerability and muscle preservation, potentially bridging the efficacy gap with bariatric surgery. However, challenges persist. High costs, supply shortages, and unequal access pose significant barriers to the widespread implementation of obesity treatment, particularly in low-resource settings. Gastrointestinal side effects and long-term safety concerns require close monitoring, while weight regain after medication discontinuation emphasizes the need for ongoing adherence and lifestyle support. This review highlights the transformative potential of incretin-based therapies while advocating for policy reforms to address cost barriers, equitable access, and preventive strategies. Future research must prioritize long-term cardiovascular outcome trials and mitigate emerging risks, such as sarcopenia and joint degeneration. A multidisciplinary approach combining pharmacotherapy, behavioral interventions, and systemic policy changes is critical to curbing the obesity epidemic and its downstream consequences. Full article

Spurred by the enormous therapeutic success of glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP1-RAs) against diabetes and obesity, glucagon family receptor pharmacology has garnered a tremendous amount of interest. Glucagon family receptors, e.g., the glucagon receptor itself (GCGR), the GLP-1R, and the glucose-dependent insulinotropic peptide receptor (GIPR), belong to the incretin receptor superfamily, i.e., receptors that increase blood glucose-dependent insulin secretion. All incretin receptors are class B1 G protein-coupled receptors (GPCRs), coupling to the G_s type of heterotrimeric G proteins which activates adenylyl cyclase (AC) to produce cyclic adenosine monophosphate (cAMP). Most GPCRs undergo desensitization, i.e., uncouple from G proteins and internalize, thanks to interactions with the βarrestins (arrestin-2 and -3). Since the βarrestins can also mediate their own G protein-independent signaling, any given GPCR can theoretically signal (predominantly) either via G proteins or βarrestins, i.e., be a G protein- or βarrestin-“biased” receptor, depending on the bound ligand. A plethora of experimental evidence suggests that the GLP-1R does not undergo desensitization in physiologically relevant tissues in vivo, but rather, it produces robust and prolonged cAMP signals. A particular property of constant cycling between the cell membrane and caveolae/lipid rafts of the GLP-1R may underlie its lack of desensitization. In contrast, GIPR signaling is extensively mediated by βarrestins and the GIPR undergoes significant desensitization, internalization, and downregulation, which may explain why both agonists and antagonists of the GIPR exert the same physiological effects. Here, we discuss this evidence and make a case for the GLP-1R being a phenotypically or functionally G_s-selective receptor. We also discuss the implications of this for the development of GLP-1R poly-ligands, which are increasingly pursued for the treatment of obesity and other diseases. Full article

Background and Objectives: Type 2 diabetes (T2D) is a global health burden with increasing prevalence, necessitating effective management strategies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as beneficial therapies, promoting both glycemic control and weight loss, yet real-world data on sex differences in response are limited. This study aimed to investigate sex-based differences in glycemic and weight outcomes, as well as adverse effects, in T2D patients treated with GLP-1 RAs at a single diabetes center. Materials and Methods: In this retrospective analysis, 114 patients (58.8% men) with T2D who were initiated on GLP-1 RA therapy between 2015 and 2023 were evaluated. Data on HbA1c, BMI, and adverse events were collected at baseline and 3, 6, and 12 months post-treatment initiation. Results: Our findings indicated a statistically significant HbA1c reduction (from 8.6% at GLP-1 RA initiation to 6.9% at 12 months in men (p < 0.001) and from 8.4% at initiation to 7.0% at 12 months after GLP-1 RA initiation (p < 0.001) in women). By 12 months, a significantly greater proportion of women compared to men achieved ≥ 5% (51.1% vs. 28.4%, p = 0.019) and ≥10% weight loss (29.8% vs. 9.0%, p = 0.006), with both differences reaching statistical significance. A statistically significant difference in weight loss in mean weight change and percent weight change in men vs. women was observed from month 6 of therapy. Conclusions: These findings underscore the effectiveness of GLP-1 RAs in improving glycemic control and weight loss in a real-world setting and suggest that women may experience greater weight reduction. Understanding these differences could inform personalized treatment strategies for optimized outcomes in T2D management. Full article

Background: Semaglutide and Liraglutide are medications in the Glucagon-like peptide-1 agonists (GLP-1 RAs) class used to manage type 2 diabetes mellitus and obesity in Saudi Arabia. Although the 1.0 mg once weekly dosage of Semaglutide does not have a labeled indication for the management of obesity, many believe that this dosage is more effective than the 3.0 mg once daily Liraglutide dosage for the management of both diabetes and obesity. Objective: To compare the effectiveness of the dosage of 1.0 mg of Semaglutide administered once weekly versus 3.0 mg of Liraglutide administered once daily in controlling HbA1c levels, promoting weight loss, and evaluating their financial implications among obese patients in Saudi Arabia using real-world data. Methods: A retrospective review of Electronic Medical Records (EMRs) from January 2021 to June 2024 was conducted on patients prescribed Semaglutide or Liraglutide for at least 12 months. Exclusion criteria included pre-existing severe conditions (e.g., cardiovascular disease, stroke, or cancer) and missing baseline data. The primary outcomes assessed were changes in HbA1c, weight, and direct medical costs. Results: Two hundred patients (100 patients on the 1.0 mg once weekly dose of Semaglutide and 100 patients on the 3.0 mg once daily dose of Liraglutide) of those randomly selected from the EMRs met the inclusion criteria and were included in the analysis. Of the 200 eligible patients (65.5% female, mean age 48.54 years), weight loss was greater with Semaglutide (−8.09 kg) than Liraglutide (−5.884 kg). HbA1c reduction was also greater with Semaglutide (−1.073%) than Liraglutide (−0.298%). The use of Semaglutide resulted in lower costs of USD −1264.76 (95% CI: −1826.82 to 33.76) and greater reductions in weight of −2.22 KG (95% CI: −7.68 to −2.784), as well as lower costs of USD −1264.76 (95% CI: (−2368.16 to −239.686) and greater reductions in HbA1c of −0.77% (95% CI: −0.923 to −0.0971) in more than 95% of the cost effectiveness bootstrap distributions. Conclusions: Semaglutide 1.0 mg weekly seems to be more effective and cost-saving in managing prediabetes, diabetes, and obesity compared to Liraglutide 3.0 mg daily. Future studies should examine these findings using a more representative sample and a robust study design. Full article

Diabetic foot ulcers (DFUs), which affect approximately 15% of individuals with diabetes mellitus (DM), result from complex molecular disturbances involving chronic hyperglycemia, immune dysfunction, and infection. At the molecular level, chronic hyperglycemia promotes the formation of advanced glycation end products (AGEs), activates the AGE-RAGE-NF-κB axis, increases oxidative stress, and impairs macrophage polarization from the pro-inflammatory M1 to the reparative M2 phenotype, collectively disrupting normal wound healing processes. The local wound environment is further worsened by antibiotic-resistant polymicrobial infections, which sustain inflammatory signaling and promote extracellular matrix degradation. The rising threat of antimicrobial resistance complicates infection management even further. Recent studies emphasize that optimal glycemic control using antihyperglycemic agents such as metformin, Glucagon-like Peptide 1 receptor agonists (GLP-1 receptor agonists), and Dipeptidyl Peptidase 4 enzyme inhibitors (DPP-4 inhibitors) improves overall metabolic balance. These agents also influence angiogenesis, inflammation, and tissue regeneration through pathways including AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), and vascular endothelial growth factor (VEGF) signaling. Evidence indicates that maintaining glycemic stability through continuous glucose monitoring (CGM) and adherence to antihyperglycemic treatment enhances antibiotic effectiveness by improving immune cell function and reducing bacterial virulence. This review consolidates current molecular evidence on the combined effects of glycemic and antibiotic therapies in DFUs. It advocates for an integrated approach that addresses both metabolic and microbial factors to restore wound homeostasis and minimize the risk of severe outcomes such as amputation. Full article

Background/Objectives: Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is a well-established pharmacologic agent for inducing weight loss in individuals with obesity and is prescribed regardless of type 2 diabetes mellitus (DM) status. However, it remains unclear whether the weight-lowering efficacy of semaglutide differs significantly between individuals with and without DM. To address this question, we conducted a systematic review and meta-analysis comparing the effects of once-weekly subcutaneous semaglutide at 2.4 mg on weight loss in adults with and without DM. Methods: A comprehensive literature search was performed using the PubMed database to identify randomized controlled trials (RCTs) involving overweight or obese adults receiving semaglutide at 2.4 mg weekly for 40 to 70 weeks. Using a random-effects model, we estimated the weighted mean differences in body weight reduction between the two groups. Nine RCTs met the inclusion criteria, among which two provided subgroup data for participants with and without DM within the same trial population. Registration number in PROSPERO: CRD420251077610. Results: In participants with DM (n = 4 studies), semaglutide was associated with a weighted mean body weight reduction of −6.34% (95% confidence interval: −6.98 to −5.69), with negligible heterogeneity across studies (I² = 0.0%). By contrast, among participants without DM (n = 7 studies), the weighted estimate of weight loss was −11.57% (95% confidence interval: −12.94 to −10.19), with moderate heterogeneity observed (I² = 63.6%). Conclusions: The observed difference in weight loss efficacy between the groups was clinically meaningful. While once-weekly semaglutide at 2.4 mg elicited significant weight loss in both populations, the magnitude of effect was notably greater in those without DM. This disparity may be explained by metabolic characteristics frequently present in individuals with DM, such as insulin resistance, hyperinsulinemia, and compensatory mechanisms related to glycemic control. Full article

Diabetes mellitus and atrial fibrillation (AF) frequently coexist, creating a complex bidirectional relationship that exacerbates cardiovascular risk and challenges clinical management. Diabetes fosters a profibrotic, pro-inflammatory, and proarrhythmic atrial substrate through a constellation of pathophysiologic mechanisms, including metabolic remodeling, oxidative stress, mitochondrial dysfunction, ion channel dysregulation, and autonomic imbalance, thereby promoting AF initiation and progression. Conventional rhythm control strategies remain less effective in diabetic individuals, underscoring the need for innovative, substrate-targeted interventions. In this context, sodium–glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as promising agents with pleiotropic antiarrhythmic properties, modulating fibrosis, inflammation, and mitochondrial integrity. Moreover, advances in anti-inflammatory, antifibrotic, and ion channel-modulating therapeutics, coupled with novel mitochondrial-targeted strategies, are reshaping the therapeutic landscape. Multi-omics approaches are further refining our understanding of diabetes-associated AF, facilitating precision medicine and biomarker-guided interventions. This review delineates the molecular nexus linking diabetes and AF, critically appraises emerging rhythm control strategies, and outlines translational avenues poised to advance individualized management in this high-risk population. Full article

HMG-CoA reductase inhibitors, statins, are extensively used to treat hyperlipidemia, coronary artery disease, and other atherosclerotic disorders. However, one of the common side effects of statin therapy is a mild elevation in liver aminotransferases, observed in less than 3% of patients. Atorvastatin and simvastatin, in particular, are most frequently associated with statin-induced liver injury, leading to treatment discontinuation. Recent research has highlighted the antioxidant and anti-inflammatory properties of glucagon-like peptide-1 receptor (GLP-1R) activation in protecting against liver injury. Nonetheless, the potential protective effects of liraglutide (LIRA), a GLP-1R agonist, against atorvastatin (ATO)-induced liver dysfunction have not been fully elucidated. In this context, the present study aimed to investigate the protective role of LIRA in mitigating ATO-induced liver injury in rats, offering new insights into managing statin-associated hepatotoxicity. Indeed, LIRA treatment improved liver function enzymes and attenuated histopathological alterations. LIRA treatment enhanced antioxidant defenses by increasing Nrf2 content and superoxide dismutase (SOD) activity, while reducing NADPH oxidase. Additionally, LIRA suppressed inflammation by downregulating the HMGB1/TLR-4/RAGE axis and inhibiting the protein expression of pY323-MAPK p38 and pS635-NFκB p65 content resulting in decreased proinflammatory cytokines (TNF-α and IL-1β). Furthermore, LIRA upregulated GLP-1R gene expression and promoted autophagic influx via the activation of the pS473-Akt/pS486-AMPK/pS758-ULK1/Beclin-1 signaling cascade, along with inhibiting apoptosis by reducing caspase-3 content. In conclusion, LIRA attenuated ATO-induced oxidative stress and inflammation via activation of the Nrf-2/SOD cascade and inhibition of the HMGB1/TLR-4/RAGE /MAPK p38/NFκB p65 axis. In parallel, LIRA stimulated autophagy via the AMPK/ULK1/Beclin-1 axis and suppressed apoptosis, thus restoring the balance between autophagy and apoptosis. Full article

Cardiovascular diseases (CVDs) are the leading cause of global mortality, with type 2 diabetes mellitus (T2DM) and obesity significantly increasing the risk of CVD. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4is) have gained attention for their potential cardioprotective effects. Therefore, this review aims to explore the molecular mechanisms underlying the cardiovascular benefits of these agents. A literature review was conducted searching PubMed databases from 1990 to January 2025, including research on the effects of GLP-1 RA and DPP-4i on cardiovascular health, specifically concerning atherosclerosis, coronary artery disease, vascular health, cardiac arrhythmias, myocardial infarction (MI), and heart failure, with a focus on the biochemical and molecular effects of these drugs. We analyzed 131 scientific publications, which indicate that GLP-1 RA and DPP-4i significantly reduce cardiovascular risk and major adverse cardiovascular events (MACEs), including atherosclerosis, myocardial infarction, and cardiac arrhythmias. These clinical outcomes are attributed to the mitigation of oxidative stress, inflammation, and endothelial dysfunction as well as improvement in mitochondrial function and lipid metabolism. GLP-1 RAs offer substantial cardiovascular benefits, making them valuable in managing T2DM and reducing CVD risk. Their integration into treatment regimens for CVD can reduce hospitalization rates, improve quality of life, and extend life expectancy. DPP-4is, while beneficial, are less effective in cardiovascular protection. Further research is needed to optimize therapeutic strategies and broaden the clinical application of these agents in cardiometabolic care. Full article