Building the Foundation for a New Era of Quadruple Therapy in Heart Failure

G. Michael Felker, MD, MHS


Circulation. 2020;141(2):112-114. 

The serial development of treatments that improve morbidity and mortality in patients with chronic heart failure with reduced ejection fraction (HFrEF) is one of the great success stories of cardiovascular therapeutics. Until recently, the combination of β-blockers, renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers), and mineralocorticoid receptor antagonists formed the foundation of triple therapy for heart failure (HF). These agents, each of which provides clear benefits on mortality and morbidity in patients with HFrEF, collectively came to be termed guideline-directed medical therapy (GDMT). This stable foundation of HF therapeutics was upended in 2014 by the stunning results of the PARADIGM-HF study (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure), demonstrating substantial improvements in outcomes with the angiotensin receptor-neprilysin inhibitor sacubitril-valsartan above and beyond the benefits provided by the angiotensin-converting enzyme inhibitor enalapril.[1] Now, only a few years later, a remarkable data set has emerged with the sodium-glucose cotransporter-2 inhibitors (SGLT2is) in HF. Initially, the diabetes cardiovascular outcome trials provided evidence of the role of these agents in preventing incident HF in patients with type 2 diabetes mellitus. Last, the recent publication of the primary results of the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure) demonstrated substantial benefits in outcomes on top of triple therapy for patients with chronic HFrEF, benefits that are remarkably similar in patients with and without diabetes mellitus.[2] So is it now time for triple therapy to evolve to quadruple therapy in patients with HFrEF?

The field of HF must now grapple with a number of questions in light of these new data in patients with established HFrEF. Is this a class effect of SGLT2is in general or specific to dapagliflozin? What about other benefits beyond morbidity and mortality? What are the specific mechanisms underlying the observed effects? And last, how should this new class of drugs be implemented, especially in groups of patients (eg, the elderly) where aggressive uptitration of triple therapy has often been a challenge? In that context, the articles by Kosiborod et al[3] and Martinez et al[4] in this issue of Circulation expand the dapagliflozin in HF story and provide greater insights into some of these critical questions.

First, Kosiborod et al[3] present a detailed analysis of the effects of dapagliflozin on health-related quality of life in the DAPA-HF study. These data are of critical importance, because improving patient-reported outcomes in HF, especially in highly symptomatic patients, is an important goal in drug development. The reported analysis from DAPA-HF shows a clinically important benefit on health-related quality of life (as measured by the well-validated Kansas City Cardiomyopathy Questionnaire score) with dapagliflozin in comparison with placebo that was sustained >8 months. In a responder analysis, patients randomly assigned to dapagliflozin were more likely to experience a 5-, 10-, or ≥15-point improvement in Kansas City Cardiomyopathy Questionnaire score (consistent with small, medium, and large improvements in health-related quality of life) than were patients on placebo. Although the mean improvement (a 2.8 change in Kansas City Cardiomyopathy Questionnaire total symptom score over placebo at 8 months) may appear modest, it should be noted that this is a similar or greater magnitude of improvement in comparison with Kansas City Cardiomyopathy Questionnaire changes with other effective HF therapies, including sacubitril-valsartan, ivabradine, and cardiac resynchronization therapy. These results confirm and extend the prior results from the DEFINE-HF study (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) in a larger population with longer follow-up.[5] Dapagliflozin therefore joins a select group of HF interventions that improve mortality, reduce hospitalizations, and improve health-related quality of life in patients with HFrEF: the 3 critical goals of HF treatment.

Another highly relevant question about the potential role of dapagliflozin in HF is how well it works across the spectrum of patients with HFrEF, in particular, groups of patients in whom it is often challenging to optimize GDMT, such as the elderly. Older patients are underrepresented in clinical trials in HF, and aggressive uptitration of GDMT in older patients is often limited by comorbidities, frailty, and polypharmacy. The article by Martinez et al[4] reports the efficacy and tolerability of dapagliflozin stratified by age group. As expected, the event rate for the primary end point (cardiovascular death or HF event) increased with age, driven primarily by a greater risk of HF events. It is reassuring that, in DAPA-HF, the treatment effect of dapagliflozin was similar across all age groups, including patients >75 years of age. Indeed, the point estimate for the treatment effect of dapagliflozin in the 1149 patients >75 years of age was numerically greatest of all age categories (hazard ratio, 0.68), and the absolute risk reduction in older patients was higher (because of a higher baseline risk than younger patients). In DAPA-HF, older patients were less likely to be aggressively treated with GDMT, consistent with other studies. As anticipated, older patients were more likely to have adverse events and drug intolerance, but this was similar in both the dapagliflozin and placebo groups.

These data emphasize another potentially attractive feature of SGLT2is as HF therapy: in general, these agents play well with others when it comes to overlapping intolerances that often limit (either in reality or in perception) the optimization of GDMT. Although SGLT2i therapy may lead to volume depletion and require adjustment of diuretics, the SGLT2is generally lack some of the other dose-limiting adverse effects (such as renal dysfunction, hyperkalemia, and hypotension) that can make aggressive uptitration of GDMT problematic, in particular, in older patients or those with more advanced disease.

Where do we go from here? It is important to acknowledge that, although well-conducted and convincing, DAPA-HF is only a single trial. Multiple ongoing studies will continue to fill out the picture of the role of SGLT2is as a class in the treatment of HF, including studies with other SGLT2s, and trials in patients with HF and preserved ejection fraction and those hospitalized with HF, as well. Although the accumulated data on this class to date certainly seem hopeful, definitive answers to some of these questions await the results of ongoing studies.

Assuming that future data confirm the benefits of SGLT2is in HF, the next critical step is implementation, a challenge that has been well documented in other aspects of GDMT despite most therapies being available as low-cost generic drugs.[6] On the basis of the recent experience with sacubitril-valsartan, it is clear that evidence generation alone is insufficient to move the needle for the uptake of new efficacious treatments.[7] Gaps in implementation can result from a combination of knowledge deficits, clinical inertia, patient reluctance to take additional medications, and barriers to access from payers. As we stand at the beginning of a new era of quadruple therapy for HFrEF with β-blockers, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonists, and SGLT2is, it is incumbent on the field to realize that the real work of getting the right drug to the right patient at the right time has only just begun.