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Ferreira JP, Marques P, Leite AR, Neves JS, Zannad F, Pitt B. Mineralocorticoid receptor antagonists and aldosterone synthase inhibitors: agent comparison with implications for clinical practice and trial design. J Card Fail 2025:S1071-9164(25)00203-9. [PMID: 40389106 DOI: 10.1016/j.cardfail.2025.05.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/21/2025]
Abstract
Steroidal (s) and non-steroidal (ns) mineralocorticoid receptor antagonists (MRA) and aldosterone synthase inhibitors (ASi) are either available for clinical use or being tested in clinical trials across cardiovascular, kidney and metabolic (CKM) conditions. All agents block the actions of aldosterone, but they present important differences in terms of mode of action, pharmacokinetics and dynamics, and side effect profile. Such differences may have clinical implications. To ascertain such potential differences, we performed a description and indirect comparison of MRA and ASi trial results in hypertension, chronic kidney disease (CKD), and heart failure (HF). Whenever possible we used data from head-to-head comparisons. We then use this information to provide clinical guidance and to suggest how to better clinical trials in the future. Notably, by performing more head-to-head comparison trials and trials with dual or triple combination therapies with sodium glucose co-transporter 2 (SGLT2) inhibitors and/or oral glucagon-like peptide 1 receptor agonists (GLP1ra). In short, this manuscript focuses on the similarities and potential differences between sMRA, nsMRA, and ASi, with implications both for clinical use and clinical trial design.
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Affiliation(s)
- João Pedro Ferreira
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto; Heart Failure Clinic, Internal Medicine Department, Centro Hospitalar de Vila Nova de Gaia, Espinho, Portugal; Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, and INSERM U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France.
| | - Pedro Marques
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto; Internal Medicine Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Ana Rita Leite
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto; Endocrinology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - João Sérgio Neves
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto; Endocrinology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Faiez Zannad
- Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, and INSERM U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
| | - Bertram Pitt
- Department of Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA
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Blum MF, Neuen BL, Grams ME. Risk-directed management of chronic kidney disease. Nat Rev Nephrol 2025; 21:287-298. [PMID: 39885336 DOI: 10.1038/s41581-025-00931-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2025] [Indexed: 02/01/2025]
Abstract
The timely and rational institution of therapy is a key step towards reducing the global burden of chronic kidney disease (CKD). CKD is a heterogeneous entity with varied aetiologies and diverse trajectories, which include risk of kidney failure but also cardiovascular events and death. Developments in the past decade include substantial progress in CKD risk prediction, driven in part by the accumulation of electronic health records data. In addition, large randomized clinical trials have demonstrated the effectiveness of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists in reducing adverse events in CKD, greatly expanding the options for effective therapy. Alongside angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, these classes of medication have been proposed to be the four pillars of CKD pharmacotherapy. However, all of these drug classes are underutilized, even in individuals at high risk. Leveraging prognostic estimates to guide therapy could help clinicians to prescribe CKD-related therapies to those who are most likely to benefit from their use. Risk-based CKD management thus aligns patient risk and care, allowing the prioritization of absolute benefit in determining therapeutic selection and timing. Here, we discuss CKD prognosis tools, evidence-based management and prognosis-guided therapies.
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Affiliation(s)
- Matthew F Blum
- University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Brendon L Neuen
- The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
| | - Morgan E Grams
- New York University Grossman School of Medicine, New York, NY, USA.
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Vaduganathan M, Claggett BL, Kulac IJ, Miao ZM, Desai AS, Jhund PS, Henderson AD, Brinker M, Lay-Flurrie J, Viswanathan P, Scheerer MF, Lage A, Lam CS, Senni M, Shah SJ, Voors AA, Zannad F, Pitt B, McMurray JJ, Solomon SD. Effects of the Nonsteroidal MRA Finerenone With and Without Concomitant SGLT2 Inhibitor Use in Heart Failure. Circulation 2025; 151:149-158. [PMID: 39340828 PMCID: PMC11732259 DOI: 10.1161/circulationaha.124.072055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Accepted: 09/17/2024] [Indexed: 09/30/2024]
Abstract
BACKGROUND Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the nonsteroidal mineralocorticoid receptor antagonist finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. METHODS FINEARTS-HF (Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure) was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity on the basis of baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during-trial use of SGLT2i in time-varying analyses. RESULTS Among 6001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6 years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio, 0.83 [95% CI, 0.60-1.16]) and without an SGLT2i at baseline (rate ratio, 0.85 [95% CI, 0.74-0.98]; Pinteraction=0.76). In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% versus 20.1%; hazard ratio, 0.86 [95% CI, 0.76-0.97]). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary end point. CONCLUSIONS The treatment benefits of the nonsteroidal mineralocorticoid receptor antagonist finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a nonsteroidal mineralocorticoid receptor antagonist may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT04435626.
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Affiliation(s)
- Muthiah Vaduganathan
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V., B.L.C., I.J.K., Z.M.M., A.S.D., S.D.S.)
| | - Brian L. Claggett
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V., B.L.C., I.J.K., Z.M.M., A.S.D., S.D.S.)
| | - Ian J. Kulac
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V., B.L.C., I.J.K., Z.M.M., A.S.D., S.D.S.)
| | - Zi Michael Miao
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V., B.L.C., I.J.K., Z.M.M., A.S.D., S.D.S.)
| | - Akshay S. Desai
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V., B.L.C., I.J.K., Z.M.M., A.S.D., S.D.S.)
| | | | | | - Meike Brinker
- Research & Development, Pharmaceuticals, Bayer, Berlin, Germany (M.B., J.L.-F., P.V., M.F.S., A.L.)
| | - James Lay-Flurrie
- Research & Development, Pharmaceuticals, Bayer, Berlin, Germany (M.B., J.L.-F., P.V., M.F.S., A.L.)
| | - Prabhakar Viswanathan
- Research & Development, Pharmaceuticals, Bayer, Berlin, Germany (M.B., J.L.-F., P.V., M.F.S., A.L.)
| | - Markus Florian Scheerer
- Research & Development, Pharmaceuticals, Bayer, Berlin, Germany (M.B., J.L.-F., P.V., M.F.S., A.L.)
| | - Andrea Lage
- Research & Development, Pharmaceuticals, Bayer, Berlin, Germany (M.B., J.L.-F., P.V., M.F.S., A.L.)
| | - Carolyn S.P. Lam
- National Heart Centre Singapore & Duke–National University of Singapore (C.S.P.L.)
| | - Michele Senni
- Papa Giovanni XXIII Hospital, University of Milano-Bicocca, Bergamo, Italy (M.S.)
| | - Sanjiv J. Shah
- Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S.)
| | | | | | | | | | - Scott D. Solomon
- Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (M.V., B.L.C., I.J.K., Z.M.M., A.S.D., S.D.S.)
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Shoji S, Kaltenbach L, Granger BB, Fonarow GC, Al‐Khalidi HR, Albert NM, Butler J, Allen LA, Lanfear DE, Thibodeau JT, Chapman BM, Oliver‐McNeil SM, Felker GM, Pina IL, Granger CB, Hernandez AF, DeVore AD. Guideline-Directed Medical Therapy After Hospitalization for Acute Heart Failure: Insights From the CONNECT-HF. J Am Heart Assoc 2024; 13:e036998. [PMID: 39655748 PMCID: PMC11935539 DOI: 10.1161/jaha.124.036998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 10/10/2024] [Indexed: 12/18/2024]
Abstract
BACKGROUND Significant gap remains in the implementation of guideline-directed medical therapy (GDMT) in patients with heart failure after a hospitalization. We aimed to evaluate the use and titration of GDMT at discharge and over a 12-month period after hospital discharge and to identify factors associated with GDMT use and titration. METHODS AND RESULTS The CONNECT-HF (Care Optimization Through Patient and Hospital Engagement Clinical Trial for Heart Failure) trial evaluated the effect of a hospital and postdischarge quality improvement intervention in participants with heart failure with reduced ejection fraction. In this secondary analysis, we examined use and titration to at least 50% of the target dose of GDMTs at hospital discharge and over time. Among 4646 participants (mean age 63 years, 34% women), GDMT use did not numerically improve from discharge to 12 months: beta blockers (84%-78%), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (73%-65%), mineralocorticoid receptor antagonists (39%-36%), and sodium-glucose cotransporter 2 inhibitors (1.5%-2.1%). Achieving ≥50% of the target dose also showed little change over 12 months: beta blockers (35%-32%), angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (28%-25%). For all medications, use of GDMT at discharge was associated with the use and achieving ≥50% of the target dose at 12 months. CONCLUSIONS Following a hospitalization for heart failure, GDMT use remained low and did not numerically improve over 12 months. Use of GDMT at discharge was significantly associated with the use of GDMT over time, highlighting the importance of initiating GDMT during hospitalization.
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Affiliation(s)
- Satoshi Shoji
- Duke Clinical Research InstituteDurhamNCUSA
- Division of Cardiology and Department of MedicineDuke University School of MedicineDurhamNCUSA
- Department of CardiologyKeio University School of MedicineTokyoJapan
| | | | - Bradi B. Granger
- Duke University School of Nursing and Duke‐Margolis Health Policy InstituteDurhamNCUSA
| | - Gregg C. Fonarow
- Division of Cardiology, Department of MedicineDavid Geffen School of Medicine at UCLALos AngelesCAUSA
| | | | - Nancy M. Albert
- Nursing Institute and Heart, Vascular and Thoracic InstituteCleveland ClinicClevelandOHUSA
| | - Javed Butler
- Baylor Scott and White Research Institute, DallasTX and University of MississippiJacksonMSUSA
| | - Larry A. Allen
- Division of Cardiology, Department of MedicineUniversity of Colorado School of MedicineAuroraCOUSA
| | - David E. Lanfear
- Division of CardiologyDepartment of Medicine, Henry Ford HospitalDetroitMIUSA
| | - Jennifer T. Thibodeau
- Division of Cardiology, Department of MedicineUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | | | | | - G. Michael Felker
- Duke Clinical Research InstituteDurhamNCUSA
- Division of Cardiology and Department of MedicineDuke University School of MedicineDurhamNCUSA
| | | | - Christopher B. Granger
- Duke Clinical Research InstituteDurhamNCUSA
- Division of Cardiology and Department of MedicineDuke University School of MedicineDurhamNCUSA
| | - Adrian F. Hernandez
- Duke Clinical Research InstituteDurhamNCUSA
- Division of Cardiology and Department of MedicineDuke University School of MedicineDurhamNCUSA
| | - Adam D. DeVore
- Duke Clinical Research InstituteDurhamNCUSA
- Division of Cardiology and Department of MedicineDuke University School of MedicineDurhamNCUSA
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Ferreira JP, Pitt B, Zannad F. Mineralocorticoid Receptor Antagonists in Heart Failure: An Update. Circ Heart Fail 2024; 17:e011629. [PMID: 39584253 DOI: 10.1161/circheartfailure.124.011629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 10/11/2024] [Indexed: 11/26/2024]
Abstract
Spironolactone, a steroidal mineralocorticoid receptor antagonist (MRA), has been used to treat patients with heart failure (HF) for more than half a century. Spironolactone improved outcomes in patients with severely symptomatic HF with reduced ejection fraction, and later, eplerenone expanded the benefits to patients with mildly symptomatic HF with reduced ejection fraction and myocardial infarction complicated by HF. Spironolactone reduced HF events in some patients with HF with preserved ejection fraction, but the results were not generalizable to all patients with HF with preserved ejection fraction. More recently, the nonsteroidal MRA finerenone improved the HF outcomes of patients with HF with preserved ejection fraction, expanding the benefits previously seen among patients with diabetes and albuminuric chronic kidney disease. The use of MRAs has been limited due to excessive concern about hyperkalemia. Education about the limited true risk associated with hyperkalemia, and about how to predict, prevent, and manage hyperkalemia, may lead to wider acceptability and use of these agents. Several ongoing trials are testing steroidal and nonsteroidal MRAs in HF populations. In this review, we perform a critical appraisal of MRA use in HF populations and point toward future directions.
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Affiliation(s)
- João Pedro Ferreira
- Department of Physiology and Cardiothoracic Surgery, Cardiovascular R&D Centre - UnIC@RISE, Faculty of Medicine of the University of Porto, Portugal (J.P.F.)
- Heart Failure Clinic, Internal Medicine Department, Unidade Local de Saude de Gaia/Espinho, Gaia, Portugal (J.P.F.)
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, Nancy, France (J.P.F., F.Z.)
| | - Bertram Pitt
- University of Michigan School of Medicine, Ann Arbor (B.P.)
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigation Clinique Plurithématique 1433, Nancy, France (J.P.F., F.Z.)
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Ferreira JP, Oliveira AC, Vasques-Novoa F, Leite AR, Mendonça L, Zannad F, Butler J, Leite-Moreira A, Saraiva F, Neves JS. Mineralocorticoid Receptor Antagonist Combined with SGLT2 Inhibitor versus SGLT2 Inhibitor Alone in Chronic Kidney Disease: A Meta-Analysis of Randomized Trials. Am J Nephrol 2024; 56:236-242. [PMID: 39510041 DOI: 10.1159/000541686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 09/25/2024] [Indexed: 11/15/2024]
Abstract
INTRODUCTION Sodium glucose co-transporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRAs) reduce the progression of kidney disease. Whether the combination of these agents provides additional benefits compared to SGLT2i alone is worth exploring using data from randomized trials designed for this purpose. The aim of the study was to assess the randomized treatment effect of MRAs combined with SGLT2i versus SGLT2i alone on markers of kidney and cardiovascular health. METHODS Random-effects meta-analysis of randomized trials testing the combination of MRAs with SGLT2i versus SGLT2i alone on albuminuria, blood pressure, estimated glomerular filtration rate (eGFR), and serum potassium among patients with chronic kidney disease (CKD). RESULTS Four randomized trials were included with a total of 272 patients with CKD: eGFR varying between 30 and 60 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) between 90 and 500 mg/g, with >60% having type 2 diabetes. Treatment with MRAs plus SGLT2i versus SGLT2i alone reduced UACR by -33.6% (-42.6 to -24.7%), p < 0.001, I2 = 0%. MRAs plus SGLT2i versus SGLT2i alone reduced systolic blood pressure by -6.1 mm Hg (-8.9 to -3.3) mm Hg, eGFR by -3.4 mm Hg (-5.2 to -1.6) mm Hg, and increased serum potassium by + 0.23 mmol/L (0.15-0.34) mmol/L; p < 0.001 for all, without significant heterogeneity between trials (I2 <25%). CONCLUSION In this meta-analysis, MRAs plus SGLT2i provided greater reductions in albuminuria and blood pressure compared to SGLT2i alone. Larger randomized trials with longer follow-up should test whether MRA/SGLT2i combination therapies improve cardiovascular and renal outcomes compared to SGLT2i alone.
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Affiliation(s)
- João Pedro Ferreira
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Heart Failure Clinic, Internal Medicine Department, Unidade Local de Saude de Gaia, Espinho, Portugal
- Centre d'Investigations Cliniques Plurithématique 1433, INSERM, Université de Lorraine, CIC 1439, Institut Lorrain du Coeur et des Vaisseaux, CHU, Vandoeuvre-lès-Nancy & F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
| | - Ana Cristina Oliveira
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Francisco Vasques-Novoa
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Internal Medicine Department, Unidade Local de Saúde de São João, Porto, Portugal
| | - Ana Rita Leite
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Endocrinology Department, Unidade Local de Saúde de São João, Porto, Portugal
| | - Luís Mendonça
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Nephrology Department, Unidade Local de Saúde de São João, Porto, Portugal
| | - Faiez Zannad
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Centre d'Investigations Cliniques Plurithématique 1433, INSERM, Université de Lorraine, CIC 1439, Institut Lorrain du Coeur et des Vaisseaux, CHU, Vandoeuvre-lès-Nancy & F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas, USA
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Adelino Leite-Moreira
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Francisca Saraiva
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - João Sérgio Neves
- Department of Surgery and Physiology, UnIC@RISE, Cardiovascular Research and Development Center, Faculty of Medicine of the University of Porto, Porto, Portugal
- Endocrinology Department, Unidade Local de Saúde de São João, Porto, Portugal
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Ahmed A, Ahmed W, Arshad MS, Suri A, Amin E, Shahid I, Memon MM. Meta-Analysis Evaluating Risk of Hyperkalemia Stratified by Baseline MRA Usage in Patients with Heart Failure Receiving SGLT2 Inhibitors. Cardiovasc Drugs Ther 2024; 38:1055-1058. [PMID: 36920647 DOI: 10.1007/s10557-023-07446-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/07/2023] [Indexed: 03/16/2023]
Abstract
BACKGROUND Both mineralocorticoid receptor antagonists (MRAs) and sodium-glucose co-transporter type 2 inhibitors (SGLT2is) have demonstrated beneficial reductions in cardiovascular outcomes. However, the risk of precipitating hyperkalemia with their concomitant usage remains unclear. METHODS MEDLINE and Cochrane were searched from inception through March 2022. Randomized controlled trials on patients with heart failure (HF) evaluating the effect of SGLT2is on clinical outcomes between MRA users and non-users were considered for inclusion. Outcomes of interest were mild and moderate/severe hyperkalemia, for which hazard ratios (HR) were pooled using a random effects model. RESULTS From the 972 articles retrieved from the initial search, three RCTs (n = 14,462 patients) were included in our meta-analysis. Pooled analysis demonstrated no significant difference in the incidence of mild hyperkalemia between MRA users (HR 0.82 [0.70-0.97]) and non-users (HR 0.95 [0.77-1.17]) (P-interaction = 0.28). The risk of severe hyperkalemia was significantly decreased in MRA users (HR 0.59 [0.44-0.78]; p = 0.0002; I2 = 0%) but not in non-users (HR 0.76 [0.56-1.02]; p = 0.07; I2 = 0%) (P-interaction = 0.22). Sensitivity analysis including patients with HF with reduced ejection fraction (HFrEF) revealed similar results across all subgroups, but no significant reduction in the incidence of mild hyperkalemia (HR 0.89 [0.76-1.04] was noted in MRA users with HFrEF. CONCLUSION MRAs reduced the risk of mild or moderate/severe hyperkalemia, when added to SGLT2is. Future clinical trials should target scrupulous assessment of the risk of mild and moderate/severe hyperkalemia when used concomitantly with MRAs.
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Affiliation(s)
- Aymen Ahmed
- Department of Medicine, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan
| | - Warda Ahmed
- Medical College, The Aga Khan University, Karachi, 74800, Pakistan
| | - Muhammad Sameer Arshad
- Department of Medicine, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan.
| | - Azeema Suri
- Department of Medicine, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan
| | - Emaan Amin
- Department of Medicine, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan
| | - Izza Shahid
- Division of Preventive Cardiology, Houston Methodist Academic Institute, Houston, TX, USA
| | - Muhammad Mustafa Memon
- Department of Medicine, Dow University of Health Sciences, Baba-e-Urdu Road, Karachi, Pakistan
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Tao SB, Lu X, Ye ZW, Tong NW. Update on evidence-based clinical application of sodium-glucose cotransporter inhibitors: Insight to uncommon cardiovascular disease scenarios in diabetes. World J Diabetes 2024; 15:1461-1476. [PMID: 39099824 PMCID: PMC11292321 DOI: 10.4239/wjd.v15.i7.1461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/28/2024] [Accepted: 05/29/2024] [Indexed: 07/08/2024] Open
Abstract
In this paper, we concentrate on updating the clinical research on sodium-glucose cotransporter inhibitors (SGLTis) for patients with type 2 diabetes who have heart failure with a preserved injection fraction, acute heart failure, atrial fibrillation, primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease, and acute myocardial infarction. We searched the data of randomized controlled trials and meta-analyses of SGLTis in patients with diabetes from PubMed between January 1, 2020 and April 6, 2024 for our review. According to our review, certain SGLTis (empagliflozin, dapagliflozin, canagliflozin, and tofogliflozin), but not sodium-glucose cotransporter 1 inhibitor (SGLT1i), exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. Proper utilization of SGLTis in these patients can foster clinical improvement and offer an alternative medication option. However, clinical trials involving SGLTis for certain diseases have relatively small sample sizes, brief intervention durations, and conclusions based on weak evidence, necessitating additional data. These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis.
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Affiliation(s)
- Shi-Bing Tao
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Research Centre for Diabetes and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Department of Endocrinology and Metabolism, Ziyang Central Hospital, Ziyang 641300, Sichuan Province, China
| | - Xi Lu
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Research Centre for Diabetes and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zi-Wei Ye
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Nan-Wei Tong
- Department of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
- Research Centre for Diabetes and Metabolism, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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Dar JA, Jacob JR. Beta Blockers in Contemporary Cardiology: Is It Better to Cast Them Out? Korean Circ J 2024; 54:165-171. [PMID: 38654562 PMCID: PMC11040266 DOI: 10.4070/kcj.2023.0209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 01/25/2024] [Accepted: 02/13/2024] [Indexed: 04/26/2024] Open
Abstract
Beta blockers are one of the commonest prescription drugs in medicine and they have been thought to revolutionize the treatment of heart failure (HF) with reduced ejection fraction (HFrEF) in the last century. In addition to HFrEF, they are prescribed for a variety of diseases in cardiology from hypertension to HF, angina, and stable coronary artery disease (CAD). The increased prescription of beta blockers in conditions like HF with preserved ejection fraction (HFpEF), and stable CAD may be doing more harm than good as per the data we have so far. The available data shows that beta blockers are associated with increased stroke risk and atrial fibrillation (AF) in hypertension and in patients with HFpEF, they have been associated with decreased exercise capacity. In patients with stable CAD and patients with myocardial infarction with normal systolic functions, beta blockers don't offer any mortality benefit. In this article, we critically review the common indications and the uses of beta blockers in patients with HFpEF, CAD, hypertension and AF and we propose that beta blockers are over-prescribed under the shadow of their beneficial effects in patients with HFrEF.
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Affiliation(s)
- Javaid Ahmad Dar
- Department of Cardiology, Christian Medical College, Vellore, India.
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10
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Zafeiropoulos S, Farmakis IT, Milioglou I, Doundoulakis I, Gorodeski EZ, Konstantinides SV, Cooper L, Zanos S, Stavrakis S, Giamouzis G, Butler J, Giannakoulas G. Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis. JACC. HEART FAILURE 2024; 12:616-627. [PMID: 37656079 DOI: 10.1016/j.jchf.2023.07.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 07/17/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023]
Abstract
BACKGROUND Medical treatment for heart failure with preserved ejection (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2is). OBJECTIVES The authors aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF. METHODS The authors performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality. RESULTS The authors identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% ± 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95% CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95% CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95% CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95% CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF ≥60%. CONCLUSIONS In patients with HF and LVEF>40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.
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Affiliation(s)
- Stefanos Zafeiropoulos
- Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, New York, USA; Feinstein Institutes for Medical Research at Northwell Health, Manhasset, New York, USA
| | - Ioannis T Farmakis
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany; Department of Cardiology, AHEPA University Hospital, Thessaloniki, Greece
| | - Ioannis Milioglou
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, Ohio, USA
| | - Ioannis Doundoulakis
- Athens Heart Center, Athens Medical Center, Athens, Greece; First Department of Cardiology, National and Kapodistrian University, "Hippokration" Hospital, Athens, Greece
| | - Eiran Z Gorodeski
- Harrington Heart and Vascular Institute, University Hospitals, Cleveland, Ohio, USA
| | - Stavros V Konstantinides
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Germany; Department of Cardiology, Democritus University of Thrace, Alexandroupoli, Greece
| | - Lauren Cooper
- Feinstein Institutes for Medical Research at Northwell Health, Manhasset, New York, USA; Department of Cardiology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, North Shore University Hospital, Manhasset, New York, USA
| | - Stavros Zanos
- Feinstein Institutes for Medical Research at Northwell Health, Manhasset, New York, USA
| | - Stavros Stavrakis
- Heart Rhythm Institute, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA
| | - Grigorios Giamouzis
- Department of Cardiology, University of Thessaly, Larissa, Greece; Faculty of Medicine, School of Health Sciences, University of Thessaly, Greece
| | - Javed Butler
- Department of Medicine, University of Mississippi School of Medicine, Jackson, Mississippi, USA; Baylor Scott and White Research Institute, Dallas, Texas, USA
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11
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Meifang W, Ying W, Wen C, Kaizu X, Meiyan S, Liming L. Advance in the pharmacological and comorbidities management of heart failure with preserved ejection fraction: evidence from clinical trials. Heart Fail Rev 2024; 29:305-320. [PMID: 37561223 DOI: 10.1007/s10741-023-10338-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/01/2023] [Indexed: 08/11/2023]
Abstract
The prevalence of heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the total heart failure population, and with the aging of the population and the increasing prevalence of hypertension, obesity, and type 2 diabetes (T2DM), the incidence of HFpEF continues to rise and has become the most common subtype of heart failure. Compared with heart failure with reduced ejection fraction, HFpEF has a more complex pathophysiology and is more often associated with hypertension, T2DM, obesity, atrial fibrillation, renal insufficiency, pulmonary hypertension, obstructive sleep apnea, and other comorbidities. HFpEF has generally been considered a syndrome with high phenotypic heterogeneity, and no effective treatments have been shown to reduce mortality to date. Diuretics and comorbidity management are traditional treatments for HFpEF; however, they are mostly empirical due to a lack of clinical evidence in the setting of HFpEF. With the EMPEROR-Preserved and DELIVER results, sodium-glucose cotransporter 2 inhibitors become the first evidence-based therapies to reduce rehospitalization for heart failure. Subgroup analyses of the PARAGON-HF, TOPCAT, and CHARM-Preserved trials suggest that angiotensin receptor-neprilysin inhibitors, spironolactone, and angiotensin II receptor blockers may be beneficial in patients at the lower end of the ejection fraction spectrum. Other potential pharmacotherapies represented by non-steroidal mineralocorticoid receptor antagonists finerenone and antifibrotic agent pirfenidone also hold promise for the treatment of HFpEF. This article intends to review the clinical evidence on current pharmacotherapies of HFpEF, as well as the comorbidities management of atrial fibrillation, hypertension, T2DM, obesity, pulmonary hypertension, renal insufficiency, obstructive sleep apnea, and iron deficiency, to optimize the clinical management of HFpEF.
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Affiliation(s)
- Wu Meifang
- Department of Cardiology, School of Clinical Medicine, Fujian Medical University, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Wu Ying
- Department of Cardiology, School of Clinical Medicine, Fujian Medical University, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Chen Wen
- Department of Cardiology, School of Clinical Medicine, Fujian Medical University, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Xu Kaizu
- Department of Cardiology, School of Clinical Medicine, Fujian Medical University, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Song Meiyan
- Department of Cardiology, School of Clinical Medicine, Fujian Medical University, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China
| | - Lin Liming
- Department of Cardiology, School of Clinical Medicine, Fujian Medical University, Affiliated Hospital of Putian University, Putian, 351100, Fujian, China.
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12
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Hamid AK, Tayem AA, Al-Aish ST, Al Sakini AS, Hadi DD, Al-Aish RT. Empagliflozin and other SGLT2 inhibitors in patients with heart failure and preserved ejection fraction: a systematic review and meta-analysis. Ther Adv Cardiovasc Dis 2024; 18:17539447241289067. [PMID: 39400108 PMCID: PMC11483696 DOI: 10.1177/17539447241289067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 09/11/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND Heart failure (HF) is a highly prevalent disease, among the primary factors contributing to morbidity and death. One of its types is heart failure with preserved ejection fraction (HFpEF) comprising 40%-50% of newly diagnosed HF cases. Despite the high prevalence of HFpEF, there is still a lack of knowledge regarding the best drugs and treatment approaches to be used. However, the sodium-glucose co-transporter 2 (SGLT2) inhibitors could be a promising treatment. OBJECTIVES To examine SGLT2 inhibitors' effect on hospitalization, cardiovascular death, and estimated glomerular filtration rate (eGFR) in HFpEF patients. SEARCH METHODS We conducted searches for randomized controlled trials (RCTs) in PubMed, Embase, Scopus, and Web of Science up to July 2024. SELECTION CRITERIA We chose RCTs that examined the effects of SGLT2 inhibitors and placebo in individuals with higher than 40% ejection fraction (HFpEF). DATA COLLECTION AND ANALYSIS The methodology for the systematic review and meta-analysis was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis. MAIN RESULTS We included 8 studies with 16,509 participants. Drugs examined in our paper included empagliflozin, dapagliflozin, sotogliflozin, and ertugliflozin. Various outcomes were analyzed in different papers. However, different SGLT2 inhibitors lead to a decreased risk of cardiovascular hospitalization and kidney injury. Our meta-analysis showed a decreased risk of cardiovascular hospitalization but not death due to cardiovascular causes or other causes. These results were regardless of baseline status of eGFR, systolic blood pressure, atrial fibrillation or flutter, diabetes mellitus, sex, body mass index, and nt-proBNP. The included studies were of moderate to high quality. CONCLUSION For individuals with HFpEF, SGLT2 inhibitors have been proven to be a safe and effective medication. However, more studies are needed for longer durations, reporting adverse events, effects on exercise tolerance, and other secondary outcomes.
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Affiliation(s)
- Abdulrahman Khaldoon Hamid
- College of Medicine, University of Alexandria, Champollion Street, Al Mesallah Sharq, Al Attarin, Alexandria Governorate 21648, Egypt
| | | | | | | | - Dalia Dhia Hadi
- Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
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13
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Mark PB, Sarafidis P, Ekart R, Ferro CJ, Balafa O, Fernandez-Fernandez B, Herrington WG, Rossignol P, Del Vecchio L, Valdivielso JM, Mallamaci F, Ortiz A, Nistor I, Cozzolino M. SGLT2i for evidence-based cardiorenal protection in diabetic and non-diabetic chronic kidney disease: a comprehensive review by EURECA-m and ERBP working groups of ERA. Nephrol Dial Transplant 2023; 38:2444-2455. [PMID: 37230946 PMCID: PMC10615631 DOI: 10.1093/ndt/gfad112] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Indexed: 05/27/2023] Open
Abstract
Chronic kidney disease (CKD) is a major public health issue affecting an estimated 850 million people globally. The leading causes of CKD is diabetes and hypertension, which together account for >50% of patients with end-stage kidney disease. Progressive CKD leads to the requirement for kidney replacement therapy with transplantation or dialysis. In addition, CKD, is a risk factor for premature cardiovascular disease, particularly from structural heart disease and heart failure (HF). Until 2015, the mainstay of treatment to slow progression of both diabetic and many non-diabetic kidney diseases was blood pressure control and renin-angiotensin system inhibition; however, neither angiotensin-converting enzyme inhibitors (ACEIs) nor angiotensin receptor blockers (ARBs) reduced cardiovascular events and mortality in major trials in CKD. The emergence of cardiovascular and renal benefits observed with sodium-glucose cotransporter-2 inhibitors (SGLT2i) from clinical trials of their use as anti-hyperglycaemic agents has led to a revolution in cardiorenal protection for patients with diabetes. Subsequent clinical trials, notably DAPA-HF, EMPEROR, CREDENCE, DAPA-CKD and EMPA-KIDNEY have demonstrated their benefits in reducing risk of HF and progression to kidney failure in patients with HF and/or CKD. The cardiorenal benefits-on a relative scale-appear similar in patients with or without diabetes. Specialty societies' guidelines are continually adapting as trial data emerges to support increasingly wide use of SGLT2i. This consensus paper from EURECA-m and ERBP highlights the latest evidence and summarizes the guidelines for use of SGLT2i for cardiorenal protection focusing on benefits observed relevant to people with CKD.
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Affiliation(s)
- Patrick B Mark
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Pantelis Sarafidis
- Department of Nephrology, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Robert Ekart
- Faculty of Medicine, University of Maribor, Taborska 8, Maribor, Slovenia
| | - Charles J Ferro
- Renal Unit, University Hospitals Birmingham and Institute of Cardiovascular Science, University of Birmingham, Birmingham, UK
| | - Olga Balafa
- Department of Nephrology, University Hospital of Ioannina, Ioannina, Greece
| | - Beatriz Fernandez-Fernandez
- Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid. Spain, Spain
| | - William G Herrington
- Medical Research Council Population Health Research Unit, Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Patrick Rossignol
- Université de Lorraine, INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
- Service de Spécialités Médicales et de Néphrologie-Hémodialyse Centre Hospitalier Princesse Grace de Monaco, Monaco, Monaco
| | | | - Jose M Valdivielso
- Vascular and Renal Translational Research Group and UDETMA, IRBLleida, Lleida, Spain
| | - Francesca Mallamaci
- CNR-IFC, Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension, Reggio Calabria, Italy
| | - Alberto Ortiz
- Division of Nephrology and Hypertension, IIS-Fundación Jiménez Díaz-Universidad Autónoma Madrid. Spain, Spain
| | - Ionut Nistor
- Faculty of Medicine, University of Medicine and Pharmacy ‘Grigore T. Popa’, Iași, Romania
| | - Mario Cozzolino
- Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy
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14
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Roddick AJ, Wonnacott A, Webb D, Watt A, Watson MA, Staplin N, Riding A, Lioudaki E, Kuverji A, Kossi ME, Holmes P, Holloway M, Fraser D, Carvalho C, Burton JO, Bhandari S, Herrington WG, Frankel AH. UK Kidney Association Clinical Practice Guideline: Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease 2023 UPDATE. BMC Nephrol 2023; 24:310. [PMID: 37880609 PMCID: PMC10598949 DOI: 10.1186/s12882-023-03339-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/19/2023] [Indexed: 10/27/2023] Open
Abstract
Large placebo-controlled trials have demonstrated kidney and cardiovascular clinical benefits of SGLT-2 inhibitors. Data from the EMPA-KIDNEY and DELIVER trials and associated meta-analyses triggered an update to the UK Kidney Association Clinical Practice Guideline on Sodium-Glucose Co-transporter-2 (SGLT-2) Inhibition in Adults with Kidney Disease. We provide a summary of the full guideline and highlight the rationale for recent updates. The use of SGLT-2 inhibitors in people with specific medical conditions, including type 1 diabetes, kidney transplants, and people admitted to hospital with heart failure is also considered, along with Recommendations for future research and Recommendations for implementation. A full "lay" summary of the guidelines is provided as an appendix to ensure that these guidelines are accessible and understandable to people who are not medical professionals.
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Affiliation(s)
- Alistair J Roddick
- The Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK
- Oxford Kidney Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - David Webb
- Diabetes Research Centre, College of Life Sciences, University of Leicester, Leicester, UK
| | | | | | - Natalie Staplin
- The Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK
| | - Alex Riding
- Royal Free London NHS Foundation Trust, London, UK
| | | | - Apexa Kuverji
- John Walls Renal Unit, Glenfield Hospital, Leicester, UK
| | | | | | - Matt Holloway
- East Kent Hospitals University NHS Foundation Trust, Canterbury, UK
| | - Donald Fraser
- Wales Kidney Research Unit, Cardiff University, Cardiff, UK
| | - Chris Carvalho
- North East London Integrated Care Board, London, UK
- Clinical Effectiveness Group, Queen Mary University of London, London, UK
| | - James O Burton
- Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
| | - Sunil Bhandari
- Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Hull, UK
| | - William G Herrington
- The Medical Research Council Population Health Research Unit at the University of Oxford, Oxford, UK
- Oxford Kidney Unit, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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15
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Ferreira JP, Blatchford JP, Teerlink JR, Kosiborod MN, Angermann CE, Biegus J, Collins SP, Tromp J, Nassif ME, Psotka MA, Comin-Colet J, Mentz RJ, Brueckmann M, Nordaby M, Ponikowski P, Voors AA. Mineralocorticoid receptor antagonist use and the effects of empagliflozin on clinical outcomes in patients admitted for acute heart failure: Findings from EMPULSE. Eur J Heart Fail 2023; 25:1797-1805. [PMID: 37540060 DOI: 10.1002/ejhf.2982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 07/18/2023] [Accepted: 07/18/2023] [Indexed: 08/05/2023] Open
Abstract
AIMS In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751). METHODS AND RESULTS In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use. CONCLUSIONS In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF.
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Affiliation(s)
- João Pedro Ferreira
- Centre d'Investigations Cliniques Plurithématique 1433, INSERM, Université de Lorraine, Nancy, France
- F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), INSERM U1116, Centre Hospitalier Régional Universitaire de Nancy, Nancy, France
- UnIC@RISE, Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Jonathan P Blatchford
- Elderbrook Solutions GmbH, Bietigheim-Bissingen, Germany on behalf of Boehringer Ingelheim, Pharma GmbH & Co. KG, Biberach, Germany
| | - John R Teerlink
- Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas, MO, USA
| | - Christiane E Angermann
- Comprehensive Heart Failure Center Würzburg, University and University Hospital Würzburg, and Department of Medicine 1, University Hospital Würzburg, Würzburg, Germany
| | - Jan Biegus
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Sean P Collins
- Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Geriatric Research and Education Clinical Care, Tennessee Valley Healthcare Facility VA Medical Center, Nashville, TN, USA
| | - Jasper Tromp
- Saw Swee Hock School of Public Health, National University of Singapore, the National University Health System, Singapore, Singapore, Singapore
| | - Michael E Nassif
- Saint Luke's Mid America Heart Institute and the University of Missouri, Kansas, MO, USA
| | | | - Josep Comin-Colet
- Hospital Universitari de Bellvitge, University of Barcelona, IDIBELL and CIBERCV, Barcelona, Spain
| | - Robert J Mentz
- Duke Clinical Research Institute and Division of Cardiology, Duke University Medical Center, Durham, NC, USA
| | - Martina Brueckmann
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
- First Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany
| | - Matias Nordaby
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Piotr Ponikowski
- Institute of Heart Diseases, Wroclaw Medical University, Wroclaw, Poland
| | - Adriaan A Voors
- Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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16
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Kalra R. Sodium-glucose cotransporter 2 inhibitors in hospitalized heart failure patients: No time like now. Eur J Heart Fail 2023; 25:1806-1807. [PMID: 37661932 DOI: 10.1002/ejhf.3022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 08/28/2023] [Indexed: 09/05/2023] Open
Affiliation(s)
- Rajat Kalra
- Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA
- Center for Resuscitation Medicine, University of Minnesota, Minneapolis, MN, USA
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17
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Banerjee M, Maisnam I, Pal R, Mukhopadhyay S. Mineralocorticoid receptor antagonists with sodium-glucose co-transporter-2 inhibitors in heart failure: a meta-analysis. Eur Heart J 2023; 44:3686-3696. [PMID: 37605637 DOI: 10.1093/eurheartj/ehad522] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/12/2023] [Accepted: 08/03/2023] [Indexed: 08/23/2023] Open
Abstract
BACKGROUND AND AIMS To investigate the cardiovascular effects of sodium-glucose co-transporter-2 inhibitors (SGLT2i) with concomitant mineralocorticoid receptor antagonist (MRA) use in heart failure (HF) regardless of ejection fraction (EF) and explore the risk of MRA-associated adverse events in individuals randomized to SGLT2i vs. placebo. METHODS PubMed/MEDLINE, Web of Science, Embase, and clinical trial registries were searched for randomized controlled trials/post-hoc analyses evaluating SGLT2i in HF with or without MRA use (PROSPERO: CRD42023397129). The main outcomes were composite of first hospitalization or urgent visit for HF/cardiovascular death (HHF/CVD), HHF, and CVD. Others were all-cause mortality, composite renal and safety outcomes. Hazard ratios (HR)/risk ratios were extracted. Fixed-effects meta-analyses and subgroup analyses were performed. RESULTS Five eligible studies were included, pooling data from 21 947 people with HF (type 2 diabetes mellitus, n = 10 805). Compared to placebo, randomization to SGLT2i showed a similar reduction in HHF/CVD and HHF in people who were or were not using MRAs [HHF/CVD: hazard ratio (HR) 0.75; 95% confidence interval (CI) 0.68-0.81 vs. HR 0.79; 95% CI 0.72-0.86; P-interaction = .43; HHF: HR 0.74; 95% CI 0.67-0.83 vs. HR 0.71; 95% CI 0.63-0.80; P-interaction = .53], with a suggestion of greater relative reduction in CVD in chronic HF people randomized to SGLT2i and using MRAs irrespective of EF (HR 0.81; 95% CI 0.72-0.91 vs. HR 0.98; 95% CI 0.86-1.13; P-interaction = .034). SGLT2i reduced all-cause mortality (P-interaction = .27) and adverse renal endpoints regardless of MRA use (P-interaction = .73) despite a higher risk of volume depletion with concomitant MRAs (P-interaction = .082). SGLT2i attenuated the risk of mild hyperkalaemia (P-interaction < .001) and severe hyperkalaemia (P-interaction = .051) associated with MRA use. CONCLUSIONS MRAs did not influence SGLT2i effects on the composite of HHF/CVD, HHF or all-cause mortality; however, findings hinted at a more pronounced relative reduction in CVD in chronic HF patients regardless of EF who were randomized to SGLT2i and receiving an MRA compared to those randomized to SGLT2i and not receiving MRAs. SGLT2i attenuated the risk of MRA-associated treatment-emergent hyperkalaemia. These findings warrant further validation in well-designed randomized controlled trials.
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Affiliation(s)
- Mainak Banerjee
- Department of Endocrinology, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Rd, Kolkata, West Bengal 700020, India
| | - Indira Maisnam
- Department of Endocrinology, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Rd, Kolkata, West Bengal 700020, India
| | - Rimesh Pal
- Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Satinath Mukhopadhyay
- Department of Endocrinology, Institute of Postgraduate Medical Education and Research, 244, AJC Bose Rd, Kolkata, West Bengal 700020, India
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Cunningham C, Jabri A, Alhuneafat L, Aneja A. A Comprehensive Guide to Sodium Glucose Cotransport Inhibitors. Curr Probl Cardiol 2023; 48:101817. [PMID: 37211299 DOI: 10.1016/j.cpcardiol.2023.101817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 05/23/2023]
Abstract
Sodium-glucose cotransport 2 inhibitors (SGLT2i) are a class of drugs initially approved by the Food and Drug Association (FDA) as antihyperglycemic agents for patients with type 2 diabetes mellitus (DM). However, lately, these agents (Canagliflozin, Empagliflozin, Ertugliflozin, Sotagliflozin, and Dapagliflozin) have become better known for their cardiovascular (CV) and reno-protective effects. In this comprehensive review and analysis, we display the advancement of Sodium Glucose Cotransport Inhibitors have shown in cardiology, specifically heart failure in a concise, yet thorough manner.
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Affiliation(s)
| | - Ahmad Jabri
- Department of Cardiovascular Disease, Henry Ford, Detroit, Michigan, USA.
| | - Laith Alhuneafat
- Department of Medicine, Allegheny Health Network, Pittsburgh, PA
| | - Ashish Aneja
- Heart and Vascular Division, The MetroHealth System, Cleveland, OH
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Kondo T, Wang X, Yang M, Jhund PS, Claggett BL, Vaduganathan M, Hernandez AF, Lam CSP, Inzucchi SE, Martinez FA, de Boer RA, Kosiborod MN, Desai AS, Køber L, Ponikowski P, Sabatine MS, Langkilde AM, Petersson M, Zaozerska N, Bachus E, Solomon SD, McMurray JJV. Efficacy of Dapagliflozin According to Geographic Location of Patients With Heart Failure. J Am Coll Cardiol 2023; 82:1014-1026. [PMID: 37610398 DOI: 10.1016/j.jacc.2023.05.056] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 08/24/2023]
Abstract
BACKGROUND Because clinical characteristics and prognosis vary by geographic region in patients with heart failure (HF), the response to treatment may also vary. A previous report suggested that the efficacy of sodium-glucose cotransporter-2 inhibitor efficacy in heart failure with reduced ejection fraction (HFrEF) may be modified by region. OBJECTIVES The goal of this study was to examine the efficacy and safety of dapagliflozin in patients with HF according to geographic region. METHODS We conducted a patient-level pooled analysis of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trials, which evaluated the effects of dapagliflozin in HFrEF and heart failure with mildly reduced ejection fraction (HFmrEF)/heart failure with preserved ejection fraction (HFpEF), respectively. The primary outcome was the composite of worsening HF or cardiovascular death. RESULTS Among 11,007 patients, 5,159 (46.9%) were enrolled in Europe, 1,528 (13.9%) in North America, 1,998 (18.2%) in South America, and 2,322 (21.1%) in Asia. The rate of the primary outcome (per 100 person-years) was higher in North America (13.9 [95% CI: 12.5-15.4]) than in other regions: Europe 10.8 (95% CI: 10.1-11.5), South America 10.0 (95% CI: 9.0-11.1), and Asia 10.5 (95% CI: 9.5-11.5). The benefit of dapagliflozin on the primary outcome was not modified by region: dapagliflozin vs placebo HR: Europe, 0.85 (95% CI: 0.75-0.96); North America, 0.75 (95% CI: 0.61-0.93); South America, 0.72 (95% CI: 0.58-0.89); and Asia, 0.74 (95% CI: 0.61-0.91) (P interaction = 0.40). This was the same when evaluated separately for HFrEF (P interaction = 0.39) and HFmrEF/HFpEF (P interaction = 0.84). Patients in North America discontinued randomized treatment more frequently than did those elsewhere (placebo discontinuation: 21.8% in North America vs 6.4% in South America), but discontinuation rates did not differ between placebo and dapagliflozin by region. CONCLUSIONS The efficacy and safety of dapagliflozin were consistent across global regions despite geographic differences in patient characteristics, background treatment, and event rates.
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Affiliation(s)
- Toru Kondo
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Xiaowen Wang
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mingming Yang
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom; Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Pardeep S Jhund
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Brian L Claggett
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Muthiah Vaduganathan
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Carolyn S P Lam
- National Heart Centre Singapore & Duke-National University of Singapore, Singapore
| | | | | | | | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, Missouri, USA
| | - Akshay S Desai
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Lars Køber
- Department of Cardiology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Piotr Ponikowski
- Department of Heart Disease, Wroclaw Medical University, Wroclaw, Poland
| | - Marc S Sabatine
- TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Anna Maria Langkilde
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, Gothenburg, Sweden
| | - Magnus Petersson
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, Gothenburg, Sweden
| | - Natalia Zaozerska
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, Gothenburg, Sweden
| | - Erasmus Bachus
- Late-Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals Research and Development, Gothenburg, Sweden
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John J V McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
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20
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Pabon M, Claggett BL, Wang X, Miao ZM, Chatur S, Bhatt AS, Vaduganathan M, Fang JC, Desai AS, Jhund P, Martinez F, de Boer RA, Kosiborod MN, Lam CSP, Shah SJ, Hernandez AF, McMurray JJV, Solomon SD, Vardeny O. Influence of background medical therapy on efficacy and safety of dapagliflozin in patients with heart failure with improved ejection fraction in the DELIVER trial. Eur J Heart Fail 2023; 25:1663-1670. [PMID: 37632711 DOI: 10.1002/ejhf.3001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/08/2023] [Accepted: 08/12/2023] [Indexed: 08/28/2023] Open
Abstract
AIMS The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER) trial demonstrated the sodium-glucose cotransporter 2 inhibitor dapagliflozin to be beneficial in patients with symptomatic heart failure (HF) with improved ejection fraction (HFimpEF; those with prior left ventricular ejection fraction ≤40% that had improved to >40% by enrolment). Whether this benefit differs by background medical therapy is unclear. The current study aims to determine the efficacy and safety of dapagliflozin among patients with HFimpEF by background medical therapy. METHODS AND RESULTS Treatment effects on the primary endpoint (worsening HF or cardiovascular death) were assessed by number of background HF medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitor, evidence-based beta-blocker, and mineralocorticoid receptor antagonist). Among the 6263 patients randomized in DELIVER, 1151 (18%) had HFimpEF. Of those, 21% of patients were on 0-1 therapies, 44% were on two therapies, and 35% were on three therapies. During 2.3 years of median follow-up, the incidence rate of the primary outcome was 9.7, 8.8, and 8.4 per 100 person-years for patients on 0-1, 2 and 3 HF medications at baseline, respectively. Treatment effects with dapagliflozin on the primary outcome may be greater in patients with HFimpEF on 0-1 therapies at baseline (pinteraction = 0.09), driven mostly by a significant interaction for HF hospitalization (pinteraction = 0.023) with no evidence of effect modification for cardiovascular death (pinteraction = 0.65). Treatment effects of dapagliflozin on the primary outcome were, however, consistent when assessed across the modified Heart Failure Collaboratory Medical Therapy Score integrating both therapeutic use and dosing (pinteraction = 0.39). The use of dapagliflozin was not associated with changes in use or doses of background HF therapies, and among patients on three HF medications at baseline, the addition of dapagliflozin did not lead to higher adverse events. CONCLUSIONS In patients with HFimpEF, the safety and efficacy of dapagliflozin were largely similar by background use and dosing of HF medical therapies. The benefit of dapagliflozin in reducing HF events tended to be greater in those patients on 0-1 medications at baseline. Among patients already on three HF medical therapies, the addition of dapagliflozin was safe without requiring de-escalation of other therapies.
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Affiliation(s)
- Maria Pabon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Brian L Claggett
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xiaowen Wang
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Zi Michael Miao
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Safia Chatur
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ankeet S Bhatt
- Kaiser Permanente San Francisco Medical Center, San Francisco, CA, USA
| | - Muthiah Vaduganathan
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - James C Fang
- University of Utah Medical Center, Salt Lake City, UT, USA
| | - Akshay S Desai
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Pardeep Jhund
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | | | - Rudolf A de Boer
- Erasmus Medical Center, Department of Cardiology, Rotterdam, The Netherlands
| | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Carolyn S P Lam
- National Heart Centre Singapore and Duke-National University of Singapore, Singapore, Singapore
| | - Sanjiv J Shah
- Department of Cardiology, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
| | | | | | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Orly Vardeny
- Minneapolis VA Center for Care Delivery and Outcomes Research, University of Minnesota, Minneapolis, MN, USA
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21
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Luo X, Xu J, Zhou S, Xue C, Chen Z, Mao Z. Influence of SGLT2i and RAASi and Their Combination on Risk of Hyperkalemia in DKD: A Network Meta-Analysis. Clin J Am Soc Nephrol 2023; 18:1019-1030. [PMID: 37256921 PMCID: PMC10564376 DOI: 10.2215/cjn.0000000000000205] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 05/24/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND This network meta-analysis investigated the effect of various combined regimens of sodium-glucose cotransporter-2 inhibitors (SGLT2is) and renin-angiotensin-aldosterone system inhibitors (RAASis) on the occurrence of hyperkalemia in diabetic kidney disease. METHODS The risk of hyperkalemia was compared using the random-effects model of network meta-analysis, with results expressed as odds ratios (ORs) with 95% confidence intervals (CIs). The comparative effects of all medications and their combinations with placebo were ranked using the surface under the cumulative ranking probabilities. RESULTS In total, 27 eligible studies involving 43,589 participants with diabetic kidney disease were included. Major findings showed that the use of mineralocorticoid receptor antagonists (MRAs) on top of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) prominently increased hyperkalemia incidence when compared with placebo (OR, 6.08; 95% CI, 2.30 to 16.08), ACEI (OR, 3.07; 95% CI, 1.14 to 8.31), ARB (OR, 2.57; 95% CI, 1.10 to 6.02), SGLT2i (OR, 9.22; 95% CI, 2.99 to 28.46), renin inhibitors+ACEI/ARB (OR, 2.23; 95% CI, 1.14 to 4.36), or SGLT2i+ACEI/ARB (OR, 4.10; 95% CI, 2.32 to 7.26). Subgroup analysis among different generations of MRA found that spironolactone had the strongest effect in combination with ACEI/ARB, even higher than the combined use of ACEI and ARB (OR, 2.89; 95% CI, 1.26 to 6.63). In addition, SGLT2i had a significantly lower incidence of hyperkalemia compared with ACEI (OR, 0.33; 95% CI, 0.12 to 0.91), ARB (OR, 0.28; 95% CI, 0.13 to 0.61), dual RAASi (ACEI combined with ARB; OR, 0.17; 95% CI, 0.06 to 0.47), or MRA or renin inhibitors combined with ACEI/ARB (OR, 0.11; 95% CI, 0.04 to 0.33; OR, 0.24; 95% CI, 0.08 to 0.76, respectively). Moreover, adding SGLT2i to the combination of MRA and ACEI/ARB, as well as the combinations of different RAASis, markedly reduced the occurrence of hyperkalemia. CONCLUSIONS Among the therapeutic drugs with the potential risk of increasing serum potassium in patients with diabetic kidney disease, MRA added an extra risk of hyperkalemia while SGLT2i had the opposite effect and could even reverse the elevation of serum potassium caused by the combined regimen, including MRAs.
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Affiliation(s)
- Xiaoling Luo
- Division of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Jing Xu
- Division of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
- State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Shoulian Zhou
- Division of Hemodialysis Center, Naval Hospital of Eastern Theater of PLA, Zhoushan, Zhejiang, China
| | - Cheng Xue
- Division of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zewei Chen
- Division of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Zhiguo Mao
- Division of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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22
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Di Lullo L, Lavalle C, Scatena A, Mariani MV, Ronco C, Bellasi A. Finerenone: Questions and Answers-The Four Fundamental Arguments on the New-Born Promising Non-Steroidal Mineralocorticoid Receptor Antagonist. J Clin Med 2023; 12:3992. [PMID: 37373685 PMCID: PMC10299719 DOI: 10.3390/jcm12123992] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 06/03/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic kidney disease (CKD) is one of the most common complications of diabetes mellitus and an independent risk factor for cardiovascular disease. Despite guideline-directed therapy of CKD in patients with type 2 diabetes, the risk of renal failure and cardiovascular events still remains high, and diabetes remains the leading cause of end-stage kidney disease in affected patients. To date, current medications for CKD and type 2 diabetes mellitus have not reset residual risk in patients due to a high grade of inflammation and fibrosis contributing to kidney and heart disease. This question-and-answer-based review will discuss the pharmacological and clinical differences between finerenone and other mineralocorticoid receptor antagonists and then move on to the main evidence in the cardiovascular and renal fields, closing, finally, on the potential role of therapeutic combination with sodium-glucose cotransporter 2 inhibitors (SGLT2is).
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Affiliation(s)
- Luca Di Lullo
- Department of Nephrology and Dialysis, L. Parodi—Delfino Hospital, 00034 Colleferro, Italy
| | - Carlo Lavalle
- Department of Clinical, Internal, Anesthesiologist and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (C.L.); (M.V.M.)
| | | | - Marco Valerio Mariani
- Department of Clinical, Internal, Anesthesiologist and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161 Rome, Italy; (C.L.); (M.V.M.)
| | - Claudio Ronco
- International Renal Research Institute (IRRIV), S. Bortolo Hospital, 36100 Vicenza, Italy
| | - Antonio Bellasi
- Department of Medicine, Division of Nephrology, Ente Ospedaliero Cantonale, 6900 Lugano, Switzerland;
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23
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Monzo L, Ferrari I, Cicogna F, Tota C, Cice G, Girerd N, Calò L. Sodium-glucose co-transporter 2 inhibitors in heart failure: an updated evidence-based practical guidance for clinicians. Eur Heart J Suppl 2023; 25:C309-C315. [PMID: 37125324 PMCID: PMC10132577 DOI: 10.1093/eurheartjsupp/suad055] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
The sodium-glucose co-transporter 2 (SGLT2) inhibitors have been shown to reduce risks of clinical events in patients with heart failure (HF), with early and sustained benefits regardless of ejection fraction, diabetic status, and care setting. As part and parcel of the modern foundational HF therapy, clinicians should be familiar with these drugs, in order to implement their use and limit the potential adverse effects. We present an up-to-date review of current evidence and a practical guide for the prescription of SGLT2 inhibitors in patients with HF, highlighting important elements for patient selection, treatment initiation, dosing, and problem solving.
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Affiliation(s)
- Luca Monzo
- Centre d'Investigation Clinique 1433 module Plurithématique, CHRU Nancy – Hôpitaux de Brabois, Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, Université de Lorraine INSERM, 4 rue du Morvan, 54500 Vandoeuvre les Nancy, France
- Department of Cardiology, Policlinico Casilino, Rome 00169, Italy
| | - Ilaria Ferrari
- Department of Cardiology, Policlinico Casilino, Rome 00169, Italy
| | | | - Claudia Tota
- Department of Cardiology, Policlinico Casilino, Rome 00169, Italy
| | - Gennaro Cice
- Department of Cardiology, Policlinico Casilino, Rome 00169, Italy
| | - Nicolas Girerd
- Centre d'Investigation Clinique 1433 module Plurithématique, CHRU Nancy – Hôpitaux de Brabois, Institut Lorrain du Cœur et des Vaisseaux Louis Mathieu, Université de Lorraine INSERM, 4 rue du Morvan, 54500 Vandoeuvre les Nancy, France
| | - Leonardo Calò
- Department of Cardiology, Policlinico Casilino, Rome 00169, Italy
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Rastogi A, Januzzi JL. Pleiotropic Effects of Sodium-Glucose Cotransporter-2 Inhibitors in Cardiovascular Disease and Chronic Kidney Disease. J Clin Med 2023; 12:2824. [PMID: 37109162 PMCID: PMC10143176 DOI: 10.3390/jcm12082824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2023] [Revised: 03/20/2023] [Accepted: 04/03/2023] [Indexed: 04/29/2023] Open
Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to improve cardiovascular and renal outcomes in patients with established cardiovascular disease, chronic kidney disease (CKD), and heart failure (HF) with reduced or preserved ejection fraction. Clinical benefit has been substantiated in patients with and without type 2 diabetes (T2D). Consequently, SGLT2is have an increasingly important role in HF and CKD management that extends beyond T2D treatment. Their pleiotropic pharmacological effects underlying their cardiovascular and renal benefits are not completely understood but include significant effects beyond blood glucose reduction. SGLT2is inhibit the reabsorption of glucose and sodium in the proximal tubule which, in addition to lowering blood glucose, activates tubuloglomerular feedback, leading to reduced glomerular hydrostatic pressure and the mitigation of glomerular filtration rate loss. SGLT2is have diuretic and natriuretic effects, leading to decreased blood pressure, preload, and left ventricular (LV) filling pressure, and improvements in other surrogates of afterload. In HF, SGLT2is mitigate the risks of hyperkalemia and ventricular arrhythmia and improve LV dysfunction. SGLT2is also reduce sympathetic tone and uric acid levels, increase hemoglobin levels, and are postulated to have anti-inflammatory properties. This narrative review discusses the multifactorial and interrelated pharmacological mechanisms underlying the cardiovascular and renal benefits of SGLT2is.
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Affiliation(s)
- Anjay Rastogi
- David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
| | - James L. Januzzi
- Massachusetts General Hospital, Boston, MA 02114, USA;
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Baim Institute for Clinical Research, Boston, MA 02215, USA
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Liang B, Li R, Zhang P, Gu N. Empagliflozin for Patients with Heart Failure and Type 2 Diabetes Mellitus: Clinical Evidence in Comparison with Other Sodium-Glucose Co-transporter-2 Inhibitors and Potential Mechanism. J Cardiovasc Transl Res 2023; 16:327-340. [PMID: 35969357 DOI: 10.1007/s12265-022-10302-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Accepted: 08/05/2022] [Indexed: 11/25/2022]
Abstract
Heart failure remains a leading cause of morbidity and mortality globally and has been recognized as a common complication of diabetes, especially type 2 diabetes mellitus. Heart failure occurs in diabetic patients even in the absence of hypertension, coronary heart disease, or valvular heart disease, and is, therefore, a major cardiovascular complication in this vulnerable population. Given the continued rise in the prevalence of type 2 diabetes mellitus worldwide, the burden of heart failure on the healthcare system will continue to increase. Recent evidence demonstrates that empagliflozin, a sodium-glucose co-transporter-2 inhibitor, brings clinical benefit to patients with established heart failure and type 2 diabetes mellitus. Herein, we critically reviewed the clinical evidence of empagliflozin for patients with heart failure and type 2 diabetes mellitus with the comparison with other sodium-glucose co-transporter-2 inhibitors and potential mechanism to provide the optimal and evidence-based management for patients with established heart failure and type 2 diabetes mellitus with the goal to be conducive to the mechanism exploration of empagliflozin to advance a more comprehensive understanding of empagliflozin.
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Affiliation(s)
- Bo Liang
- Nanjing University of Chinese Medicine, Nanjing, China
- Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Rui Li
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Peng Zhang
- Neijiang Health Vocational College, Neijiang, China
| | - Ning Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
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26
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Yang M, Butt JH, Kondo T, Jering KS, Docherty KF, Jhund PS, de Boer RA, Claggett BL, Desai AS, Hernandez AF, Inzucchi SE, Kosiborod MN, Lam CS, Langkilde AM, Martinez FA, Petersson M, Shah SJ, Vaduganathan M, Wilderäng U, Solomon SD, McMurray JJ. Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan. Eur J Heart Fail 2022; 24:2307-2319. [PMID: 36342375 PMCID: PMC11497302 DOI: 10.1002/ejhf.2722] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 10/15/2022] [Indexed: 11/09/2022] Open
Abstract
AIMS The effects of adding a sodium-glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. METHODS AND RESULTS The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74-1.01) for MRA non-users versus 0.76 (95% CI 0.64-0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73-0.92) and 0.74 (95% CI 0.45-1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. CONCLUSIONS The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF.
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Affiliation(s)
- Mingming Yang
- British Heart Foundation Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
- Department of Cardiology, Zhongda Hospital, School of MedicineSoutheast UniversityNanjingChina
| | - Jawad H. Butt
- British Heart Foundation Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
- Department of CardiologyCopenhagen UniversityCopenhagenDenmark
| | - Toru Kondo
- British Heart Foundation Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
- Department of CardiologyNagoya University Graduate School of MedicineNagoyaJapan
| | | | - Kieran F. Docherty
- British Heart Foundation Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
| | - Pardeep S. Jhund
- British Heart Foundation Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
| | | | | | - Akshay S. Desai
- Cardiovascular DivisionBrigham and Women's HospitalBostonMAUSA
| | | | | | | | - Carolyn S.P. Lam
- National Heart Center Singapore and Duke–National University of SingaporeSingapore
| | - Anna Maria Langkilde
- Late‐Stage Development, Cardiovascular, Renal and MetabolismBioPharmaceuticals Research and DevelopmentGothenburgSweden
| | | | - Magnus Petersson
- Late‐Stage Development, Cardiovascular, Renal and MetabolismBioPharmaceuticals Research and DevelopmentGothenburgSweden
| | - Sanjiv J. Shah
- Northwestern University Feinberg School of MedicineChicagoILUSA
| | | | - Ulrica Wilderäng
- Late‐Stage Development, Cardiovascular, Renal and MetabolismBioPharmaceuticals Research and DevelopmentGothenburgSweden
| | | | - John J.V. McMurray
- British Heart Foundation Cardiovascular Research CentreUniversity of GlasgowGlasgowUK
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Tsukamoto S, Morita R, Yamada T, Urate S, Azushima K, Uneda K, Kobayashi R, Kanaoka T, Wakui H, Tamura K. Cardiovascular and kidney outcomes of combination therapy with sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis. Diabetes Res Clin Pract 2022; 194:110161. [PMID: 36403681 DOI: 10.1016/j.diabres.2022.110161] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/25/2022] [Accepted: 11/14/2022] [Indexed: 11/18/2022]
Abstract
AIMS Both sodium-glucose cotransporter-2 (SGLT-2) inhibitors and mineralocorticoid receptor antagonists (MRAs) have been shown to reduce cardiovascular (CV) event in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, little evidence pertains to the benefits of their combined use. METHODS We systematically searched the PubMed, MEDLINE, EMBASE, and Cochrane Library databases through July 2022. We selected randomized controlled trials comparing SGLT-2 inhibitors, MRAs, or SGLT-2 inhibitor + MRA combination therapy, with placebo in patients with T2D and CKD. We performed a network meta-analysis to indirectly compare the treatments. The primary outcome was a composite of CV events. RESULTS Eight studies were selected with 36,186 patients. The primary outcome was significantly improved in the combination therapy group compared with the other groups (RR [95% CI]; vs SGLT-2 inhibitors, 0.76 [0.60; 0.96]; vs MRAs, 0.66 [0.53; 0.82]; vs placebo, 0.58 [0.47; 0.73]). Additionally, the combination therapy was associated with a considerable reduction in the risk of hyperkalemia (RR vs MRA, 0.43 [0.23; 0.79]). CONCLUSION Combination of SGLT-2 inhibitors and MRAs potentially reduced CV events compared with SGLT-2 inhibitors or MRAs alone. This combination may be a candidate treatment strategy for patients with T2D and CKD.
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Affiliation(s)
- Shunichiro Tsukamoto
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryutaro Morita
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takayuki Yamada
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Shingo Urate
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kengo Azushima
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kazushi Uneda
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Kampo Medicine, Aizu Medical Center, Fukushima Medical University, Aizuwakamatsu, Japan
| | - Ryu Kobayashi
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Kanaoka
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiromichi Wakui
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Brust-Sisti L, Rudawsky N, Gonzalez J, Brunetti L. The Role of Sodium-Glucose Cotransporter-2 Inhibition in Heart Failure with Preserved Ejection Fraction. PHARMACY 2022; 10:pharmacy10060166. [PMID: 36548322 PMCID: PMC9788031 DOI: 10.3390/pharmacy10060166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 11/19/2022] [Accepted: 11/23/2022] [Indexed: 12/03/2022] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of antidiabetic mediations found to also reduce cardiovascular morbidity and mortality and hospitalization for heart failure. Positive results from the EMPEROR-Preserved (empagliflozin) and PRESERVED-HF (dapagliflozin) studies led to recommendations for SGLT2 inhibitors in HFpEF within major international heart failure guidelines. However, studies of ipragliflozin and luseogliflozin, agents approved outside the United States (U.S.), reported different outcomes relative to pivotal trials and failed to realize benefits in the HFpEF population. Varying definitions of HFpEF and outcomes studied complicate the interpretation of study results. SGLT2 inhibitors may cause common adverse events (genital mycotic infections, volume depletion) in addition to rare but severe sequela, including euglycemic diabetic ketoacidosis, Fournier's gangrene, and lower limb amputation. While evidence of CV benefits grows, SGLT2 inhibitor prescribing has lagged, particularly among patients without diabetes. In the U.S., high cost and administrative hurdles may contribute to decreased patient and clinician uptake of this drug class. Future trial results and clinical experience with SGLT2 inhibitors may lead to expanded use and greater uptake among patients with heart failure.
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Affiliation(s)
- Lindsay Brust-Sisti
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Nicole Rudawsky
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Jimmy Gonzalez
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
| | - Luigi Brunetti
- Department of Pharmacy Practice and Administration, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ 08854, USA
- Correspondence: ; Tel.: +1-848-445-6815
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Sciatti E, Gori M, D’elia E, Iacovoni A, Senni M. Empagliflozin in heart failure with preserved ejection fraction: first success in mission impossible. Eur Heart J Suppl 2022; 24:I153-I159. [DOI: 10.1093/eurheartjsupp/suac106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Abstract
Heart failure and preserved ejection fraction (EF) is a common disease with a poor prognosis and increasing prevalence in the community. The current treatment paradigm includes symptomatic therapy, such as diuretics, risk factor control, and treatment of comorbidities. According to the most recent European guidelines, there is no effective therapy in patients with heart failure and left ventricular EF ≥50%, while the pharmacological compounds normally used in heart failure with reduced EF could also be implemented in patients with EF slightly reduced (between 40 and 50%), with a recommendation class IIB. The recently published Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) study challenged current guidelines, showing for the first time in patients with heart failure and EF >40% better outcomes with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin than with placebo. This result was consistent in patients with and without diabetes, as well as in those with EF below and above 50%. The purpose of the review is to describe the rationale for this important finding and the main results of the EMPEROR-Preserved study and to provide some suggestions for the daily clinical management of SGLT2 inhibitors.
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Affiliation(s)
- Edoardo Sciatti
- Cardiology Unit, Cardiovascular Department, ASST Papa Giovanni XXIII
| | - Mauro Gori
- Cardiology Unit, Cardiovascular Department, ASST Papa Giovanni XXIII
| | - Emilia D’elia
- Cardiology Unit, Cardiovascular Department, ASST Papa Giovanni XXIII
| | - Attilio Iacovoni
- Cardiology Unit, Cardiovascular Department, ASST Papa Giovanni XXIII
| | - Michele Senni
- Cardiology Unit, Cardiovascular Department, ASST Papa Giovanni XXIII
- Bicocca University of Milan
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30
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Zhang X, Zhang Y, Hu Y. Knowledge domain and emerging trends in empagliflozin for heart failure: A bibliometric and visualized analysis. Front Cardiovasc Med 2022; 9:1039348. [DOI: 10.3389/fcvm.2022.1039348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
ObjectiveEmpagliflozin (EMPA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), is recommended for all patients with Heart failure (HF) to reduce the risk of Cardiovascular death, hospitalization, and HF exacerbation. Qualitative and quantitative evaluation was conducted by searching relevant literatures of EMPA for Heart Failure from 2013 to 2022, and visual analysis in this field was conducted.MethodsThe data were from the Web of Science Core Collection database (WOSCC). The bibliometric tools, CiteSpace and VOSviewer, were used for econometric analysis to probe the evolvement of disciplines and research hotspots in the field of EMPA for Heart Failure.ResultsA total of 1461 literatures with 43861 references about EMPA for Heart Failure in the decade were extracted from WOSCC, and the number of manuscripts were on a rise. In the terms of co-authorship, USA leads the field in research maturity and exerts a crucial role in the field of EMPA for Heart Failure. Multidisciplinary research is conducive to future development. With regards to literatures, we obtained 9 hot paper, 93 highly cited literatures, and 10 co-cited references. The current research focuses on the following three aspects: EMPA improves left ventricular remodeling, exert renal protection, and increases heart rate variability.ConclusionBased on methods such as bibliometrics, citation analysis and knowledge graph, this study analyzed the current situation and trend of EMPA for Heart Failure, sorted out the knowledge context in this field, and provided reference for current and future prevention and scientific research.
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Ferreira JP, Pitt B, McMurray JJV, Pocock SJ, Solomon SD, Pfeffer MA, Zannad F, Rossignol P. Steroidal MRA Across the Spectrum of Renal Function: A Pooled Analysis of RCTs. JACC. HEART FAILURE 2022; 10:842-850. [PMID: 36328653 DOI: 10.1016/j.jchf.2022.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 06/14/2022] [Accepted: 06/27/2022] [Indexed: 06/16/2023]
Abstract
BACKGROUND Mineralocorticoid receptor antagonists (MRAs) are underused in patients with kidney dysfunction, and their efficacy among patients with chronic kidney disease (CKD) is uncertain. OBJECTIVES The goal of this study was to analyze the efficacy and safety of steroidal MRAs across the spectrum of estimated glomerular filtration rates (eGFRs) in randomized controlled trials. The study included patients with heart failure (HF) or myocardial infarction and advanced CKD who participated in the RALES (Randomized Aldactone Evaluation Study), EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure), TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) in the Americas, and EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trials. METHODS This study used individual patient data meta-analysis using Cox models stratified by trial with treatment-by-eGFR interaction terms. eGFR was recalculated by using the Chronic Kidney Disease Epidemiology Collaboration creatinine formula. RESULTS A total of 12,700 patients were included, of whom 331 (2.6%) had an eGFR ≤30 mL/min/1.73 m2 (mean eGFR: 26.8 ± 3.2 mL/min/1.73 m2). Patients with advanced CKD had higher annualized event rates for all studied outcomes: placebo event rate for the composite of cardiovascular death or HF hospitalization was ∼3-fold higher in patients with eGFR ≤30 compared with those with eGFR >90 mL/min/1.73 m2: 41.6 vs 14.6 events per 100 person-years. MRAs (vs placebo) reduced the composite of cardiovascular death or HF hospitalization, but the effect was attenuated as eGFR decreased: the corresponding HRs by eGFR categories were: HR for >90 mL/min/1.73 m2: 0.62 (95% CI: 0.49-0.78); HR for 61-90 mL/min/1.73 m2: 0.69 (95% CI: 0.61-0.77); HR for 46-60 mL/min/1.73 m2: 0.84 (95% CI: 0.74-0.95); HR for 31-45 mL/min/1.73 m2: 0.79 (95% CI: 0.68-0.91); and HR for ≤30 mL/min/1.73 m2: 0.96 (95% CI: 0.70-1.32) (treatment-by-eGFR interaction P for trend = 0.033). Investigator-reported hyperkalemia and worsening renal function were more frequent (2- to 3-fold) among MRA users, and hyperkalemia was more frequent as eGFR decreased (treatment-by-eGFR interaction P for trend = 0.002). CONCLUSIONS Steroidal MRAs reduced HF hospitalizations and mortality across a wide range of eGFR. However, declining benefit and worsening safety may limit their use in patients with lower eGFR, particularly those with levels ≤30 mL/min/1.73 m2.
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Affiliation(s)
- João Pedro Ferreira
- Unic@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal; Université de Lorraine, Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
| | - Bertram Pitt
- Department of Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
| | - John J V McMurray
- BHF Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Stuart J Pocock
- Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, United Kingdom
| | - Scott D Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Marc A Pfeffer
- Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Faiez Zannad
- Université de Lorraine, Inserm, Centre d'Investigations Cliniques-Plurithématique 14-33, and Inserm U1116, CHRU, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France
| | - Patrick Rossignol
- Université de Lorraine, INSERM CIC-P 1433, CHRU de Nancy, INSERM U1116, F-CRIN INI-CRCT (Cardiovascular and Renal Clinical Trialists), Nancy, France; Department of Medical Specialties and Nephrology-Hemodialysis, Princess Grace Hospital, Monaco, and Centre d'Hémodialyse Privé de Monaco, Monaco.
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32
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Zannad F. Heart Failure and Kidney Disease in Type 2 Diabetes. J Am Coll Cardiol 2022; 80:1732-1734. [DOI: 10.1016/j.jacc.2022.08.773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 08/22/2022] [Indexed: 11/30/2022]
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Pipilas A, Martyn T, Lindenfeld J. Heart Failure Medical Therapy: A Review for Structural/Interventional Cardiologists. STRUCTURAL HEART : THE JOURNAL OF THE HEART TEAM 2022; 6:100082. [PMID: 37288122 PMCID: PMC10242575 DOI: 10.1016/j.shj.2022.100082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/11/2022] [Accepted: 07/22/2022] [Indexed: 11/06/2022]
Abstract
Medical therapy for heart failure (HF) has expanded rapidly in the last decade contributing to improved morbidity and mortality for patients living with HF. The indicated treatments have been traditionally stratified based on left ventricular ejection fraction. The optimization of HF medical therapy is important for interventional and structural cardiologists as HF remains among the most common causes of periprocedural hospitalization and death. Additionally, optimization of medical therapy for HF prior to the utilization of device-based therapies as well as enrollment in clinical trials is crucial. This review will serve to highlight medical therapy indicated across the left ventricular ejection fraction strata.
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Affiliation(s)
- Alexandra Pipilas
- Department of Cardiovascular Medicine, Boston University, Boston, Massachusetts, USA
| | - Trejeeve Martyn
- Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - JoAnn Lindenfeld
- Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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34
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Kunz M, Götzinger F, Emrich I, Schwenger V, Böhm M, Mahfoud F. Cardio-renal interaction - Clinical trials update 2022. Nutr Metab Cardiovasc Dis 2022; 32:2451-2458. [PMID: 36064690 DOI: 10.1016/j.numecd.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 10/31/2022]
Abstract
AIMS Chronic kidney disease is a common cardiovascular risk indicator and strongly associated with increased morbidity and mortality. The heart and kidneys are pathophysiologically closely connected, which becomes particularly obvious in patients with cardiorenal syndrome. This review summarizes clinically relevant studies on the cardio-renal interaction published in 2021 and 2022. DATA SYNTHESIS Selected trials published in high-impact journals were chosen from the database Pubmed and included in this review. New evidence about the selective mineralocorticoid receptor antagonist finerenone and the renoprotective sodium-glucose co-transporter-2-inhibitors (SGLT2-Inhibitors) are discussed and we update on novel insights about the treatment of arterial hypertension in patients with severe chronic kidney disease with the thiazide-like diuretic chlorthalidone. Finally, data on infective endocarditis in patients on chronic hemodialysis and the treatment of secondary hyperparathyroidism with the calcimimetic drug etelcalcetide in patients with end stage kidney disease are critically reviewed. CONCLUSION Several important studies investigating cardio-renal interactions were recently published may affect clinical practice. The graphical abstract (Fig. 1) depicts the most relevant clinical studies investigating cardio-renal interactions.
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Affiliation(s)
- Michael Kunz
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital Saarland, Saarland University, 66424 Homburg, Germany.
| | - Felix Götzinger
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital Saarland, Saarland University, 66424 Homburg, Germany
| | - Insa Emrich
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital Saarland, Saarland University, 66424 Homburg, Germany
| | - Vedat Schwenger
- Department of Nephrology, Klinikum der Landeshauptstadt Stuttgart gKAöR - Katharinenhospital, 70174 Stuttgart, Germany
| | - Michael Böhm
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital Saarland, Saarland University, 66424 Homburg, Germany
| | - Felix Mahfoud
- Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, University Hospital Saarland, Saarland University, 66424 Homburg, Germany
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35
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Arshad MS, Ahmed A, Ejaz A, Ahmed W, Farooqi SMH, Memon MM, Shahid I. Effect of mineralocorticoid receptor antagonist at baseline on the efficacy of sodium-glucose cotransporter-2 inhibitors in patients with heart failure: a meta-analysis of randomized controlled trials. Eur J Prev Cardiol 2022; 29:e334-e337. [PMID: 35938308 DOI: 10.1093/eurjpc/zwac171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/01/2022] [Accepted: 08/04/2022] [Indexed: 11/14/2022]
Affiliation(s)
- Muhammad Sameer Arshad
- Department of Medicine, Dow University of Health Sciences, 74200 Baba-e-Urdu Road, Karachi, Sindh, Pakistan
| | - Aymen Ahmed
- Department of Medicine, Dow University of Health Sciences, 74200 Baba-e-Urdu Road, Karachi, Sindh, Pakistan
| | - Arooba Ejaz
- Department of Medicine, Dow University of Health Sciences, 74200 Baba-e-Urdu Road, Karachi, Sindh, Pakistan
| | - Warda Ahmed
- Department of Medicine, Aga Khan University, 74800 Stadium Road, Karachi, Sindh, Pakistan
| | | | - Muhammad Mustafa Memon
- Department of Medicine, Dow University of Health Sciences, 74200 Baba-e-Urdu Road, Karachi, Sindh, Pakistan
| | - Izza Shahid
- Department of Medicine, Ziauddin University, 75510 Shahrah-e-Iran Clifton Road, Karachi, Sindh, Pakistan
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Jang HY, Kim IW, Oh JM. Using real-world data for supporting regulatory decision making: Comparison of cardiovascular and safety outcomes of an empagliflozin randomized clinical trial versus real-world data. Front Pharmacol 2022; 13:928121. [PMID: 36110539 PMCID: PMC9468970 DOI: 10.3389/fphar.2022.928121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/20/2022] [Indexed: 11/13/2022] Open
Abstract
Aims: In countries where a randomized clinical trial (RCT) is difficult to perform, a real-world evidence (RWE) study with a design similar to an RCT may be an option for drug regulatory decision-making. In this study, the objective was to find out to what extent the safety of empagliflozin from the RWE study in Korea is different from the one in RCT by emulating the design of foreign RCT. The outcome covers various safety outcomes including cardiovascular safety. Methods: The EMPA-REG OUTCOME trial (NCT01131676) was selected for comparison. The inclusion/exclusion criteria and follow-up method for the RWE were matched to the comparison RCT. Major adverse cardiovascular events (MACEs) were used as a primary outcome and 15 other outcomes were also included for analysis. Result: We followed 23,126 matched patients with type 2 diabetes mellitus (11,563 empagliflozin users and 11,563 sitagliptin users) for 2.7 years (median). Empagliflozin use was associated with a significantly decreased risk of MACEs [EMPA-REG DUPLICATE RWE: adjusted HR 0.87, 95% confidence interval (CI) 0.79–0.96]. The predefined estimate agreement, regulatory agreement, and standardized difference for RCT duplication were achieved [EMPA-REG OUTCOME RCT: adjusted HR 0.86, 95% (CI) 0.74–0.99]. According to the predefined criteria for 15 outcomes, 10 outcomes were evaluated as good, and three as moderate. Conclusion: Our study results suggest that RWE in one country in comparison with an RCT has the potential for providing evidence for future regulatory decision-making in an environment where RCT could not be performed.
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Ageev FT. [Three ages of spironolactone. Evolution of views on spironolactone capabilities in the treatment of patients with heart failure.]. KARDIOLOGIIA 2022; 62:3-11. [PMID: 35989624 DOI: 10.18087/cardio.2022.7.n2233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 07/19/2022] [Indexed: 06/15/2023]
Abstract
The article describes the history of the discovery of aldosterone and the creation of its antagonist, spironolactone. The effects of aldosterone associated with the stimulation of two types of receptors. Long-term effect (nuclear or genomic) and fast - term (membrane). They are manifested not only by the influence on the water-salt metabolism and the volume of extracellular fluid, but also in the regulation of vascular tone and elasticity of the vascular wall and, most interestingly, the effect on cardiac remodeling. Early after its development Spironolactone was considered as a medicine for water-salt metabolism regulation, diuresis and normalization of blood pressure. In the following period, Spironolactone embraced a new area - systolic heart failure. The drug was considered not only to enhance safe diuresis, but also to eliminate the phenomenon of escape of the antialdosterone effect angiotensin-converting enzyme inhibitors. The change in the paradigm of heart failure towards the prevailing changes in her diastolic phenotype, which is based on excessive diffuse myocardial fibrosis, changed role of spironolactone in the treatment of heart failure. Currently, it is considered as an independent drug, due to its powerful antifibrotic effect, blocking which controls the whole complex of endo- and paracrine effects of aldosterone.
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Affiliation(s)
- F T Ageev
- Federal State Budgetary Institution NATIONAL MEDICAL RESEARCH CENTRE OF CARDIOLOGY NAMED AFTER ACADEMICIAN E.I.CHAZOV. Of the Ministry of Health of the Russian Federation
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Empagliflozin and Elderly Patients With Preserved Ejection Fraction Heart Failure: Is Age Just a Number? J Am Coll Cardiol 2022; 80:19-21. [PMID: 35772912 DOI: 10.1016/j.jacc.2022.04.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 04/11/2022] [Indexed: 12/23/2022]
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Verma S, Dhingra NK, Pandey AK, Cosentino F. Emerging role for SGLT2 inhibitors in mitigating the risk of hyperkalaemia in heart failure. Eur Heart J 2022; 43:2994-2996. [PMID: 35680380 DOI: 10.1093/eurheartj/ehac304] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Subodh Verma
- Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Nitish K Dhingra
- Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Arjun K Pandey
- Division of Cardiac Surgery, St. Michael's Hospital, University of Toronto, Toronto, Canada
| | - Francesco Cosentino
- Cardiology Unit, Department of Medicine Solna, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden
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40
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Can we stop reflexively discontinuing mineralocorticoid antagonists for patients with heart failure and hyperkalemia? J Card Fail 2022; 28:1464-1468. [PMID: 35691481 DOI: 10.1016/j.cardfail.2022.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 11/20/2022]
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Koufakis T, Mustafa OG, Ajjan RA, Garcia-Moll X, Zebekakis P, Dimitriadis G, Kotsa K. From Skepticism to Hope: The Evolving Concept of the Initiation and Use of Sodium-Glucose Cotransporter 2 Inhibitors in Hospitalized Patients. Drugs 2022; 82:949-955. [PMID: 35678922 PMCID: PMC9178534 DOI: 10.1007/s40265-022-01730-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 01/10/2023]
Abstract
The management of hyperglycemia in patients admitted to hospital is mainly based on insulin therapy. However, the positive and rapid effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on cardiorenal outcomes raises the possibility that they might confer benefits to hospitalized patients. In recent, well designed, randomized trials (SOLOIST-WHF and EMPULSE) recruiting inpatients with heart failure (HF), SGLT2i demonstrated the potential to improve survival and quality of life and reduce the number of HF events, time to first HF event, hospitalizations, and urgent visits for HF compared with placebo. They were also well tolerated, whereas incidence of diabetic ketoacidosis was low. In EMBODY, empagliflozin was shown to be protective against the deleterious effects of cardiac injury in patients with acute myocardial infarction. In DARE-19, the administration of dapagliflozin to inpatients with cardiometabolic risk factors and COVID-19 was based on the hypothesis that the anti-inflammatory properties of SGLT2i could alleviate organ damage. Although the findings did not reach statistical significance, the efficacy and safety profiles of the drug were encouraging. These promising findings in the field of cardiometabolic medicine set the stage for future research to explore whether the benefits of gliflozins can expand to inpatients with non-cardiometabolic disorders, including sepsis, cirrhotic ascites, and malignancies. The concept of inpatient use of SGLT2i has evolved greatly over the past few years. The latest evidence suggests that SGLT2i may be effective and safe in the hospital setting, provided patients are carefully selected and closely monitored. Real-world data will prove whether present hope about inpatient use of gliflozins will transform into future confidence.
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Affiliation(s)
- Theocharis Koufakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - Omar G Mustafa
- Department of Diabetes, King's College Hospital, London, UK
| | - Ramzi A Ajjan
- Leeds Institute for Cardiovascular and Metabolic Medicine, University of Leeds Ringgold Standard Institution, Leeds, UK
| | - Xavier Garcia-Moll
- Cardiology Department, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma, 91 Mas Casanova, 08041, Barcelona, Spain
| | - Pantelis Zebekakis
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece
| | - George Dimitriadis
- Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kalliopi Kotsa
- Division of Endocrinology and Metabolism and Diabetes Center, First Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 St. Kiriakidi Street, 54636, Thessaloniki, Greece.
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Konstam MA. The Cardiovascular Pharmaceutical Cornucopia: A Conundrum of Riches. J Am Coll Cardiol 2022; 79:1138-1140. [PMID: 35331407 DOI: 10.1016/j.jacc.2022.01.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 01/26/2022] [Accepted: 01/27/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Marvin A Konstam
- The CardioVascular Center, Tufts Medical Center, Boston, Massachusetts, USA; Tufts University School of Medicine, Boston, Massachusetts, USA.
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