Background: Combination therapy with glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium-glucose co-transporter 2 inhibitors (SGLT2i), and/or finerenone offers a strategy to reduce the risk of adverse cardiovascular and renal outcomes. This study aimed to quantify the cardiorenal benefits of combination regimens with GLP-1RA, SGLT2i, and/or finerenone versus corresponding monotherapies. Methods: MEDLINE and Embase were systematically searched, yielding four post hoc analyses of randomized controlled trials (RCTs) and ten observational studies that met prespecified inclusion criteria. Among RCTs, a random-effects meta-regression was performed to assess whether the effect of GLP-1RAs on cardiorenal outcomes differed based on baseline SGLT2i use. Additionally, for observational studies, random-effects meta-analyses were performed to estimate the effect of combination therapy versus monotherapy on the risk of cardiorenal outcomes. Results: Across RCTs, p for interaction was > 0.05 for major adverse cardiac events (MACE) (p = 0.730), cardiovascular (CV) mortality (p = 0.889), non-fatal myocardial infarction (MI) (p = 0.237), non-fatal stroke (p = 0.696), all-cause mortality (p = 0.682), heart failure (HF) hospitalization (p = 0.257), and renal composite outcome (p = 0.890), supporting that GLP-1RAs result in a consistent reduction in outcomes irrespective of baseline SGLT2i use. In observational trials, compared to SGLT2i monotherapy, GLP-1RA and SGLT2i combination therapy significantly reduced MACE (HR 0.59, 95% CI 0.47–0.75), MI (HR 0.73, 95% CI 0.61–0.88), stroke (HR 0.72, 95% CI 0.53–0.97), all-cause mortality (HR 0.57, 95% CI 0.48–0.67), and HF hospitalization/events (HR 0.71, 95% CI 0.59–0.86). Compared to GLP-1RA monotherapy, SGLT2i and GLP-1RA combination therapy significantly reduced CV mortality (HR 0.35, 95% CI 0.15–0.81), MI (HR 0.93, 95% CI 0.88–0.97), stroke (HR 0.92, 95% CI 0.88–0.96), all-cause mortality (HR 0.59, 95% 0.49–0.70), HF hospitalization/events (HR 0.84, 95% CI 0.81–0.88), and serious renal events (HR 0.43, 95% CI 0.23–0.80). Compared to either SGLT2i or finerenone monotherapy, SGLT2i and finerenone combination therapy significantly reduced all-cause mortality and major adverse kidney events. Conclusion: Combination therapy with GLP-1RA, SGLT2i, or finerenone confers cardiorenal protection beyond monotherapy in T2D, as supported by concordant evidence from RCTs and large real-world cohorts. These findings support broader clinical adoption of dual-agent strategies but also underscore the need for dedicated prospective trials powered to assess hard clinical outcomes with dual-agent strategies.

Background: Several societies recommend sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and finerenone for cardiorenal risk reduction in select populations. This updated meta-analysis assessed the impact of SGLT2i, incretin-based therapies (i.e. GLP-1RAs and tirzepatide), and finerenone on cardiorenal outcomes in established and emerging populations. Additionally, a network meta-analysis (NMA) compared the relative efficacy between treatment classes. Methods: A systematic search of MEDLINE and CENTRAL from January 2023 to April 2025, supplemented by studies evaluated in our prior meta-analyses, identified 33 randomized controlled trials. Random-effects models were used to generate hazard ratios for outcomes including cardiovascular (CV) mortality, all-cause mortality, heart failure (HF) hospitalization/event, non-fatal myocardial infarction (MI), non-fatal stroke, and kidney composite outcomes in various subpopulations including patients with type 2 diabetes (T2D) with atherosclerotic cardiovascular disease (ASCVD) or high CV risk, chronic kidney disease (CKD), HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF), HFpEF with obesity, post-MI, acute HF, and ASCVD with overweight/obesity without T2D. NMA was performed when two or more treatment classes were reported for a given outcome within a subpopulation. Results: Incretin-based therapies decreased CV mortality, all-cause mortality, non-fatal MI, and kidney composite outcomes in CKD, and reduced these outcomes as well as HF hospitalization/events and non-fatal stroke in T2D with ASCVD/high CV risk. In HFpEF with obesity, incretin-based therapies reduced HF hospitalization/events. SGLT2i reduced CV mortality, all-cause mortality, HF hospitalization/events, and kidney composite outcomes in HFrEF, and reduced these outcomes as well as non-fatal MI in CKD and T2D with ASCVD/high CV risk. SGLT2i decreased HF hospitalization/events in HFpEF, and lowered HF hospitalizations in post-MI and acute HF populations. Finerenone reduced HF hospitalizations and kidney composite outcomes in diabetic CKD and reduced HF hospitalizations in HFpEF. Using placebo as the common comparator in the NMA, SGLT2i conferred significantly greater reductions in HF hospitalization/events and kidney composite outcomes compared to incretin-based therapies in T2D with ASCVD/high CV risk and CKD. Conclusions: These findings confirm the role of SGLT2i, incretin-based therapies, and finerenone in cardiorenal risk reduction across established high-risk groups, including T2D and CKD, and extend benefits to newer populations, including acute HF and post-MI for SGLT2i, and HFpEF with obesity for incretin-based therapies. Indirect NMA evidence further suggests SGLT2i may reduce HF hospitalization/events and kidney composite outcomes more than incretin-based therapies in T2D with ASCVD/high CV risk and CKD populations.

Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is increasingly recognized as a systemic condition with cardiovascular implications. Among these, heart failure has emerged as a significant complication. The aim of this narrative review was to explore the cellular and molecular pathways that link IBD and heart failure. Drawing upon findings from epidemiologic studies, experimental models, and clinical research, we examined the pathways through which IBD may promote cardiac dysfunction. Chronic systemic inflammation in IBD, driven by cytokines such as TNF-α and IL-1β, can impair myocardial structure and function. Furthermore, intestinal barrier dysfunction and gut dysbiosis can facilitate the translocation of proinflammatory microbial metabolites, including lipopolysaccharide and phenylacetylglutamine, and deplete cardioprotective metabolites like short-chain fatty acids, thereby exacerbating heart failure risk. Additional contributing factors include endothelial and microvascular dysfunction, autonomic dysregulation, nutritional deficiencies, shared genetic susceptibility, and adverse pharmacologic effects. IBD contributes to heart failure pathogenesis through multifactorial and interrelated mechanisms. Recognizing the role of the gut–heart axis in IBD is crucial for the early identification of cardiovascular risk, providing guidance for integrating care and developing targeted therapies to reduce the risk of heart failure in this vulnerable population.

The purpose of this review is to summarize the current understanding of the therapeutic effect of stem cell-based therapies, including hematopoietic stem cells, for the treatment of ischemic heart damage. Following PRISMA guidelines, we conducted electronic searches in MEDLINE, and EMBASE. We screened 592 studies, and included RCTs, observational studies, and cohort studies that examined the effect of hematopoietic stem cell therapy in adult patients with heart failure. Studies that involved pediatric patients, mesenchymal stem cell therapy, and non-heart failure (HF) studies were excluded from our review. Out of the 592 studies, 7 studies met our inclusion criteria. Overall, administration of hematopoietic stem cells (via intracoronary or myocardial infarct) led to positive cardiac outcomes such as improvements in pathological left-ventricular remodeling, perfusion following acute myocardial infarction, and NYHA symptom class. Additionally, combined death, rehospitalization for heart failure, and infarction were significantly lower in patients treated with bone marrow-derived hematopoietic stem cells. Our review demonstrates that hematopoietic stem cell administration can lead to positive cardiac outcomes for HF patients. Future studies should aim to increase female representation and non-ischemic HF patients.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used therapies for cardiovascular risk reduction in type 2 diabetes (T2D). With the emergence of the SURPASS-CVOT trial, tirzepatide (a dual GIP/GLP-1 receptor agonist) has entered the therapeutic landscape; however, its comparative effect on cardiovascular outcomes compared to placebo and individual GLP-1RAs remains undefined. Methods: We conducted a systematic review and frequentist network meta-analysis (NMA) of RCTs enrolling adults with type 2 diabetes (T2D) and established atherosclerotic cardiovascular disease (ASCVD) or high cardiovascular (CV) risk. Eligible RCTs evaluated tirzepatide or GLP-1RAs and reported major adverse cardiovascular events (MACE), CV mortality, all-cause mortality, non-fatal myocardial infarction (MI) or non-fatal stroke. A class-level NMA was conducted to estimate the incremental benefit of tirzepatide and GLP-1RAs over placebo, and an agent-level NMA was conducted to explore differences between tirzepatide and individual GLP-1RA agents. Subgroup analyses, including established cardiovascular disease populations, and leave-one-out sensitivity analyses were performed. Results: Eleven trials met inclusion criteria (10 GLP-1RA trials and 1 tirzepatide trial [SURPASS-CVOT]). In the class-level analysis, tirzepatide significantly reduced MACE (HR 0.79, 95% CI 0.69–0.91), CV mortality (HR 0.77, 95% CI 0.66–0.90), all-cause mortality (HR 0.74, 95% CI 0.65–0.83), non-fatal MI (HR 0.77, 95% CI 0.61–0.97), and non-fatal stroke (HR 0.79, 95% CI 0.64–0.97) compared to placebo. Formal statistical comparisons between tirzepatide and the GLP-1RA class could not be performed within the constraints of the NMA; however, point estimates across outcomes numerically favored tirzepatide compared with placebo. In the agent-level analysis, tirzepatide reduced MACE compared to placebo (HR 0.81, 95% CI 0.70–0.94) and lixisenatide (HR 0.79, 95% CI 0.65–0.97). Subgroup and sensitivity analyses did not substantially change point estimates. Conclusion: Among adults with T2D and established ASCVD or high CV risk, class-level analysis demonstrated that tirzepatide significantly reduced the risk of cardiovascular events compared to placebo; at the agent-level, tirzepatide demonstrated comparable efficacy to individual GLP-1RAs. These findings suggest that tirzepatide provides cardiovascular benefit at least comparable to established GLP-1RAs, supporting its emerging role in cardiovascular risk reduction in T2D. Graphical