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Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure: Racial Differences and a Potential for Reducing Disparities

2021; Lippincott Williams & Wilkins; Volume: 143; Issue: 24 Linguagem: Inglês

10.1161/circulationaha.120.052821

1524-4539

Alanna A. Morris, Jeffrey M. Testani, Javed Butler,

Heart Failure Treatment and Management

HomeCirculationVol. 143, No. 24Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure: Racial Differences and a Potential for Reducing Disparities Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBSodium-Glucose Cotransporter-2 Inhibitors in Heart Failure: Racial Differences and a Potential for Reducing Disparities Alanna A. Morris, MD, MSc, Jeffrey M. Testani, MD, MTR and Javed Butler, MD, MPH, MBA Alanna A. MorrisAlanna A. Morris Correspondence to: Alanna A. Morris, MD, MSc, 1462 Clifton Rd, Ste 504, Atlanta GA 30322. Email E-mail Address: [email protected] https://orcid.org/0000-0002-8033-3707 Division of Cardiovascular Medicine, Emory University, Atlanta, GA (A.A.M.). , Jeffrey M. TestaniJeffrey M. Testani https://orcid.org/0000-0001-5285-0419 Cardiology Division, Yale University, New Haven, CT (J.M.T.). and Javed ButlerJaved Butler https://orcid.org/0000-0001-7683-4720 Department of Medicine, University of Mississippi, Jackson (J.B.). Originally published14 Jun 2021https://doi.org/10.1161/CIRCULATIONAHA.120.052821Circulation. 2021;143:2329–2331Two recent clinical trials with sodium-glucose cotransporter-2 (SGLT2) inhibitors, dapagliflozin and empagliflozin, have now demonstrated a reduction in heart failure (HF) hospitalization or cardiovascular mortality risk in patients with HF and reduced ejection fraction, independent of the presence of comorbid diabetes.1 Although the prespecified subgroup analyses examining the efficacy of SGLT2 inhibitors in patients with HF and reduced ejection fraction show a consistent benefit across subgroups irrespective of race-ethnicity, there appears to be a signal of a potentially greater effect in Black and Asian patients randomly assigned to treatment compared with other groups (Figure [A]). The ability to show this degree of benefit in Black patients, who only made up 4% to 7% of the patients enrolled, is compelling and merits further investigation given the overwhelming disparities in risk, prevalence, and clinical outcomes for Black patients with HF and reduced ejection fraction. The ≈50% relative risk reduction in the primary end point demonstrates an effect size in Black patients that is striking, unlikely to be attributable to chance, and should not be ignored.Download figureDownload PowerPointFigure. Effect of SGLT2 inhibitors on primary composite outcome according to prespecified subgroup analyses by race-ethnicity (A), and potential mechanisms for racial differences that could explain overwhelming benefit of SGLT2-inhibitors in Black patients with heart failure and a reduced ejection fraction, and racial disparities that could impact real-world access to SGLT2 inhibitors for Black patients (B).A meta-analysis of the pooled treatment effects of empagliflozin and dapagliflozin on the composite end point of cardiovascular death or first hospitalization for heart failure in subgroups by race-ethnicity demonstrates a greater effect in Black patients (A, adapted from Zannad et al1 with permission. Copyright © 2020, Elsevier). Numerous mechanisms have been suggested that may contribute to higher renal reabsorption of sodium in subjects of African ancestry, with biomarkers or receptors with known racial differences depicted in orange (B). The putative decongestive properties induced through use of SGLT2 inhibitors are outlined and may help overcome this pathophysiology, translating to improved clinical outcomes for Black patients enrolled in these clinical trials. However, various mechanisms could reduce access to SGLT2 inhibitors for Black patients, serving to actually worsen preexisting health care disparities. ANP indicates atrial natriuretic peptide; BNP, B-type natriuretic peptide; DAPA-HF, Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; DCT, distal convoluted tubule; ENaC, epithelial sodium channel; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; GDMT, guideline-directed medical therapy; GLUT2, glucose transporter-2; GRK-4, G protein–coupled receptor kinase 4; HR, hazard ratio; NEDD4, neural precursor cell expressed, developmentally downregulated 4; NHE3, sodium-hydrogen exchanger 3; PCT proximal convoluted tubule; RAAS, renin-angiotensin-aldosterone system; SGLT2, sodium-glucose cotransporter-2; SNS, sympathetic nervous system; and SCNN1B, sodium channel epithelial 1 beta subunit.To understand the potential benefits of SGLT2 inhibition, it is worth noting the distinction between racial differences and disparities, both of which contribute to the unique epidemiology of HF in Black patients. According to the Institute of Medicine, health disparities are differences that result from the operation of health care systems, legal and regulatory climates, and discriminatory biases, stereotyping, and uncertainty, as well.2 Conversely, racial differences are defined as clinical, biological, genetic, or epigenetic factors associated with disease risk, outcome, or treatments not caused by social factors.2 Our central hypothesis is that the pleiotropic effects on decongestion, blood pressure, and other factors induced by treatment with SGLT2 inhibitors are of particular benefit for patients who have HF with impaired natriuresis, in particular, Black patients whose renal sodium handling may be uniquely influenced by ancestry and predispose to volume retention. Without proper attention, however, health disparities including differential prescribing patterns by clinicians, financial toxicity of novel therapeutic agents, and other factors may attenuate the clinical efficacy of SGLT2 inhibitors in a real-world setting.Low urinary sodium concentration predicts adverse outcomes in HF. SGLT2 inhibitors induce natriuresis by blocking sodium reabsorption in the proximal convoluted tubule (Figure [B]), resulting in decreased blood volume attributable to both osmotic and natriuretic diuretic effects, particularly when combined with loop diuretics.3 In subjects with hypertension and HF, hyperactivity of the sympathetic nervous and renin-angiotensin-aldosterone systems leads to subtle renal microvascular and tubulointerstitial injury, and an imbalance in the expression of vascular tone in favor of vasoconstriction, impairing urinary sodium excretion. Although this pathophysiology occurs in many patients, it may be particularly relevant for Black individuals who have the highest prevalence of salt sensitivity (SS, up to 75% of Black individuals with hypertension) and the highest prevalence of HF. Previous studies have documented a higher renal reabsorption of sodium in persons of African ancestry (Figure [B]), suggestive of higher renal sodium avidity.4 After similar states of sodium and volume loading, Black subjects excrete less urinary sodium than White subjects, with greater elevations in blood pressure and more fluid retention. Although no single genotype has been determined to be causative, this SS phenotype is characterized by lower levels of plasma renin and aldosterone in patients with normal blood pressure, patients with high blood pressure, and patients with HF as well. The additional natriuresis, reductions in plasma volume and blood pressure, and improvements in inflammation, oxidative stress, and overall metabolism induced using SGLT2 inhibitors may help to overcome this pathophysiology, translating to markedly improved clinical outcomes for Black patients.With the explosion of new therapeutic agents showing morbidity and mortality benefit in HF and reduced ejection fraction, clinicians will have an unprecedented number of drugs to choose from to treat patients with HF. Despite robust trial data showing drug efficacy, medical inertia and other barriers often lead to slow uptake of novel therapies among providers. Despite higher rates of death and hospitalization from HF, Black patients are less likely to receive novel pharmacological and device-based therapies, and they are unlikely to receive established guideline-directed medical therapy with proven benefit, namely hydralazine-isosorbide dinitrate that remains grossly underutilized in this population. A recent retrospective analysis of Medicare claims data on >1 million US adults with diabetes demonstrated that Black patients were less likely than White patients to be prescribed SGLT2 inhibitors.5 Although the relative cost and potential for financial toxicity with these agents must be considered, failure to prescribe novel therapeutic compounds with proven efficacy in high-risk populations will only serve to exacerbate preexisting health care disparities.Because Black patients have a high prevalence of HF, diabetes, and chronic kidney disease, and a high risk of adverse outcomes, the identification of a pharmaceutical class with such great potential for therapeutic benefit should be of great interest for patients, clinicians, and scientists alike. In this respect, further mechanistic research is warranted. Future studies might investigate racial differences in renal sodium avidity. Although the exact mechanisms underpinning SS are not entirely clear, and there have been mixed results using other diuretics in HF, this physiology is a well-accepted cause for racial differences in hypertension, but has been largely unexplored as a mechanistic contributor to volume overload in patients with HF, and may be associated with the disparate rates of HF hospitalization between Black individuals and other race-ethnic groups. An ongoing clinical trial will examine the financial burden associated with novel therapeutics for patients with HF (Cost and Shared Decision-Making for Heart Failure; ClinicalTrials.gov identifier NCT04793880). Much work remains to achieve health equity in HF; however, the results from these recent SGLT2 inhibitor trials offer a glimmer of hope.Sources of FundingNone.Disclosures Dr Morris has received grants from National Heart, Lung, and Blood Institute (R03 HL146874), the Woodruff Foundation, and the Association of Black Cardiologists. Dr Testani has received grants and personal fees on unrelated projects from Sequana Medical, BMS, 3ive labs, Boehringer Ingelheim, Sanofi, FIRE1, and personal fees from Astra Zeneca, Novartis, Cardionomic, Bayer, MagentaMed, Renalguard, W.L. Gore, and grants from Otsuka and Abbott. Dr Butler is a consultant for Abbott, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, CVRx, Eli Lilly, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Sequana, StealthPeptide, and Vifor.Footnoteswww.ahajournals.org/journal/circThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 2331.Correspondence to: Alanna A. Morris, MD, MSc, 1462 Clifton Rd, Ste 504, Atlanta GA 30322. Email [email protected]eduReferences1. Zannad FFerreira JPPocock SJAnker SDButler JFilippatos GBrueckmann MOfstad APPfarr EJamal W, et al.; SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.Lancet. 2020; 396:819–829. doi: 10.1016/S0140-6736(20)31824-9CrossrefMedlineGoogle Scholar2. Smedley BDStith AYNelson AR, eds. Unequal Treatment: Confronting Racial and Ethnic Disparities in Health CareNational Academies Press2003Google Scholar3. Griffin MRao VSIvey-Miranda JFleming JMahoney DMaulion CSuda NSiwakoti KAhmad TJacoby D, et al.; Empagliflozin in heart failure: diuretic and cardiorenal effects.Circulation. 2020; 142:1028–1039. doi: 10.1161/CIRCULATIONAHA.120.045691LinkGoogle Scholar4. Spence JDRayner BL. Hypertension in blacks: individualized therapy based on renin/aldosterone phenotyping.Hypertension. 2018; 72:263–269. doi: 10.1161/HYPERTENSIONAHA.118.11064LinkGoogle Scholar5. McCoy RGDykhoff HJSangaralingham LRoss JSKaraca-Mandic PMontori VMShah ND. Adoption of new glucose-lowering medications in the U.S.–the case of SGLT2 inhibitors: nationwide cohort study.Diabetes Technol Ther. 2019; 21:702–712. doi: 10.1089/dia.2019.0213CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByAlbert M, Carnethon M and Watson K (2021) Disparities in Cardiovascular Medicine, Circulation, 143:24, (2319-2320), Online publication date: 15-Jun-2021. June 15, 2021Vol 143, Issue 24Article InformationMetrics © 2021 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.052821PMID: 34125562 Originally publishedJune 14, 2021 Keywordsethnic groupshealthcare disparitiesraceheart failuresalt tolerancesodium-glucose transporter 2 inhibitorsPDF download Advertisement SubjectsDisparitiesHeart FailureRace and Ethnicity