Cardiovascular Efficacy Research Articles

SELECT: Glucagon-like peptide-1 receptor agonist in obese patients with cardiovascular disease in the absence of diabetes.

Obesity is a global epidemic affecting 2.5 billion people and is recognized as the fourth leading cause of global mortality. Obesity is characterized by excessive accumulation of body fat and is associated with a range of health consequences, including an elevated risk of cardiovascular disease (CVD). Glucagon-like peptide-1 (GLP-1) receptor agonists have been proven to reduce cardiovascular outcomes in patients with diabetes. Study and results: The SELECT trial was a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, conducted at 804 clinical sites in 41 countries. Patients were randomly assigned in a 1:1 ratio, to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular efficacy endpoint was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, assessed in a time-to-first-event analysis. A total of 17,604 patients were recruited, with a mean age of 61.6 years and 72.3% males. The mean duration of exposure to semaglutide or placebo in the overall trial population was 34.2±13.7 months. The primary CVD endpoint occurred in 6.5% (n=569) of the semaglutide group and 8% (n=701) in the placebo group (hazard ratio, 0.80; 95% CI, 0.72 to 0.90; P<0.001). There was also a significant reduction of 9.39% in body weight among the patients taking semaglutide over 104 weeks after randomization versus 0.88% among the placebo group. Semaglutide reduces the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in obese and overweight non-diabetic patients with preexisting cardiovascular disease.

Consensus on glycemic management for patients with coronary heart disease and type 2 diabetes.

The prevalence of patients with coronary heart disease (CHD) and diabetes mellitus is notably high, posing significant residual cardiovascular risks even after routine interventions such as antihypertensive, lipid-lowering, and antithrombotic treatments. Recent studies have demonstrated that certain glucose-lowering medications confer cardiovascular benefits for patients with type 2 diabetes. However, a survey indicates that cardiologists may not be fully acquainted with the optimal screening timing, indicators, and diagnostic criteria for type 2 diabetes, and there is insufficient awareness and a low rate of prescription of novel glucose-lowering medications with proven cardiovascular efficacy, such as glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose co-transporter-2 inhibitors (SGLT-2i). In this context, based on domestic and international guidelines or consensus and the latest evidence-based evidence, this consensus aims to standardize the glycemic management for patients with acute coronary syndrome, chronic coronary syndrome, and perioperative management for percutaneous coronary intervention. It highlights the key points of screening and diagnosis of type 2 diabetes, and the comprehensive management of cardiovascular risk in patients with CHD. The consensus elaborates on the principles and algorithms of glycemic management for CHD patients, without involving acute complications of diabetes, clarifies the clinical practice of glucose-lowering medications with cardiovascular benefits, and promotes the standardized use of these medications in cardiovascular and other related specialty fields. Additionally, it addresses the glucose-lowering treatment to comprehensively reduce cardiovascular risks.

Target Cell Extraction and Spectrum-Effect Relationship Coupled with BP Neural Network Classification for Screening Potential Bioactive Components in Ginseng Extract with a Protective Effect against Myocardial Damage.

Cardiovascular disease has become a common ailment that endangers human health, having garnered widespread attention due to its high prevalence, recurrence rate, and sudden death risk. Ginseng possesses functions such as invigorating vital energy, enhancing vein recovery, promoting body fluid and blood nourishment, calming the nerves, and improving cognitive function. It is widely utilized in the treatment of various heart conditions, including palpitations, chest pain, heart failure, and other ailments. Although numerous research reports have investigated the cardiovascular activity of single ginsenoside, there remains a lack of systematic research on the specific components group that predominantly contribute to cardiovascular efficacy in ginseng medicinal materials. In this research, the spectrum-effect relationship, target cell extraction, and BP neural network classification were used to establish a rapid screening system for potential active substances. The results show that red ginseng extract (RGE) can improve the decrease in cell viability and ATP content and inhibit the increase in ROS production and LDH release in OGD-induced H9c2 cells. A total of 70 ginsenosides were identified in RGE using HPLC-Q-TOF-MS/MS analysis. Chromatographic fingerprints were established for 12 batches of RGE by high-performance liquid chromatography (HPLC). A total of 36 common ingredients were found in 12 batches of RGE. The cell viability, ATP, ROS, and LDH of 12 batches RGE were tested to establish gray relationship analysis (GRA) and partial least squares discrimination analysis (PLS-DA). BP neural network classification and target cell extraction were used to narrow down the scope of Spectral efficiency analysis and screen the potential active components. According to the cell experiments, RGE can improve the cell viability and ATP content and reduce the oxidative damage. Then, seven active ingredients, namely, Ginsenoside Rg1, Rg2, Rg3, Rb1, Rd, Re, and Ro, were screened out, and their cardiovascular activity was confirmed in the OGD model. The seven ginsenosides were the main active substances of red ginseng in treating myocardial injury. This study offers a reference for quality control in red ginseng and preparations containing red ginseng for the management of cardiovascular diseases. It also provides ideas for screening active ingredients of the same type of multi-pharmacologically active traditional Chinese medicines.

Enalapril Is Superior to Lisinopril in Improving Endothelial Function without a Difference in Blood-Pressure-Lowering Effects in Newly Diagnosed Hypertensives.

Here, we tested if lipophilicity affects the efficacy of ACE inhibitory drugs when used as the first therapy in newly identified hypertensives in a prospective study. We tested the differences in the cardiovascular efficacy of the hydrophilic lisinopril (8.3 ± 3.0 mg/day) and the lipophilic enalapril (5.5 ± 2.3 mg/day) (n = 59 patients). The cardiovascular parameters were determined using sonography (flow-mediated dilation (FMD) in the brachial artery, intima-media thickness of the carotid artery), 24 h ambulatory blood pressure monitoring (peripheral arterial blood pressure), and arteriography (aortic blood pressure, augmentation index, and pulse wave velocity) before and after the initiation of ACE inhibitor therapy. Both enalapril and lisinopril decreased blood pressure. However, lisinopril failed to improve arterial endothelial function (lack of effects on FMD) when compared to enalapril. Enalapril-mediated improved arterial endothelial function (FMD) positively correlated with its blood-pressure-lowering effect. In contrast, there was no correlation between the decrease in systolic blood pressure and FMD in the case of lisinopril treatment. The blood-pressure-lowering effects of ACE inhibitor drugs are independent of their lipophilicity. In contrast, the effects of ACE inhibition on arterial endothelial function are associated with lipophilicity: the hydrophilic lisinopril was unable to improve, while the lipophilic enalapril significantly improved endothelial function. Moreover, the effects on blood pressure and endothelial function did not correlate in lisinopril-treated patients, suggesting divergent mechanisms in the regulation of blood pressure and endothelial function upon ACE inhibitory treatment.

Comparing the drug target effects of Cholesteryl ester transfer protein (CETP) on cardiovascular diseases in East Asian and European populations

Abstract Introduction Cholesteryl ester transfer protein (CETP) is a drug target originally evaluated for raising HDL-C, for efficacy against coronary heart disease (CHD). Previous attempts to develop a licensed drug compound inhibiting CETP have heterogeneous CHD effects, which are likely attributable to the developed compound rather than CETP itself. Currently, novel CETP inhibitors are being pursued for the treatment of CHD. Drug target Mendelian randomization studies, leveraging genetic evidence, have shown that on-target CETP inhibition reduces CHD risk in individuals of European ancestries. However, similar MR studies conducted in East Asian ancestries have failed to show a CHD effect, questioning the value of pharmacological inhibition of CETP in this population. Purpose In this study, we compared drug target MR effects of CETP inhibition in Europeans and East Asians, focusing on cardiovascular efficacy outcomes, and relevant safety outcomes. Methods We used ancestry-specific GWAS summary statistics for Europeans (n=1,320,016) and East Asians (n=146,492) from the Global Lipids Genetics Consortium, taking variants from within and around ±50 kbp of the CETP locus. Colocalization was employed to determine potential trans-ancestry signals between CETP variants for HDL-C and LDL-C. Subsequently, drug target MR was used to estimate ancestry-specific effects of on-target CETP inhibition on 11 plasma biomarkers and 15 clinical outcomes between East Asian and European populations. Differences between ancestries were evaluated using interaction tests. Results There was strong support (posterior probability: 99.8%) of a shared causal CETP variant affecting HDL-C in both populations. Given the absence of a LDL-C signal in East Asians, similar colocalization was not observed for LDL-C. Employing drug target MR scaled to a standard deviation increase in HDL-C, we found that lower CETP had more pronounced decreasing effects in Europeans on LDL-C, LP[a], systolic blood pressure and pulse pressure (interaction p-values &amp;gt;1.9×10-3). Nevertheless, lower CETP protected against CHD, angina, intracerebral haemorrhage, and heart failure in both ancestries, for example for CHD (OR, 0.89; 95%CI, 0.84-0.94) in East Asians, compared to Europeans (OR, 0.95; 95%CI, 0.92-0.99, interaction p-value: 0.05). Exploring potential safety outcomes, lower CETP was protective against pneumonia in Europeans and East Asians (interaction p-value=0.53) and had a potential harmful effect on asthma and chronic kidney disease in East Asians (interaction p-value &amp;gt; 1.9×10-3). Conclusion In conclusion, on-target and sufficiently potent CETP inhibition is anticipated to prevent cardiovascular diseases in both European and East Asian populations.

Cardiovascular efficacy and safety of antidiabetic agents: A network meta-analysis of randomized controlled trials.

An important characteristic of glucose-lowering therapies (GLTs) is their ability to prevent cardiovascular complications. We aimed to investigate the cardiorenal efficacy and general safety of GLTs. Multicentre, randomized, clinical trials that included over 100 participants comparing antidiabetic agents with a placebo or a different antidiabetic agent and reporting major adverse cardiovascular events (MACEs), or primarily reporting heart failure, were searched in the PubMed, Embase and Cochrane databases. Data were extracted independently for random-effects network meta-analyses to calculate the hazard ratio estimates. Forty-three trials that compared nine types of GLTs were included in the present analysis. The risk of three-point MACE was reduced in the presence of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose cotransporter-2 inhibitors (SGLT-2is) and thiazolidinedione therapy compared with the placebo, dipeptidyl peptidase-4 inhibitors, or insulin therapy. GLP-1 RAs were favourable for cardiovascular and renal outcomes. SGLT-2is reduced renal outcomes by ~40%, which was superior to other GLTs. Thiazolidinedione therapy increased the risks of hospitalization for heart failure and had no benefits on mortality. Adverse events leading to drug discontinuation were higher with GLP-1 RAs and thiazolidinediones than placebo. GLP-1 RAs, SGLT-2is and thiazolidinediones reduced three-point MACE compared with other GLTs. Each drug class had unique advantages and disadvantages.

Nattokinase Supplementation and Cardiovascular Risk Factors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

As a fibrinolytic enzyme from fermented soybean, nattokinase has been shown to be potentially beneficial for cardiovascular health, but current clinical evidences regarding the nattokinase supplementation on cardiovascular risk factors are various. This study aims to evaluate the cardiovascular efficacy of nattokinase. Four electronic databases were systematically searched to collect eligible randomized controlled trials. Data were extracted and summarized in a pre-designed form by two independent reviewers. Review Manager 5.4 software (Cochrane Library Software, Oxford, U.K.) was used for meta-analysis and bias risk assessment. Six studies were eligible for quantitative analysis with 546 participants. The overall methodological quality of included studies was high. Relatively low total dosage of nattokinase had a negative effect on blood total cholesterol (MD [mean difference] = 5.27, 95% CI [confidence intervals]: 3.74 to 6.81, p 0.00001), high-density lipoprotein cholesterol (MD = -2.76, 95% CI: -3.88 to -1.64, p 0.00001), and low-density lipoprotein cholesterol (MD = 6.49, 95% CI: 0.83 to 12.15, p = 0.02). Nattokinase supplementation significantly reduced systolic blood pressure (MD = -3.45, 95% CI: -4.37 to -2.18, p 0.00001) and diastolic blood pressure (MD = -2.32, 95% CI: -2.72 to -1.92, p 0.00001), and led a slight increase in blood glucose (MD = 0.40, 95% CI: 0.20 to 0.60, p 0.0001) as compared to placebo. Nattokinase group with relatively high total dosage also had a higher total cholesterol (MD = 3.18, 95% CI: 2.29 to 4.06, p 0.00001) than control interventions, but no significant differences were found in levels of high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. No significant correlation was found between nattokinase supplementation and triglyceride (p = 0.71). No notable adverse events were reported in all studies due to intake of nattokinase. This study further supports that nattokinase can be used as an effective adjunctive therapy for hypertension, but relatively low-dose supplementation of nattokinase may have no significant lipid-lowering effect. More work will need to be done to determine whether the positive efficacy of nattokinase on cardiovascular risk factors is dose-dependent. This work has been registered on PROSPERO (CRD42022315020).

Cardiovascular Efficacy of Lipid-Lowering Drug Targets Is Not Entirely Explained by Apolipoprotein B Reduction: Mendelian Randomization Evidence.

Cardiovascular Efficacy of Lipid-Lowering Drug Targets Is Not Entirely Explained by Apolipoprotein B Reduction: Mendelian Randomization Evidence.

Pragmatic trials, a step forward to assess cardiovascular efficacy of new glucose-lowering agents

Pragmatic trials, a step forward to assess cardiovascular efficacy of new glucose-lowering agents

Plant Sterols and Plant Stanols in Cholesterol Management and Cardiovascular Prevention.

Atherosclerotic cardiovascular disease (ASCVD) remains the major mortality cause in developed countries with hypercholesterolaemia being one of the primary modifiable causes. Lifestyle intervention constitutes the first step in cholesterol management and includes dietary modifications along with the use of functional foods and supplements. Functional foods enriched with plant sterols/stanols have become the most widely used nonprescription cholesterol-lowering approach, despite the lack of randomized trials investigating their long-term safety and cardiovascular efficacy. The cholesterol-lowering effect of plant-sterol supplementation is well-established and a potential beneficial impact on other lipoproteins and glucose homeostasis has been described. Nevertheless, experimental and human observational studies investigating the association of phytosterol supplementation or circulating plant sterols with various markers of atherosclerosis and ASCVD events have demonstrated controversial results. Compelling evidence from recent genetic studies have also linked elevated plasma concentrations of circulating plant sterols with ASCVD presence, thus raising concerns about the safety of phytosterol supplementation. Thus, the aim of this review is to provide up-to-date data on the effect of plant sterols/stanols on lipid-modification and cardiovascular outcomes, as well as to discuss any safety issues and practical concerns.

Effect of Caffeine Consumption on Cardiovascular Disease: An Updated Review

The incidence of cardiovascular diseases has significantly increased with the expansion of the industrialization of societies, which is notably linked to lifestyle changes and an unhealthy diet. Hence, determining the healthiest diet habits and supplements seems to be an appropriate way to decrease the global burden of cardiovascular diseases. Currently, caffeine, one of the most widely consumed compounds in the world, has emerged with some promising results in the treatment of numerous pathophysiological conditions of cardiovascular diseases. A literature search was conducted in PubMed, Scopus, Science Direct, Google Scholar, and Web of Science databases for the relevant articles regarding the pharmacology, preclinical, and clinical studies on the potential effects of caffeine on cardiovascular diseases. While caffeine could improve cardiovascular outcomes through several mechanisms of action, the literature review revealed controversial clinical effects of caffeine on blood pressure, cardiac arrhythmias, acute coronary syndrome, stable angina, and heart failure. In the case of dyslipidemia, coffee consumption increased total cholesterol, triglyceride, and low-density lipoprotein. Taken together, the existence of multiple confounding factors in the caffeine studies has resulted in inconclusive data interpretation. Further well-designed studies with adequate control of the confounding factors are warranted to draw a clear conclusion on the cardiovascular efficacy and safety of caffeine.

Effects of Spironolactone on Arrhythmias in Hemodialysis Patients: Secondary Results of the SPin-D Randomized Controlled Trial.

Background Patients receiving maintenance hemodialysis (HD) have a high incidence of cardiovascular events, including arrhythmia and sudden death. Spironolactone reduces the risk of cardiovascular events and sudden death in patients with heart failure, but the effects of spironolactone on arrhythmic events in patients treated with maintenance HD are unclear. Methods The Safety and Cardiovascular Efficacy of Spironolactone in Dialysis-Dependent ESRD (SPin-D) trial, was a 36-week randomized, placebo-controlled, double-blind trial comparing 3 different doses of spironolactone with placebo in maintenance HD patients. We performed a post-hoc analysis in a subset (n=57) who underwent extended electrocardiographic monitoring using a wearable device at baseline and follow-up. Generalized estimating equations models were fit to determine the associations of spironolactone (individual doses and combined) versus placebo on the incidence rate of predefined categories of arrhythmic events. Results The average age of participants was 55 ±12 years; 61% were male; and 77% were Black. The overall proportion of patients with at least one arrhythmia event was 43% (15/35) at baseline and 81% (43/53) at the end of follow-up. At the end of follow-up, the rate of bradycardic events or conduction blocks was higher in the combined spironolactone group, compared with placebo, (82.4 versus 38.7 events/100 patient days; P<0.001). Similar findings were noted in adjusted models, but did not meet statistical significance (adjusted rate ratio of 2.04; 95%CI 0.83 - 5.05). Conclusions In a 36-week trial of patients receiving maintenance hemodialysis, a higher frequency of bradycardia and conduction blocks was observed among those treated with spironolactone treatment compared with placebo. Larger studies are required to investigate the longer-term effects of spironolactone on cardiac conduction in patients receiving hemodialysis.

260 EFFICACY OF SGLT2 INHIBITORS IN PATIENTS WITH AND WITHOUT HEART FAILURE AND ACROSS THE SPECTRUM OF LEFT VENTRICULAR EJECTION FRACTION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Abstract Background Sodium-glucose cotransporter 2 (SGLT-2) inhibitors have demonstrated to reduce heart failure (HF) and renal outcomes irrespective of diabetes status. The cardiovascular efficacy and the mortality benefit of these agents in patients without HF and across the spectrum of left ventricular ejection fraction (EF) are a matter of debate. Methods This study-level meta-analysis included 11 controlled randomized trials and 76,520 patients randomized to a SGLT-2 inhibitor (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin and sotagliflozin) or placebo in different clinical settings including diabetes, HF with reduced or preserved EF and chronic kidney disease. Data were stratified by history of HF, HF with reduced EF (≤40%), mid-range EF (40-49%) and preserved EF (≥50%). The incidence of the following outcomes, when available, was evaluated: HF composite outcome, defined as cardiovascular death or hospitalization/urgent visit for HF, its individual components and all-cause mortality. An additional sensitivity analysis tested the efficacy of SGLT-2 inhibitors in patients with extremely reduced EF (≤30%). Results Overall, there were 22,653 patients with HF (33.8%) and 44,304 patients without HF (66.2%). In patients without history of HF, SGLT-2 inhibitors significantly reduced the risk of HF outcomes (HR 0.76, 95% CI 0.68-0.86) and all-cause mortality (HR 0.84, 95% CI 0.73-0.95). In patients with HF, a significant reduction in the composite of cardiovascular death and HF events was consistently observed in those with reduced EF (HR 0.71, 95% CI 0.65-0.78), mid-range EF (HR 0.68, 95% CI 0.57-0.81) and preserved EF (HR 0.78, 95% CI 0.69-0.89; Figure). There was a significant reduction in all-cause mortality also in patients with HF treated with SGLT-2 inhibitors (HR 0.87, 95% CI 0.80-0.95). Conclusions SGLT-2 inhibitors demonstrated cardiovascular and mortality benefits irrespective from history of HF and across the spectrum of left ventricular EF.

Familial Hypercholesterolemia and Lipoprotein(a): A Gordian Knot in Cardiovascular Prevention.

Familial hypercholesterolemia (FH) is the most frequent genetic disorder resulting in increased low-density lipoprotein cholesterol (LDL-C) levels from childhood, leading to premature atherosclerotic cardiovascular disease (ASCVD) if left untreated. FH diagnosis is based on clinical criteria and/or genetic testing and its prevalence is estimated as being up to 1:300,000-400,000 for the homozygous and ~1:200-300 for the heterozygous form. Apart from its late diagnosis, FH is also undertreated, despite the available lipid-lowering therapies. In addition, elevated lipoprotein(a) (Lp(a)) (&gt;50 mg/dL; 120 nmol/L), mostly genetically determined, has been identified as an important cardiovascular risk factor with prevalence rate of ~20% in the general population. Novel Lp(a)-lowering therapies have been recently developed and their cardiovascular efficacy is currently investigated. Although a considerable proportion of FH patients is also diagnosed with high Lp(a) levels, there is a debate whether these two entities are associated. Nevertheless, Lp(a), particularly among patients with FH, has been established as a significant cardiovascular risk factor. In this narrative review, we present up-to-date evidence on the pathophysiology, diagnosis, and treatment of both FH and elevated Lp(a) with a special focus on their association and joint effect on ASCVD risk.

Kidney Angiotensin in Cardiovascular Disease: Formation and Drug Targeting.

The concept of local formation of angiotensin II in the kidney has changed over the last 10–15 years. Local synthesis of angiotensinogen in the proximal tubule has been proposed, combined with prorenin synthesis in the collecting duct. Binding of prorenin via the so-called (pro)renin receptor has been introduced, as well as megalin-mediated uptake of filtered plasma-derived renin-angiotensin system (RAS) components. Moreover, angiotensin metabolites other than angiotensin II [notably angiotensin-(1-7)] exist, and angiotensins exert their effects via three different receptors, of which angiotensin II type 2 and Mas receptors are considered renoprotective, possibly in a sex-specific manner, whereas angiotensin II type 1 (AT1) receptors are believed to be deleterious. Additionally, internalized angiotensin II may stimulate intracellular receptors. Angiotensin-converting enzyme 2 (ACE2) not only generates angiotensin-(1-7) but also acts as coronavirus receptor. Multiple, if not all, cardiovascular diseases involve the kidney RAS, with renal AT1 receptors often being claimed to exert a crucial role. Urinary RAS component levels, depending on filtration, reabsorption, and local release, are believed to reflect renal RAS activity. Finally, both existing drugs (RAS inhibitors, cyclooxygenase inhibitors) and novel drugs (angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors, soluble ACE2) affect renal angiotensin formation, thereby displaying cardiovascular efficacy. Particular in the case of the latter three, an important question is to what degree they induce renoprotection (e.g., in a renal RAS-dependent manner). This review provides a unifying view, explaining not only how kidney angiotensin formation occurs and how it is affected by drugs but also why drugs are renoprotective when altering the renal RAS.Significance StatementAngiotensin formation in the kidney is widely accepted but little understood, and multiple, often contrasting concepts have been put forward over the last two decades. This paper offers a unifying view, simultaneously explaining how existing and novel drugs exert renoprotection by interfering with kidney angiotensin formation.

Exploring heterogeneities of cardiovascular efficacy and effectiveness of SGLT2 inhibitors in patients with type 2 diabetes: an umbrella review of evidence from randomized clinical trials versus real-world observational studies.

We aimed to explore possible contributors to discrepancies between randomized controlled trials (RCTs) and real-world observational studies (OS) in cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes (T2D) patients. Wesearched PubMed and EMBASE to identify meta-analyses of RCTs and OS oncardiovascular effects of SGLT2 inhibitors in T2D patients. Cardiovascular outcomes included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), all-cause mortality (ACM), hospitalization for heart failure(HHF), andatrial fibrillation (AF). We examined the summary relative risk (RR) and 95% confidence interval (CI) for each endpoint from meta-analyses of RCTs. We identified and included 15 eligible meta-analyses, 13 for RCTs and 2 for OS, with moderatelystrong evidence. The results revealed a significant discrepancy between RCTs and OS for MI (RR, 95% CI 1.05, 0.82-1.38; I = 91.5% versus odds ratio (OR), 95% CI 0.77, 0.73-0.81; I = 15.0%), stroke (RR, 95% CI 0.99, 0.76-1.29; I = 93.4%versus OR, 95% CI 0.75, 0.72-0.78; I = 23.0%), and AF (RR, 95% CI 0.72, 0.62-0.85; I = 0.0% versus OR, 95% CI 0.92,0.83-1.02; I = 0.0%). OS presented significant benefits of SGLT2 inhibitors both on primary and secondary preventions of MACE, MI, stroke, ACM, CVM, and HHF; RCTs did not. Given the spectrum of T2D patient characteristics and the strength of overall evidence, our review underscored the importance of constant integration of all available information and critical interpretation of all inconsistencies to optimize evidence-based diabetes care.

META-ANALYSIS OF DEDICATED HEART FAILURE TRIALS EVALUATING THE EFFECT OF SACUBITRIL/VALSARTAN ON MAJOR CARDIAC RHYTHM DISORDERS

Objective: The important role of major cardiac rhythm disorders in the prognosis of subjects with heart failure (HF) has been discussed extensively. Sacubitril/valsartan has revolutionized treatment strategy for patients with HF with reduced left ventricular ejection fraction (HFrEF), while it is cardiovascular safe -but not efficacious- in patients with HF with preserved ejection fraction (HFpEF). Anti-arrhythmogenic effect of sacubitril/valsartan has been demonstrated in several, recent experimental studies, however the clinical implications of that observations remain largely unknown. Design and method: We sought to determine the effect of sacubitril/valsartan compared to active comparator on major cardiac rhythm disorders in patients with HF, pooling data from the dedicated HF outcome trials. We evaluated the following outcomes of interest: atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation and cardiac arrest. The latter outcome was assessed in the light of recent evidence that arrhythmias account for almost 7% of cardiac arrest cases, both in in-hospital and out-of-hospital settings. Results: We pooled data from 3 trials in a total of 14,128 enrolled subjects with HF regardless of LVEF, assigned either to sacubitril/valsartan or valsartan.Sacubitril/valsartan compared to valsartan alone did not result in a significant risk reduction for atrial fibrillation (RR = 1.05, 95% CI; 0.89–1.24, I2 = 0%), atrial flutter (RR = 1.01, 95% CI; 0.55–1.86, I2 = 34%), ventricular tachycardia (RR = 0.92, 95% CI; 0.53–1.58, I2 = 32%) and ventricular fibrillation (RR = 0.79, 95% CI; 0.47–1.32, I2 = 0%). However, we demonstrated that sacubitril/valsartan compared to valsartan conferred a significant risk reduction in cardiac arrest by 47% (RR = 0.53, 95% CI; 0.38–0.76, I2 = 0%). Conclusions: Therefore, despite the cardiovascular efficacy and safety of sacubitril/valsartan among patients with HF, and its established role in the treatment of patients with HFrEF, it does not prevent major cardiac arrhythmias. However, its preventive role against cardiac arrest is of utmost importance and should be assessed in future randomized controlled trials as a surrogate outcome.

META-ANALYSIS EVALUATING THE EFFICACY OF SODIUM-GLUCOSE CO-TRANSPORTER-2 INHIBITORS IN SUBJECTS WITH HEART FAILURE WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION

Objective: Heart failure (HF) is a chronic, disabling and deadly disease. Subjects with HF feature an increased risk for death and recurrent ospitalisation for HF decompensation. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a novel class of drugs primarily developed for patients with diabetes mellitus. SGLT-2 inhibitors have proven cardiovascular efficacy in HFrEF; however, their efficacy in subjects with HFpEF has not be elucidated. Therefore, we sought to determine the effect of SGLT-2 inhibitors on surrogate cardiovascular outcomes in HFpEF, utilizing both data from ospitalis controlled trials and real-world studies. Design and method: We searched PubMed and the Cochrane Library for RCTs and observational studies enrolling adult subjects with HFpEF regardless of concomitant type 2 diabetes mellitus (T2DM), assigned to a SGLT-2 inhibitor versus placebo or active comparator. We set as primary efficacy outcome the composite of cardiovascular death or ospitalisation for HF decompensation. We set as secondary efficacy outcome that of all-cause death. Results: We pooled data from four RCTs and one observational study for a total of 7,920 subjects with HFpEF. We demonstrated that treatment with SGLT-2 inhibitors versus placebo or active comparator produced a significant decrease in the risk for the primary composite outcome by 30% (RR = 0.70, 95% CI; 0.52 – 0.93, I2 = 48%, p = 0.01). As far as all-cause death is concerned, we showed that SGLT-2 inhibitors compared to control did not produce a significant effect on the corresponding risk (RR = 0.65, 95% CI; 0.34 – 1.26, I2 = 67%, p = 0.21). Overall risk of bias was evaluated as low across the selected studies. Conclusions: Current evidence suggests that SGLT-2 inhibitors are also efficacious in HFpEF. Although total mortality was not significantly reduced, the trend towards beneficial effects along with the demonstrated morbidity benefits point towards the use of SGLT-2 inhibitors in this patient population.

Proprotein convertase subtilisin/kexin type 9 inhibition after acute coronary syndrome or prior myocardial infarction.

Lowering low-density lipoprotein cholesterol (LDL-C) with statins or ezetimibe reduces major adverse cardiovascular events (MACE) in patients with coronary heart disease. Additional treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may lower LDL-C to levels not achievable with conventional lipid-lowering agents. This review summarizes findings from two large, placebo-controlled trials that evaluated the cardiovascular efficacy of monoclonal antibodies directed against PCSK9, added to background statin therapy, in patients with established atherosclerotic cardiovascular disease (ASCVD) or recent acute coronary syndrome (ACS) and persistent elevation of atherogenic lipoproteins despite statin treatment. The FOURIER trial with evolocumab and the ODYSSEY OUTCOMES trial with alirocumab demonstrated 15% overall reductions in MACE compared to placebo, associated with average achieved LDL-C levels as low as 30-40 mg/dl. Alirocumab treatment was associated with fewer deaths after ACS. Subgroups with large absolute treatment benefit included those with baseline LDL-C ≥100 mg/dl, diabetes, polyvascular or peripheral artery disease, prior coronary bypass surgery, statin intolerance, or elevated lipoprotein(a) levels. No safety concerns arose with use of PCSK9 monoclonal antibodies, even in patients who achieved LDL-C levels below 20 mg/dl. In selected patients with established ASCVD or recent ACS, PCSK9 inhibitors can play an important role in reducing the risk of MACE, and may also reduce the risk of death after ACS.

META-ANALYSIS ASSESSING THE IMPACT OF PRIOR HEART FAILURE AND CHRONIC KIDNEY DISEASE ON THE CARDIOVASCULAR EFFICACY OF GLUCAGON-LIKE PEPTIDE-1 RECEPTOR AGONISTS

Objective: Chronic kidney disease (CKD) and heart failure (HF) represent common co-morbidities in patients with type 2 diabetes mellitus (T2DM), constituting an additional burden that boosts overall morbidity and mortality. Therefore, we sought to determine whether history of HF or CKD affects the cardiovascular efficacy of GLP-1RAs, also utilizing data from the recently published FREEDOM Cardiovascular Outcomes Trial, which evaluated the cardiovascular safety of delivering a continuous subcutaneous infusion of the GLP-1RA exenatide (ITCA 650) in T2DM. Design and method: We searched the relevant, hallmark, cardiovascular outcome trials of GLP-1RAs in T2DM. We set as primary efficacy outcome the effect of GLP-1RAs versus placebo on the risk for a major adverse cardiovascular event (MACE) according to the prior history of HF, while we also assessed as a secondary efficacy outcome the effect of GLP-1RAs on the risk for MACE according to a prior diagnosis of CKD. Results: We finally pooled data from 4 trials for a total of 26,272 enrolled participants with T2DM. Regarding the primary efficacy outcome, we demonstrated that GLP-1RAs versus placebo resulted in a significant decrease by 14% (RR = 0.86, 95% CI; 0.76 – 0.97, I2 = 50%), regardless of history of HF (p-value for subgroup differences = 0.88). Concerning the secondary efficacy outcome, we showed that GLP-1RA treatment was superior to placebo in reducing the risk for a MACE (RR = 0.87, 95% CI; 0.75 – 1.02, I2 = 70%), while prior status of CKD did not affect the generated results (p-value for subgroup differences = 1.00). Conclusions: GLP-1RAs seem to constitute a safe and efficacious treatment option in patients with T2DM and established or at high risk for atherosclerotic cardiovascular disease, while HF or CKD status at baseline do not substantially affect the observed cardio-protective effect against hard cardiovascular endpoints.