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.

Interrelationship of Sarcopenia and Cardiovascular Diseases: A Review of Potential Mechanisms and Management.

Sarcopenia refers to an age-related reduction of lean body mass. It showed a reciprocal relationship with cardiovascular diseases. Thus, it is imperative to explore pathophysiological mechanisms explaining the relationship between sarcopenia and cardiovascular diseases, along with the clinical assessment, and associated management. In this review, we discuss how processes such as inflammation, oxidative stress, endothelial dysfunction, neural and hormonal modifications, as well as other metabolic disturbances influence sarcopenia as well as its association with cardiovascular diseases. Moreover, this review provides an overview of both non-pharmacological and pharmacological management for patients with sarcopenia and cardiovascular diseases, with a focus on the potential role of cardiovascular drugs to mitigate sarcopenia.

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.

Sex differences in cardiovascular outcomes of SGLT-2 inhibitors in heart failure randomized controlled trials: A systematic review and meta-analysis.

Background: In patients with heart failure (HF), randomized controlled trials (RCTs) of sodium-glucose transporter-2 inhibitors (SGLT-2is) have proven to be effective in decreasing the primary composite outcome of cardiovascular death and hospitalizations for HF. A recently published meta-analysis showed that the use of SGLT-2is among women with diabetes resulted in less reduction in primary composite outcomes compared with men. This study aims to explore potential sex differences in primary composite outcomes among patients with HF treated with SGLT-2is. Methods: We systematically searched the medical database from 2017 to 2022 and retrieved all the RCTs using SGLT-2is with specified cardiovascular outcomes. We used the PRISMA (Preferred Reporting Items for a Review and Meta-analysis) method to screen for eligibility. We evaluated the quality of studies using the Cochrane Risk of Bias tool. We pooled the hazard ratio (HR) of the primary composite outcomes in both sexes, performed a meta-analysis, and calculated the odds ratio (OR) of the primary composite outcomes based on sex. Results: We included 5 RCTs with a total number of 21,947 patients. Of these, 7837 (35.7 %) were females. Primary composite outcomes were significantly lower in males and females taking SGLT-2is compared to placebo (males - HR 0.77; 95 % CI 0.72 to 0.84; p = 0.00001; females - HR 0.75; 95 % CI 0.67 to 0.84; p = 0.00001). Pooled data from four of the RCTs (n = 20,725) revealed a greater occurrence of the primary composite outcomes in females compared with males (OR 1.32; 95 % CI 1.17 to 1.48; p = 0.0002). Conclusion: SGLT-2is reduce the risk of primary composite outcomes in patients with HF, regardless of sex; however, the benefits were less pronounced in women. Further research needs to be done to better explain these observed differences in outcomes.

Locking the Revolving Door: Racial Disparities in Cardiovascular Disease.

Racial disparities in cardiovascular disease are unjust, systematic, and preventable. Social determinants are a primary cause of health disparities, and these include factors such as structural and overt racism. Despite a number of efforts implemented over the past several decades, disparities in cardiovascular disease care and outcomes persist, pervading more the outpatient rather than the inpatient setting, thus putting racial and ethnic minority groups at risk for hospital readmissions. In this article, we discuss differences in care and outcomes of racial and ethnic minority groups in both of these settings through a review of registries. Furthermore, we explore potential factors that connote a revolving door phenomenon for those whose adverse outpatient environment puts them at risk for hospital readmissions. Additionally, we review promising strategies, as well as actionable items at the policy, clinical, and educational levels aimed at locking this revolving door.

Assessing and Addressing Social Determinants of Cardiovascular Health: JACC State-of-the-Art Review.

Social determinants of health (SDOH) are the social conditions in which people are born, live, and work. SDOH offers a more inclusive view of how environment, geographic location, neighborhoods, access to health care, nutrition, socioeconomics, and so on are critical in cardiovascular morbidity and mortality. SDOH will continue to increase in relevance and integration of patient management, thus, applying the information herein to clinical and health systems will become increasingly commonplace. This state-of-the-art review covers the 5 domains of SDOH, including economic stability, education, health care access and quality, social and community context, and neighborhood and built environment. Recognizing and addressing SDOH is an important step toward achieving equity in cardiovascular care. We discuss each SDOH within the context of cardiovascular disease, how they can be assessed by clinicians and within health care systems, and key strategies for clinicians and health care systems to address these SDOH. Summaries of these tools and key strategies are provided.

Evidence for intensive LDL-C lowering for acute coronary syndrome: Recommendations from the Lipid Association of India.

Patients with acute coronary syndrome (ACS) have a high risk of subsequent adverse cardiovascular outcomes, particularly within the first 30 days. Although it is well documented that initiation of statin therapy in the setting of ACS improves short- and long-term cardiovascular outcomes, and achievement of lower levels of low density lipoprotein cholesterol (LDL-C) incrementally improves outcomes, many patients with ACS have persistent hypercholesterolemia after discharge from the hospital. This is a missed opportunity that prompted the Lipid Association of India to develop recommendations for earlier initiation of more aggressive LDL-C lowering treatment, particularly for patients of South Asian descent who are well-documented to have earlier onset of more aggressive atherosclerotic cardiovascular disease. The Lipid Association of India recommends individualized aggressive LDL-C goals after ACS, which can be rapidly achieved with high intensity statin therapy and subsequent goal-directed adjunctive treatment with ezetimibe and PCSK9 inhibitors. Improved treatment of hypercholesterolemia achieved within weeks after ACS has the potential to reduce the high rate of morbidity and mortality in these high risk patients.

The role of amputation as an outcome measure in cellular therapy for critical limb ischemia: implications for clinical trial design.

BACKGROUND: Autologous bone marrow-derived stem cells have been ascribed an important therapeutic role in No-Option Critical limb Ischemia (NO-CLI). One primary endpoint for evaluating NO-CLI therapy is major amputation (AMP), which is usually combined with mortality for AMP-free survival (AFS). Only a trial which is double blinded can eliminate physician and patient bias as to the timing and reason for AMP. We examined factors influencing AMP in a prospective double-blinded pilot RCT (2:1 therapy to control) of 48 patients treated with site of service obtained bone marrow cells (BMAC) as well as a systematic review of the literature. METHODS: Cells were injected intramuscularly in the CLI limbs as either BMAC or placebo (peripheral blood). Six month AMP rates were compared between the two arms. Both patient and treating team were blinded of the assignment in follow-up examinations. A search of the literature identified 9 NO-CLI trials, the control arms of which were used to determine 6 month AMP rates and the influence of tissue loss. RESULTS: Fifteen amputations occurred during the 6 month period, 86.7% of these during the first 4 months. One amputation occurred in a Rutherford 4 patient. The difference in amputation rate between patients with rest pain (5.6%) and those with tissue loss (46.7%), irrespective of treatment group, was significant (p = 0.0029). In patients with tissue loss, treatment with BMAC demonstrated a lower amputation rate than placebo (39.1% vs. 71.4%, p = 0.1337). The Kaplan-Meier time to amputation was longer in the BMAC group than in the placebo group (p = 0.067). Projecting these results to a pivotal trial, a bootstrap simulation model showed significant difference in AFS between BMAC and placebo with a power of 95% for a sample size of 210 patients. Meta-analysis of the literature confirmed a difference in amputation rate between patients with tissue loss and rest pain. CONCLUSIONS: BMAC shows promise in improving AMP-free survival if the trends in this pilot study are validated in a larger pivotal trial. The difference in amp rate between Rutherford 4 & 5 patients suggests that these patients should be stratified in future RCTs.

Intensive statin therapy for Indians: Part-I. Benefits.

The underlying disorder in the vast majority of cases of cardiovascular disease (CVD) is atherosclerosis, for which low-density lipoprotein cholesterol (LDL-C) is recognized as the first and foremost risk factor. HMG-CoA reductase inhibitors, popularly called statins, are highly effective and remarkably safe in reducing LDL-C and non-HDL-C levels. Evidence from clinical trials have demonstrated that statin therapy can reduce the risk of myocardial infarction (MI), stroke, death, and the need for coronary artery revascularization procedures (CARPs) by 25-50%, depending on the magnitude of LDL-C lowering achieved. Benefits are seen in men and women, young and old, and in people with and without diabetes or prior diagnosis of CVD. Clinical trials comparing standard statin therapy to intensive statin therapy have clearly demonstrated greater benefits in CVD risk reduction (including halting the progression and even reversing coronary atherosclerosis) without any corresponding increase in risk. Numerous outcome trials of intensive statin therapy using atorvastatin 80 mg/d have demonstrated the safety and the benefits of lowering LDL-C to very low levels. This led the USNCEP Guideline Committee to standardize 40 mg/dL as the optimum LDL-C level, above which the CVD risk begins to rise. Recent studies have shown intensive statin therapy can also lower CVD events even in low-risk individuals with LDL-C <110 mg/dL. Because of the heightened risk of CVD in Asian Indians, the LDL-C target is set at 30 mg/dL lower than that recommended by NCEP. Accordingly, the LDL-C goal is < 70 mg/dL for Indians who have CVD, diabetes, metabolic syndrome, or chronic kidney disease. Intensive statin therapy is often required in these populations as well as others who require a > or = 50% reduction in LDL-C. Broader acceptance of this lower LDL-C targets and its implementation could reduce the CVD burden in the Indian population by 50% in the next 25 years. Clinical trial data support an extremely favorable benefit-to-risk ratio of intensive statin therapy with some but not all statins. Atorvastatin 80 mg/d is 100 times safer than aspirin 81 mg/d and 10 times safer than diabetic medications. Intensive statin therapy is more effective and safe compared to intensive control of blood sugar or blood pressure in patients with diabetes.

Prevention of atherosclerotic cardiovascular disease in South Asians in the US: A clinical perspective from the National Lipid Association.

It is now well recognized that South Asians living in the US (SAUS) have a higher prevalence of atherosclerotic cardiovascular disease (ASCVD) that begins earlier and is more aggressive than age-matched people of other ethnicities. SA ancestry is now recognized as a risk enhancer in the US cholesterol treatment guidelines. The pathophysiology of this is not fully understood but may relate to insulin resistance, genetic and dietary factors, lack of physical exercise, visceral adiposity and other, yet undiscovered biologic mechanisms. In this expert consensus document, we review the epidemiology of ASCVD in this population, enumerate the challenges faced in tackling this problem, provide strategies for early screening and education of the community and their healthcare providers, and offer practical prevention strategies and culturally-tailored dietary advice to lower the rates of ASCVD in this cohort.

Treatment of dyslipidemia in patients with type 2 diabetes.

Type 2 diabetes is associated with significant cardiovascular morbidity and mortality. Although low-density lipoprotein cholesterol levels may be normal in patients with type 2 diabetes, insulin resistance drives a number of changes in lipid metabolism and lipoprotein composition that render low-density lipoprotein cholesterol and other lipoproteins more pathogenic than species found in patients without type 2 diabetes. Dyslipidemia, which affects almost 50% of patients with type 2 diabetes, is a cardiovascular risk factor characterized by elevated triglyceride levels, low high-density lipoprotein cholesterol levels, and a preponderance of small, dense, low-density lipoprotein particles. Early, aggressive pharmacological management is advocated to reduce low-density lipoprotein cholesterol levels, regardless of baseline levels. A number of lipid-lowering agents, including statins, fibrates, niacin, and bile acid sequestrants, are available to target normalization of the entire lipid profile. Despite use of combination and high-dose lipid-lowering agents, many patients with type 2 diabetes do not achieve lipid targets. This review outlines the characteristics and prevalence of dyslipidemia in patients with type 2 diabetes and discusses strategies that may reduce the risk of cardiovascular disease in this population.

JCL roundtable: South Asian atherosclerotic risk.

South Asian risk for atherosclerotic cardiovascular disease (ASCVD) has received special emphasis in the 2018 US AHA/ACC/Multisociety Cholesterol Guidelines. The term "South Asian" refers specifically to the countries of India, Pakistan, Nepal, Bhutan, Bangladesh, Sri Lanka, and Maldives and to the worldwide diaspora of families from these countries. With this definition, approximately 25% of the world's population is South Asian, but about 50% of ASCVD occurs in this group. In this JCL Roundtable, we discuss the roles of visceral adiposity, diabetes, and features of the metabolic syndrome; lipoprotein(a); and diet and lifestyle, including the transition of both diet and lifestyle over the past 40 to 50 years. Genetic and/or hidden risk is an area of ongoing research. Individual patient assessment and intervention should recognize the earlier onset of ASCVD and the value of screening for traditional risk factors as well as waist circumference, coronary artery calcium scoring, and lipoprotein(a) assay. Culturally acceptable dietary strategies are available, although not widely implemented or evaluated as yet. In very-high-risk cases of secondary prevention, one should consider combining medications to drive low-density lipoprotein cholesterol much lower than 70 mg/dL. Our discussion concludes by insisting that the signal of alarm must be accompanied by decisive action.