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Introduction: The cumulative impact of metabolic syndrome (MetS) components on micro‐ and macrovascular disease in metabolic dysfunction‐associated steatotic liver disease (MASLD) is unclear. We aimed to determine whether the number of the MetS components increases the risk of micro‐ and macrovascular disease in patients with MASLD. Methods: We performed a retrospective cohort study of electronic medical records using the TriNetX network, a global federated database. The exposure arm was patients with hepatic steatosis (defined via International Classification of Diseases, 10th Revision coding, or modified hepatic steatosis index), and ≥1 MetS components (obesity/central adiposity, insulin resistance, hypertension, or dyslipidaemia), compared with a reference arm of adults without any MetS components or hepatic steatosis. Our propensity score matched (1:1) for confounders with 5 years of follow‐up. Primary outcomes included microvascular (peripheral neuropathy, retinopathy, and nephropathy) and macrovascular (cardiovascular events, cerebrovascular accidents, and peripheral vascular disease) disease. Secondary analyses assessed the impact of additional MetS components on these outcomes, as well as the impact of sex. Results: MASLD, defined by hepatic steatosis and insulin resistance (n = 15 937), carried the highest risk of microvascular disease (HR 13.93 (95% CI 8.55–22.68)), whilst MASLD, defined by hepatic steatosis and hypertension (n = 53 028), carried the highest risk of macrovascular disease (7.23 (6.45–8.13)). MASLD with all MetS components carried greatest risk of both micro‐ (31.20 (28.88–33.70) (n = 462 789)) and macrovascular (8.04 (7.33–8.82) (n = 336 010)) disease. Conclusion: We demonstrate a differential effect of MetS components on micro‐ and macrovascular disease risk in patients with MASLD, with a cumulative impact of multiple MetS on overall risk. The impact of MetS components was most pronounced in women. Aggressive metabolic risk factor management is critical for prevention of micro‐ and macrovascular complications. [ABSTRACT FROM AUTHOR]

Background and Aims: We examined the impact of a co‐diagnosis of metabolic dysfunction‐associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes. Methods: Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time‐to‐event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper.1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes‐related, and cancer events over 5 years. Results: Analysis 1 (n = 95 275): a co‐diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver‐related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co‐diagnosis of MASLD significantly increased risk of all‐cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation. Conclusions: T2D significantly potentiates the risk of cardiovascular, malignancy and liver‐related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Aim: Sodium–glucose cotransporter 2 inhibitors (SGLT2is), used as a glucose‐lowering therapy in people with type 2 diabetes (T2D), have significant cardiorenal benefits, reducing hospitalization for heart failure (HF) and cardiovascular mortality in patients with and without T2D. Recent clinical trial evidence suggests their potential utility in preventing incident T2D among the high‐risk HF populations. Therefore, we aimed to assess whether this finding was reproducible in a real‐world setting. Methods: We performed a retrospective cohort analysis of 484 643 patients with HF, without baseline diabetes, prescribed either angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers with/without SGLT2is (treatment, n = 42 018; reference, n = 442 625) across 95 global health care organizations, using a large real‐world ecosystem. Propensity score matching balanced arms 1:1 for confounders (n = 39 168 each arm). Subgroup analysis further evaluated the impact on patients with prediabetes and the efficacy of dapagliflozin/empagliflozin, specifically, on incident T2D and secondary outcomes, including all‐cause mortality, acute pulmonary oedema and hospitalization. Results: Treatment with SGLT2is significantly reduced incident T2D {hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.63, 0.75]} in patients with HF. The analysis of patients with prediabetes found that SGLT2is further reduced incident T2D [HR 0.62 (95% CI 0.45, 0.80)]. The magnitude of reduction in incident T2D was higher in patients prescribed dapagliflozin [HR 0.47 (95% CI 0.39, 0.56)] versus empagliflozin [HR 0.81 (95% CI 0.70, 0.93)]. Conclusion: Treatment with SGLT2is in patients with HF was associated with a reduced risk of incident T2D, most strikingly in people with prediabetes. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long‐term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all‐cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta‐analysis. Methods: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long‐term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random‐effects meta‐analysis. Risk of bias and evidence quality were assessed using Cochrane‐endorsed tools. Results: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78‐0.88]). Secondary analysis showed significant risk reduction in all‐cause mortality (0.79 [0.72‐0.87]) and foot ulceration (0.67 [0.53‐0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta‐analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79‐0.87]) (I2 = 10.76%). Conclusions: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all‐cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D. [ABSTRACT FROM AUTHOR]

We aimed to determine the extent of multiorgan fat accumulation and fibroinflammation in individuals living with type 2 diabetes. We deeply phenotyped individuals with type 2 diabetes (134 from secondary care, 69 from primary care) with multiorgan, quantitative, multiparametric MRI and compared with 134 matched control individuals without diabetes and 92 control individuals with normal weight. We examined the impact of diabetes duration, obesity status, and glycemic control. Ninety-three of the individuals with type 2 diabetes were reevaluated at 7 months (median). Multiorgan abnormalities were more common in individuals with type 2 diabetes (94%) than in age- and BMI-matched healthy individuals or healthy individuals with normal weight. We demonstrated a high burden of combined steatosis and fibroinflammation within the liver, pancreas, and kidneys (41%, 17%, and 10%) associated with visceral adiposity (73%) and poor vascular health (82%). Obesity was most closely associated with advanced liver disease, renal and visceral steatosis, and multiorgan abnormalities, while poor glycemic control was associated with pancreatic fibroinflammation. Pharmacological therapies with proven cardiorenal protection improved liver and vascular health unlike conventional glucose-lowering treatments, while weight loss or improved glycemic control reduced multiorgan adiposity (P ≤ 0.01). Quantitative imaging in people with type 2 diabetes highlights widespread organ abnormalities and may provide useful risk and treatment stratification. Article Highlights: Type 2 diabetes is a multisystem disease, but multiorgan imaging studies are lacking. The objective was to quantify organ abnormalities (steatosis and fibroinflammation) in type 2 diabetes using multiparametric MRI (mpMRI). In 126 of 134 individuals with type 2 diabetes, multiorgan abnormalities (steatosis and fibroinflammation) were detected with mpMRI, which persisted despite glucose-lowering therapy over 7 months. The therapeutic impact of new diabetes therapies on preventing or reversing end-organ damage can be measured by mpMRI. [ABSTRACT FROM AUTHOR]

A bovine milk oligosaccharide (BMO) library, prepared from cow colostrum, with 34 structures was generated and used to rapidly screen oligosaccharides in domestic animal milks and a whey permeate powder. The novel library was entered into a custom Personal Compound Database and Library (PCDL) and included accurate mass, retention time, and tandem mass spectra. Oligosaccharides in minute-sized samples were separated using nanoliquid chromatography (nanoLC) coupled to a high resolution and sensitive quadrupole-Time of Flight (Q-ToF) MS system. Using the PCDL, 18 oligosaccharides were found in a BMO-enriched product obtained from whey permeate processing. The usefulness of the analytical system and BMO library was further validated using milks from domestic sheep and buffaloes. Through BMO PCDL searching, 15 and 13 oligosaccharides in the BMO library were assigned in sheep and buffalo milks, respectively, thus demonstrating significant overlap between oligosaccharides in bovine (cow and buffalo) and ovine (sheep) milks. This method was shown to be an efficient, reliable, and rapid tool to identify oligosaccharide structures using automated spectral matching.

Aims: We compared the glycaemic and cardiorenal effects of combination therapy involving metformin, pioglitazone, sodium-glucose-linked-cotransporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) versus a more conventional glucocentric treatment approach combining sulphonylureas (SU) and insulin from the point of type 2 diabetes (T2D) diagnosis. Methods: We performed a retrospective cohort study using the Global Collaborative Network in TriNetX. We included individuals prescribed metformin, pioglitazone, an SGLT2i, and a GLP-1 RA for at least 1-year duration, within 3 years of a T2D diagnosis, and compared with individuals prescribed insulin and a SU within the same temporal pattern. Individuals were followed up for 3 years. Results: We propensity score-matched (PSM) for 26 variables. A total of 1762 individuals were included in the final analysis (n = 881 per cohort). At 3-years, compared to the insulin/SU group, the metformin/pioglitazone/SGLT2i/GLP-1 RA group had a lower risk of heart failure (HR 0.34, 95% CI 0.13–0.87, p = 0.018), acute coronary syndrome (HR 0.29, 95% CI 0.12–0.67, p = 0.002), stroke (HR 0.17, 95% CI 0.06–0.49, p < 0.001), chronic kidney disease (HR 0.50, 95% CI 0.25–0.99, p = 0.042), and hospitalisation (HR 0.59, 95% CI 0.46–0.77, p < 0.001). Conclusions: In this real-world study, early, intensive polytherapy, targeting the distinct pathophysiological defects in T2D, is associated with significantly more favourable cardiorenal outcomes, compared to insulin and SU therapy. [ABSTRACT FROM AUTHOR]

Summary: The social and economic constructs of the United Kingdom (UK) provide a fertile food environment for the dramatic expansion in the ultra‐processed food (UPF) market, driving increased UPF consumption. This has coincided with the significant increase in the incidence and prevalence of non‐communicable diseases (NCDs) such as obesity, type 2 diabetes, cardiovascular disease, and cancer, with an inherent impact on morbidity and mortality. Our review aims to assess the current epidemiological and public health trends in the United Kingdom, specifically examining consumption of UPFs and subsequent development of NCDs, summarizing existing meta‐analytical and experimental approaches. First, we address important socioeconomic and psychosocial domains that may contribute to increased availability and consumption of UPF. Additionally, we explore the putative mechanistic basis for the association between UPFs and NCDs: partly attributable to their energy density, the macro‐ and micronutrient composition (including high refined carbohydrate, saturated, and trans fats composition, in addition to low fiber and protein content), and artificially engineered additives and other compounds that adversely affect health in inadequately researched pathophysiological pathways. This review highlights the importance of promoting minimally processed diets to both clinical and political decision makers. [ABSTRACT FROM AUTHOR]