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Combined effects of ARNI and SGLT2 inhibitors in diabetic patients with heart failure with reduced ejection fraction.
Kim, HM, Hwang, IC, Choi, W, Yoon, YE, Cho, GY
Scientific reports. 2021;(1):22342
Abstract
Angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose co-transporter-2 inhibitor (SGLT2i) have shown benefits in diabetic patients with heart failure with reduced ejection fraction (HFrEF). However, their combined effect has not been revealed. We retrospectively identified diabetic patients with HFrEF who were prescribed an ARNI and/or SGLT2i. The patients were divided into groups treated with both ARNI and SGLT2i (group 1), ARNI but not SGLT2i (group 2), SGLT2i but not ARNI (group 3), and neither ARNI nor SGLT2i (group 4). After propensity score-matching, the occurrence of hospitalization for heart failure (HHF), cardiovascular mortality, and changes in echocardiographic parameters were analyzed. Of the 206 matched patients, 92 (44.7%) had to undergo HHF and 43 (20.9%) died of cardiovascular causes during a median 27.6 months of follow-up. Patients in group 1 exhibited a lower risk of HHF and cardiovascular mortality compared to those in the other groups. Improvements in the left ventricular ejection fraction and E/e' were more pronounced in group 1 than in groups 2, 3 and 4. These echocardiographic improvements were more prominent after the initiation of ARNI, compare to the initiation of SGLT2i. In diabetic patients with HFrEF, combination of ARNI and SGT2i showed significant improvement in cardiac function and prognosis. ARNI-SGLT2i combination therapy may improve the clinical course of HFrEF in diabetic patients.
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Safety and Tolerability of the Chymase Inhibitor Fulacimstat in Patients With Left Ventricular Dysfunction After Myocardial Infarction-Results of the CHIARA MIA 1 Trial.
Düngen, HD, Kober, L, Nodari, S, Schou, M, Otto, C, Becka, M, Kanefendt, F, Winkelmann, BR, Gislason, G, Richard, F, et al
Clinical pharmacology in drug development. 2019;(7):942-951
Abstract
The chymase inhibitor fulacimstat is developed as a first-in-class treatment option for the inhibition of adverse cardiac remodeling in patients with left ventricular dysfunction (LVD) after acute myocardial infarction (MI). The aim of the study was to examine the safety and tolerability of fulacimstat in patients with LVD after remote MI. A multicenter, multinational randomized, placebo-controlled study was performed in clinically stable patients (40-79 years of age, left ventricular ejection fraction ≤ 45% because of MI in medical history) who were on stable evidence-based standard-of-care therapies for LVD post-MI including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker at doses of at least half the recommended target dose. Patients were treated for 2 weeks with either placebo (n = 12) or 4 different doses of fulacimstat (5 mg twice daily, n = 9; 10 mg twice daily, n = 9; 25 mg twice daily, n = 10; 50 mg once daily, n = 9). Fulacimstat was safe and well tolerated at all examined doses. There were no clinically relevant effects on vital signs or potassium levels compared with placebo treatment. Mean plasma concentrations of fulacimstat increased with the administered dose and reached exposures predicted to be therapeutically active. The safety profile and the absence of effects on blood pressure or heart rate in a chronic patient population having similar comorbidities and receiving similar comedication as patients after acute MI support future clinical trials with fulacimstat in patients after acute MI.
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Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade.
Weber, MA, Mansfield, TA, Alessi, F, Iqbal, N, Parikh, S, Ptaszynska, A
Blood pressure. 2016;(2):93-103
Abstract
Hypertension and type 2 diabetes mellitus (T2DM) are risk factors for cardiovascular disease. Dapagliflozin improves glycemic control and systolic blood pressure (SBP) in T2DM patients. This double-blind phase III study evaluated the effects of dapagliflozin on glycemic control and blood pressure in patients with inadequately controlled T2DM and hypertension, despite ongoing therapy with a renin-angiotensin system blocker. Patients were randomized to receive dapagliflozin 10 mg (n = 302) or placebo (n = 311) once daily for 12 weeks. Endpoints were change from baseline to week 12 in seated SBP and glycosylated hemoglobin (HbA1c); longitudinal repeated-measures analysis was performed. Additional endpoints included other hemodynamic measures, serum uric acid, fasting plasma glucose, body weight, blood lipids and heart rate. After 12 weeks, dapagliflozin-treated versus placebo-treated patients showed significant reductions in HbA1c (-0.6% vs -0.1%, p < 0.0001), mean seated SBP (-10.4 vs -7.3 mmHg, p = 0.0010) and mean 24 h ambulatory SBP (-9.6 vs -6.7 mmHg, p = 0.0043). Dapagliflozin also reduced body weight compared with placebo (-1.0 vs -0.3 kg). Dapagliflozin was well tolerated, with adverse events consistent with previous studies. Dapagliflozin improved glycemic control, and reduced SBP as well as body weight in patients with poorly controlled T2DM and hypertension.
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A new class of drugs for systolic heart failure: The PARADIGM-HF study.
Sabe, MA, Jacob, MS, Taylor, DO
Cleveland Clinic journal of medicine. 2015;(10):693-701
Abstract
The PARADIGM-HF trial (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) found a combination drug containing sacubitril (a neprilysin inhibitor) and valsartan (an angiotensin II receptor blocker) superior to enalapril (an angiotensin-converting enzyme inhibitor) in patients with systolic heart failure. Recently approved by the US Food and Drug Administration, sacubitril-valsartan is the first new drug in over a decade to decrease death rates in patients with systolic heart failure.
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Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction.
Ito, S, Satoh, M, Tamaki, Y, Gotou, H, Charney, A, Okino, N, Akahori, M, Zhang, J
Hypertension research : official journal of the Japanese Society of Hypertension. 2015;(4):269-75
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Abstract
This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.
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Circadian rhythm of urinary potassium excretion during treatment with an angiotensin receptor blocker.
Ogiyama, Y, Miura, T, Watanabe, S, Fuwa, D, Tomonari, T, Ota, K, Kato, Y, Ichikawa, T, Shirasawa, Y, Ito, A, et al
Journal of the renin-angiotensin-aldosterone system : JRAAS. 2014;(4):509-14
Abstract
INTRODUCTION We have reported that the circadian rhythm of urinary potassium excretion (U(K)V) is determined by the rhythm of urinary sodium excretion (U(Na)V) in patients with chronic kidney disease (CKD). We also reported that treatment with an angiotensin receptor blocker (ARB) increased the U(Na)V during the daytime, and restored the non-dipper blood pressure (BP) rhythm into a dipper pattern. However, the circadian rhythm of U(K)V during ARB treatment has not been reported. MATERIALS AND METHODS Circadian rhythms of U(Na)V and U(K)V were examined in 44 patients with CKD undergoing treatment with ARB. RESULTS Whole-day U(Na)V was not altered by ARB whereas whole-day U(K)V decreased. Even during the ARB treatment, the significant relationship persisted between the night/day ratios of U(Na)V and U(K)V (r=0.56, p<0.0001). Whole-day U(K)V/U(Na)V ratio (p=0.0007) and trans-tubular potassium concentration gradient (p=0.002) were attenuated but their night/day ratios remained unchanged. The change in the night/day U(K)V ratio correlated directly with the change in night/day U(Na)V ratio (F=20.4) rather than with the changes in aldosterone, BP or creatinine clearance. CONCLUSIONS The circadian rhythm of U(K)V was determined by the rhythm of UNaV even during ARB treatment. Changes in the circadian U(K)V rhythm were not determined by aldosterone but by U(Na)V.
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Type 2 diabetes mellitus complicated by hypertension in Japanese patients: switching treatment from high-dose angiotensin II receptor blockers to losartan plus hydrochlorothiazide.
Yamamoto, S, Okada, Y, Mori, H, Nishida, K, Uriu, K, Tanaka, Y
Internal medicine (Tokyo, Japan). 2014;(12):1283-9
Abstract
OBJECTIVE The aim of the present study was to assess changes in blood pressure and metabolism after switching treatment from maximum-dose angiotensin II receptor blocker (ARB) therapy to a mixture of conventional-dose ARBs and low-dose diuretics. METHODS This study was conducted among 43 Japanese patients with type 2 diabetes complicated with hypertension in whom continuous treatment with high doses of ARBs did not reduce their blood pressure to the target level (a systolic blood pressure of 130 mmHg or lower and a diastolic blood pressure of 80 mmHg or lower). The antihypertensive and metabolic effects of switching from high-dose ARBs to a combination of losartan (50 mg/day) plus hydrochlorothiazide (12.5 mg/day) were examined. The primary endpoint was a decrease in blood pressure at 24 weeks. RESULTS The combination treatment significantly decreased both systolic (baseline: 147±11; 24 weeks: 133±13 mmHg) and diastolic (baseline: 79±8; 24 weeks: 72±10 mmHg) blood pressure. This treatment was also associated with a significant increase in the HbA1c level (baseline: 7.0±0.8%; 24 weeks: 7.2±0.9%) and a significant decrease in the urinary albumin-creatinine ratio (baseline: 280±590; 24 weeks: 110±253 mg/g creatinine). However, the combination treatment had no effect on lipid metabolism or the serum uric acid or potassium levels. CONCLUSION In patients with diabetes, sodium reabsorption in the renal tubules is enhanced, which leads to the development of salt-sensitive hypertension. Therefore, the concurrent use of a diuretic that promotes sodium excretion can increase the antihypertensive effects of other drugs. This study demonstrated that switching from high-dose ARB treatment to losartan/hydrochlorothiazide combination therapy results in significant control of blood pressure.
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Risk of hyperkalemia in patients with moderate chronic kidney disease initiating angiotensin converting enzyme inhibitors or angiotensin receptor blockers: a randomized study.
Espinel, E, Joven, J, Gil, I, Suñé, P, Renedo, B, Fort, J, Serón, D
BMC research notes. 2013;:306
Abstract
BACKGROUND Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are renoprotective but both may increase serum potassium concentrations in patients with chronic kidney disease (CKD). The proportion of affected patients, the optimum follow-up period and whether there are differences between drugs in the development of this complication remain to be ascertained. METHODS In a randomized, double-blind, phase IV, controlled, crossover study we recruited 30 patients with stage 3 CKD under restrictive eligibility criteria and strict dietary control. With the exception of withdrawals, each patient was treated with olmesartan and enalapril separately for 3 months each, with a 1-week wash-out period between treatments. Patients were clinically assessed on 10 occasions via measurements of serum and urine samples. We used the Cochran-Mantel-Haenszel statistics for comparison of categorical data between groups. Comparisons were also made using independent two-sample t-tests and Welch's t-test. Analysis of variance (ANOVA) was performed when necessary. We used either a Mann-Whitney or Kruskal-Wallis test if the distribution was not normal or the variance not homogeneous. RESULTS Enalapril and olmesartan increased serum potassium levels similarly (0.3 mmol/L and 0.24 mmol/L respectively). The percentage of patients presenting hyperkalemia higher than 5 mmol/L did not differ between treatments: 37% for olmesartan and 40% for enalapril. The mean e-GFR ranged 46.3 to 48.59 ml/mint/1.73 m2 in those treated with olmesartan and 46.8 to 48.3 ml/mint/1.73 m2 in those with enalapril and remained unchanged at the end of the study. The decreases in microalbuminuria were also similar (23% in olmesartan and 29% in enalapril patients) in the 4 weeks time point. The percentage of patients presenting hyperkalemia, even after a two month period, did not differ between treatments. There were no appreciable changes in sodium and potassium urinary excretion. CONCLUSIONS Disturbances in potassium balance upon treatment with either olmesartan or enalapril are frequent and without differences between groups. The follow-up of these patients should include control of potassium levels, at least after the first week and the first and second month after initiating treatment. TRIAL REGISTRATION The trial EudraCT "2008-002191-98".
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Clinical features and outcome in hospitalized heart failure in Japan (from the ATTEND Registry).
Sato, N, Kajimoto, K, Keida, T, Mizuno, M, Minami, Y, Yumino, D, Asai, K, Murai, K, Muanakata, R, Aokage, T, et al
Circulation journal : official journal of the Japanese Circulation Society. 2013;(4):944-51
Abstract
BACKGROUND Hospitalized heart failure (HHF) is a critical issue in Japan. To improve its management and outcomes, the clinical features, in-hospital management, and outcomes should be analyzed to improve the guidelines for HHF. METHODS AND RESULTS The acute decompensated heart failure syndromes (ATTEND) registry is the largest study of HHF in Japan. The present report covers the clinical features and in-hospital management of HHF patients. The data from 4,842 enrolled patients have demonstrated that most Japanese HHF patients are elderly, with new onset, and a history of hypertension and orthopnea on admission. During hospitalization, furosemide and carperitide were commonly used and the length of stay was extremely long (mean 30 days), with 6.4% in-hospital mortality. CONCLUSIONS The findings of the present study suggest the following: (1) the focus for hypertensive elderly and diabetic patients should be on primary prevention of HHF,(2) more intensive management with noninvasive positive pressure ventilation should be performed at the urgent stage, (3) it is necessary to clarify the clinical benefit of carperitide and angiotensin-receptor blockers, because they are commonly used in Japan, and (4) it is necessary to clarify the relationship between in-hospital mortality and length of stay from the viewpoint of both outcome and cost of patient care.
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Long-term effects of addition of mineralocorticoid receptor antagonist to angiotensin II receptor blocker in patients with diabetic nephropathy: a randomized clinical trial.
Esteghamati, A, Noshad, S, Jarrah, S, Mousavizadeh, M, Khoee, SH, Nakhjavani, M
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;(11):2823-33
Abstract
BACKGROUND Addition of spironolactone (SPR) to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) might provide antiproteinuric effects beyond what is gained by either medication alone. This study was designed to assess the long-term efficacy of SPR/ARB combination in comparison with the standard ACE/ARB regimen in diabetic nephropathy. METHODS In an open-label, parallel-group, single-center, randomized clinical trial (NCT01667614), 136 patients with diabetes and proteinuria, already treated with enalapril and losartan, were included. In 74 patients, ACE inhibitors were discontinued. After a wash-out period of 2 weeks, 25 mg SPR daily was initiated. The remainder of the patients (n = 62) received ACE inhibitors and ARBs as before. Patients were followed every 3 months for 18 months. During each visit, systolic and diastolic blood pressure (BP), urinary albumin excretion (UAE), serum creatinine, estimated glomerular filtration rate (eGFR) and serum potassium concentrations were determined. RESULTS After 18 months, three patients in the SPR/ARB group developed asymptomatic hyperkalemia. SPR/ARB significantly reduced both systolic and diastolic BP (P < 0.001 and 0.001, respectively). SPR/ARB decreased UAE by 46, 72 and 59% after 3, 12 and 18 months, respectively. Compared with the continuation regimen, SPR/ARB was superior in UAE reduction (P = 0.017 after 18 months), independent of BP change. In both groups, eGFR declined significantly over the trial course and the decline rate did not differ significantly between the two groups. CONCLUSIONS Addition of SPR to ARB provides added benefits with respect to BP control and proteinuria diminution. These antiproteinuric effects are not accompanied by prevention of eGFR loss compared with conventional therapy with ACE/ARB.