The aim of this study was to provide robust evidence on the long-term use of non-nutritive sweetened (NNS) beverages on weight management, by comparing NNS beverages and water during 1 year of assisted weight management followed by a voluntary, unassisted 1-year extension. In this parallel-group, open-label, controlled equivalence trial, 493 adults with body mass index 27-35 kg/m2 who regularly consumed cold beverages were randomised 1:1 to water (n 246) or NNS beverages (n 247). Participants joined a group behavioural weight-management programme comprising assisted meetings weekly (12-week weight-loss phase) then monthly (40-week weight-maintenance phase), followed by unassisted monitoring for 52 weeks with a final meeting at week 104. The final 52 week unassisted phase was completed by 220 participants (water: n 117; NNS beverages: n 103), 27·7% of whom were NNS beverage-naïve (naïve was defined as NNS beverages comprising ≤ 25% of beverages in the 5 years before screening). In the unassisted monitoring phase, the primary endpoint was weight change from baseline at week 104 (equivalence: two-sided P > 0·05). Participants consuming water maintained a weight loss of 3·7 kg over 104 weeks, compared with 4·8 kg with NNS beverages; the between-group difference was not significant. After the final 52-week unassisted phase of the 104-week behavioural weight-management programme, water and NNS beverages showed equivalence regarding weight change from baseline. Our findings suggest people can lose weight, and maintain it for two years, when drinking either NNS beverages or water and taking part in weight-management programmes.

BACKGROUND:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally. Menopause is associated with increased hepatic fat deposition and thus metabolic dysfunction, contributing to heightened risk of progressive liver and cardiovascular disease. Hormone replacement therapy (HRT), supported by pre-clinical data, may be associated with a lower risk. METHODS:We performed a retrospective cohort study using the TriNetX global federated research network. Eligible participants were peri-menopausal women (ICD-10 codes N95/Z78.0, AND age 40-65 years) with pre-existing MASLD (based on ICD-10 codes K76.0/K75.81 or positive modified hepatic steatosis index plus ≥ 1 metabolic syndrome, MetS, trait). Patients initiating HRT (oestrogen ± progesterone) were compared with untreated controls using 1:1 propensity score matching for demographics, comorbidities, biochemistry and medications. The primary outcome was a composite of major adverse liver outcomes (MALO: portal hypertension, varices, ascites, spontaneous bacterial peritonitis, encephalopathy, hepatorenal/pulmonary syndromes, cirrhosis, decompensated liver disease, hepatocellular carcinoma, liver transplant). Secondary outcomes were individual MALO components, type 2 diabetes (T2D), major adverse cardiovascular events (MACE), breast and endometrial cancer, and venous thromboembolism (VTE). Cox regression generated hazard ratios (HRs) with 95% CIs over 5 years. Sensitivity analyses adjusted for geography, hormone type, and degree of obesity. RESULTS:After matching, 21 639 patients were included in each treatment arm. HRT was associated with a significantly reduced risk of MALO (HR 0.80; 0.71, 0.9), largely driven by reductions in ascites and SBP (0.78; 0.64, 0.95), and liver cirrhosis (0.75; 0.63, 0.90), and reduced risk of cardiometabolic outcomes: T2D (0.90; 0.84, 0.96), and MACE (0.90; 0.83, 0.98). HRT was not associated with increased risk of breast cancer or VTE, whilst endometrial cancer risk was reduced (0.49; 0.40, 0.61). Oestrogen was linked to greater benefits compared to progesterone, and patients with mild-moderate obesity experienced more significant risk reduction. CONCLUSION:Treatment of peri-menopausal symptoms with HRT, in patients with pre-existing MASLD, is associated with a lower 5-year risk of major liver and cardiometabolic disease. These findings support early basic science research and should prompt a closer examination through clinical trials.

AIMS:Evidence suggests sodium glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists may reduce the onset/progression of dementia. The effect of the dual GLP1/GIP receptor agonist tirzepatide on dementia outcomes remains unknown. We compared tirzepatide, semaglutide and SGLT2-i in relation to incident dementia in patients with type 2 diabetes. METHODS:Three target trial emulations (TTE) were conducted using real-world data from the TriNetX global federated network: TTE1: tirzepatide vs. SGLT2-i, TTE2: semaglutide vs. SGLT2-i and TTE3: tirzepatide vs. semaglutide. Eligible adults with type 2 diabetes without dementia at baseline were included. Follow-up was two years. First diagnosis of dementia, MACE, and all-cause mortality were analysed using survival analysis after propensity score matching. RESULTS:After matching, TTE1 included 14,462 patients; TTE2, 57,959; TTE3 12,246. Tirzepatide was associated with a lower risk of dementia versus semaglutide (HR 0.69, 95% CI 0.48-0.99, p = 0.04) and SGLT2-i (HR 0.66, 95% CI 0.47-0.93, p = 0.02), and lower mortality (HR 0.72, 95% CI 0.58-0.90, p < 0.01; HR 0.29, 95% CI 0.23-0.37, p < 0.01). Tirzepatide and semaglutide reduced MACE vs SGLT2-i. CONCLUSIONS:Tirzepatide is associated with a lower risk of dementia versus semaglutide and SGLT2-i in type 2 diabetes. Our findings are hypothesis generating, requiring confirmation in randomised controlled trials.

BACKGROUND:Obesity and type 2 diabetes (T2D) each independently increase cancer risk, but their combined impact is less understood. With rising early-onset obesity, T2D, and cancer in younger populations, we assessed how diagnoses of both obesity and T2D affect adiposity-related cancer incidence compared to each condition alone, focussing on age-specific trends. METHODS:We performed a retrospective (real-world) cohort analysis in a large global federated database (TriNetX, Cambridge MA, USA). Three cohorts were generated and compared with a reference arm, patients without obesity or T2D: cohort 1-patients with obesity, without T2D; cohort 2-patients with T2D, without obesity, and cohort 3-patients with both obesity and T2D. Cohorts underwent propensity score matching (PSM) 1:1 of confounders. We examined 5-year rates of incident cancer (including thirteen (traditional) adiposity-related cancers and an expanded list of 24 adiposity-related cancers), performing stratified analyses by age (younger, middle-aged, and older adults (< 40, 40-60, > 60 years), respectively), ethnicity (white, and non-white), and sex (male and female). RESULTS:After PSM, we compared 2,655,891 people with only obesity, 290,965 with only T2D and 705,499 people with both obesity and T2D, against the reference (1:1). The highest risk was observed in patients with both obesity and T2D (traditional cancers (HR 1.48 [95% CI 1.15, 1.51]) and all adiposity-related cancers (1.30 [1.27, 1.32])). T2D increased the risk of both traditional (1.35 [1.31, 1.39]) and all adiposity-related cancers (1.27 [1.23, 1.31]) to a greater extent than obesity only (increased risk of traditional adiposity-related cancers (1.07 [1.05, 1.09]), but not all adiposity-related cancers (0.99 [0.98, 1.01]). Concerningly, the highest risk of all traditional and adiposity-related cancers was seen in younger (< 40 years) adults with obesity and T2D (1.40 [1.10, 1.79] and 1.58 [1.21, 2.05], respectively). CONCLUSIONS:Risk of incident adiposity-related cancer is driven most strongly by the combination of obesity and T2D, versus either alone, across all age groups, including those with early-onset disease. The impact of early-onset obesity and T2D provides a critical public health problem that demands targeted screening and management.

Type 2 diabetes (T2D) is a risk factor for the progression of liver disease, particularly relating to metabolic dysfunction-associated steatotic liver disease (MASLD), and consequent major adverse liver outcomes (MALO). Given that diabetic neuropathy reflects advanced metabolic and microvascular injury, we investigated whether somatic and autonomic neuropathy in T2D is associated with MALO. In this retrospective cohort study using a large, federated health research network (TriNetX), adults with T2D were stratified into (i) diabetes alone, without coding of neuropathy, (ii) diabetes with peripheral neuropathy coding, (iii) diabetes with autonomic neuropathy coding, and (iv) diabetes with combined peripheral and autonomic neuropathy coding. Propensity score matching was performed to balance demographic, metabolic, and comorbidity profiles. The primary outcome was incident MALO, defined as hepatic decompensation, portal hypertension/stable varices, hepatocellular carcinoma, liver failure, or liver transplantation. Secondary outcomes included individual MALO endpoints, major adverse cardiovascular events (MACE) and all-cause mortality. Cox proportional hazards models were used to estimate hazard ratios (HRs). After matching, a clear gradient was evident between the increased risk of MALO and the presence of neuropathy: peripheral neuropathy and risk of MALO (HR 1.95 [95

Introduction and Objective: BMI-based criteria may not be sufficiently sensitive to identify people at-risk of poor cardiometabolic outcomes. We evaluated whether multi-organ imaging could improve prediction of obesity-related health outcomes and inform treatment allocation. Methods: We tested associations between 14 imaging-derived phenotypes and incident type 2 diabetes (T2D), cardiovascular (CV) and liver events (LRE), and mortality. Associations between clinical measures in standard of care (BMI ≥30 kg/m2, adiposity-based preclinical and clinical obesity, T2D, hypertension, dyslipidaemia) were also examined. We modelled the impact of risk-guided treatment from published outcome data, using tirzepatide as an example. Results: 23,087 UK Biobank participants were included (median age 64 years, 50% female, 18% BMI ≥30 kg/m2, 30% had preclinical obesity and 31% had clinical obesity). The median follow-up time was 4.3 years.Clinical obesity, elevated pancreatic and liver fat and elevated iron-corrected T1 (cT1, a measure of liver disease activity and severity) were associated with an increased risk of incident T2D (adjusted Cox proportional hazard ratio, HR, 27, 95% CI 16-47).Addition of information from multi-organ MRI improved stratification of individuals at highest risk of any incident hospitalisation (HR 6.3, 2.0-19) compared to clinical measures alone (HR 2.5, 2.0-3.2).Elevated liver cT1, reduced LVEF, and low skeletal muscle were together associated with increased all-cause mortality (HR 4.4, 1.1-18.0). Adding MRI measurements of LVEF and cT1, to obesity status for guiding allocation of tirzepatide treatment, reduced the number needed to treat to prevent one death from 159 to 20. Conclusion: Quantitative multi-organ MRI, of the liver, pancreas, heart and body composition, could refine stratification of individuals with obesity to predict new-onset diabetes, and provides a framework for identifying individuals likely to benefit most from obesity treatment. Disclosure E. Jackson: Employee; Current; Perspectum Ltd. T. Kailayanathan: Employee; Current; Perspectum. H.B. Thomaides Brears: Employee; Current; Perspectum Ltd. Stock/Shareholder; Current; Perspectum Ltd. M. Harhay: None. L.F. Cardiel Castro: None. A. Dinani: Consultant; Current; Madrigal Pharmaceuticals, Inc. Advisory Panel; Current; Madrigal Pharmaceuticals, Inc., Novo Nordisk. Consultant; Current; Novo Nordisk, Petauri. Other - Site PI; Current; Akero Therapeutics, Inc., 89bio, Inc. Other - SITE PI; Current; Hanmi Pharm. Co., Ltd. Other - FUNDING TO INSTITUTION; Current; National Institutes of Health. N. Desai: Consultant; Current; Amgen Inc. Research Support; Current; AstraZeneca. Consultant; Current; Bayer AG. Research Support; Current; Boehringer Ingelheim International GmbH. Consultant; Current; Merck & Co., Inc., Novartis AG. N.R. Samala: Consultant; Ended; Novo Nordisk. Research Support; Current; GlaxoSmithKline plc., Eli Lilly and Company, Regeneron Pharmaceuticals Inc. M. Davies: Advisory Panel; Current; AbbVie Inc., Amgen Inc., Biomea Fusion, Roche Pharmaceuticals, Regeneron Pharmaceuticals Inc., Daewoong Pharmaceutical. Other - Advisory Panel and Speaker Bureau; Current; Sanofi. Advisory Panel; Current; Zealand Pharma A/S, GlaxoSmithKline plc. Other - Advisory Panel, Speaker Bureau, Grants in support of Trials; Current; AstraZeneca. Other - Consultant/Advisor/Speaker Bureau/Grants in support of Trials; Current; Boehringer Ingelheim International GmbH. Other - Consultant/Advisor/Speaker Bureau; Current; Eli Lilly and Company. Other - Consultant/Advisor/Speaker Bureau/Grants in support of Trials; Current; Novo Nordisk. Speaker's Bureau; Current; Zuellig Pharma Holdings Pte. Ltd. Advisory Panel; Current; EktaH. D.J. Cuthbertson: Consultant; Current; Madrigal Pharmaceuticals, Inc. Research Support; Current; Novo Nordisk, AstraZeneca. J. Almandoz: Consultant; Current; AbbVie Inc., Amgen Inc., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Kailera, Novo Nordisk, Metsera, Rhythm Pharmaceuticals, Inc., Rivus. A. Banerjee: None. Funding UK Biobank accessed under application 9914

INTRODUCTION:This narrative review explores the epidemiological evidence and potential underlying pathophysiological defects underlying the disproportionately greater risk of Type 2 diabetes (T2D) and cardiometabolic disease in people of South Asian and African Caribbean ancestry compared with White Europeans. Differences in (i) insulin dynamics, (ii) body composition and liver and pancreas triglyceride accumulation, and (iii) dysregulated fat metabolism likely contribute to this obesity-related susceptibility. INSULIN DYNAMICS:Insulin resistance and hyperinsulinemia are key pathophysiological defects in T2D, although the primary defect is uncertain. Many believe that insulin resistance precedes compensatory hyperinsulinemia; much data suggest that hyperinsulinemia precedes insulin resistance. Hyperinsulinemia, related to reduced hepatic insulin clearance, may represent the primary defect in people of African Caribbean ancestry. BODY COMPOSITION:Ectopic fat, particularly visceral, liver, and pancreatic fat, is associated with impairments in insulin action/secretion: Higher liver fat is specifically related to hepatic insulin resistance and higher pancreatic fat to impaired beta cell function. People of South Asian ancestry exhibit greater ectopic particularly liver fat, compared with White Europeans, and more severe insulin resistance, driving hyperinsulinemia. People of African Caribbean ancestry have lower visceral and liver fat and greater muscle mass. DYSREGULATED FAT METABOLISM:Dysregulated fat metabolism in adipose tissue/liver may increase serum fatty acids and triglyceride concentrations exposing non-adipose tissues to increased lipid. Differential T2D susceptibility likely reflects diverse but ethnic group-specific metabolic phenotypes representing genetic and environmentally mediated pathophysiological traits, consistent with the "palette" model of T2D.

Cardiorespiratory fitness (CRF) is a powerful predictor of numerous health outcomes; however, its relationship with liver health remains unclear. This study examined the associations of CRF with non-invasive markers of liver steatosis and fibrosis in a large, health-screening cohort, and explored potential effect modification by demographic, cardiometabolic, and clinical factors. In this independent healthcare-based cross-sectional study of 39,197 UK adults (32

Aim We compared the impact of metabolic bariatric surgery (MBS) versus semaglutide on clinical outcomes in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D).Methods Patients with MASLD and T2D who had MBS or semaglutide in 2018-2023 were identified (TriNetX database). The primary outcome was a composite of major adverse liver outcomes (MALO): decompensation events or liver transplant. Secondary outcomes included a composite of major adverse cardiovascular events (MACE), first diagnosis of cirrhosis, heart failure, or obesity-associated cancer (OAC), and all-cause mortality (ACM). Subgroup analyses were performed for Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG).Results MBS, compared with semaglutide, was associated with a higher hazard rate (HR) of MALO (HR 1.63; 95% CI 1.12-2.37); this was driven by RYGB (2.01; 1.26-3.20) but not by SG (0.97; 0.52-1.78). However, after excluding patients with pre-existing cirrhosis, MBS was associated with a reduced HR of new cirrhosis (0.46; 0.29-0.73). For extrahepatic events, MBS was associated with a reduced HR of MACE (0.51; 0.38-0.67), heart failure (0.41; 0.27-0.62), and OAC (0.56; 0.34-0.92). There was no difference in ACM between MBS and semaglutide, but in subgroup analysis, RYGB was associated with increased ACM compared to semaglutide (1.64; 1.01-2.67).Conclusion In patients with MASLD and T2D, MBS, and specifically RYGB, as compared to semaglutide, may drive a relatively increased risk of MALO despite protection against MACE, the first diagnosis of cirrhosis, heart failure, and OAC. Liver evaluation in individuals with T2D referred for MBS may help optimize their treatment.

AIMS:An update to the NICE Type 2 diabetes (T2DM) guideline in February 2022 recommended an SGLT2 inhibitor be offered to people with cardiovascular disease (CVD) or heart failure (HF) as comorbidities and considered for people at high CVD risk. We report uptake of this guideline in England 18 months after its publication. MATERIALS AND METHODS:Observational cohort study using Clinical Practise Research Data Link records linked to hospital admissions. Presence of a current prescription for an SGLT2 inhibitor was evaluated in people with T2DM on 1 September 2023, stratified by CVD category (CVD only; HF only; both; high CVD risk; low CVD risk) and chronic kidney disease status, and by age, gender, ethnicity, deprivation and T2DM duration. Adjusted associations between patient characteristics and uptake were evaluated using logistic regression. RESULTS:In the cohort of 587 826 people with T2DM, the percentage with a current prescription was 19.5% for people with CVD, 29.4% for people with HF, 30.5% for people with both CVD and HF, and 19.9% and 20.2% respectively for people at high and low CVD risk. In age-stratified analyses, uptake was higher in people with more comorbidities. In adjusted models, uptake was lower in people aged > 60, women, Black people and people living in areas of higher deprivation. CONCLUSIONS:Whilst prescribing of SGLT2 inhibitors continues to rise in England, recent trends indicate an opportunity remains to increase uptake. Action is necessary to address inequalities by ethnicity and deprivation, and lower uptake for people with T2DM and CVD without HF.

Background Health inequalities remain a major public health challenge in England, with people living in more deprived areas experiencing poorer outcomes. Although SGLT2 inhibitors (SGLT2i) are clinically and cost-effective for type 2 diabetes mellitus (T2DM) and related cardiovascular and renal conditions, little is known about how their health benefits are distributed across deprivation groups. We examined the distribution of health benefits associated with SGLT2i across deprivation and clinical subgroups, and the implications for health inequalities. Methods We used data from a 2023 cross-sectional analysis of the Clinical Practice Research Datalink (CPRD), linked to Hospital Episodes Statistics (HES) and small-area deprivation data in England. T2DM prevalence and selected comorbidities and SGLT2i uptake were estimated across deprivation quintiles. A distributional cost-effectiveness analysis was used to estimate total and net health benefits (QALYs) and opportunity costs. Scenario analyses examined increased uptake and alternative distributions of opportunity costs. Results T2DM and associated comorbidities were more prevalent in more deprived areas across all subgroups. SGLT2i uptake varied modestly by deprivation but more substantially across clinical subgroups. SGLT2i generated positive net health benefits across all groups, with the largest gains accruing to more deprived populations, reflecting disease burden and baseline risk. Increasing uptake increased health gains, with similar distributional patterns across deprivation groups. Conclusions SGLT2i generate substantial net health benefits across all deprivation groups, with the greatest gains in more deprived populations. Improving uptake represents an important opportunity to improve population health while reducing health inequalities.

Background Sarcopenia is prevalent in heart failure (HF), but its role in incident HF and underlying metabolic mechanisms remains unclear. We examined the interplay between sarcopenia phenotypes, circulating metabolic profiles, and incident HF. Methods We analyzed UK Biobank participants without baseline HF. Associations between sarcopenia phenotypes and HF incidence were assessed using Cox regression. Nuclear magnetic resonance metabolomics was used to characterize sarcopenia‐related profiles. Cox regression was applied to test metabolite–HF associations, and least absolute shrinkage and selection operator regression was further used to refine predictors. Incremental predictive value beyond clinical risk factors was evaluated using discrimination and reclassification metrics. Results During a median 15.3 years, 10 233 of 267 335 participants (mean age 56.5 ± 8.1 years; 44.6% men) developed HF. Groups with confirmed sarcopenia (n=1993) and low handgrip strength (normalized to body mass index) only (n=18 796) were associated with higher HF risk (hazard ratio [HR], 1.63 [95% CI, 1.44–1.85]; HR, 1.76 [95% CI, 1.66–1.85]) compared with the reference group, with stronger effects observed in younger adults and women. Metabolomic profiling revealed sarcopenia‐related alterations (higher glycoprotein acetyls, glucose–lactate, phenylalanine, tyrosine, 3‐hydroxybutyrate; lower omega‐3 fatty acids, docosahexaenoic acid, glycine, glutamine, histidine), which also predicted higher HF risk (Bonferroni‐adjusted P < 0.05). Selected metabolites are significant mediators and modestly improved HF prediction (15‐year net reclassification improvement 14%–15%; integrated discrimination improvement 0.9%–1.0%). Conclusions Sarcopenia, particularly reduced handgrip strength, was a strong predictor for incident HF. Lipid‐, amino acid‐, and energy metabolism–related alterations modestly improved risk prediction and partially mediated the association.

AIM:Metabolic bariatric surgery (MBS) improves histological endpoints in steatotic liver disease (SLD), but data on longer-term clinical outcomes in this population are scarce. Here, we assessed the impact of MBS on hepatic and extrahepatic morbidity and mortality in individuals with SLD. METHODS:Patients with SLD, with/without a history of MBS (MBS/no-MBS cohorts, respectively) between 01/01/2004 and 31/10/2019, were identified using the TriNetX platform. Cohorts were balanced with propensity score matching (PSM). Maximum follow-up was set to 5 years. The primary outcome was a composite of major adverse liver outcomes (MALO): cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver transplant. Secondary outcomes included major cardiovascular (MACE) and kidney (MAKE) adverse events, obesity-associated cancers, and all-cause mortality (ACM). We performed sub-group analyses according to sex, MBS type, and risk factors (BMI ≥50 kg/m2 and type 2 diabetes (T2D)). RESULTS:We identified 15,262 and 540,031 patients (for the MBS and no-MBS cohorts, respectively); 14,970 patients/cohort after PSM (mean age: 46.7 vs. 47.4; female: 74.3% vs. 75.7%; mean follow-up, 4.1 years). MBS was associated with reduced HR of MALO (0.84, 95% CI 0.75-0.95), MACE (0.52, CI 0.47-0.57), MAKE (0.54, CI 0.41-0.72), obesity-related cancers (0.58, CI 0.50-0.67), and ACM (0.49, 0.43-0.56). In subgroup analyses, MBS was associated with reduced HR of MALO, MACE, MAKE, obesity-related cancers, and ACM in females, patients with T2D, BMI > 50 kg/m2 and irrespective of surgery type. CONCLUSION:In patients with SLD, MBS is associated with significant reductions in the rates of adverse hepatic and extrahepatic outcomes and all-cause mortality over 4 years' follow-up.

BACKGROUND:Clinical trials suggest GLP-1 receptor agonists (RAs) and dual glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) RAs improve metabolic dysfunction associated with steatohepatitis (MASH) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to compare the estimate of the relative effect of tirzepatide, semaglutide, and liraglutide in reducing the risk of major adverse liver outcomes (MALOs) in patients with type 2 diabetes (T2D). DESIGN, SETTING AND PARTICIPANTS:We emulated target trials based on a real-world network of electronic health records (EHRs) from over 150 million patients. Three target trials were emulated, among eligible patients with T2D who had no prior MALO diagnosis, by comparing therapy involving tirzepatide, semaglutide, and liraglutide versus DPP4 inhibitor (DPP4i) therapy. We identified the first-ever diagnosis of MALO occurring within a 2-year follow-up period and compared across the treatment groups using Kaplan-Meier survival analyses. Cohorts underwent propensity score matching 1:1 for confounders. We performed sensitivity analyses relating to geographical location, combination with metformin, and by treatment adherence. We also performed head-to-head analyses of the incretin-based therapies. RESULTS:After matching, we identified three target trials comprised of 10 165, 56 702, and 8 301 patients treated with tirzepatide, semaglutide, and liraglutide, respectively (1:1 with reference patients) for a 2-year period. Tirzepatide (HR 0.53 [95% CI 0.40, 0.71]) and semaglutide (HR 0.81 [0.72, 0.90]) were associated with a significant reduction in the risk of incident MALO compared with DPP4i, whereas liraglutide was not (HR 1.04 [95% CI 0.79, 1.36]). In head-to-head comparisons, tirzepatide was associated with a significantly lower risk of incident MALO compared with liraglutide (HR 0.56 [95% CI 0.39, 0.79]), but not semaglutide (HR 0.83 [95% CI 0.63, 1.09]). Semaglutide was not associated with a reduced risk compared with liraglutide (HR 0.77 [95% CI 0.57, 1.05]). CONCLUSION:Treatment with tirzepatide and, to a lesser extent, semaglutide, in patients with T2D, was associated with a lower incidence of MALO compared with DPP4i after 2 years; largely driven by a reduction in the rates of compensated and decompensated cirrhosis. A reduction in MALO was not demonstrated with the use of liraglutide. These findings highlight a comparative benefit of tirzepatide (and semaglutide) versus DPP4i and should prompt more robust, longer-term randomised controlled studies to evaluate their role in preventing MALO in this increasingly prevalent patient population with co-existing T2D and MASLD.

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are treatments for type 2 diabetes (T2D). Beyond glucose-lowering and cardiorenal protection, these drugs may protect against pneumonia and sepsis.AimsThis study assesses the impact of SGLT2i and GLP-1 RAs on the risk of incident pneumonia and severe sepsis.MethodsA retrospective cohort study was conducted using anonymised electronic medical records from TriNetX, a global federated database. Two intention-to-treat analyses were performed, each with two cohorts of adult T2D patients. The first analysis compared individuals prescribed SGLT2i, and the second individuals prescribed GLP-1 RAs, with those prescribed dipeptidyl peptidase-4 inhibitors (DPP-4i). An active comparator new user design was used, with outcomes defined as time-to-incident pneumonia and severe sepsis. Propensity score matching (1:1) was applied to control for potential confounders, and patients were followed for 12 months. Secondary analyses compared SGLT2i and GLP-1 RAs against other glucose-lowering therapies.ResultsAfter propensity score matching, 352 687 patients were included in the SGLT2i versus DPP-4i comparison. SGLT2i treatment was associated with a risk reduction in incident pneumonia (HR 0.75 (95% CI 0.73, 0.78)) and severe sepsis (0.75 (0.73, 0.77)). In the GLP-1 RA versus DPP-4i comparison, 331 863 patients were included. GLP-1 RA treatment was associated with a risk reduction in incident pneumonia (0.60 (0.58, 0.62)) and severe sepsis (0.61 (0.59, 0.63)).ConclusionSGLT2i and GLP-1 RAs are associated with a reduced risk of incident pneumonia and severe sepsis in patients with T2D. Further research and focused randomised controlled trials are warranted to explore the broader clinical implications of these treatments.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with an increased incidence of hepatic and extrahepatic cancers, in particular those linked to obesity. In people with chronic liver disease, aspirin may confer protection against hepatocellular carcinoma (HCC). We explore the potential chemoprotective effect of aspirin/other anti-platelet agents on obesity-related cancers, including HCC in people with NAFLD. Methods We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (Cambridge, MA, USA), a global federated database. We identified adults aged 18 or over with a diagnosis of NAFLD, prior to commencing antiplatelet agents. Two groups were created: antiplatelet (1) versus no antiplatelet use (2). We propensity score matched for nine variables. Antiplatelet use was defined as aspirin, ticagrelor, cangrelor, clopidogrel or prasugrel use for at least 1 year. The outcomes of interest were incidence of HCC and other obesity-related cancers. Follow-up was for 5 years. We performed subgroup analyses on aspirin users only and stratified findings for sex and age. Sensitivity analysis was conducted on individuals with 3- and 5-year aspirin exposure. Results Post matching, there were 42,192 people per group. Antiplatelet use in people with NAFLD was associated with statistically significant reduction in all obesity-related cancers (HR 0.71, 95% CI 0.65–0.78, p < 0.001) and individually for HCC (HR 0.52, 95% CI 0.40–0.68, p < 0.001), breast carcinoma (HR 0.78, 95% CI 0.66–0.92, p = 0.003), pancreatic carcinoma (HR 0.61, 95% CI 0.47–0.78, p < 0.001) and colorectal carcinoma (HR 0.68, 95% CI 0.56–0.84, p < 0.001). For women, there was a significant reduction in risk of ovarian carcinoma (HR 0.75, 95% CI 0.57–0.98, p = 0.034). Aspirin monotherapy was similarly associated with reduced incidence of HCC (HR 0.46, 95% CI 0.32–0.64, p < 0.001) and all obesity-related cancers (HR 0.71, 95% CI, 0.56–0.90, p = 0.004), with benefits observed in males (HR 0.71, 95% CI 0.56–0.90, p = 0.004), females (HR 0.77, 95% CI 0.67–0.88, p < 0.001) and in older (HR 0.72, 95% CI 0.63–0.82, p < 0.001) but not younger people (HR 0.78, 95% CI 0.60–1.03, p = 0.589). Conclusions Aspirin/antiplatelet agents may have a role in primary cancer prevention in people living with NAFLD.

Introduction Type 2 diabetes (T2D) is a global health challenge conferring significant morbidity and mortality with accelerated cardiovascular, renovascular and cerebrovascular disease. Periodontitis has a higher prevalence in people with diabetes. We aimed to evaluate the risk of incident cardiovascular-related diseases in people with type 2 diabetes with and without periodontitis. Methods We conducted a retrospective cohort study using TriNetX, a global federated health research network of patients ≥18 years with a diagnosis of T2D after the initiation of insulin. Cohorts were divided based on the absence or presence of periodontitis identified using ICD-10 (International Classification of Diseases) codes. Outcomes were recorded at three years from initiation of insulin. The primary outcomes of interest were: 1) mortality; 2) myocardial infarction; 3) stroke; 4) dementia; 5) atrial fibrillation; 6) atrial flutter; 7) diabetic nephropathy; 8) diabetic retinopathy; and 9) infective endocarditis. Results After propensity score matching (1:1), a total of 56,525 patients were identified in each cohort. At three years, patients with periodontitis had similar mortality risk as the control group (risk ratio [RR] plus 95% confidence interval [CI]) (RR: 1.014, 0.979–1.049; p = 0.44). However, the periodontitis cohort demonstrated higher risk of stroke (RR: 1.264, 1.189–1.344; p <0.0001), myocardial infarction (RR: 1.151, 1.084–1.222; p <0.0001), atrial fibrillation (RR: 1.141, 1.08–1.205; p <0.0001), atrial flutter (RR: 1.21, 1.1–1.331; p <0.0001), diabetic retinopathy (RR: 1.735, 1.648–1.826; p <0.0001), diabetic nephropathy (RR: 1.433, 1.35–1.521; p <0.0001), infective endocarditis (RR: 1.83, 1.627–2.059; p <0.0001) and dementia (RR: 1.364, 1.254–1.483; p <0.0001). Conclusion Our findings add to the growing body of evidence that periodontitis is associated with long-term cardiovascular consequences in people with T2D. However, due to the study's retrospective nature, there is a need for well-designed, prospective research, including mechanistic and interventional studies to further explore this relationship.

Objectives Primary aldosteronism (PA) is a common but under-recognised cause of secondary hypertension. Early diagnosis with targeted medical and/or surgical intervention is important to prevent irreversible end-organ damage. An Endocrine Society Clinical Practice Guideline was used to define audit standards against which to assess current United Kingdom (UK) laboratory practice. Methods A survey comprising 22 questions, which captured information on screening, confirmatory testing and adrenal vein sampling (AVS), was distributed to all UK Clinical Biochemistry laboratories by the Association for Laboratory Medicine. Consultation with clinical colleagues was encouraged. Results 50 of 147 laboratories (34.0%) responded, 17 of which provided an analytical service for plasma aldosterone concentration (PAC) and renin, measured as plasma renin activity (PRA) or direct renin concentration (DRC). PRA/DRC, PAC and aldosterone:renin ratios were used to screen for PA. Saline infusion testing was the most common confirmatory test. AVS was used to aid lateralisation. Chemiluminescence immunoassay and liquid chromatography tandem mass spectrometry were the preferred analytical methods for PAC and PRA/DRC. However, there was considerable variation across centres in respect of reference intervals and cutoffs, which were not fully accounted for by differences in analytical platforms. Although diagnostic algorithms, with pre- and post-analytical support, were in evidence in some centres, these were not universal or always embedded in a multidisciplinary team setting. Conclusions We observed significant heterogeneity in the laboratory investigation of PA across the United Kingdom. Therefore, this work serves as a stimulus for greater collaboration to permit national harmonisation/standardisation of analytical and clinical aspects of UK PA practice.