Search Results (5,509)

Background/Objectives: The relationship between hyperuricemia and diabetic retinopathy (DR) remains controversial despite both conditions being associated with vascular endothelial dysfunction. This study aimed to investigate the longitudinal association between hyperuricemia and the onset and progression of DR in patients with type 2 diabetes mellitus (T2D). Methods: We conducted a retrospective cohort study using patient data from initial visits between 2005 and 2022. Patients were categorized at baseline as having no DR (NDR), simple DR (SDR). The primary endpoint was the onset of DR from NDR, and the secondary endpoint was the progression of DR from SDR. Kaplan–Meier and Cox proportional hazards analyses were employed for statistical evaluation. Results: The study included 1972 patients (1702 with NDR and 270 SDR). In the overall NDR cohort, hyperuricemia was not significantly associated with the onset or progression of DR. However, upon stratification by baseline HbA1c, hyperuricemia was significantly associated with a higher incidence of DR within the high-HbA1c subgroup (≥9%) of the NDR cohort (HR 2.40, 95% CI [1.27–4.55]). Similarly, within the SDR cohort, a Kaplan–Meier analysis demonstrated a significantly higher rate of DR progression in the hyperuricemia group, exclusively among patients with HbA1c ≥ 9% (p = 0.01). Conclusions: Hyperuricemia is independently associated with the onset and progression of DR in T2D patients with poor glycemic control While often co-occurring with other DR risk factors, hyperuricemia may serve as a potential marker for the development of retinopathy in this high-risk population. Full article

Background and Objectives: Physical inactivity is a major modifiable lifestyle factor associated with type 2 diabetes mellitus (T2DM). However, real-world primary care datasets often rely on pragmatic clinical estimates of physical activity (PA) and may lack HbA1c, fasting glucose, dietary data, diabetes duration, and detailed medication information. Therefore, PA–T2DM associations in routine care must be interpreted within the limitations of cross-sectional observational data. Materials and Methods: This cross-sectional observational study analyzed 863 adult patients from a real-world primary care cohort. Participants were categorized into low, moderate, and high PA groups according to self-reported habitual weekly activity levels estimated during routine physician interviews. PA categories were based on clinically meaningful weekly activity thresholds consistent with public health recommendations. The primary outcome was documented T2DM. Secondary variables included lipid profile, blood pressure, body mass index, waist circumference, smoking status, and statin therapy. Multivariable logistic regression models were used to assess associations between PA category and T2DM, with high PA as the reference group. Results: T2DM prevalence showed a graded inverse cross-sectional association across PA categories, being highest in the low PA group (29.7%), intermediate in the moderate PA group (16.7%), and lowest in the high PA group (8.9%) (p < 0.001). In the fully adjusted model, low PA was strongly associated with higher odds of T2DM compared with high PA (odds ratio [OR] 4.32, 95% confidence interval [CI] 2.61–7.15, p < 0.001). Moderate PA was also associated with higher odds of T2DM compared with high PA (OR 2.07, 95% CI 1.23–3.48, p = 0.006). LDL-C differed significantly across PA groups, with the lowest values observed in the high PA group, whereas most other cardiometabolic parameters were comparable. Conclusions: Lower self-reported PA was strongly associated with higher T2DM prevalence after multivariable adjustment in this real-world primary care cohort. These findings support routine PA assessment as part of lifestyle-based cardiometabolic risk stratification. Because dietary intake, HbA1c, diabetes duration, glucose-lowering medication details, and regulatory biomarkers were not available, causal and mechanistic conclusions cannot be drawn. Future studies should integrate PA, nutritional assessment, glycemic markers, medication data, and physiological regulatory measures to better characterize lifestyle-related diabetes risk. Full article

Background and Objectives: Although the association between frailty and constipation in older adults has attracted growing attention, evidence linking the Clinical Frailty Scale (CFS) to colonic transit time (CTT) remains scarce. In this retrospective study, we examined this association using colon capsule endoscopy (CCE). Materials and Methods: We enrolled 124 older adults (64 men, 60 women) aged ≥ 65 years (mean age 74.6 ± 5.6) who underwent CCE for colorectal polyp screening at Aishinkai Nakae Hospital, Japan, between January 2014 and July 2024. CTT was determined at the time of CCE, and frailty was assessed with the Japanese version of the CFS. To avoid the oversimplification inherent in a strict dichotomy, participants were analyzed primarily as three ordered categories—Robust (CFS 1–2; n = 73), Intermediate (CFS 3–4; n = 43), and Frail (CFS 5–7; n = 8)—and, for comparability with previous reports, also as a Robust versus Non-robust (CFS 3–7; n = 51) dichotomy. The independent association between CFS and CTT was examined with three complementary multivariable linear regression models (Model 2: CFS continuous; Model 3: CFS three-category ordinal; Model 3b: CFS three-category dummy with Robust as reference), each adjusted for 10 covariates: age, sex, body mass index, type 2 diabetes mellitus, laxative use, anticholinergic drug use, psychotropic drug use, hypothyroidism, smoking history, and history of abdominal surgery. Results: CTT rose stepwise across the three frailty categories (Robust: 132.0 min [IQR 81.0–229.0], 157.9 ± 99.9; Intermediate: 198.0 min [90.5–267.0], 186.1 ± 99.8; Frail: 241.5 min [199.0–320.5], 295.8 ± 181.3; Kruskal–Wallis p = 0.027; Jonckheere–Terpstra P for trend = 0.017); the dichotomous comparison was concordant (median 214.0 vs. 132.0 min; Mann–Whitney U U = 1441.5; p = 0.033). A graded dose–response-like relationship was further supported by Spearman correlation between the CFS score and CTT (ρ = 0.232; p = 0.009). Women had significantly longer CTT than men (median 189 vs. 121 min; p = 0.013), and the three-group trend was significant within the female subgroup (Kruskal–Wallis p = 0.032) but not within men (p = 0.138). In multivariable analysis, CFS remained independently associated with CTT prolongation both as a continuous score (Model 2: β = 36.6 per 1-point increase; 95% CI 17.3 to 56.0; p < 0.001) and as an ordinal three-category predictor (Model 3: β = 52.7 per one-step advance; 95% CI 19.7 to 85.8; p = 0.002). In the dummy-coded specification (Model 3b), the Frail-versus-Robust contrast was markedly significant (β = 155.4 min; 95% CI 71.5 to 239.3; p < 0.001), whereas the Intermediate-versus-Robust contrast was not (β = 27.0; 95% CI −15.5 to 69.5; p = 0.210). Female sex retained independent significance across models (β ≈ 47–49 min; p = 0.016–0.021). The original dichotomous Non-robust versus Robust specification (Model 1) was no longer significant after full adjustment (p = 0.372). Conclusions: Frailty progression, as assessed by the CFS, is independently and monotonically associated with prolonged CTT in older adults, with the effect becoming statistically manifest predominantly at the more advanced end of the frailty spectrum and particularly in women. Although these findings do not establish causality between frailty and constipation—and frailty itself reflects a multifactorial age-related process that may not be fully reversible—CCE-measured CTT provides an objective, radiation-free physiological biomarker of frailty-related bowel dysfunction that may support risk stratification and inform future interventional trials targeting potentially modifiable components of the gut–muscle axis. Full article

Background: Anemia is frequently observed in patients undergoing transcatheter aortic valve implantation (TAVI) and may reflect persistent biological vulnerability in the post-procedural period. The relationship between systemic immune–inflammatory burden and anemia at entry into structured cardiac rehabilitation (CR) after TAVI remains insufficiently explored. Methods: This retrospective observational study included 80 consecutive patients referred to CR after successful TAVI. Anemia was defined by World Health Organization (WHO) criteria (hemoglobin <13 g/dL in men; <12 g/dL in women). Systemic inflammatory burden was assessed using C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and the systemic immune–inflammation index (SII = platelet × neutrophil/lymphocyte). Multivariable logistic regression, adjusted for age, sex, body mass index (BMI), type 2 diabetes mellitus, and estimated glomerular filtration rate (eGFR), was used to evaluate independent associations with anemia. Results: Anemia was present in 67.5% of patients at CR entry. Compared with non-anemic patients, anemic patients exhibited significantly higher CRP (4.25 vs. 2.58 mg/L; p = 0.014), NLR (2.86 vs. 2.34; p = 0.004), PLR (132.33 vs. 102.13; p = 0.003), and SII (566.01 vs. 448.30; p = 0.011). In multivariable models, NLR (OR 4.09; 95% CI 1.50–11.19; p = 0.006), PLR (OR 4.89; 95% CI 1.41–17.02; p = 0.013), SII (OR 4.96; 95% CI 1.35–18.14; p = 0.016), and CRP (OR 2.17; 95% CI 1.07–4.39; p = 0.032) were independently associated with anemia. Area under the ROC curve (AUC) was 0.70 for NLR and PLR, 0.68 for SII, and 0.67 for CRP. Conclusions: Systemic inflammatory burden is independently associated with anemia at the time of entry into CR facility after TAVI. These findings support an integrated approach to patient evaluation and provide a basis for future mechanistic and interventional studies. Full article

Background: Although conventional cardiovascular risk scores are widely used, they do not fully capture the molecular mechanisms underlying vascular injury in type 2 diabetes mellitus (T2DM). This study investigated the association between the miR-34a/SIRT1 regulatory axis and cardiometabolic risk in T2DM by integrating biomarkers of inflammation, oxidative stress, and endothelial dysfunction. Methods: A cross-sectional study included 128 adults (96 with T2DM and 32 non-diabetic controls). Cardiometabolic risk was stratified using the Framingham Risk Score. Circulating miR-34a expression was quantified by RT-qPCR, whereas SIRT1 and biomarkers of inflammation (IL-6, TNF-α, and hs-CRP), oxidative stress (MDA and TAC), and endothelial dysfunction (VCAM-1 and ICAM-1) were measured using ELISA or standardized biochemical assays. Multivariate regression and receiver operating characteristic (ROC) analyses were performed. Results: Compared with medium-risk patients, individuals classified as high risk exhibited longer diabetes duration, higher body mass index, blood pressure, fasting glucose, and HbA1c levels (all p < 0.05), together with increased circulating miR-34a, inflammatory, oxidative stress, and endothelial dysfunction biomarkers, whereas SIRT1 and total antioxidant capacity were significantly reduced (all p < 0.001). These molecular alterations remained independently associated with risk after adjustment for age, sex, body mass index, smoking status, physical activity, dyslipidemia, HbA1c, and medication use. The combined biomarker model integrating miR-34a, SIRT1, hs-CRP, MDA, and VCAM-1 demonstrated excellent discriminatory performance for identifying high-risk individuals (AUC = 0.92; sensitivity = 86.4%; specificity = 85.5%). Conclusions: Cardiometabolic risk in T2DM is associated with a coordinated molecular signature characterized by miR-34a upregulation, SIRT1 suppression, systemic inflammation, oxidative stress, and endothelial dysfunction. These findings suggest that integrated biomarker profiling may complement conventional risk assessment and support future precision cardiometabolic strategies. Full article

Background/Objectives: Depression ranks among the most prevalent mental health disorders worldwide. Numerous studies have linked the C-1019G (rs6295) polymorphism in the serotonin 1A (5-HT1A) receptor gene to increased susceptibility to depression. In this study, sociodemographic variables and clinical characteristics were integrated with targeted genotyping of the C-1019G polymorphism to identify risk factors associated with depressive symptoms in a Mexican cohort. Methods: Sociodemographic and clinical data were collected from 257 volunteers (202 healthy controls, 55 with depressive symptoms). Genotyping for C-1019G was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Sociodemographic variables, clinical characteristics, and genotype frequencies were analyzed relative to Beck Depression Inventory II (BDI-II) scores. Results: BDI scores were significantly lower among males, participants aged < 40 years, unmarried individuals, and those with a high school education (p < 0.05). Females were three times more likely to exhibit depressive symptoms than males (p = 0.004; OR = 3.08). Compared with participants aged < 40 years, those aged 40–65 and >65 years were two (p = 0.026; OR = 2.19) and five times (p < 0.001; OR = 5.71) more likely to report depressive symptoms, respectively. Participants with type 2 diabetes mellitus had twice the odds of depressive symptoms (p = 0.025; OR = 2.38). Odds increased twelvefold among those with diabetes plus arterial hypertension (p < 0.001; OR = 12.25). Among males, the C/C genotype was observed exclusively in controls (p = 0.010). Furthermore, the genotypic distribution of this study population differed from that of European and Asian populations. Conclusions: These findings advance the understanding of depressive symptoms’ multifactorial etiology and may inform targeted screening and prevention strategies. Full article

Background/Objectives: Metabolic syndrome (MetS), defined by abdominal obesity, dysglycemia, dyslipidemia, hypertension, and insulin resistance, markedly increases the risk of type 2 diabetes mellitus and cardiovascular disease. Affecting an estimated 25–30% of the global adult population, MetS represents a major and growing public health challenge. A growing body of evidence supports a significant bidirectional relationship between MetS and oral health, particularly periodontitis. The present study aimed to synthesize current evidence on the pathophysiological mechanisms, epidemiological associations, interventional outcomes, and clinical implications of the bidirectional relationship between metabolic syndrome (MetS) and periodontitis. Methods: A narrative review following the SANRA framework was performed. PubMed, Scopus, and Web of Science were searched for articles published in January 2021–March 2026 using MeSH and free-text terms including “metabolic syndrome”, “periodontal disease”, “insulin resistance”, and “oral microbiota”. Eligible studies included original research and systematic reviews in English with full-text availability; animal and in vitro studies were included if directly informative of mechanistic pathways. Results: A total of 64 references were selected for inclusion. Shared mechanisms include chronic systemic inflammation, insulin resistance, oxidative stress, adipokine imbalance, endothelial dysfunction, and oral–gut microbiome dysbiosis. Cross-sectional and longitudinal studies show that MetS components are independently associated with higher prevalence and severity of periodontitis; meta-analyses report pooled odds ratios of 1.7–1.9 compared with metabolically healthy controls. Non-surgical periodontal therapy produces modest but significant reductions in glycated hemoglobin (HbA1c) and systemic inflammatory markers. Sodium–glucose cotransporter-2 (SGLT2) inhibitors may alter oral microbiota composition and cause mucosal changes, while glucagon-like peptide-1 (GLP-1) receptor agonists may increase caries risk through gastrointestinal side effects and xerostomia; both drug classes warrant proactive dental monitoring. Conclusions: The bidirectional relationship between MetS and oral health supports integrated screening and interdisciplinary management. Routine periodontal assessment should be integrated into the metabolic risk management pathway, and dental professionals should screen patients with severe periodontitis for metabolic risk factors. The oral microbiome emerges as a promising target for future mechanistic research and therapeutic intervention. Recognition of oral health as an integral component of metabolic health may improve risk stratification, prevention, and long-term patient outcomes. Large-scale randomized controlled trials with standardized endpoints are needed to establish causal directionality and optimize combined therapeutic strategies. Full article

Dapagliflozin (DAPA), a selective sodium–glucose cotransporter 2 inhibitor, is widely used in the management of type 2 diabetes mellitus, with additional indications in heart failure and chronic kidney disease. The growing analytical demand for DAPA determination in pharmaceutical formulations, fixed-dose combinations, and biological matrices has stimulated the development of diverse analytical methods. This review provides a comprehensive evaluation of reported techniques for DAPA quantification in different matrices. Approaches discussed include chromatographic methods (TLC, RP-HPLC, UHPLC, LC-MS/MS), electromigration techniques (CE), and spectroscopic methods (UV–Vis, spectrofluorimetry). Emphasis is placed on key performance characteristics such as selectivity, sensitivity, linearity, robustness, and applicability to stability studies and bioanalysis. Recent trends, including the application of Quality by Design, green analytical chemistry principles, and advanced hyphenated techniques, are also addressed. While RP-HPLC remains widely used for routine quality control due to its robustness and accessibility, LC-MS/MS is generally regarded as the method of choice for trace-level bioanalysis owing to its superior sensitivity and selectivity. CE and spectroscopic techniques offer cost-effective and environmentally friendly alternatives, though with certain limitations. This review highlights current methodological gaps and outlines future directions for developing more sensitive and sustainable analytical strategies. Full article

Background and Clinical Significance: Marfan syndrome (MFS) is an autosomal-dominant connective-tissue disorder caused by pathogenic FBN1 variants. Aortic-root dilation and dissection are the canonical complications, whereas spontaneous vertebral artery dissection (VAD) is described only sporadically. Yet, cerebrovascular events are several-fold more common in MFS, and up to 74% of patients exhibit increased vertebral artery tortuosity, a validated predictor of dissection; Case Presentation: A 32-year-old African man with hypertension, type 2 diabetes mellitus, tobacco use, and headaches labelled as migraine presented with acute agitation, visual disturbance, vertigo, dysarthria, and right-sided weakness of two hours’ duration. Examination disclosed previously unrecognised marfanoid stigmata: arachnodactyly with positive wrist and thumb signs, reduced upper-to-lower segment ratio, increased arm-span-to-height ratio, dolichocephaly, pectus excavatum, and a high-arched palate. Non-contrast CT showed left occipital and posterior inferior cerebellar hypodensities. CT angiography demonstrated discontinuous intraluminal filling defects in the left vertebral artery at C4 and C2, and MR angiography confirmed long-segment occlusion/stenosis of the intracranial left vertebral artery. Echocardiography revealed mild aortic-root dilation (4.0 cm; Z-score +2.53) and a small patent foramen ovale (PFO) with a positive bubble study. The patient received intravenous thrombolysis followed by antiplatelet therapy, a high-intensity statin, antihypertensive therapy, and intensified glycaemic control. Because the infarct territory matched the dissected vessel and the small PFO carried no high-risk features (RoPE score 6; PASCAL category “unlikely”), VAD was designated the culprit lesion and the PFO incidental; Conclusions: Spontaneous VAD may be the inaugural manifestation of unrecognised MFS, antedating aortic complications. In young adults with cryptogenic posterior-circulation stroke and marfanoid features, early cervical imaging and Ghent assessment are warranted, and a coexistent PFO should not be assumed causal. Multidisciplinary evaluation supports accurate attribution and surveillance. Full article

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening condition characterized by elevated pulmonary vascular resistance eventually causing right ventricular failure and premature death. Despite advances in targeted therapies, morbidity and mortality levels remain high, highlighting the need for additional treatment strategies that address the disease’s multifactorial pathophysiology. Attention has recently centred on two pharmacological groups with proven roles in other cardiovascular settings: sodium–glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs). SGLT2 inhibitors have demonstrated robust clinical benefits in heart failure (HF), type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), extending survival and reducing hospitalizations. Although their primary actions involve renal glucose and sodium handling, accumulating evidence suggests they may also exert favourable effects on the pulmonary vasculature, endothelial function, and right ventricular performance. In parallel, elevated aldosterone levels have been implicated in vascular remodelling, inflammation, and fibrosis in PAH, suggesting a potential therapeutic role for MRAs. However, the strength and clinical significance of these associations remain under investigation. The aim of this review is to synthesize and critically appraise the current evidence regarding the potential role of SGLT2 inhibitors and MRAs in the treatment of pulmonary arterial hypertension, exploring their mechanistic rationale, preclinical findings, and available clinical data to determine whether these agents may offer additional therapeutic benefit in PAH management. Full article

Background: Food insecurity (FI), which is defined as limited or uncertain access to sufficient, nutritious food, disproportionately affects low-income populations and has been linked to poor control of chronic diseases including type 2 diabetes mellitus (T2DM) with North Louisiana having one of the highest rates of FI in the United States. The interaction between FI and neighborhood-level socioeconomic disadvantage has not been well characterized in relation to microvascular diabetic complications. Objective: This study aimed to evaluate the relationship between FI, socioeconomic disadvantage, and microvascular complications in patients with T2DM. Methods: A retrospective cohort study of 163 adult patients with T2DM who received care at Ochsner LSU Health clinics in Shreveport and Monroe, Louisiana, between January 2018 and January 2023 were reviewed. FI status, Area Deprivation Index (ADI), a validated measure on neighborhood socioeconomic disadvantage, and microvascular complication outcomes including nephropathy, neuropathy, and retinopathy were obtained from electronic medical records. FI was assessed using the validated two-item Hunger Vital Sign screening tool. Results: The study found that FI alone was not a statistically significant predictor of nephropathy based on microalbumin-to-creatinine ratio (MACR). However, the combination of FI and high ADI (≥7) was significantly associated with neuropathy (p = 0.024) and retinopathy (p < 0.001), particularly among patients with T2DM for more than five years. Additionally, the interaction between FI and high ADI was also found to influence MACR values significantly (p = 0.026), indicating that socioeconomic stressors may exacerbate kidney dysfunction. Conclusions: Food insecurity, coupled with socioeconomic adversity, was associated with an increased risk of microvascular complications in T2DM. These results highlight the importance of integrating FI screening and addressing social determinants of health in high-risk populations. Early identification and targeted interventions could help mitigate disease progression and reduce health disparities. Full article

Background/Objectives: Atherogenic dyslipidemia is a major cardiometabolic risk factor characterized by elevated circulating triglycerides (TGs), reduced HDL-C, and increased levels of atherogenic lipoproteins. Curcumin, a polyphenolic compound considered the main bioactive component of turmeric (Curcuma longa), has attracted growing interest because of its potential lipid-modifying and anti-inflammatory properties. This scoping review aimed to evaluate evidence from randomized controlled trials (RCTs) on the efficacy of curcumin supplementation in the management of atherogenic dyslipidemia and to summarize current mechanistic evidence related to curcumin absorption, metabolism, and regulation of lipid homeostasis. Methods: A PRISMA-ScR-guided scoping review was performed across five databases (PubMed, Scopus, Web of Science, Cochrane Library, and Embase). RCTs evaluating curcumin supplementation in atherogenic dyslipidemia or related cardiometabolic conditions were systematically identified and synthesized. Mechanistic and preclinical evidence was identified through separate topic-specific searches of PubMed, Scopus, and Web of Science, supplemented by citation searching, and was synthesized narratively. Results: Twenty-two RCTs published between 2008 and 2025 were included. Most studies involved patients with cardiometabolic disorders, including type 2 diabetes mellitus with hyperlipidemia, metabolic syndrome, and polycystic ovary syndrome. Curcumin supplementation, administered in various formulations and dosages, showed overall favorable effects on plasma lipid profiles, particularly TGs and LDL-C, although the magnitude of these effects varied across studies. Mechanistic and preclinical evidence suggested that curcumin may modulate multiple pathways involved in lipid homeostasis, including intestinal cholesterol uptake, hepatic lipogenesis, cholesterol synthesis, fatty acid oxidation, bile acid metabolism, and reverse cholesterol transport. Conclusions: Current evidence suggests that curcumin may improve atherogenic lipid profiles through pleiotropic effects on lipid metabolism and cholesterol homeostasis. The clinical efficacy of curcumin appears to depend substantially on formulation-related bioavailability. Despite inter-study heterogeneity, curcumin shows potential as an adjunctive strategy for the management of atherogenic dyslipidemia and associated metabolic disorders. Full article

Cardiometabolic residual risk in type 2 diabetes mellitus (T2D) persists despite major advances in glucose-lowering therapy, lipid management, blood pressure control, weight reduction, and organ-protective strategies. This residual burden should not be interpreted solely as the consequence of incomplete achievement of conventional therapeutic targets, but rather as the clinical expression of persistent molecular activity involving multiple interconnected organs and pathways. Insulin resistance, metaflammation, oxidative stress, mitochondrial dysfunction, lipotoxicity, endothelial impairment, hepatic metabolic dysregulation, renal inflammation, fibrotic remodeling, and metabolic memory interact within a dynamic network linking adipose tissue, liver, kidney, immune cells, and vasculature. In this review, we discuss the biochemical and molecular drivers of cardiometabolic residual risk in T2D, with particular emphasis on impaired insulin receptor substrate/PI3K/Akt signaling, stress-kinase activation, NLRP3 inflammasome priming and assembly, MASLD-related lipotoxicity and fibrogenesis, podocyte and tubular injury, endothelial nitric oxide synthase uncoupling, AGE-RAGE signaling, and thrombo-inflammatory vascular injury. These pathways explain why biological vulnerability may persist even when conventional clinical parameters appear adequately controlled. We also examine the role of translational biomarkers and simple clinical indices, including TyG-derived indices, adiposity markers, hepatic steatosis and fibrosis scores, albuminuria, eGFR, and lipid-related markers, as accessible windows into active biological pathways. Finally, we review how contemporary therapeutic strategies may modulate selected components of this residual-risk network. A pathway-centered interpretation of T2D may support more precise residual-risk phenotyping and help move cardiometabolic care beyond isolated target control toward mechanism-based prevention. This review further links these mechanisms to the contemporary cardiovascular–kidney–metabolic (CKM) framework, as defined by the 2026 AHA/ACC/ADA/ASN CKM Guideline, and disaggregates the underlying molecular network into organ-specific pathway cascades that make the causal relationships between metabolic, inflammatory, hepatic, renal, and vascular injury more explicit. Full article

Background/Objectives: Diabetes mellitus type 2 (T2DM) is often associated with hypertension, necessitating treatment with combinations of medications that address both glycemic control and blood pressure. Whether commonly co-prescribed antihypertensives modify the glycemic efficacy of a sulfonylurea remains insufficiently characterized in controlled preclinical models. Methods: One hundred adult male Wistar rats were allocated to ten parallel groups (n = 10): healthy and diabetic untreated controls; glimepiride, bisoprolol or amlodipine monotherapy (in healthy and diabetic animals); and the diabetic combinations glimepiride+bisoprolol and glimepiride+amlodipine. T2DM was induced with a high-fat diet plus low-dose streptozotocin (35 mg/kg, i.p.) and confirmed by fasting blood glucose ≥ 200 mg/dL. Glycated hemoglobin (HbA1c) was measured weekly for 11 weeks. Non-parametric inference (Kruskal–Wallis, Dunn’s with Bonferroni correction, Mann–Whitney U, Wilcoxon signed-rank) was complemented by Random Forest regression and PCA/K-means clustering. Results: Week-11 HbA1c differed markedly across groups (Kruskal–Wallis H = 94.3, p < 0.001). Glimepiride + bisoprolol achieved near-normal control (4.37% ± 0.15), statistically indistinguishable from healthy groups (p ≥ 0.33), and was the only diabetic regimen with a declining trajectory (−0.66 percentage points; Wilcoxon p = 0.004). Adding either antihypertensive to glimepiride did not worsen glycemic control. Amlodipine monotherapy did not attenuate hyperglycemia (8.47% ± 0.20), approaching that of untreated diabetic controls (9.31% ± 0.18), consistent with the absence of intrinsic glucose-lowering activity. All agents showed pronounced disease-state dependence (healthy–diabetic divergence 2.33–3.13 points). Random Forest prediction was accurate (R² = 0.985), and unsupervised clustering separated effective from ineffective regimens, corroborating the statistical findings. Conclusions: In this model, bisoprolol co-administration enhanced and amlodipine co-administration preserved glimepiride-mediated glycemic control. Glimepiride+bisoprolol emerged as the most effective regimen, supporting cardioselective β-blockade as a metabolically favorable antihypertensive partner for sulfonylurea therapy and warranting clinical confirmation. More broadly, these results provide a preclinical, evidence-based rationale for selecting metabolically favorable antihypertensives in patients with coexisting T2DM and hypertension, with the potential to improve glycemic outcomes and reduce the risk of adverse drug–disease interactions during combination therapy. Full article