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Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence.
Natali, A, Nesti, L, Tricò, D, Ferrannini, E
Cardiovascular diabetology. 2021;(1):196
Abstract
The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.
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PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling.
Oppedisano, F, Mollace, R, Tavernese, A, Gliozzi, M, Musolino, V, Macrì, R, Carresi, C, Maiuolo, J, Serra, M, Cardamone, A, et al
Nutrients. 2021;(9)
Abstract
Heart failure (HF) characterized by cardiac remodeling is a condition in which inflammation and fibrosis play a key role. Dietary supplementation with n-3 polyunsaturated fatty acids (PUFAs) seems to produce good results. In fact, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have anti-inflammatory and antioxidant properties and different cardioprotective mechanisms. In particular, following their interaction with the nuclear factor erythropoietin 2 related factor 2 (NRF2), the free fatty acid receptor 4 (Ffar4) receptor, or the G-protein coupled receptor 120 (GPR120) fibroblast receptors, they inhibit cardiac fibrosis and protect the heart from HF onset. Furthermore, n-3 PUFAs increase the left ventricular ejection fraction (LVEF), reduce global longitudinal deformation, E/e ratio (early ventricular filling and early mitral annulus velocity), soluble interleukin-1 receptor-like 1 (sST2) and high-sensitive C Reactive protein (hsCRP) levels, and increase flow-mediated dilation. Moreover, lower levels of brain natriuretic peptide (BNP) and serum norepinephrine (sNE) are reported and have a positive effect on cardiac hemodynamics. In addition, they reduce cardiac remodeling and inflammation by protecting patients from HF onset after myocardial infarction (MI). The positive effects of PUFA supplementation are associated with treatment duration and a daily dosage of 1-2 g. Therefore, both the European Society of Cardiology (ESC) and the American College of Cardiology/American Heart Association (ACC/AHA) define dietary supplementation with n-3 PUFAs as an effective therapy for reducing the risk of hospitalization and death in HF patients. In this review, we seek to highlight the most recent studies related to the effect of PUFA supplementation in HF. For that purpose, a PubMed literature survey was conducted with a focus on various in vitro and in vivo studies and clinical trials from 2015 to 2021.
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Impact of empagliflozin on right ventricular parameters and function among patients with type 2 diabetes.
Sarak, B, Verma, S, David Mazer, C, Teoh, H, Quan, A, Gilbert, RE, Goodman, SG, Bami, K, Coelho-Filho, OR, Ahooja, V, et al
Cardiovascular diabetology. 2021;(1):200
Abstract
BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular events in type 2 diabetes (T2DM) and is associated with a reduction in left ventricular (LV) mass index. However, the impact on right ventricular (RV) remodeling is unknown. Accordingly, the objective of this study was to assess the impact of SGLT2 inhibition on RV parameters and function in T2DM and coronary artery disease (CAD). METHODS In EMPA-HEART CardioLink-6, 97 patients with T2DM and CAD were randomly assigned to empagliflozin 10 mg (n = 49) once daily or placebo (n = 48). Cardiac magnetic resonance imaging was performed at baseline and after 6 months. RV mass index (RVMi), RV end-diastolic and end-systolic volume index (RVEDVi, RVESVi) and RV ejection fraction (RVEF) were assessed in blinded fashion. RESULTS At baseline, mean RVMi (± SD) (11.8 ± 2.4 g/m2), RVEF (53.5 ± 4.8%), RVEDVi (64.3 ± 13.2 mL/m2) and RVESVi (29.9 ± 6.9 mL/m2) were within normal limits and were similar between the empagliflozin and placebo groups. Over 6 months, there were no significant differences in RVMi (- 0.11 g/m2, [95% CI - 0.81 to 0.60], p = 0.76), RVEF (0.54%, [95% CI - 1.4 to 2.4], p = 0.58), RVEDVi (- 1.2 mL/m2, [95% CI - 4.1 to 1.7], p = 0.41) and RVESVi (- 0.81 mL/m2, [95% CI - 2.5 to 0.90], p = 0.35) in the empaglifozin group as compared with the placebo group. In both groups, there was no significant correlation between RVMi and LVMi changes from baseline to 6 months. CONCLUSIONS In this post-hoc analysis, SGLT2 inhibition with empagliflozin had no impact on RVMi and RV volumes in patients with T2DM and CAD. The potentially differential effect of empagliflozin on the LV and RV warrants further investigation. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov/ct2/show/NCT02998970?cond=NCT02998970&draw=2&rank=1 . Unique identifier: NCT02998970.
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Effect of atorvastatin versus rosuvastatin on inflammatory biomarkers and LV function in type 2 diabetic patients with dyslipidemia.
Werida, R, Khairat, I, Khedr, NF
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;:111179
Abstract
BACKGROUND Statins are potential drugs for decreasing risk of atherosclerotic cardiovascular complications in type 2 diabetic (T2D) patients. PURPOSE To examine the efficacy of both rosuvastatin (ROSUVA) and atorvastatin (ATORVA) on LV function and markers of inflammation in T2D patients with dyslipidemia. METHODS One hundred-sixty T2D patients were assigned to receive either atorvastatin (ATORVA group, n = 80, 40 mg) or rosuvastatin (ROSUVA group, n = 80, 10 mg), daily for 6 months. Blood was collected for biochemical analysis. The prevalence of left ventricular abnormalities was determined by echocardiography and two-dimensional Speckle-Strain to assess Global Longitudinal Strain (GLS). RESULTS ROSUVA vs. ATORVA resulted in significant (p < 0.001) reduction in HbA1c % (9.13 vs 2.35%), LDL-C (22.23% vs. 14.75%), triglycerides (13.56 % vs. 8.21 %), total cholesterol (16.10 % vs. 10.81 %), atherogenic index (18.08. % vs. 10.97%), hs-CRP (23.51 % vs.18.96%), sortilin (33.33 % % vs. 15.08 %), and leptin (31.81 % vs. 23.17 %) but increased adiponectin (97.99 % vs.76.47.1 %) and HDL-C (76.47 % vs. 0.21 %) compared with baseline, respectively. Negative correlations between adiponectin and each of hs-CRP, HbA1c%, total cholesterol, LDL-C, atherogenic index and leptin were found. Also, left ventricular functions were correlated with adiponectin, lipids, HbA1c% and hs-CRP. The areas under receiver operating characteristic curve (AUC) showed that hs-CRP, leptin, sortlin, leptin, and adiponectin were good predictors for cardiovascular events. CONCLUSION ROSUVA is more efficacious in improving lipid profile, atherogenic index and modulation of inflammatory biomarkers in dyslipidemic T2D patients compared with ATROVA. However, both statins are equivalent as cardioprotective agents in dyslipidemic T2D patients.
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Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis.
Yu, YW, Zhao, XM, Wang, YH, Zhou, Q, Huang, Y, Zhai, M, Zhang, J
Cardiovascular diabetology. 2021;(1):25
Abstract
BACKGROUND Although the benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiovascular events have been reported in patients with type 2 diabetes mellitus (T2DM) with or without heart failure (HF), the impact of SGLT2i on cardiac remodelling remains to be established. METHODS We searched the PubMed, Embase, Cochrane Library and Web of Science databases up to November 16th, 2020, for randomized controlled trials reporting the effects of SGLT2i on parameters of cardiac structure, cardiac function, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level or the Kansas City Cardiomyopathy Questionnaire (KCCQ) score in T2DM patients with or without chronic HF. The effect size was expressed as the mean difference (MD) or standardized mean difference (SMD) and its 95% confidence interval (CI). Subgroup analyses were performed based on the stage A-B or stage C HF population and HF types. RESULTS Compared to placebo or other antidiabetic drugs, SGLT2i showed no significant effects on left ventricular mass index, left ventricular end diastolic volume index, left ventricular end systolic volume index, or left atrial volume index. SGLT2i improved left ventricular ejection fraction only in the subgroup of HF patients with reduced ejection fraction (MD 3.16%, 95% CI 0.11 to 6.22, p = 0.04; I2 = 0%), and did not affect the global longitudinal strain in the overall analysis including stage A-B HF patients. SGLT2i showed benefits in the E/e' ratio (MD - 0.45, 95% CI - 0.88 to - 0.03, p = 0.04; I2 = 0%), plasma NT-proBNP level (SMD - 0.09, 95% CI - 0.16 to - 0.03, p = 0.004; I2 = 0%), and the KCCQ score (SMD 3.12, 95% CI 0.76 to 5.47, p = 0.01; I2 = 0%) in the overall population. CONCLUSION The use of SGLT2i was associated with significant improvements in cardiac diastolic function, plasma NT-proBNP level, and the KCCQ score in T2DM patients with or without chronic HF, but did not significantly affect cardiac structural parameters indexed by body surface area. The LVEF level was improved only in HF patients with reduced ejection fraction.
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Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.
Docherty, KF, Campbell, RT, Brooksbank, KJM, Dreisbach, JG, Forsyth, P, Godeseth, RL, Hopkins, T, Jackson, AM, Lee, MMY, McConnachie, A, et al
Circulation. 2021;(3):199-209
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Abstract
BACKGROUND Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects. METHODS We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire. RESULTS From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change. CONCLUSIONS In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.
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Effects of sacubitril/valsartan on ventricular remodeling in patents with left ventricular systolic dysfunction following acute anterior wall myocardial infarction.
Wang, H, Fu, X
Coronary artery disease. 2021;(5):418-426
Abstract
OBJECTIVE The aim of this study was to investigate the effect of sacubitril/valsartan (Sal/Val) on left ventricular (LV) remodeling in patients with LV systolic dysfunction following acute anterior wall myocardial infarction (AAMI). METHODS AAMI patients with LV systolic dysfunction were enrolled in this study. All patients underwent percutaneous coronary intervention. After hemodynamic stabilization, patients were randomly assigned either to group T (Sal/Val treatment) or group C (enalapril treatment). Changes in echocardiographic parameters and plasma biochemical markers were used to evaluate the effects of Sal/Val on LV remodeling and cardiac function. The incidence of major cardiac adverse events (MACEs) and adverse reactions during follow-ups was also recorded. RESULTS In total, 137 eligible patients were prospectively included. Compared to group C, LV ejection fraction significantly improved (P < 0.05), while the LV end-systolic volume index and wall motion score index showed a tendency to decrease in group T. There was no difference in the LV end-diastolic volume index between groups. During follow-ups, the plasma N-terminal pro-B-type natriuretic peptide and soluble suppression of tumorigenesis-2 levels in both groups decreased (all P < 0.05), and the change was more prominent in group T. Additionally, drug-related adverse effects were similar between the two groups (P > 0.05); however, the incidence of MACEs was lower in group T than in group C (39.71% vs. 53.62%, P = 0.103), although the difference was insignificant. CONCLUSION Sac/Val attenuated LV remodeling and dysfunction and was safe and effective in LV systolic dysfunction patients post AAMI.
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Empagliflozin and left ventricular diastolic function following an acute coronary syndrome in patients with type 2 diabetes.
Lan, NSR, Yeap, BB, Fegan, PG, Green, G, Rankin, JM, Dwivedi, G
The international journal of cardiovascular imaging. 2021;(2):517-527
Abstract
Sodium-glucose cotransporter 2 inhibitors can improve heart failure outcomes, however, the effects on left ventricular (LV) function remain unclear. This prospective observational study aimed to investigate whether initiating empagliflozin therapy was associated with improved LV diastolic function following an acute coronary syndrome (ACS) in patients with type 2 diabetes (T2D). Patients with ACS and T2D were identified during hospitalisation in a cardiology unit. Empagliflozin was initiated at discharge in eligible patients (i.e. HbA1c > 7%) without contraindications or precautions. Transthoracic echocardiography was performed during admission and after 3-6 months. Changes in echocardiographic parameters were compared between patients initiated on empagliflozin versus not initiated on empagliflozin (control). There were 22 patients in each group (n = 44). Baseline characteristics, medications and echocardiographic parameters were similar except HbA1c (empagliflozin: 9.8 ± 1.6% versus control: 6.6 ± 0.7%, p < 0.001). Baseline LV global longitudinal strain (GLS) (empagliflozin: - 12.4 ± 2.8 versus control: - 13.0 ± 3.6%) and ejection fraction (51.1 ± 11.3 versus 54.9 ± 10.8%) were similar. The difference in change from baseline to follow-up was significant for LV mass index (empagliflozin: - 14.1 ± 21.6 versus control: 3.6 ± 18.7 g/m2, p = 0.006), left atrial volume index (- 2.1 ± 8.1 versus 3.4 ± 9.5 ml/m2, p = 0.045), mitral valve E-wave velocity (- 0.14 ± 0.23 versus 0.03 ± 0.16 m/s, p = 0.007) and average E/e' (- 2.1 ± 2.6 versus 0.9 ± 3.4, p = 0.002). There were no significant between-group differences in change for LV GLS, ejection fraction and volume. In patients with ACS and T2D, addition of empagliflozin to ACS therapy at discharge was associated with a reduction in LV mass and favourable changes in diastolic function parameters. Further studies are warranted to investigate these findings.
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Effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors on left ventricular remodelling and longitudinal strain: a prospective observational study.
Gamaza-Chulián, S, Díaz-Retamino, E, González-Testón, F, Gaitero, JC, Castillo, MJ, Alfaro, R, Rodríguez, E, González-Caballero, E, Martín-Santana, A
BMC cardiovascular disorders. 2021;(1):456
Abstract
BACKGROUND Sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower cardiovascular events in type 2 diabetes mellitus (T2DM) patients, although the mechanisms underlying these benefits are not clearly understood. Our aim was to study the effects of SGLT2i on left ventricular remodelling and longitudinal strain. METHODS Between November 2019 and April 2020, we included 52 patients with T2DM ≥ 18 years old, with HbA1c between 6.5 and 10.0%, and estimated glomerular filtration ≥ 45 ml/min/1.73 m2. Patients were classified into SGLT2i group and control group, according to prescribed treatment by their referring physician. Conventional and speckle tracking echocardiography were performed by blinded sonographers, at baseline and after 6 months of treatment. RESULTS Among the 52 included patients (44% females, mean age 66.8 ± 8.6 years, mean HbA1c was 7.40 ± 0.7%), 30 patients were prescribed SGLT2i and 22 patients were classified as control group. Mean change in indexed left ventricular mass (LVM) was - 0.85 ± 3.31 g/m2 (p = 0.003) in the SGLT2i group, and + 2.34 ± 4.13 g/m2 (p = 0.58) in the control group. Absolute value of Global Longitudinal Strain (GLS) increased by a mean of 1.29 ± 0.47 (p = 0.011) in the SGLT2i group, and 0.40 ± 0.62 (p = 0.34) in the control group. We did not find correlations between changes in LVM and GLS, and other variables like change in HbA1c. CONCLUSIONS Among patients with T2DM, SGLT2i were associated with a significant reduction in indexed LVM and a significant increment in longitudinal strain measured by speckle tracking echocardiography, which may explain in part the clinical benefits found in clinical trials.
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Impact of low-dose prasugrel on platelet reactivity and cardiac dysfunction in acute coronary syndrome patients requiring primary drug-eluting stent implantation: A randomized comparative study.
Kitano, D, Takayama, T, Fukamachi, D, Migita, S, Morikawa, T, Tamaki, T, Kojima, K, Mineki, T, Murata, N, Akutsu, N, et al
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2020;(1):E8-E16
Abstract
OBJECTIVE The aim of this study was to compare how prasugrel and clopidogrel affect platelet aggregation reactivity, cardiac enzyme release, cardiac remodeling, and the formation of in-stent thrombi after primary percutaneous coronary intervention (PCI). BACKGROUND The advantages of using prasugrel over clopidogrel in cardiac injury following acute coronary syndrome (ACS) remain unclear. METHODS A total of 78 ACS patients were randomly allocated into clopidogrel (300 mg loading/75 mg maintenance) or prasugrel (20 mg loading/3.75 mg maintenance) treatment groups, followed by undergoing primary PCI. Platelet reactivity and cardiac enzymes were measured before and after primary PCI. Moreover, cardiac function was measured by ultrasound echocardiography and coronary angioscopic observation was after primary PCI up to 8 months later. RESULTS Antiplatelet reactivity in the prasugrel treatment group reached optimal levels (P2Y12 reaction units [PRU] less than 262) immediately after the administration and was maintained even at 8 months, independently of the CYP2C19 genotype. Prasugrel treatment significantly suppressed creatine kinase elevation compared to clopidogrel treatment (median value 404 IU/L to 726 IU/L vs. 189 IU/L to 1,736 IU/L, p = 0.018 for maximum values) and reduced left ventricular mass (217.2-168.8 g in prasugrel, p = 0.045; 196.9-176.4 g in clopidogrel, p = 0.061). There were no significant differences in the incidence of in-stent attached thrombi between the two groups. CONCLUSIONS Compared to clopidogrel, prasugrel produced a stable platelet aggregation inhibitory effect in patients with ACS regardless of CYP2C19 genotype, reduced cardiac enzyme release, and prevented cardiac remodeling after ACS.