Search Results (407)

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a prevalent condition with a significant annual incidence, particularly increasing with age. Its pathophysiology is explained by Virchow’s triad (venous stasis, vascular injury, and hypercoagulability). Tirzepatide, a dual receptor agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is approved for type 2 diabetes mellitus (T2DM) and obesity, showing efficacy in lowering HbA_1c and promoting weight loss. Recent case reports have linked tirzepatide to VTE events, particularly in patients experiencing significant weight loss, raising concerns about its safety profile. We present a case of a male T2DM subject who developed PE after five injections of tirzepatide in a patient with grade I obesity. We also review emerging literature on VTE associated with tirzepatide, emphasizing the need for further research to clarify the drug’s risk and underlying mechanisms. Full article

Mineralocorticoid receptor antagonists (MRAs) are the cornerstone of the management of heart failure and chronic kidney disease. A well-known adverse event, hyperkalemia, is associated with fatal arrhythmia and discontinuation of MRA. Our narrative review discusses the personalized treatment of MRAs, focusing on the pharmacological profile and drug–drug interactions to address safety concerns related to hyperkalemia. Clinicians should scrupulously monitor potassium levels, especially during dose titration, and review each patient’s medication list. Cytochrome P450 3A4 (CYP3A4) inhibitors are pharmacokinetic precipitators that interact with most MRAs, except spironolactone, and adversely affect the risk of hyperkalemia, although suggestive evidence is scarce. Potassium-elevating drugs synergistically increase serum potassium levels when co-administered with an MRA (e.g., renin-angiotensin aldosterone inhibitors, co-trimoxazole, non-steroidal anti-inflammatory drugs, calcineurin inhibitors, and β blockers). Additional approaches include correction of metabolic acidosis using sodium bicarbonate, potassium-lowering therapy using loop and thiazide diuretics, and sodium-glucose cotransporter 2 inhibitors. Novel potassium binders enable patients to receive the maximum-tolerated MRA with fewer gastrointestinal side effects. Individualized interventions for hyperkalemia risk are important in treatment using MRA. Full article

Chronic kidney disease (CKD) is a major global health burden associated with substantially increased risks of morbidity and mortality. Cardiovascular disease remains the leading cause of death across all stages of CKD. Over the past few decades, several pharmacologic therapies—including renin–angiotensin system inhibitors, sodium–glucose cotransporter-2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, and lipid-lowering agents—have demonstrated substantial cardio-nephroprotective benefits and are recommended in international guidelines. However, real-world implementation of these therapies remains incomplete, and emerging evidence highlights important sex-based disparities in prescribing patterns. Although CKD is more prevalent in women worldwide, women with CKD are consistently less likely than men to receive guideline-directed cardioprotective and nephroprotective medications. This treatment gap spans both traditional therapies, such as angiotensin-converting enzyme inhibitors and statins, and newer agents with proven outcome benefits. Women are less likely to initiate treatment, less likely to receive high-intensity or target doses, and less likely to achieve recommended blood pressure and lipid goals. Importantly, the presence of CKD attenuates the usual female survival advantage, and the relative excess cardiovascular risk associated with CKD may be particularly pronounced in women. The under-prescription of cardio-renal therapies in women with CKD reflects a complex interplay of factors. These include older age at presentation, higher reported rates of adverse drug reactions, concerns regarding tolerability and safety in advanced kidney disease, therapeutic inertia, underestimation of cardiovascular risk, and persistent underrepresentation of women in clinical trials. Biological differences in pharmacokinetics and pharmacodynamics, as well as structural and system-level barriers, further contribute to inequities in care. Addressing these disparities requires improved risk recognition, sex-informed prescribing practices, enhanced representation of women in clinical research, and implementation strategies that incorporate sex-disaggregated performance metrics. Reducing treatment gaps is essential to improving cardiovascular and renal outcomes and to achieving equitable, precision-based care for women with CKD. Full article

A quantitative NMR assay was utilized to identify methylglyoxal-scavenging natural products from Rhodophytes, Chondrus crispus and Gracilaria vermiculophylla. This revealed the activity of guanylurea-containing amino acid derivatives, gongrine and gigartinine. The molecules share structural features with the frontline blood glucose-lowering drug and plant natural product derivative, metformin, and scavenge methylglyoxal via the same mechanism, resulting in an imidazole-containing Advanced Glycation Endproduct or AGE. The protective effect of the molecules reported here was evaluated in a cell-based model for reactive aldehyde stress using methylglyoxal exposure to reduce cell viability. Gongrine, gigartinine, and metformin all preserve cell viability in HepG2 following methylglyoxal exposure. This is the first report of methylglyoxal scavenging and cell viability protection of these macroalgae-derived guanylurea-containing natural products, which can be found in high abundance in commonly consumed and industrially produced macroalgae species. The compounds presented here, along with their algal sources, offer a unique opportunity to produce guanylureas with therapeutic potential through sustainable production methods from easily cultivated algal sources. Full article

The obesity–metabolic syndrome–diabetes continuum is driven by interconnected mechanisms including insulin resistance, dysfunctional adiposity, chronic inflammation and progressive cardio–renal–metabolic injury. This triggered a need for therapies that extend beyond glucose lowering alone. The benefits of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as disease-modifying drugs include weight loss, cardiovascular risk reduction, glycemic control and renal protection. However, treatment burden, adherence issues and access restrictions may limit the long-term effects of injectable formulations. One significant translational development that aims to close this gap is oral GLP-1-based treatments. In this review, we examine the mechanistic rationale, formulation science and clinical development of oral GLP-1 RAs. Oral semaglutide is presented as the first validated proof of concept for systemic peptide delivery by the gastrointestinal route. The biological barriers to oral peptide absorption, including enzymatic degradation, low epithelial permeability, pharmacokinetic variability and epithelial safety constraints, are critically discussed. Enabling technologies such as SNAC-based gastric absorption, nanocarriers, mucoadhesive systems and stability-optimization platforms are evaluated. Evidence from the PIONEER program and related studies demonstrating meaningful glycemic and weight-loss efficacy, acceptable safety and clinical utility in patients with type 2 diabetes and chronic kidney disease is further synthesized. Beyond first-generation oral peptide platforms, we discuss the emerging landscape of non-peptide oral GLP-1 RAs, dual and triple incretin agonists, precision dosing strategies and model-informed drug development. Oral GLP-1-based therapeutics are shifting from a formulation breakthrough to a broader translational strategy for disease modification across the obesity–metabolic syndrome–diabetes continuum. Long-term renal outcomes, access and implementation barriers remain important priorities for future research. Full article

This study formulated and characterized metformin-loaded chitosan nanoparticles (NPs) using the ionic gelation technique and evaluated the drug release kinetics. Characterization confirmed successful drug encapsulation, with Fourier-transform infrared spectroscopy (FTIR) indicating compatibility, and X-ray diffraction (XRD) showing attenuation of characteristic metformin reflections consistent with reduced crystalline contribution after encapsulation. Particle sizes ranged from 74.28 to 86.82 nm. The NPs exhibited stable zeta potentials (+42.38 to +49.06 mV) and high entrapment efficiencies (68.42–81.26%). In vitro drug release studies at pH 7.4 and pH 2.0 demonstrated an initial burst release, followed by sustained release over 24 h. The cumulative drug release ranged from 81.92% to 97.72% at pH 7.4 and 89.4% to 98.1% at pH 2.0, with a faster release at pH 2.0. Drug release kinetics followed first-order for batch MN1, while batches MN2 and MN3 best fitted into the Higuchi model, indicating diffusion-controlled release through the chitosan polymeric network. The formulated metformin nanoparticles demonstrated significant potent dose-related and time-dependent cytotoxic effect against ovarian cancer cell lines and in vivo blood glucose lowering effect compared to the conventional dosage forms and control (p < 0.05). These findings highlight the potential of metformin-loaded chitosan NPs for sustained drug delivery, which may enhance patient compliance by reducing dosing frequency. Future studies should further explore their clinical applications. Full article

Background: Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis, including reducing fat mass and lowering hyperglycemia, insulin resistance and dyslipidemia. It also increased metabolic syndrome (MS) and cardiovascular risk in breast cancer (BC) survivors treated with aromatase inhibitors (AIs) aimed at reducing cancer recurrence. We evaluated whether blood FGF21 concentration is associated with MS and its five criteria in postmenopausal women treated with AIs, and whether this persists after multimodal interventions that reduce MS. Methods: A quasi-experimental longitudinal study in 31 postmenopausal women with localized BC on Ais, assessed via a 12-week multimodal program. Their MS was evaluated per the NCEP-ATP III guidelines (waist circumference, blood pressure, fasting glucose, triglycerides, HDL-cholesterol). Plasma FGF21 was measured pre/post-intervention via fasting blood samples, centrifugation, and ELISA assay. Results: Pre-intervention FGF21 median: 377.62 pg/mL (38.40–1616.42). Plasma FGF21 concentrations positively correlated with MS criteria number pre- and post-intervention (all p < 0.05). Linear regression confirmed pre-intervention MS criteria (β = 127.262, p = 0.006) and antihypertensive drugs as predictors of post-FGF21 levels. Analysis of individual MS criteria revealed significant associations with blood pressure (p = 0.028 and p = 0.022 for systolic and diastolic pressure, respectively) and fasting glucose changes (p = 0.008). Conclusions: Plasma FGF21 may act as a biomarker for monitoring exercise-based interventions which reduce MSs, particularly hypertension and hyperglycemia, in AI-treated BC survivors. Full article

People affected by diabetes mellitus (DM), chronic kidney disease (CKD), or heart failure are often prescribed sodium–glucose cotransporter-2 inhibitors (SGLT2is) as a method of treatment. These drugs favorably affect glucose metabolism, as patients taking them have lower serum glucose levels. Another promising positive impact is protection against microvascular damage, cardiovascular disease, and chronic kidney disease. Nevertheless, fungal infections, urinary tract infections, and ketoacidosis are the adverse effects that might happen during the SGLT2i treatment. Fungal infections are more common among patients treated with these medications, including vulvovaginal Candidiasis in women and balanitis or balanoposthitis in men. Given the difficulty of treating fungal infections in patients with co-occurring diseases, we recommend that ongoing supervision of patients treated with SGLT2i include prevention and early detection of fungal infections. Full article

Acute mountain sickness (AMS) arises from hypobaric hypoxia at high altitude and still lacks effective pharmacological treatments. Although hypoxic preconditioning via gradual ascent prevents AMS, the underlying molecular adaptations have not yielded therapeutics. Here, inspired by metabolic reprogramming during stepwise altitude adaptation, we screened for anti-hypoxia compounds and identified H0802 (N-(pyridin-2-yl) pyridine-2-carbothioamide) as the most promising candidate. H0802 markedly enhances hypoxic tolerance in mice, prolongs survival under acute hypoxia, improves survival during simulated high-altitude exposure, and attenuates hypoxia-induced lung injury, accompanied by combined anti-inflammatory and antioxidant effects. Transcriptomic profiling shows that H0802 elicits a gene expression signature resembling hypoxia, including key hypoxia-related genes (Edn1, Angptl4, Mt1, Gdf15, Slc7a5, and Hif-3α) involved in glucose and oxygen metabolism. Mechanistically, H0802 stabilizes endogenous hypoxia-inducible factor (HIF) proteins under normoxia by preventing ubiquitin-dependent degradation, thereby activating hypoxia-responsive genes. In vivo, H0802 pretreatment lowers circulating glucose and hepatic glycogen while increasing brain glucose uptake, suggesting a metabolic shift that preserves cerebral energy during acute hypoxic stress; it also modulates whole-body oxygen consumption. H0802 represents a candidate for anti-AMS therapy, and phenotypic optimization of H0802 provides a potential route for drug discovery. Full article

Background: Ectopic fat deposition has been demonstrated to play a critical role in the onset and progression of renal dysfunction. However, research on renal parenchymal fat deposition and its association with renal dysfunction in type 2 diabetes mellitus (T2DM) remains limited, particularly regarding its association with early kidney injury. The present study aimed to further investigate the relationship between renal fat fraction (FF) and biomarkers of kidney injury, thereby providing new evidence for the potential link between intrarenal fat accumulation and early renal impairment in T2DM. Methods: This cross-sectional study enrolled 60 patients with T2DM. Renal FF was quantitatively assessed using magnetic resonance imaging (MRI). Clinical characteristics, body composition parameters, and biochemical indices were collected. Levels of kidney injury biomarkers, including tumor necrosis factor receptors 1 (TNF-R1), tumor necrosis factor receptors 2 (TNF-R2), chitinase-3-like protein 1 (YKL-40), and kidney injury molecule-1 (KIM-1), were measured using enzyme-linked immunosorbent assay (ELISA). To evaluate the correlations between fat distribution and inflammatory biomarkers, Pearson correlation analysis was performed. Furthermore, linear regression analysis was conducted to explore the associations between renal FF and kidney injury biomarkers with adjustments for potential confounders such as smoking status, diabetes duration, and visceral fat. Lasso regression was used to screen variables. Results: The results demonstrated that renal FF was significantly positively correlated with serum YKL-40 (r = 0.3, p = 0.021), TNF-R1 (r = 0.246, p = 0.042), and urinary KIM-1 (r = 0.396, p = 0.004), indicating a close association between renal fat accumulation and early kidney injury biomarkers. In regression analyses adjusted for age, sex, and duration of diabetes, the associations between renal FF and these biomarkers remained significant. After further adjustment for potential confounders, including smoking history, alcohol consumption, hypertension, renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporters 2 (SGLT2) inhibitors, glucagon-Like Peptide-1 (GLP-1) receptor agonists, and lipid-lowering drugs, renal FF remained significantly associated with TNF-R1 (β = 0.327, p = 0.015), KIM-1 (β = 0.352, p = 0.021), and YKL-40 (β = 0.275, p = 0.025). Moreover, even after additional adjustment for visceral fat, the associations of renal FF with TNF-R1 and KIM-1 persisted. After using the Benjamini–Hochberg procedure for false discovery rate, the relationship between renal FF and KIM-1 had a significant difference. Variables of age and gender were excluded to build the parsimonious modeling using Lasso regression. It suggested that renal fat accumulation may contribute to kidney injury independently of visceral adiposity. Conclusions: The study systematically demonstrates a significant association between renal FF and early biomarkers of kidney injury in T2DM, which may suggest the potential role of renal fat accumulation in the pathogenesis of diabetic nephropathy. These findings provide clinical data support for the development of a fat-targeted intervention study. Future research should further elucidate the long-term mechanistic role of renal FF in diabetic nephropathy, as well as its potential value in early diagnosis and therapeutic applications. Full article

Hypoxia activates hypoxia-inducible factors (HIFs), which regulate genes involved in erythropoiesis, angiogenesis, and metabolism. HIF stability is controlled by oxygen-dependent HIF prolyl 4-hydroxylases (HIF-P4Hs). Pharmacological HIF-P4H inhibitors are approved for the treatment of anaemia in chronic kidney disease (CKD). Beyond erythropoiesis, these drugs have been linked to improved lipid profiles in CKD, and preclinical studies suggest benefits for glucose tolerance and cardiovascular protection. However, cardiometabolic effects of HIF-P4H inhibitors have not been systematically examined in healthy or non-anaemic individuals. This investigator-initiated, double-blind, placebo-controlled, randomised crossover trial evaluates the systemic effects of roxadustat, an orally administered pan-HIF-P4H inhibitor. The study consists of two 10-day study arms separated by a minimum 4-week washout. Participants receive 70 mg of roxadustat or a placebo thrice a week. The primary hypothesis is that roxadustat lowers plasma total cholesterol. Secondary outcomes include changes in LDL cholesterol, triglycerides, insulin sensitivity, glucose tolerance, body composition, 24 h blood pressure, exercise capacity, autonomic cardiovascular regulation, and skeletal muscle microcirculation. Healthy volunteers (n = 24) aged 18–40 years will be enrolled. This study will provide insights into the potential of HIF-P4H inhibitors for obesity, dyslipidaemia, insulin resistance, and hypertension, and may inform future therapeutic strategies for metabolic syndrome, type 2 diabetes, and cardiovascular disease. Full article

Background: Elevated prolactin levels are associated with disturbances in female sexual function. While long-term therapy with dopamine agonists has been shown to improve these disturbances, the therapeutic benefits appear to be reduced in the presence of vitamin D deficiency or insufficiency. Therefore, the present study aimed to examine whether vitamin D status modulates the effects of metformin—a medication with less pronounced prolactin-lowering properties—on sexual function and depressive symptoms. Methods: The study cohort comprised three groups of reproductive-age women with drug-induced hyperprolactinemia and prediabetes, matched for age, glycated hemoglobin, and prolactin concentrations. Group I included 25 women with normal vitamin D status who were not receiving vitamin D supplementation. Group II consisted of 25 women with vitamin D deficiency or insufficiency that was adequately corrected through supplementation, while group III included 25 women with untreated vitamin D deficiency or insufficiency. All participants received metformin throughout the six-month study period. Female sexual function and depressive symptoms were assessed before and after metformin therapy using the Female Sexual Function Index (FSFI) and the Beck Depression Inventory-II (BDI-II), respectively. Additional outcome measures included plasma 25-hydroxyvitamin D, fasting plasma glucose, glycated hemoglobin (HbA_1c), the homeostatic model assessment of insulin resistance (HOMA-IR), prolactin, gonadotropins, and sex hormones. Results: Improvements in glucose homeostasis were observed across all groups; however, these changes were more pronounced in groups I and II than in group III. Reductions in prolactin concentrations (total and monomeric), accompanied by increases in gonadotropins, estradiol, and testosterone, were observed exclusively in women with normal vitamin D status. In groups I and II, metformin therapy resulted in significant improvements in total FSFI scores as well as in all individual domain scores. In contrast, in group III, the effects of metformin were limited to increases in the domain scores for lubrication and sexual satisfaction. Improvements in sexual function were positively associated with baseline 25-hydroxyvitamin D levels, reductions in prolactin concentrations, and, to a lesser extent, treatment-related changes in HbA_1c and increases in testosterone. A treatment-induced reduction in total BDI-II scores was observed only among women with normal vitamin D status. Conclusions: Low vitamin D status diminishes the beneficial effects of metformin on sexual function and depressive symptoms in reproductive-age women with iatrogenic hyperprolactinemia. Full article

Sodium-glucose co-transporter (SGLT) inhibitors are a novel class of glucose-lowering drugs with beneficial pleiotropic effects that have been widely investigated in the past decade in several experimental models and patients in the absence of diabetes. There are two types of transporters: the SGLT1 isoform that is distributed across a broad range of tissues, including the cardiovascular system, and the SGLT2 isoform, which is mostly expressed in renal proximal tubular cells. It is known that inflammation and oxidative stress are key contributors to vascular damage and the progression of atherosclerosis. SGLT inhibitors have demonstrated multiple benefits that contribute to improved vascular health, including alleviation of endothelial function, anti-inflammatory and antioxidative effects, and mitigation of arterial stiffness, all contributing to blood pressure decrease. An increasing body of research has tackled the molecular and cellular mechanisms of their chronic and, more recently, acute cardiovascular beneficial effects. This narrative review specifically delves into the direct vasculoprotective effects of SGLT2 and dual SGLT1/2 inhibitors, summarizing their off-target mechanisms described in various experimental settings (animal models, animal and human cell lines/samples). Full article

Ovarian cancer is a devastating disease that is often diagnosed in the late stages. The typical therapeutic approach includes surgery plus cytotoxic drugs such as carboplatin and paclitaxel. In recent years, the advent of poly ADP-ribose polymerase (PARP) inhibitors such as olaparib has offered additional treatment opportunities for patients with BRCA mutations or homologous recombination deficiencies. Nevertheless, resistance to therapy usually occurs, leading to poor overall survival. Therefore, novel treatments are needed for this disease. One of the obstacles to successful treatment is the highly immunosuppressive nature of the ovarian cancer microenvironment. Recent strategies for the treatment of ovarian cancer and other types of cancer involve targeting the metabolism of cancer cells and other cells of the tumor microenvironment. One drug that has been investigated both in preclinical studies and clinical trials as an antitumor agent is metformin. This drug, typically used for the treatment of type-2 diabetes for its capability to lower blood glucose, can directly affect cancer cell growth and survival by activating the AMPK (adenosine monophosphate-activated protein kinase) pathway. Furthermore, it can affect the phenotype of other cells of the tumor microenvironment such as macrophages and T cells. In this review, we summarize the main characteristics of ovarian cancer and describe preclinical studies and clinical trials involving metformin as a therapeutic agent for this disease. Full article

Background: Understanding patient-specific patterns of medication intensification and de-intensification is essential for personalizing diabetes management and minimizing hypoglycemia risk in patients with type 2 diabetes. Objectives: To assess treatment changes in hypoglycemia-associated medications over five years and explore patient characteristics associated with these changes. Methods: We conducted a longitudinal cohort study using the IADB.nl database containing prescription data from Dutch community pharmacies. Individuals aged ≥35 years with at least two dispensations of glucose-lowering medications were identified. We estimated transition probabilities of changes in hypoglycemia-associated medications (sulfonylureas and/or insulin) using a Markov model for each year of follow-up. Associations with age, sex, and estimated hypoglycemia risk were explored with regression analysis. Results: Overall, 25,057 patients were included. Medication remained unchanged for the majority of the patients in the follow-up period. De-intensification increased from 4.7% (Year 1) to 6.5% (Year 5), while intensification decreased from 7.7% to 6.9% over the same period. Markov models showed that patients predominantly remained in a no change state over 5 years (transition probabilities: 0.92–0.94). High estimated hypoglycemia risk, age and being female were associated with intensification and/or de-intensification. Conclusions: While treatment regimens remained unchanged for most patients, de-intensification of hypoglycemia-associated medications increased modestly over five years. Factors like hypoglycemia risk, age and sex influenced changes. These findings support the need for personalized, risk-stratified approaches to diabetes medication management. Full article