Metabolic syndrome traits differentially and cumulatively influence micro- and macrovascular disease risk in patients with MASLD.

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.

Effect of combination pioglitazone with sodium-glucose cotransporter-2 inhibitors or glucagon-like peptide-1 receptor agonists on outcomes in type 2 diabetes: A systematic review, meta-analysis, and real-world study from an international federated database.

AIMS: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database. METHODS: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack. RESULTS: The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001). CONCLUSION: Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy.

SGLT2i and GLP-1 RA therapy in type 1 diabetes and reno-vascular outcomes: a real-world study.

AIMS/HYPOTHESIS: Insulin is the primary treatment for type 1 diabetes. However, alternative glucose-lowering therapies are used adjunctively, but importantly are off-label in type 1 diabetes. Little work has previously been undertaken to evaluate safety with long-term efficacy and cardio-renal benefits of such therapies. We sought to investigate the real-world impact of sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapy in individuals with type 1 diabetes in relation to effect on blood glucose levels, adverse events and cardio-renal outcomes. METHODS: We performed a retrospective cohort study of all patients aged 18 or over with type 1 diabetes on the TriNetX platform, a global collaborative network providing access to real-time, anonymised medical records. We included patients who had been treated with an SGLT2i or GLP-1 RA for at least 6 months and analysed the efficacy, safety and cardio-renal outcomes 5 years after initiation of therapy. RESULTS: We identified 196,691 individuals with type 1 diabetes, 13% of whom were treated with adjunctive glucose-lowering therapy in addition to insulin. Included in the core analysis were 1822 patients treated with a GLP-1 RA and 992 individuals treated with an SGLT2i. Both agents provided clinically meaningful reductions in HbA1c (-2.6 mmol/mol [-0.2%] with SGLT2i and -5.4 mmol/mol [-0.5%] with GLP-1 RA). The SGLT2i treated cohort showed preservation of eGFR over a 5-year period compared with the GLP-1 RA treated cohort (+3.5 ml/min per 1.73 m2 vs -7.2 ml/min per 1.73 m2, respectively), including patients with established chronic kidney disease (CKD). The SGLT2i treated cohort experienced higher rates of diabetic ketoacidosis (DKA) (RR 2.08 [95% CI 1.05, 4.12] p=0.0309) and urinary tract infection/pyelonephritis (RR 2.27 [95% CI 1.12, 4.55] p=0.019) compared with the GLP-1 RA treated cohort. However, the SGLT2i treated cohort were less likely to develop heart failure (RR 0.44 [95% CI 0.23, 0.83] p=0.0092), CKD (RR 0.49 [95% CI 0.28, 0.86] p=0.0118) and be hospitalised for any cause (RR 0.59 [95% CI 0.46, 0.76] p≤0.0001) when compared with the GLP-1 RA treated cohort. CONCLUSIONS/INTERPRETATION: Both SGLT2is and GLP-1 RAs have potential benefits as adjunctive agents in type 1 diabetes. SGLT2is provide cardio-renal benefits, despite an increase in the risk of DKA and urinary tract infection compared with GLP-1 RA therapy. Long-term evaluation of the efficacy and safety of these adjunctive therapies is required to guide their use in individuals with type 1 diabetes.

The trends and outcomes of inflammatory bowel disease surgery during the COVID-19 pandemic: A retrospective propensity score-matched analysis from a multi-institutional research network.

Background and Aims: The coronavirus disease 2019 (COVID-19) pandemic has affected the management of inflammatory bowel disease (IBD) patients. Elective operations and surveillance endoscopies were postponed for IBD patients to preserve healthcare resources and to prevent the spread of COVID-19. This study aimed to describe the trends and outcomes of IBD surgery during the pandemic. Methods: This was a retrospective propensity score-matched analysis using data extracted from TriNetX, a multi-institutional research database. IBD patients admitted for surgery were identified between March 2019 to February 2020 (prepandemic) and March 2020 to February 2023 (pandemic). The monthly volume of IBD surgical procedures was compared during the pandemic to the prepandemic period. After matching, the risk of adverse outcomes following IBD surgery was compared between the 3 years of the pandemic compared to the prepandemic cohort. Results: There was a reduction in both elective and emergency IBD operations during the pandemic. These trends were not significant. After matching, the risks of returning to theaters and hospital readmission were comparable across the 3 years of the pandemic. In the first and second years of the pandemic, elective patients were at a greater risk of mortality (risk ratio [RR], 2; 95% confidence interval [CI], 1.160-3.448 and RR, 1.778; 95% CI, 1.003-3.150, respectively) and the emergency cohort had a higher risk of critical care admission (RR, 1.759; 95% CI, 1.126-2.747 and RR, 1.742; 95% CI, 1.131-2.682, respectively). Conclusion: Our study highlights the impact of the COVID-19 pandemic on the management of IBD patients undergoing surgery. These results provide insights into the management of IBD surgery during times of crisis and can help guide decision-making and resource allocation for IBD patients requiring surgical intervention.

Treating Type 2 Diabetes With Early, Intensive, Multimodal Pharmacotherapy: Real-World Evidence From an International Collaborative Database.

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.

SGLT2 Inhibitors, but Not GLP-1 Receptor Agonists, Reduce Incidence of Gout in People Living With Type 2 Diabetes Across the Therapeutic Spectrum.

PURPOSE: This study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data. METHODS: We conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation. FINDINGS: Prior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], P < 0.0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74-0.92], P < 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], P < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], P < 0.0001). IMPLICATIONS: In this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population.

Incidence of new onset type 2 diabetes in adults living with obesity treated with tirzepatide or semaglutide: real world evidence from an international retrospective cohort study.

Background: Tirzepatide, a novel dual agonist of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), has demonstrated greater magnitude of weight loss compared to semaglutide in a phase 3 clinical trial. However, the effect of tirzepatide on incidence of type 2 diabetes (T2D) in individuals with overweight and obesity, and the effect on major adverse cardiovascular outcomes in individuals with pre-existing T2D, remains unknown. Methods: We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (TriNetX LLC, Cambridge, MA, USA) a global federated database. The data used in this study was collected on 5th June 2024. Two cohorts of individuals were generated: 1) without pre-existing T2D and, 2) with T2D. We adopted an active comparator new user design on new initiations of either tirzepatide or semaglutide therapy. Analysis began from the index event which was defined as individuals on respective therapy for 6 months only. Analysis of outcomes was conducted off-drug, in individuals without a pre-existing history of the disease of interest. Individuals were followed up for 12 months post the index event. Primary outcome for cohort 1 was incidence of T2D, and for cohort 2 was composite: all-cause mortality, cerebral infarction, acute coronary syndrome, and heart failure. Secondary outcomes for cohort 1 were change in HbA1c and body weight and for cohort 2: incidence of micro- and macrovascular complications, suicidal ideation and/or attempt, and all-cause mortality. We propensity score matched (1:1) for potential confounders: baseline demographics, socioeconomic circumstances, HbA1c, weight, relevant co-morbidities, and anti-obesity, hypoglycaemic and cardioprotective agents. Findings: The study population without T2D consisted of 13,846 individuals, equally split between tirzepatide and semaglutide users. Tirzepatide was associated with both lower risk for incident T2D (HR 0.73, 95% CI 0.58-0.92, p < 0.001) and greater weight loss (-7.7 kg, [95% CI -6.8, -8.5 kg], p < 0.001), compared to semaglutide (-4.8 kg, [95% CI -3.9, -5.6 kg], p < 0.001). In individuals with pre-existing T2D (n = 8446), tirzepatide was associated with lower risk of the composite outcome (HR 0.54, 95% CI 0.38-0.76, p < 0.001), cerebral infarction (HR 0.45, 95% CI 0.24-0.84, p = 0.010) and all-cause mortality (HR 0.33, 95% CI 0.15-0.73, p = 0.004) compared to semaglutide. Interpretation: Tirzepatide is associated with significantly reduced risk of developing T2D and major adverse cardiovascular events in individuals living with obesity and T2D respectively. Randomised controlled trials investigating the utility of dual incretin agonists in the primary prevention of T2D and cardiovascular disease in higher risk populations are now required. Funding: Nil.