Could a Low-Dose Diuretic Polypill Improve Outcomes in Heart Failure With Preserved Ejection Fraction?

Abstract

HomeCirculation: Heart FailureVol. 14, No. 3Could a Low-Dose Diuretic Polypill Improve Outcomes in Heart Failure With Preserved Ejection Fraction? Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBCould a Low-Dose Diuretic Polypill Improve Outcomes in Heart Failure With Preserved Ejection Fraction? Sadiya S. Khan, MD, MSc Mark D. Huffman, MD, MPH Sanjiv J. ShahMD Sadiya S. KhanSadiya S. Khan Correspondence to: Sadiya S. Khan, MD, MS, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0643-1859 Division of Cardiology, Department of Medicine (S.S.K.,M.D.H., S.J.S.), Northwestern University Feinberg School of Medicine, Chicago, IL. Department of Preventive Medicine (S.S.K., M.D.H.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author , Mark D. HuffmanMark D. Huffman https://orcid.org/0000-0001-7412-2519 Division of Cardiology, Department of Medicine (S.S.K.,M.D.H., S.J.S.), Northwestern University Feinberg School of Medicine, Chicago, IL. Department of Preventive Medicine (S.S.K., M.D.H.), Northwestern University Feinberg School of Medicine, Chicago, IL. The George Institute for Global Health, University of New South Wales, Sydney, Australia (M.D.H.). Search for more papers by this author and Sanjiv J. ShahSanjiv J. Shah https://orcid.org/0000-0002-5655-8201 Division of Cardiology, Department of Medicine (S.S.K.,M.D.H., S.J.S.), Northwestern University Feinberg School of Medicine, Chicago, IL. Search for more papers by this author Originally published5 Mar 2021https://doi.org/10.1161/CIRCHEARTFAILURE.120.008090Circulation: Heart Failure. 2021;14:e008090Heart failure (HF) contributes to over 300 000 deaths1 and nearly 1 million hospitalizations annually.2 HF with preserved ejection fraction (HFpEF) accounts for over 50% of all HF, and prevalence continues to increase given an aging population and rising prevalence of obesity and diabetes.3 Despite significant advances in the treatment of HF with reduced ejection fraction,4 disease-modifying therapies in HFpEF remain limited. Targeting congestion with loop and thiazide diuretic therapy remains the cornerstone of treatment,5,6 but emerging data on the benefits of adjunctive therapies, mineralocorticoid receptor antagonists (MRA), and sodium glucose co-transporter 2 inhibitors (SGLT2i), are promising with at least 14 ongoing studies examining these agents in HFpEF. However, gaps in uptake are likely to persist, if not grow, given challenges with clinical inertia, adherence, and increasing polypharmacy in patients with HFpEF. Herein, we describe the clinical need, summarize our rationale for, address potential arguments against, and provide a roadmap for a fixed low-dose combination therapy (or “polypill”) for HFpEF, incorporating loop diuretics, thiazide, or thiazide-like diuretics, MRA, and SGLT2i.Clinical Need for a New Approach to HFpEFClinical practice guidelines for HFpEF provide a class of recommendation I, level of evidence C for use of loop diuretics to improve symptoms and a class of recommendation IIb, level of evidence B-R for MRA to decrease HF hospitalizations.7 The American College of Cardiology recently issued recommendations for SGLT2i in patients with diabetes to reduce HF hospitalizations.8 While dedicated trials in patients with HFpEF are ongoing, data now also support benefits of SGTL2i in HF with reduced ejection fraction9 and chronic kidney disease10 in patients without diabetes. However, 3 clear limitations exist in our current paradigm for HFpEF management: underutilization of evidence-based therapies, risk of diuretic resistance, and polypharmacy.First, utilization of MRA in HFpEF is low. In the American Heart Association Get With The Guidelines-Heart Failure Program, among 34 233 patients hospitalized for HFpEF between 2009 and 2014, only 12% were prescribed an MRA at discharge.11 In the CAPACITY HFpEF (Effect of Praliciguat on Peak Rate of Oxygen Consumption in Patients With Heart Failure With Preserved Ejection Fraction) clinical trial, where more than half of the patients had a history of diabetes, only 1.7% were on SGLT2i.12 Taken together, these data identify that nonloop adjunctive therapies largely remain underutilized.Second, patients with HFpEF often present with congestion for which loop diuretic monotherapy is the initial treatment approach. However, this strategy has several limitations. While loop diuretics are initially effective at preventing sodium reabsorption, chronic loop diuretic monotherapy results in compensatory mechanisms and diuretic resistance. As a result, many ambulatory HFpEF patients have undertreated congestion as demonstrated by invasive hemodynamic monitoring.13 Prevention of diuretic resistance may be proactively achieved by combined use of loop and thiazide.14 Further, emerging data suggest augmented diuretic response when loop diuretics are combined with SGLT2i,15 which have demonstrated benefits related to glucose lowering, natriuresis, favorable cardiovascular remodeling, and nephroprotective effects.Third, since HFpEF is common among older adults and often coexists with comorbidities, rates of polypharmacy are high. In an analysis of older adults aged ≥65 years who were hospitalized with HFpEF, 43% were on 10 or more medications.16 As a result, adherence may be challenging given the high burden of multiple prescription therapies.Thus, there is a need for innovative approaches to target clinical inertia, prevent diuretic resistance, and reduce polypharmacy and improve adherence to improve outcomes in HFpEF.Rationale and Potential Benefits for Low-Dose, Combination Diuretic TherapyRobust evidence supports the role of fixed-dose combination therapies for a variety of chronic diseases, including cardiovascular and noncardiovascular diseases such as HIV. We posit that a polypill-based approach represents an appealing strategy for HFpEF. We draw upon existing approaches from other chronic diseases (eg, hypertension for which a thiazide/MRA combination exists) and similar proposals that have been described for HF with reduced ejection fraction and management of diuretic resistance. While the idea needs testing in randomized clinical trials, we propose that a polypill may improve clinical utilization, adherence, and effectiveness. Because multiple HFpEF therapies target the kidney (in addition to other systemic effects), combining drugs at low doses may also offer a more effective and safer approach to decongestion through sequential nephron blockade (Figure).Download figureDownload PowerPointFigure. We propose a diuretic polypill for heart failure with preserved ejection fraction. Panel (A) demonstrates a schematic of a nephron demonstrating the potential for sequential nephron blockade with a low-dose combination therapy to disrupt the existing paradigm in HFpEF. Panel (B) proposes potential future randomized clinical trials to study varying polypill approaches in patients with HFpEF. CKD indicates chronic kidney disease; DM, diabetes; MACE, major adverse cardiovascular event; MRA, mineralocorticoid receptor antagonist; and SGLT2, sodium glucose co-transporter 2.Addressing Potential PITFALLS for Testing a HFpEF PolypillIn spite of accumulating evidence on the effectiveness of polypills in other cardiovascular conditions, several potential arguments exist. First, there is concern that fixed-dose combination therapies detract from a personalized approach. While HFpEF is a heterogeneous syndrome and precision approaches to target the underlying pathophysiology are needed, congestion is a final common pathway. Second, dose titration may be difficult in patients who require different doses of diuretics (eg, those with chronic kidney disease who often have multifactorial diuretic resistance and may require more aggressive decongestion). By combining multiple classes of diuretics at low doses (eg, quarter- or half-standard doses), safety profiles may be better given the log-linear relationship between dose and side effects in these drug classes. This would need to be rigorously investigated in prospective clinical trials with careful monitoring and attention to safety (eg, electrolyte abnormalities and euglycemic diabetic ketoacidosis). In addition, if a particular target dose of SGTL2i were identified to be beneficial in HFpEF, then a polypill with a target SGLT2i dose and low doses of other components could be formulated and would require study before clinical application. Validation of the ideal MRA dose and type (steroidal/nonsteroidal17) also requires study. Ultimately, a polypill approach does not have to be a “one-size fits all”, and multiple dosing options and various combinations of each component should be tested (Figure). Third, cost of dapagliflozin may be a barrier to uptake; however, the patent ended in October 2020, and the emergence of generic SGLT2i will further amplify the feasibility of this strategy. Lastly, it remains to be determined what the optimal comparator group should be for polypill RCTs.ConclusionsAs HFpEF continues to be a leading cause of morbidity and mortality, a polypill strategy may be a promising new paradigm for improving utilization, adherence, and outcomes. This approach warrants investigation with mechanistic, as well as traditional and pragmatic clinical trials, to examine whether it will improve symptoms, quality of life, and outcomes in HFpEF compared with current standard of care.AcknowledgmentsThe funding sponsor did not contribute to design and conduct of the interpretation of the data or preparation, review, or approval of the article. The authors take responsibility for decision to submit the article for publication.Sources of FundingThis study was supported by grants from the National Institutes of Health (KL2TR001424, P30AG059988; P30DK092939) and the American Heart Association (#19TPA34890060) to Dr Khan. Research reported in this publication was supported, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant Number KL2TR001424 (Dr Khan). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Dr Shah is supported by grants from the National Institutes of Health (R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423) and the American Heart Association (#16SFRN28780016).Disclosures Dr Huffman has received support from the American Heart Association, Verily, and AstraZeneca for work unrelated to this research. The George Institute for Global Health has a patent, license, and has received investment funding with intent to commercialize fixed-dose combination therapy through its social enterprise business, George Medicines. Dr Shah has received research grants from Actelion, AstraZeneca, Corvia, Novartis, and Pfizer and has served as a consultant, scientific advisory board member, and/or executive committee/steering committee member for Abbott, Actelion, AstraZeneca, Amgen, Axon Therapeutics, Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb, Cardiora, CVRx, Cytokinetics, Eisai, GSK, Ionis, Ironwood, Merck, MyoKardia, Novartis, Pfizer, Sanofi, Shifamed, Tenax, and United Therapeutics. The authors plan to submit a patent for a polypill.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 410.Correspondence to: Sadiya S. Khan, MD, MS, Northwestern University Feinberg School of Medicine, Chicago, IL 60611. Email [email protected]edu