Daily Cardiology Research Analysis
A living network meta-analysis in BMJ synthesizing 869 RCTs (493,168 participants) updates comparative cardio-renal efficacy and harms across type 2 diabetes medications, reinforcing SGLT-2 inhibitors, GLP-1RAs, and finerenone as foundational therapies. Mechanistic work in Circulation identifies ANGPTL4 as a protector of endothelial identity via KLF2 restoration and EndMT suppression, linking to human plaque complexity and coronary microvascular dysfunction. A large multicenter TAVI registry val
Summary
A living network meta-analysis in BMJ synthesizing 869 RCTs (493,168 participants) updates comparative cardio-renal efficacy and harms across type 2 diabetes medications, reinforcing SGLT-2 inhibitors, GLP-1RAs, and finerenone as foundational therapies. Mechanistic work in Circulation identifies ANGPTL4 as a protector of endothelial identity via KLF2 restoration and EndMT suppression, linking to human plaque complexity and coronary microvascular dysfunction. A large multicenter TAVI registry validates VARC-HBR bleeding-risk stratification, showing graded in-hospital bleeding and long-term adverse event risks across categories.
Research Themes
- Cardiometabolic therapy and outcomes
- Endothelial biology and atherosclerosis mechanisms
- Structural heart intervention risk stratification
Selected Articles
1. Medications for adults with type 2 diabetes: a living systematic review and network meta-analysis.
This living NMA (869 RCTs; 493,168 participants) confirms cardiovascular and kidney benefits of SGLT-2 inhibitors, GLP-1RAs, and finerenone, with substantial weight loss from tirzepatide and several GLP-1RAs. It quantifies class-specific harms (for example, SGLT-2 inhibitor–related ketoacidosis, finerenone-related hyperkalaemia) and provides risk-stratified absolute effects via an interactive tool.
Impact: It aggregates the highest-quality comparative evidence across all major T2D drug classes with living updates, directly informing cardiometabolic therapy choices with quantified benefits and harms.
Clinical Implications: Prioritize SGLT-2 inhibitors and GLP-1RAs for patients at high cardiovascular/renal risk; consider finerenone in CKD. Use risk-stratified absolute effects to tailor choices and monitor class-specific harms (e.g., ketoacidosis, hyperkalaemia).
Key Findings
- SGLT-2 inhibitors, GLP-1RAs, and finerenone confer cardiovascular and kidney protection (moderate-to-high certainty).
- Tirzepatide showed the greatest mean weight loss (~8.6 kg), followed by orforglipron and multiple GLP-1RAs.
- SGLT-2 inhibitors increase genital infections and diabetic ketoacidosis; finerenone increases severe hyperkalaemia; GLP-1RAs (especially tirzepatide) increase severe GI events.
- Absolute benefits vary with baseline risk; interactive tool provides risk-stratified estimates.
Methodological Strengths
- Living systematic review with frequent updates and GRADE-based certainty ratings
- Frequentist random-effects network meta-analysis across 869 RCTs (493,168 participants) and 26 outcomes
- Pre-registered (PROSPERO) with transparent protocol and interactive absolute-effect tool
Limitations
- Heterogeneity across trials and populations; some outcomes (e.g., neuropathy, dementia) have low/very low certainty
- Medication harms and benefits depend on baseline risk; indirectness remains for certain subgroups
Future Directions: Sustain living updates, expand subgroup analyses (e.g., HFpEF, older-old), and integrate patient-reported outcomes and cost-effectiveness with absolute risk tools.
2. ANGPTL4 Prevents Atherosclerosis by Preserving KLF2 to Suppress EndMT and Mitigates Endothelial Dysfunction.
ANGPTL4 preserves endothelial identity by restoring KLF2 and suppressing TGF-β–Smad2 signaling, thereby limiting EndMT, inflammation, and barrier disruption. In human plaques, EndMT correlates with complexity, and plasma ANGPTL4 is lower in CAD with microvascular dysfunction and correlates with coronary flow reserve.
Impact: It uncovers a mechanistic ANGPTL4–KLF2 axis governing EndMT and endothelial dysfunction with translational links to human disease and a potential biomarker, opening avenues for anti-EndMT therapeutics.
Clinical Implications: Suggests ANGPTL4 modulation as a strategy to prevent EndMT-driven plaque instability and coronary microvascular dysfunction; supports exploring ANGPTL4 as a biomarker linked to coronary flow reserve.
Key Findings
- ANGPTL4 suppresses TNF-α/IL-1β-induced endothelial inflammation and preserves barrier integrity in vitro and in vivo.
- ANGPTL4 inhibits TGF-β-driven EndMT by attenuating Smad2 signaling and restoring KLF2; KLF2 knockdown abolishes protection.
- In human plaques, EndMT markers correlate with plaque complexity; plasma ANGPTL4 is reduced in CAD with coronary microvascular dysfunction and correlates with coronary flow reserve.
Methodological Strengths
- Multimodal mechanistic study integrating in vitro, in vivo, and human tissue/biomarker analyses
- Causal pathway interrogation (KLF2 dependence, TGF-β–Smad2 signaling) with functional readouts of barrier and EndMT
Limitations
- Primarily preclinical; therapeutic modulation of ANGPTL4 not yet tested in clinical trials
- Patient biomarker findings are associative and require prospective validation
Future Directions: Evaluate ANGPTL4-targeted interventions in models of plaque instability and microvascular dysfunction; validate ANGPTL4 as a prognostic/theranostic biomarker in prospective cohorts.
3. Prevalence and prognostic implications of the Valve Academic Research Consortium-High Bleeding Risk criteria in patients undergoing transcatheter aortic valve implantation.
In 8,464 TAVI patients across 18 centers, VARC-HBR categories were common (∼60% high/very high) and showed graded increases in in-hospital major/life-threatening bleeding and 2-year adverse events. Post-bleeding mortality risk was markedly elevated, particularly in the first 3 months.
Impact: Validates a pragmatic bleeding risk framework for TAVI, quantifying both acute hemorrhagic events and longer-term adverse outcomes for risk-informed care pathways.
Clinical Implications: Incorporate VARC-HBR categorization into pre-TAVI planning to guide antithrombotic strategies, access planning, and hemostasis optimization; intensify early post-bleed surveillance given high 3‑month mortality.
Key Findings
- VARC-HBR high/very high risk was present in ~62% of TAVI patients.
- In-hospital major/life-threatening bleeding rose stepwise from low to very high risk (11.0% to 22.2%).
- Two-year major adverse events increased with higher VARC-HBR categories; bleeding was associated with higher mortality, especially within 3 months.
Methodological Strengths
- Large, multicenter contemporary registry with standardized VARC-HBR and VARC-2 definitions
- Time-adjusted analyses accounting for calendar trends; graded risk assessment across categories
Limitations
- Retrospective observational design with potential residual confounding and selection bias
- Practice changes over long inclusion period (2007–2022) may influence event rates
Future Directions: Prospective validation of VARC-HBR-guided antithrombotic and access strategies; integrate bleeding risk with thrombotic risk to personalize peri-TAVI management.