Search Results (373)

Endothelial dysfunction is a key mechanism linking obesity, metabolic disturbances, and cardiovascular disease, contributing to the development and progression of atherosclerosis and other vascular complications. This review provides a comprehensive overview of the molecular mechanisms underlying endothelial dysfunction in obesity and discusses current diagnostic approaches and therapeutic strategies aimed at restoring vascular homeostasis. The available evidence indicates that chronic inflammation, oxidative stress, insulin resistance, reduced nitric oxide bioavailability, increased reactive oxygen species production, and dysregulated adipokine signaling play central roles in endothelial impairment. Recent advances in functional vascular assessment, circulating biomarkers, and imaging techniques have improved the early identification of endothelial dysfunction and cardiovascular risk. Current therapeutic strategies include pharmacological agents, such as glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter 2 inhibitors, metformin, and dipeptidyl peptidase-4 inhibitors, together with lifestyle interventions based on healthy dietary patterns and regular aerobic and resistance exercise. These approaches improve glycemic control, reduce inflammation and oxidative stress, enhance endothelial function, and contribute to cardiovascular protection. Overall, the evidence supports an integrated and personalized management strategy targeting both metabolic and vascular abnormalities to reduce cardiovascular risk and improve long-term clinical outcomes in individuals with obesity. Full article

Type 2 diabetes mellitus (T2DM) is often linked to metabolic dysfunction-associated steatotic liver disease (MASLD), a metabolic liver condition defined by excessive lipid deposition within hepatocytes and is frequently accompanied by increased circulating liver enzyme levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors, such as linagliptin, may exert pleiotropic effects on hepatic metabolism; however, their effects on liver enzyme profiles remain uncertain. This systematic review and meta-analysis aimed to evaluate the impact of linagliptin on liver enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT), in patients with T2DM. A systematic literature search was performed across five electronic databases up to 11 May 2026 following the PRISMA 2020 guidelines. Randomized controlled trials and cohort studies were included, and pooled mean differences (MDs) were calculated using random-effects models. Eight studies involving 1262 participants were analyzed. Linagliptin was associated with a modest reduction in AST (MD −1.58 U/L, 95% CI −2.85 to −0.31) with low heterogeneity, whereas the change in ALT was not statistically significant (MD −1.86 U/L, 95% CI −4.14 to 0.42), and substantial heterogeneity was observed. No significant effects were observed for GGT, while evidence for ALP was limited to a single study and was insufficient to determine the effect of linagliptin. Overall, linagliptin demonstrated limited and inconsistent effects on liver enzyme profiles. Full article

As the prevalence of type 2 diabetes increases rapidly, the demand for natural origin dipeptidyl peptidase-IV (DPP-IV) inhibitors with fewer side effects is increasing. In this study, protein-rich Limnospira platensis was investigated as a source of bioactive peptides to enhance its value as a functional food ingredient. Hydrolysates were prepared using three food-processing proteases, individually and in two-step combinations, followed by in silico analysis and peptide identification via liquid chromatography–tandem mass spectrometry. Subsequently, the thermal stability, gastrointestinal resistance, and intestinal permeability (using Caco-2 cells) of the identified peptides were evaluated. It was revealed that the Orientase 22BF digest exhibited high DPP-IV inhibitory activity. From the digest, three novel peptides—SPSPN (IC₅₀ = 144.1 ± 2.2 μM), VPSV (IC₅₀ = 93.6 ± 5.8 μM), and IPIGG (IC₅₀ = 13.4 ± 2.3 μM)—were identified, exhibiting DPP-IV inhibitory potencies comparable to or higher than previously reported Limnospira-derived peptides. Although VPSV exhibited low epithelial permeability (P_app = 4.02 ± 0.69 × 10⁻⁸ cm/s), it remained stable under simulated gastrointestinal digestion conditions, suggesting potential local luminal inhibitory activity within the small intestine. Overall, these findings highlight Limnospira-derived VPSV as a promising functional ingredient candidate with high bioactivity and digestive stability. Full article

Background and Objectives: Sodium–glucose cotransporter-2 (SGLT2) inhibitors provide cardio-renal protection in type 2 diabetes, but tolerability-related discontinuation is common, creating a need for effective replacement therapy. Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used as follow-on agents, yet the clinical course after such a switch has not been systematically characterized, and whether individual DPP-4 inhibitors differ in efficacy in this setting is unknown. Materials and Methods: We conducted a single-center retrospective cohort study at Chungnam National University Hospital (Daejeon, Republic of Korea) between January 2013 and January 2025, including 117 adults with type 2 diabetes who switched from an SGLT2 inhibitor to a DPP-4 inhibitor and met pre-specified criteria for medication stability and follow-up. The primary outcome was the change in glycated hemoglobin (HbA1c) from baseline to 3 months; secondary outcomes were changes in body weight, body mass index, blood pressure, and renal parameters. A pre-specified subgroup analysis compared teneligliptin (n = 60) with other DPP-4 inhibitors as a class (n = 57). Results: In the overall cohort, body weight rose by 0.7 kg and systolic blood pressure by 4.3 mmHg at 3 months (both p < 0.05), whereas HbA1c was unchanged (p = 0.157). In the subgroup analysis, HbA1c fell significantly with teneligliptin (−0.36%; 95% confidence interval, −0.62 to −0.10; p = 0.009) but not with other DPP-4 inhibitors (+0.13%). The between-group difference was −0.49% (95% confidence interval, −0.83 to −0.15; p = 0.005) and persisted after adjustment for baseline HbA1c and estimated glomerular filtration rate (p = 0.007). Conclusions: Switching preserved overall glycemic control at 3 months but produced modest, anticipated increases in body weight and blood pressure. Teneligliptin was associated with a greater HbA1c reduction than the pooled group of other DPP-4 inhibitors; this association persisted after adjustment for the two available baseline covariates but could not be adjusted for diabetes duration, medication adherence, diabetic complications, or other unmeasured factors. Because confounding by indication and other residual confounding cannot be excluded in this short-term, single-center analysis, this finding is hypothesis-generating only and requires confirmation in adequately powered prospective head-to-head trials. Importantly, this study evaluated only the glucose-lowering effect of the switch; because the cardio-renal protection of SGLT2 inhibition is not reproduced by DPP-4 inhibitors, a DPP-4 inhibitor should be regarded as an unavoidable substitute when an SGLT2 inhibitor cannot be maintained rather than a therapeutically equivalent replacement, and preserved HbA1c at 3 months does not establish clinical equivalence between the two strategies. Full article

Background: Hereditary angioedema (HAE) is a rare, potentially life-threatening disease in which delayed recognition and inappropriate medication use may result in preventable morbidity and mortality. We aimed to assess physicians’ knowledge regarding HAE-related triggers, clinical features, and management strategies across multiple medical specialties. Methods: This single-center, cross-sectional survey was conducted among 350 physicians at a tertiary training and research hospital. A structured electronic questionnaire assessed knowledge of HAE pathophysiology, diagnosis, medication-related triggers, and management. A predefined composite knowledge score (0–14) was calculated. Results: Although self-reported familiarity with HAE was high, overall disease-specific knowledge was limited. Awareness of critical medication-related triggers—including angiotensin-converting enzyme inhibitors, dipeptidyl peptidase-4 inhibitors, and estrogen-containing therapies—was low across all specialties, with no significant between-group differences. Substantial knowledge gaps were identified in the recognition of clinical features, diagnostic evaluation, and acute management. In multivariable analysis, prior clinical exposure to HAE patients was the only independent predictor of higher knowledge scores (B = 1.097, p = 0.001), whereas specialty group, gender, and years of professional experience were not independently associated with knowledge scores. However, the regression model explained only a small proportion of the variance in knowledge scores. Conclusions: Significant gaps in clinically relevant HAE knowledge persist among physicians from multiple medical specialties. Prior clinical exposure was associated with higher knowledge scores, whereas specialty group, gender, and years of professional experience were not independently associated with physician knowledge. Targeted, practice-oriented educational interventions focusing on medication-related triggers and acute management may help bridge these knowledge gaps, complement experiential learning, and ultimately enhance patient safety. Full article

Papillary thyroid cancer (PTC) exhibits Warburg-type metabolic reprogramming with enhanced glycolysis and dependence on glucose-driven pathways. This study evaluated the effects of antihyperglycemic interventions on cytokine secretion, angiogenic signaling, metabolic activity, and proliferation in thyroid-derived cell models. Two PTC cell lines (MDA-T32 and SCC147) and a normal thyroid line (Nthy-ori) were analyzed for intracellular and extracellular cytokines, secretion efficiency (index), relative metabolic index (RMI), and marker of proliferation (Ki-67) expression following exposure to vandetanib (VDT), sodium–glucose cotransporter 2 (SGLT2), or dipeptidyl peptidase (DPP) inhibitors. Baseline analysis revealed distinct cell line-specific profiles. Compared with Nthy-ori cells, MDA-T32 cells exhibited increased vascular endothelial growth factor (VEGF) concentrations in lysates and conditioned medium (p < 0.001, q < 0.001) with enhanced VEGF secretion efficiency (p = 0.002, q = 0.008), elevated intracellular fibroblast growth factor (FGF) (p < 0.001, q < 0.001) with reduced FGF secretion index (p = 0.004, q = 0.01), and lower interleukin 8 (IL-8) concentrations accompanied by increased IL-8 secretion efficiency (p = 0.006, q = 0.02). In contrast, SCC147 cells demonstrated reduced VEGF secretion (p < 0.001, q < 0.001), decreased intracellular IL-8 (p = 0.008, q = 0.02), reduced chemokines of the growth-regulated oncogene GROβ family (GROβ) secretion (p = 0.01, q = 0.04), increased IL-8 secretion efficiency (p = 0.01, q = 0.03), and decreased GROβ secretion efficiency (p = 0.008, q = 0.02). Nthy-ori cells displayed a balanced profile. Among the investigated interventions, VDT produced the most pronounced effects. In MDA-T32 cells, VDT significantly reduced VEGF levels (p < 0.001, q < 0.001) and increased IL-8 and GROβ concentrations in conditioned medium (q < 0.05), whereas no significant effects after FDR correction were observed in SCC147 or Nthy-ori cells. SGLT2 and DPP inhibitors produced only nominal effects (p < 0.05), which did not remain significant after correction for multiple testing. VDT reduced RMI by approximately 50% in MDA-T32 cells while Ki-67 expression increased, whereas SCC147 cells remained largely unchanged. In Nthy-ori cells, SGLT2 inhibition increased RMI and decreased Ki-67 expression. These findings demonstrate marked heterogeneity among PTC cell lines and suggest that alterations in metabolic activity were not consistently accompanied by proportional changes in proliferative status under the experimental conditions used. VDT predominantly affected angiogenic and inflammatory signaling in MDA-T32 cells, whereas SGLT2 and DPP inhibition exerted limited measurable effects at clinically achievable concentrations. Full article

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests these agents may influence athletic performance through effects on body composition, energy metabolism, and cardiovascular function. This narrative review critically evaluates whether incretin therapies could constitute doping under World Anti-Doping Agency (WADA) criteria. We narratively reviewed the literature on incretin pharmacology, metabolic effects relevant to athletic performance, and anti-doping regulations, searching PubMed, Scopus, and Web of Science using terms including “GLP-1 receptor agonists”, “DPP-4 inhibitors”, “doping”, “athletic performance”, “WADA”, and “sports pharmacology”, without date restrictions. GLP-1 RAs (semaglutide, liraglutide, tirzepatide, exenatide) induce substantial weight loss (predominantly fat mass) but also reduce lean mass by 20–30% of total weight loss. Preclinical studies demonstrate enhanced exercise endurance, mitochondrial biogenesis, and glucose uptake via GLP-1R/AMPK signaling. However, clinical trials show no consistent improvement in physical performance in humans. Currently, incretin therapies are not listed on the WADA Prohibited List. While incretin therapies offer theoretical performance-enhancing potential through weight management and metabolic optimization, current evidence does not support classification as doping agents. Continued surveillance is warranted as misuse patterns emerge. Full article

Marine rest raw materials are often undervalued or wasted despite their nutrient and bioactive composition. Calanus finmarchicus, harvested primarily for its omega-3-rich oil, yields a side-stream protein hydrolysate, C. finmarchicus hydrolysate (CFH), during commercial enzyme-assisted extraction. Although currently used as a feed ingredient, CFH contains low-molecular-weight peptides and free amino acids with potential for human health applications. This study evaluated the gastrointestinal stability of CFH and the impact of digestion on bioactivity using a static in vitro gastrointestinal digestion model. Fresh-frozen and freeze-dried C. finmarchicus were included to provide comparative data. Antioxidant capacity was measured by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays, and antidiabetic activity by dipeptidyl peptidase-IV (DPP-IV) and protein tyrosine phosphatase 1B (PTP1B) inhibition assays. The hydrolysate maintained its antioxidant capacity throughout digestion (at 165 min: FRAP: 27.5 ± 0.6 µmol TE/g dry weight (DW); ORAC: 411 ± 37 µmol TE/g DW). Digestion increased its DPP-IV inhibitory activity, with the inhibitory concentration (IC₅₀) decreased from 3.73 to 1.96 mg/mL (p ≥ 0.05). PTP1B inhibitors were nonselective and detected only at 0 and 30 min. These findings support our hypothesis that CFH may serve as a nutraceutical for humans and provide a rationale for subsequent in vivo studies. However, further identification of bioactive components and in vivo validation are warranted. Full article

Background: Linagliptin, a potent and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes, enhances glucagon-like peptide-1 (GLP-1) signaling. Because GLP-1 receptors are widely expressed in the brain, DPP-4 inhibitors have emerged as potential modulators of central nervous system function. The present study investigated the effects of linagliptin (10 and 20 mg/kg, i.p.) on ketamine- (10 mg/kg, i.p.) and diazepam-induced (2 mg/kg, i.p.) deficits in passive avoidance performance in mice. Behavioral effects were assessed using the passive avoidance test, and brain-derived neurotrophic factor (BDNF) levels in the prefrontal cortex and hippocampus were determined by enzyme-linked immunosorbent assay (ELISA). Linagliptin attenuated ketamine- and diazepam-induced deficits in passive avoidance performance. In addition, both acute and chronic administration of linagliptin increased BDNF levels in the prefrontal cortex but not in the hippocampus. These findings provide preliminary evidence that linagliptin modulates passive avoidance performance in mice and is associated with increased BDNF levels in the prefrontal cortex. Further studies employing complementary behavioral paradigms and additional molecular approaches are required to clarify the neuropharmacological mechanisms underlying these effects. Full article

Dipeptidyl peptidase-4 (DPP-4) is a key therapeutic target for type 2 diabetes (T2D). Several synthetic anti-DPP-4 drugs are currently available for the treatment of T2D; however, the need for safe and effective therapies remains unmet due to the side effects associated with existing DPP-4 inhibitors. This study aimed to integrate structure-based and machine learning (ML)-based virtual high-throughput screening to identify natural DPP-4 inhibitors. Random forest, logistic regression, support vector machine (SVM), and multilayer perceptron (MLP) models were trained on DPP-4 IC₅₀ datasets. Among these, the SVM and MLP models achieved high predictive performance, with areas under the curve of 0.928 and 0.923, respectively. Screening of a natural compound database identified 107 compounds for further analysis. Subsequent structure-based screening, using sitagliptin as a positive control, identified sennidin B and doxorubicin hydrochloride as promising candidates with strong binding affinity for DPP-4. Molecular dynamics simulations (200 ns) and MM-PBSA calculations confirmed stable interactions with DPP-4. Further, sennidin B and doxorubicin hydrochloride inhibited DPP-4 activity in a concentration-dependent manner, with estimated IC₅₀ values of 39.39 and 19.78 μM, respectively. Sennidin B also reduced DPP-4 mRNA and protein expression levels in Caco-2 cells. Overall, sennidin B shows promise as a natural DPP-4 inhibitor and warrants further investigation as a potential antidiabetic agent. Full article

Background: Chronic kidney disease presents a significant health challenge among the elderly, with recent data indicating a 13.9% prevalence for early stages (1–3) and a lower 0.6% prevalence for advanced stages. Notably, many geriatric patients die from cardiovascular complications before reaching end-stage kidney disease, highlighting the critical interplay between renal and cardiovascular health. Central to this connection is endothelial dysfunction, considered the initial trigger for cardiovascular mortality. We aimed to investigate the correlation between different measurement methods demonstrating endothelial dysfunction and sVE-cadherin levels. Another objective was to examine the relationship between decreased glomerular filtration rate (GFR) and sVE-cadherin levels. We hypothesized an inverse relationship between impaired renal function, endothelial dysfunction, and sVE-cadherin. Methods: The study included geriatric patients with CKD who were not receiving RRT. Non-geriatric patients, those with cardiovascular disease, atrial fibrillation, heart failure, active immunosuppressive use, active infection, history of active malignancy, Raynaud’s phenomenon, and renal transplantation patients were excluded. Demographic data of the patients, nailfold capillary measurements, carotid intima-media thickness, flow-mediated dilatation, sVE-cadherin, and serum fibroblast growth factor 23 (FGF23) levels were measured. Results: We analyzed 96 patients. Key findings revealed a significant inverse correlation between serum sVE-cadherin levels and glomerular filtration rate (GFR), suggesting that, as kidney function declines, endothelial integrity is compromised. Interestingly, patients treated with sodium–glucose co-transporter-2 inhibitors had notably lower sVE-cadherin levels, indicating the possible modulatory effect of these drugs on endothelial function. Additional correlations were observed: fibroblast growth factor 23 levels were positively related to capillary diameter, and carotid intima-media thickness was associated with mean platelet volume. Declining GFR corresponded to reductions in capillary count, while use of dipeptidyl peptidase-4 inhibitors was linked to higher capillary density. Over a 2.3-year follow-up, survivors had higher lymphocyte counts (p = 0.088, not statistically significant) and baseline sVE-cadherin levels tended to be higher in those who died, although this was not statistically significant. Conclusions: These findings suggest that uremic toxins may worsen endothelial injury by disrupting intercellular connections, highlighting the complex pathogenic environment in CKD. Given these insights, the need for standardized diagnostic thresholds for endothelial dysfunction in geriatric CKD patients is clear. Serum sVE-cadherin emerges as a promising novel biomarker for assessing endothelial health, offering potential for earlier intervention and improved cardiovascular outcomes. It may be a potent indicator of endothelial dysfunction and should be featured in future studies of elderly CKD patients. Full article

Dipeptidyl peptidase-4 (DPP-4) is an established therapeutic target in the treatment of type 2 diabetes mellitus (T2DM), primarily due to its role in regulating incretin activity and glucose homeostasis. Although clinically approved DPP-4 inhibitors are widely used, their moderate efficacy has driven the search for novel compounds with improved properties. In this context, natural products have attracted considerable attention as a source of structurally diverse and biologically active molecules. At the same time, molecular docking has emerged as a key computational tool for the identification and evaluation of potential DPP-4 inhibitors. This review summarizes and critically analyzes current molecular docking studies of natural compounds targeting DPP-4. Over 150 studies were evaluated with respect to docking methodologies, selection of protein structures, and validation strategies. The results reveal substantial variability in computational protocols. Frequently used protein structures include ligand-bound DPP-4 models such as 1X70 and 6B1E. Among the investigated compounds, flavonoids represent the most extensively studied class, followed by alkaloids, phenolics, terpenoids, and peptides. Despite numerous reports of favorable binding interactions within the DPP-4 active site, many studies rely solely on docking results without further validation. The limited use of molecular dynamics simulations and experimental assays highlights a significant gap in the current literature. Overall, while molecular docking provides valuable preliminary insights, improved standardization and integration with complementary approaches are essential to enhance the reliability and translational relevance of in silico findings. Full article

Cathepsin C (CTSC), also known as dipeptidyl peptidase I, is an upstream activator of serine protease networks that may promote metastatic progression through inflammatory amplification and microenvironmental remodeling. Increasing evidence suggests that CTSC contributes to cancer progression not simply as an overexpressed lysosomal protease, but as a context-dependent regulator of metastatic traits. This review summarizes the structure, maturation, and biological functions of CTSC, with emphasis on its protease-activating capacity and its links to tumor-associated inflammation. Current evidence connecting CTSC to epithelial–mesenchymal transition, extracellular matrix remodeling, neutrophil extracellular trap formation, and immune microenvironment reprogramming is then synthesized across hepatocellular carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, non-small-cell lung cancer, and glioma. Available data most strongly support a pro-metastatic role for CTSC in breast cancer and colorectal cancer, whereas evidence in several other malignancies remains predominantly preclinical and mechanistically incomplete. Importantly, CTSC is better viewed as a targetable protease network hub than as a universal pan-cancer metastatic driver. The biomarker potential and therapeutic relevance of CTSC are also evaluated, with particular attention to the opportunities and limitations of current DPP-1/CTSC inhibitors and the need for tumor-specific translational strategies. Overall, CTSC represents a promising but still incompletely validated target in oncology, and future work should prioritize tissue-specific dependency, biomarker qualification, and rational combination approaches. Full article

Background/Objectives: Uncontrolled diabetes and associated comorbidities disproportionately affect African American (AA) adults. Medication adherence is key to diabetes control yet is often suboptimal, particularly among AA adults. This study examined associations between patient characteristics and adherence among AA adults with uncontrolled diabetes and compared two medication adherence instruments for predicting diabetes control. Methods: This cross-sectional analysis used baseline data from the Management of Diabetes in Everyday Life (MODEL) study, a clinical trial to improve diabetes self-care among AA adults with uncontrolled diabetes. Internal consistency of the 12-item Adherence to Medication Refills and Medications Scale for diabetes medications (ARMS-D) was evaluated by comparing its Cronbach α to the standardized Cronbach α calculated from MODEL data. Associations with variables were examined using correlations, t-tests, or ANOVA, as appropriate. Stepwise multiple regression identified predictors of diabetes control assessed by hemoglobin A1c (HbA1c). Results: Among 665 participants (mean age = 54 years, HbA1c = 10.24%; 67% female; 73% high health literacy), 75% reported perfect adherence on the Summary of Diabetes Self-Care Activities Medications Subscale (SDSCA-MS) versus 7.3% on ARMS-D. ARMS-D showed strong internal consistency (α = 0.81). Lower adherence by ARMS-D was associated with younger age, higher social complexity, and depression (all p ≤ 0.001). ARMS-D score, age, depression, and insulin, dipeptidyl peptidase 4 inhibitor, and sodium-glucose co-transporter 2 inhibitor use predicted baseline HbA1c. Conclusions: This study demonstrates that younger age, depression, and high social complexity are associated with lower medication adherence measured using the ARMS-D. Adherence gaps identified by ARMS-D may validly predict diabetes control and help guide interventions to improve diabetes care in AA adults with uncontrolled diabetes. Full article

Background: Epilepsy is a frequent neurological comorbidity in type 2 diabetes. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) exert metabolic, vascular, and anti-inflammatory actions beyond glucose lowering, suggesting potential neuroprotective properties. We assessed whether SGLT2i use is associated with a reduced incidence of epilepsy compared with dipeptidyl peptidase-4 inhibitors (DPP-4i). Methods: We emulated a target trial using a retrospective observational cohort of adults with type 2 diabetes initiating SGLT2i or DPP-4i from a large real-world database. Propensity scores were estimated using a SuperLearner algorithm, and stabilized inverse probability of treatment weights were applied to balance baseline characteristics. Weighted Kaplan–Meier and Cox regression models were used to estimate hazard ratios (HRs) for incident epilepsy. Results: Among 176,728 patients (mean age 68 years; 39% women), 43% received SGLT2i. The weighted incidence of epilepsy was 2.05 versus 2.45 per 1000 person-years for SGLT2i and DPP-4i, respectively. SGLT2i treatment was associated with a significantly lower risk of epilepsy (HR 0.72, 95% CI 0.61–0.86; p < 0.001). Conclusions: In this large real-world study, initiation of SGLT2 inhibitors was associated with a lower incidence of epilepsy compared with DPP-4 inhibitors. The absolute difference in event rates was small (2.05 vs. 2.45 cases per 1000 person-years), and residual confounding cannot be excluded. These findings should therefore be regarded as hypothesis-generating and warrant prospective research to confirm causality and clarify potential mechanisms. Full article