The Roles of Non-Pharmacologic and Emerging Pharmacologic Management of Non-alcoholic Fatty Liver Disease and Sarcopenia: A Narrative Review.

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent causes of chronic liver disease worldwide which is often seen in patients with metabolic abnormalities such as those with obesity and insulin resistance. On the other hand, sarcopenia is a generalized and progressive skeletal muscle disorder characterized by low muscle strength, low muscle quality, low physical performance, or a combination of the three. Both disease entities share several underlying risk factors and pathophysiologic mechanisms. These include: (1) cardiometabolic overlaps such as insulin resistance, chronic systemic inflammation, decreased vitamin D levels, sex hormone modifications; (2) muscle-related factors such as those mitigated by myostatin signaling, and myokines (i.e., irisin); and (3) liver-dysfunction related factors such as those associated with growth hormone/insulin-like growth factor 1 Axis, hepatokines (i.e., selenoprotein P and leukocyte cell-derived chemotaxin-2), fibroblast growth factors 21 and 19 (FGF21 and FGF19), and hyperammonemia. This narrative review will examine the pathophysiologic overlaps that can explain the links between NAFLD and sarcopenia. Furthermore, this review will explore the emerging roles of nonpharmacologic (e.g., weight reduction, diet, alcohol, and smoking cessation, and physical activity) and pharmacologic management (e.g., roles of ß-hydroxy-ß-methylbutyrate, branched-chain amino acid supplements, and testosterone therapy) to improve care, intervention sustainability, and acceptability for patients with sarcopenia-associated NAFLD.

Sex, racial, ethnic, and geographical disparities in major adverse cardiovascular outcome of glucagon-like peptide-1 receptor agonists among patients with and without diabetes mellitus: A meta-analysis of placebo-controlled randomized controlled trials.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been pivotal in the management of type 2 diabetes mellitus (T2DM) and in the reduction of major adverse cardiovascular events (MACE). Notably, large cardiovascular outcomes trials (CVOTs) demonstrate significant disparities in inclusion, based on sex, race, ethnicity, and geographical regions. OBJECTIVES: We examined the impact of GLP-1RA on MACE in patients with or without T2DM, based on sex, race, ethnicity, and geography. METHODS: A literature search for placebo controlled RCTs on GLP-1RA treatment was conducted. Thorough data extraction and quality assessment were carried out, focusing on key outcome, and ensuring a robust statistical analysis using a random effects model to calculate log odds ratio with 95% confidence intervals (CIs). RESULTS: A total of 8 CVOTs comprising 71,616 patients were included. Compared with placebo, GLP-1RAs significantly reduced MACE in both sexes (females: logOR -0.19, (95% CI, -0.28 to -0.10), p < 0.01] versus males: logOR -0.17, 95% CI, -0.23 to -0.10), p < 0.01], (p interaction NS)], and among Asians (logOR -34 (95% CI, -0.53 to -0.15, p < 0.01), and Whites (logOR -17 (95% CI, -0.25 to -0.09, p < 0.01), with no difference in MACE among Blacks and Hispanics. Odds of MACE were also reduced in Asia (logOR -31 (95% CI, -0.50 to -0.11, p < 0.01), and Europe (logOR -27 (95% CI, -0.40 to -0.13, p < 0.01), but there was no statistical difference in MACE in North America and Latin America. CONCLUSION: Significant reductions in MACE with GLP-1RA treatment were demonstrated between both sexes and across certain ethnicities and certain geographical regions.

Impact of Chronic Kidney Disease on the Outcomes of Patients Undergoing Percutaneous Left Atrial Appendage Occlusion: Insights from a Large National Database.

BACKGROUND: Studies exploring the effectiveness and safety of percutaneous left atrial appendage occlusion (pLAAO) in patients with chronic kidney disease (CKD) are limited. OBJECTIVES: We aimed to analyze trends and outcomes following pLAAO in patients with CKD. METHODS: We utilized the National Inpatient Sample (NIS) to identify hospitalizations for pLAAO from 2016-2020 and further identified cases with concomitant CKD. The primary outcome was mortality, and secondary outcomes were cerebrovascular accidents, major bleeding, vasopressor requirements, percutaneous coronary intervention, cardiac arrest, acute respiratory failure, transfusion, length of stay (LOS), and total hospital charges. Multivariable logistic regression was performed to further adjust for covariates. RESULTS: A total of 89,309 pLAAO procedures from 2016 to 2020 were identified, of which 21,559 (24.1%) reported concomitant CKD, with males comprising the majority (62.2%). An increasing trend in pLAAO procedures was seen from 2.24 to 13.9 per 10,000 patients from 2016 to 2020. Despite patients with CKD having a higher rate of most comorbidities, there was no difference in mortality (non-CKD vs. CKD, 0.07% vs. 0.42%; aOR: 1.3, 95% CI: 0.4 - 4.4, p=0.686) and complications for CKD and non-CKD patients, while CKD patients had longer LOS and higher total hospital charge. No significant sex differences in outcomes among CKD patients were observed except for a longer LOS in females. CONCLUSION: Despite generally having more comorbidities, outcomes of patients with CKD following pLAAO are similar to those without CKD, suggesting that pLAAO can be offered as a safe option for the treatment of AF in eligible patients with CKD.

Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression.

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Sex differences in transcatheter aortic valve replacement outcomes among patients with bicuspid aortic stenosis.

BACKGROUND: Despite comprising almost half of all patients undergoing valvular repair, data on transcatheter aortic valve replacement (TAVR) in patients with bicuspid aortic stenosis (BAS) are limited. OBJECTIVE: We aimed to evaluate whether there are any sex differences in trends and outcomes of TAVR in this population. METHODS: We utilized the National Inpatient Sample from 2012 to 2020 to identify admissions with BAS who underwent TAVR and analyzed trends and outcomes. Our primary outcome was in-hospital mortality and secondary outcomes were in-hospital complications. We used two models to adjust for demographics (A) and interventions (B). RESULTS: Between 2012 to 2020, there were 76,540 hospitalizations for BAS patients who underwent AVR, among which 6,010 (7.9 %) underwent TAVR. There was an overall increasing trend in number of TAVR cases with a decreasing trend in mortality (2013: 8.7 %, 2020: 1.3 %). TAVR was performed more in males (61.1% vs 38.9 %). Despite the worse baseline characteristics in males, in-hospital mortality (2.4% vs. 1.5 %; OR: 1.584; 95 % CI: 0.621-4.038; p = 0.335) and secondary outcomes were similar across both sexes, even after adjusting for demographics and interventions. CONCLUSION: TAVR in BAS has grown rapidly in the last decade. Males comprised the majority and had more comorbidities, but mortality and complications were similar in both sexes. Despite the increasing number of cases, a decreasing trend in mortality was observed for both sexes ultimately approaching that of SAVR, suggesting that TAVR may be a safe alternative among eligible males and females with bicuspid AS.

Cardiovascular and renal outcomes of glucagon-like peptide 1 receptor agonists among patients with and without type 2 diabetes mellitus: A meta-analysis of randomized placebo-controlled trials.

Background: Multiple cardiovascular outcomes trials (CVOTs) have shown the efficacy of GLP-1RAs in reducing major adverse cardiovascular events (MACEs) for high-risk patients. However, some CVOTs failed to demonstrate cardiovascular benefits. Objectives: We analyzed the impact of GLP-1RA on cardiovascular and renal outcomes in patients with or without T2DM, with subgroup analysis based on sex, estimated glomerular filtration rate (eGFR), body mass index (BMI), and history of cardiovascular disease (CVD). Methods: A comprehensive database search for placebo-controlled RCTs on GLP-1RA treatment was conducted until April 2024. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with log odds ratios and 95 % confidence intervals (CIs). Results: A total of 13 CVOTs comprising 83,258 patients were included. GLP-1RAs significantly reduced MACE (OR 0.86, 95 % CI: 0.80 to 0.94, p < 0.01) all-cause mortality OR 0.87, 95 % CI: 0.82 to 0.93, p < 0.001, CV mortality (OR 0.87, 95 % CI: 0.81 to 0.94, p < 0.001), stroke (fatal: OR 0.74, 95 % CI: 0.56 to 0.96, p = 0.03; non-fatal: OR 0.87, 95 % CI: 0.79 to 0.96, p = 0.005), coronary revascularization (OR 0.86, 95 % CI: 0.74 to 0.99, p = 0.023), and composite kidney outcome (OR 0.76, 95 % CI: 0.67 to 0.85, p < 0.001. GLP-1RA significantly reduced MACE in both sexes. Furthermore, GLP-1RA reduced MACE regardless of CVD history, BMI, and eGFR level. Conclusion: Significant reductions in MACE, overall and CV mortality, stroke, coronary revascularization, and composite kidney outcome with GLP-1RA treatment were noted across all subgroups.

Sex differences in trends and in-hospital outcomes of acute myocardial infarction in patients with familial hypercholesterolemia: insights from a large national database.

BACKGROUND: Sex differences in clinical outcomes following acute myocardial infarction (AMI) are well known. However, data on sex differences among patients with familial hypercholesterolemia (FH) are limited. We aimed to explore sex differences in outcomes of AMI among patients with FH from a national administrative dataset. RESEARCH DESIGN AND METHODS: We utilized the National Inpatient Sample to identify admissions with a primary diagnosis of AMI and a secondary diagnosis of FH. Our primary outcome of interest was in-hospital mortality; secondary outcomes were performance of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), respiratory complications, use of inotropes, use of mechanical circulatory support (MCS), bleeding complications, transfusion and facility discharge. We adjusted for demographics (model A), comorbidities (model B), and intervention (model C). RESULTS: Between October 2016 and December 2020, 5,714,993 admissions with a primary diagnosis of AMI were identified, of which 3,035 (0.05%) had a secondary diagnosis of FH. In-hospital mortality did not differ between men and women (Model C, adjusted OR = 0.85; 95% CI 0.28-2.60, p = 0.773). There was no sex difference in the secondary outcomes. CONCLUSION: Despite generally being older and having more comorbidities, women with FH fair equally with men with FH in terms of mortality during AMI admission.

Glucagon-like peptide-1 receptor agonists modestly reduced blood pressure among patients with and without diabetes mellitus: A meta-analysis and meta-regression.

AIM: The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. METHODS: A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. RESULTS: Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. CONCLUSION: Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.

End-Of-Life Care for Patients With End-Stage Heart Failure, Comparisons of International Guidelines.

Heart failure (HF) is a chronic, debilitating condition associated with significant morbidity, mortality, and socioeconomic burden. Patients with end-stage HF (ESHF) who are not a candidate for advanced therapies will continue to progress despite standard medical therapy. Thus, the focus of care shifts from prolonging life to controlling symptoms and improving quality of life through palliative care (PC). Because the condition and prognosis of HF patients evolve and can rapidly deteriorate, it is imperative to begin the discussion on end-of-life (EOL) issues early during HF management. These include the completion of an advance directive, do-not-resuscitate orders, and policies on device therapy and discontinuation as part of advance care planning (ACP). ESHF patients who do not have indications for advanced therapies or those who wish not to have a left ventricular assist device (LVAD) or heart transplant (HT) often experience high symptom burden despite adequate medical management. The proper identification and assessment of symptoms such as pain, dyspnea, nausea, depression, and anxiety are essential to the management of ESHF and may be underdiagnosed and undertreated. Psychological support and spiritual care are also crucial to improving the quality of life during EOL. Caregivers of ESHF patients must also be provided supportive care to prevent compassion fatigue and improve resilience in patient care. In this narrative review, we compare the international guidelines and provide an overview of end-of-life and palliative care for patients with ESHF.

Sex differences in permanent pacemaker implantation after transcatheter aortic valve replacement: a systematic review and meta-analysis.

BACKGROUND: There is limited evidence on the effect of sex on permanent pacemaker implantation (PPMI) after transcatheter aortic valve replacement (TAVR). The primary objective of this meta-analysis was to determine the role of sex among patients requiring PPMI post-TAVR. METHODS: A literature search was conducted using the SCOPUS, MEDLINE, and CINAHL databases for studies published until October 2022. Eligible studies included published randomized controlled trials (RCTs) and Observational Cohort Studies (OCS) articles that reported PPMI as an outcome of pacemaker status following TAVR. This study was performed per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Publication bias was estimated using a Funnel plot and Egger's test. Data were pooled using a random-effects model. The primary endpoint was the sex difference in PPMI after TAVR, with odds ratios and 95% confidence intervals (CIs) extracted. RESULTS: Data was obtained from 63 studies, and a total of 79,655 patients were included. The cumulative PPMI rate was 15.5% (95% CI, 13.6%-17.7%). The pooled analysis revealed that while there were more females than males undergoing TAVR (51.6%, 95% CI 50.4%-52.8%), males have a 14.5% higher risk for post-TAVR PPMI than females (OR 1.145, 95% CI 1.047-1.253, P < 0.01). CONCLUSIONS: Males are more likely to experience PPMI after TAVR than females. Further research needs to be done to better explain these observed differences in outcomes.