Significant Reduction In Composite Research Articles

Efficacy of sodium glucose cotransporter 2 inhibitors for heart failure with preserved and mildly reduced ejection fraction: a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background SGLT2 inhibition has been a breakthrough approach in the treatment for heart failure. A most recent trial of Dapagliflozin has shown its robust benefit in patients with HFpEF and HFmrEF. However, the positive outcomes of other SGLT2i have yet to be elucidated to establish its class effect. Purpose We evaluated the cardiovascular outcomes of SGLT2i for HFpEF and HFmrEF. Methods Randomized controlled trials on SGLT2i versus placebo in patients with left ventricular ejection fraction of more than 40% reporting CV outcomes were searched using Pubmed, CENTRAL, and ScienceDirect. Primary outcome was the composite of hospitalization for heart failure or CV death. Secondary outcomes were the individual HHF, CV death, as well as all-cause mortality. Pooled hazard ratios with 95% confidence intervals were used as effect estimates using fixed-effects model. Results Seven studies were included with a total of 16,713 patients. In the combined HFmrEF and HFpEF population, there was a significant reduction in composite of cardiovascular death and heart failure hospitalization in the SGLT2i group (HR 0.80, 95% CI 0.74-0.87, p<0.00001) compared to placebo, driven by a significant reduction in heart failure hospitalization (HR 0.75, 95% CI 0.68-0.83, p< 0.00001). In the distinct HFpEF population, there was a significant reduction in composite of cardiovascular death and heart failure hospitalization in the SGLT2i group (HR 0.77, 95% CI 0.67-0.87, p<0.0001) compared to placebo. Conclusion SGLT2i provides significant risk reduction in HF hospitalization or CV death among patients with HFpEF compared to placebo.

Efficacy of sodium glucose cotransporter 2 inhibitors for heart failure with preserved and mildly reduced ejection fraction: a systematic review and meta-analysis

Abstract Background SGLT2 inhibition has been a breakthrough approach in the treatment for heart failure. A recent guideline has recommended SGLT2i for the treatment of patients with HFrEF to reduce the risk of HF hospitalization and death, regardless of presence of type 2 diabetes (1). However, its benefit in HFpEF and HFmrEF have yet to be established. Purpose We evaluated the cardiovascular outcomes of SGLT2i for HFpEF and HFmrEF. Methods Randomized controlled trials on SGLT2i versus placebo in patients with left ventricular ejection fraction of more than 40% reporting CV outcomes were searched using Pubmed, CENTRAL, and ScienceDirect. Primary outcome was the composite of hospitalization for heart failure or CV death. Secondary outcomes were the individual HHF, CV death, as well as all-cause mortality. Pooled hazard ratios with 95% confidence intervals were used as effect estimates using fixed-effects model. Results Six studies were included with a total of 10,450 patients. In the combined HFmrEF and HFpEF population, there was a significant reduction in composite of cardiovascular death and heart failure hospitalization in the SGLT2i group (HR 0.79, 95% CI 0.71–0.88, p<0.0001) compared to placebo, driven by a significant reduction in heart failure hospitalization (HR 0.73, 95% CI 0.63–0.84, p<0.00001). In the distinct HFpEF population, there was a significant reduction in composite of cardiovascular death and heart failure hospitalization in the SGLT2i group (HR 0.75, 95% CI 0.63–0.88, p=0.0007) compared to placebo. Conclusion SGLT2i provides significant risk reduction in HF hospitalization or CV death among patients with HFpEF compared to placebo. Funding Acknowledgement Type of funding sources: None.

Gastrointestinal Incretins-Glucose-Dependent Insulinotropic Polypeptide (GIP) and Glucagon-like Peptide-1 (GLP-1) beyond Pleiotropic Physiological Effects Are Involved in Pathophysiology of Atherosclerosis and Coronary Artery Disease-State of the Art.

Simple SummaryThe presented manuscript contains the most current and extensive summary of the role of the most predominant gastrointestinal hormones—GIP and GLP-1 in the pathophysiology of atherosclerosis and coronary artery disease both in animals and humans. We have described GIP and GLP-1 as (1) expressed in many human tissues, (2) emphasized relationship between GIP and GLP-1 and inflammation, (3) highlighted importance of GIP and GLP-1-dependent pathways in atherosclerosis and coronary artery disease and (4) proved that GIP and GLP-1 could be used as markers of incidence, clinical course and recurrence of coronary artery disease, and related to extent and severity of atherosclerosis and myocardial ischemia. Our initial review may state a cornerstone for the future, however, there are still many unknowns and understatements on this topic. Due to the widespread growing interest for the potential use of incretins in cardiovascular diseases, we think that further research in this direction is desirable. For the future, we would like to recognize GIP and GLP-1 as widely implemented into clinical practice as new biomarkers of atherosclerosis and coronary artery disease. Coronary artery disease (CAD), which is the manifestation of atherosclerosis in coronary arteries, is the most common single cause of death and is responsible for disabilities of millions of people worldwide. Despite numerous dedicated clinical studies and an enormous effort to develop diagnostic and therapeutic methods, coronary atherosclerosis remains one of the most serious medical problems of the modern world. Hence, new markers are still being sought to identify and manage CAD optimally. Trying to face this problem, we have raised the question of the most predominant gastrointestinal hormones; glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), mainly involved in carbohydrates disorders, could be also used as new markers of incidence, clinical course, and recurrence of CAD and are related to extent and severity of atherosclerosis and myocardial ischemia. We describe GIP and GLP-1 as expressed in many animal and human tissues, known to be connected to inflammation and related to enormous noncardiac and cardiovascular (CV) diseases. In animals, GIP and GLP-1 improve endothelial function and lead to reduced atherosclerotic plaque macrophage infiltration and stabilize atherosclerotic lesions by directly blocking monocyte migration. Moreover, in humans, GIPR activation induces the pro-atherosclerotic factors ET-1 (endothelin-1) and OPN (osteopontin) but also has anti-atherosclerotic effects through secretion of NO (nitric oxide). Furthermore, four large clinical trials showed a significant reduction in composite of CV death, MI, and stroke in long-term follow-up using GLP-1 analogs for DM 2 patients: liraglutide in LEADER, semaglutide in SUSTAIN-6, dulaglutide in REWIND and albiglutide in HARMONY. However, very little is known about GIP metabolism in the acute phase of myocardial ischemia or for stable patients with CAD, which constitutes a direction for future research. This review aims to comprehensively discuss the impact of GIP and GLP-1 on atherosclerosis and CAD and its potential therapeutic implications.

Cardiorenal effects of SGLT2i in combination with ARNI for HFrEF: a systematic review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: None. Background Recent recommendations suggest a combination of Angiotensin receptor neprilysin inhibitor (ARNI) and beta blocker with other classes of medications in heart failure with reduced ejection fraction (HFrEF) (1). Despite currently available treatment options, mortality remains high (2). From the recent robust clinical trials, both SGLT2 inhibitor (SGLT2i) and ARNI have been found to decrease HF hospitalizations and CV death (3-5). This paper aims to determine the efficacy of SGLT2i and ARNI combination versus ARNI alone in the management of HFrEF. Methods Randomized controlled, prospective or retrospective cohort trials on ARNI with SGLT2i versus ARNI without SGLT2i in patients with left ventricular ejection fraction of 40% or less were included. A search using Pubmed, CENTRAL, and ScienceDirect was conducted on April 29, 2021. Risk of bias was assessed using Cochrane’s Collaboration tool for RCTs and STROBE checklist for cohort, case-control and cross-sectional studies. Review Manager version 5.4 software was used for data synthesis and analysis. Outcomes were measured as mean differences and risk ratio for continuous data and dichotomous data with 95% confidence interval. Results Three studies were screened with a total of 1,742 patients; 759 received a combination of SGLT2i and ARNI while 983 received standard care plus ARNI. There was a significant reduction in composite of cardiovascular death and heart failure hospitalization in the combination SGLT2i/ARNI group (HR 0.69, 95% CI 0.56-0.85, and p value of 0.0005). There was significant reduction in heart failure hospitalization in the treatment group with SGLT2i (HR of 0.61, a 95% CI 0.49-0.78) compared to the group without treatment of a SGLT2 inhibitor (< 0.0001). Composite renal event favors combination of ARNI and SGLT2i in some studies (HR of 0.73, with a 95% CI 0.39-1.38), however was not statistically significant (p value = 0.34). Conclusion Addition of SGLT2i with ARNI provides significant decrease in mortality and hospitalization among patients with HFrEF compared to control as well as improvement in renal function.

SAVOR-TIMI to DECLARE-TIMI: A Review on Cardiovascular Outcome Trials of Incretin-modulators and Gliflozins.

Introduction:Since 2008 United State (US) food drug administration mandate, several newer anti-diabetic drugs (ADD) have undergone a mandatory cardiovascular (CV) outcome trial (CVOT) in type diabetes (T2DM) patients with high CV risk. These includes CVOT done with dipeptidyl-peptidase-4 inhibitors, sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 receptor agonist (GLP-1RAs). Several double-blind, randomized, placebo-controlled CVOT have been presented and published in the last decade (2008-2018).Aims and Objectives:We systematically searched the database of PubMed and ClinicalTrials.gov from January 1, 2008 to December 31, 2018 using specific key words. Subsequently, we pooled the data of different cardiovascular endpoints and made a comparative forest plot using GraphPad software Inc. Prism Version 8, US.Results and Conclusion:Saxagliptin, alogliptin, sitagliptin and linagliptin are CV neutral drugs. Saxagliptin showed a significantly higher hospitalization due to heart failure (HHF). Empagliflozin and canagliflozin have shown a significant reduction in composite of 3-point major cardiac adverse events (3P-MACE). Additionally, empagliflozin, canagliflozin and dapagliflozin significantly reduced the HHF and the composite of CV death or HHF. Moreover, empagliflozin showed significant reduction in CV- and all-cause death in patients with T2DM with established CV disease. While both exendin-backbone-based GLP-1RAs such as lixisenatide and extended-release exenatide were CV neutral; GLP-1-backbone-based GLP-1RAs such as liraglutide, semaglutide and albiglutide shown a significant reduction in the composite of 3-P MACE. Additionally, liraglutide shown a significant reduction in CV- and all-cause death. Moreover, semaglutide reduced non-fatal stroke and albiglutide reduced myocardial infarction, while extended-release exenatide reduced all-cause death; however, P value of significance for these outcomes should be considered nominal.