Daily Cardiology Research Analysis

OBJECTIVE: To provide up-to-date evidence on key benefits, harms, and uncertainties regarding medications for adults with type 2 diabetes. DESIGN: Living systematic review and network meta-analysis (NMA), using frequentist random effects and GRADE (grading of recommendations, assessment, development and evaluation) approaches. Updates are planned at least two times a year. DATA SOURCES: Medline and Embase, searched up to 31 July 2024 for the current iteration. STUDY SELECTION: Randomised controlled trials of at least 24 weeks comparing one or more medications with standard treatment, placebo, or each other. RESULTS: The systematic review and NMA includes 493 168 participants from 869 trials (adding 53 trials since October 2022) reporting data for 13 drug classes (63 drugs) and 26 outcomes of interest. Regarding benefits, moderate to high certainty evidence confirms the well established cardiovascular and kidney benefits of sodium-glucose cotransporter-2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and finerenone (the last for patients with established chronic kidney disease). The most effective drugs in reducing body weight were tirzepatide (mean difference (MD) -8.63 kg (95% confidence interval -9.34 to -7.93); moderate certainty) and orforglipron (MD -7.87 kg (-10.24 to -5.50); low certainty), followed by eight other GLP-1RAs (high to moderate certainty). Absolute benefits of medications vary substantially depending on the baseline risk of cardiovascular and kidney outcomes; risk-stratified absolute effects of medications are summarised using an interactive multiple comparisons tool (https://matchit.magicevidence.org/250709dist-diabetes/#!/). Regarding medication-specific harms, SGLT-2 inhibitors increase genital infections (odds ratio (OR) 3.29 (95% CI 2.88 to 3.77); high certainty) and ketoacidosis due to diabetes (OR 2.08 (1.45 to 2.99); high certainty), and probably increase amputations (OR 1.27 (1.01 to 1.61); moderate certainty); tirzepatide and GLP-1RAs probably increase severe gastrointestinal events (most increased risk with tirzepatide (OR 4.21 (1.87 to 9.49); moderate certainty)); finerenone increases severe hyperkalaemia (OR 5.92 (3.02 to 11.62); high certainty); and thiazolidinediones increase major osteoporotic fractures and probably increase hospitalisation for heart failure. Sulfonylureas, insulin, and dipeptidyl peptidase-4 inhibitors probably increase the risk of severe hypoglycaemia. There is low to very low certainty evidence for effects on other diabetes-related complications, including neuropathy and visual impairment. Despite interest in the issue, there is uncertainty about whether GLP-1RAs may reduce dementia (OR 0.92 (0.83 to 1.02); low certainty). CONCLUSIONS: This living systematic review provides a comprehensive summary of the cardiovascular, kidney, and weight loss benefits, as well as medication-specific harms of medications for adults with type 2 diabetes, including effects of SGLT-2 inhibitors, GLP-1RAs, finerenone and tirzepatide.

BACKGROUND: Atherosclerosis progresses through endothelial dysfunction, vascular inflammation, endothelial-to-mesenchymal transition (EndMT), and plaque instability. While ANGPTL4 (angiopoietin-like 4) is known for its metabolic functions, its role in endothelial homeostasis remains unclear. METHODS: We investigated the protective effects of ANGPTL4 on endothelial inflammation, vascular integrity, and EndMT using RESULTS: ANGPTL4 suppressed TNF-α (tumor necrosis factor alpha)-induced and IL-1β (interleukin-1 beta)-induced endothelial inflammation and preserved vascular barrier integrity in vitro and in vivo. It also inhibited TGF-β (transforming growth factor-β)-driven EndMT by restoring endothelial markers and suppressing mesenchymal marker expression. Mechanistically, ANGPTL4 attenuated TGF-β-Smad2 (suppressor of mothers against decapentaplegic 2) signaling and restored KLF2 (Krüppel-like factor 2) expression, which was essential for its anti-inflammatory and anti-EndMT effects. KLF2 knockdown abolished ANGPTL4-mediated endothelial protection, confirming its pivotal role in maintaining endothelial identity. In human atherosclerotic plaques, EndMT marker expression strongly correlated with plaque complexity, suggesting that EndMT exacerbates atherosclerosis progression. Plasma ANGPTL4 levels were significantly reduced in patients with coronary artery disease with coronary microvascular dysfunction and were positively correlated with coronary flow reserve, supporting its potential as a biomarker and preventive modulator of endothelial dysfunction. CONCLUSIONS: These findings identify ANGPTL4 as a critical modulator of endothelial inflammation and EndMT via suppression of TGF-β-Smad2 signaling and restoration of KLF2. By preserving vascular integrity and promoting endothelial homeostasis, ANGPTL4 may serve as a preventive modulator in EndMT-driven vascular pathology and coronary microvascular dysfunction.

BACKGROUND: The Valve Academic Research Consortium (VARC) recently proposed a definition of high bleeding risk (HBR) for patients undergoing transcatheter aortic valve implantation (TAVI). This study aims to evaluate the prevalence and distribution of the VARC-HBR criteria and their ability to predict in-hospital bleeding. METHODS: Patients undergoing TAVI at 18 European sites between 2007 and 2022 and included in the Transfusion Requirements in Transcatheter Aortic Valve Implantation (NCT03740425) registry were stratified into low, moderate, high or very high bleeding risk using the VARC-HBR criteria. The primary outcome was in-hospital major or life-threatening bleeding (VARC-2 definition). RESULTS: Among 8464 patients, bleeding risk was very high in 1966 (23.2%), high in 3311 (39.1%), moderate in 2075 (24.5%) and low in 1112 (13.1%). In-hospital bleeding occurred in 11.0% of those at low risk, compared with 17.2%, 20.0% and 22.2% of patients at moderate, high and very high risk (p<0.001). The association between VARC-HBR criteria and bleeding remained significant after adjustment for calendar time. At 2 years, the incidence of major adverse cardiovascular events ranged from 13.8% in low-risk patients to 13.1%, 18.6% and 25.4% among those at moderate, high and very high risk (p<0.001). Mortality was higher after a bleeding event (HR 1.71, 95% CI 1.50 to 1.95), especially within the first 3 months (HR 2.88, 95% CI 2.33 to 3.56). CONCLUSIONS: Up to 60% of patients undergoing TAVI are at high or very high bleeding risk. The VARC-HBR criteria identified those at greater risk of adverse events. In-hospital bleeding complications and long-term cardiovascular events increased progressively across VARC-HBR categories.