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By Jamie L.W. Kennedy, MD, FACC
Associate Professor, Division of Cardiology, Advanced Heart Failure & Transplant Cardiology, University of California, San Francisco
Dr. Kennedy reports no financial relationships relevant to this field of study.
SYNOPSIS: Treatment with dapagliflozin for 12 weeks resulted in improved health status, either a reduction in NT-proBNP or improvement in quality of life measures, in systolic heart failure patients with or without type 2 diabetes mellitus.
SOURCE: Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin effects on biomarkers, symptoms and functional status in patients with heart failure with reduced ejection fraction, the DEFINE-HF trial. Circulation 2019;140:1463-1476.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors increase urinary excretion of glucose, thereby lowering blood sugar. Several large clinical trials of SGLT2 inhibitors in diabetic patients have shown reductions in heart failure hospitalizations. However, these trials were limited by low numbers of patients with heart failure and lack of details on their cardiac disease, such as prevalence of systolic dysfunction. Of course, heart failure remains a highly morbid and mortal disease despite currently available evidence-based interventions such as medications and devices.
Nassif et al studied the use of one SGLT2 inhibitor, dapagliflozin, in patients with established symptomatic systolic heart failure, defined as ejection fraction ≤ 40% with New York Heart Association (NYHA) class II to III symptoms. Patients with and without type 2 diabetes mellitus were enrolled. Type 1 diabetes patients were excluded, as were patients with recent heart failure hospitalizations and chronic kidney disease stage 4 or 5. Patients were randomized to dapagliflozin or placebo for 12 weeks. The two primary endpoints were a little complex. The first endpoint was the average of six- and 12-week mean NT-proBNP. The second endpoint was a composite of the proportion of patients who achieved a meaningful improvement in health status, defined as either a five-point increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) or a 20% decrease in the average of six- and 12-week NT-proBNP. There were a range of prespecified subgroups and secondary endpoints, too, including heart failure events as an exploratory endpoint.
The 263 patients enrolled in the trial were typical of heart failure studies: 73% male, with average age 61 years; 40% were African-American. Sixty-two percent of patients had type 2 diabetes mellitus, 40% had atrial fibrillation, and 53% had ischemic cardiomyopathy. Two-thirds of patients exhibited NYHA class II symptoms, one-third class III. They were a well-managed group: 97% prescribed beta-blockers, 92% angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers/angiotensin receptor-neprilysin inhibitors (ACE/ARB/ARNI), and 61% aldosterone antagonist. Sixty-two percent presented with implantable cardioverter-defibrillators, and 35% presented with cardiac resynchronization therapy devices. The average left ventricular ejection fraction was 26%, and the median NT-proBNP on enrollment was 1,136 pg/mL.
The authors did not observe any difference between the groups in the first primary endpoint, the average six- and 12-week mean NT-proBNP (1,133 pg/mL vs. 1,191 pg/mL; P = 0.43). However, the second primary endpoint revealed a significant improvement in health status in 61.5% of patients in the treatment arm vs. 50.4% in the control arm (P = 0.039). Both components of this composite endpoint favored dapagliflozin: 42.9% vs. 32.5% of patients with a five- or more point increase in KCCQ and 44.0% vs. 29.4% with 20% or more reduction in NT-proBNP.
Overall, safety events were similar between groups, although there were more episodes of volume depletion in the dapagliflozin arm (12 events vs. seven events). Interestingly, there were no differences in the rates of severe hypoglycemia (one patient in each arm, both of whom were diabetics). There was no difference in response rate for diabetics vs. nondiabetics. The authors concluded that treatment with dapagliflozin for 12 weeks resulted in improved health status in systolic heart failure patients with or without type 2 diabetes mellitus.
The DEFINE-HF study was published contemporaneously with DAPA-HF, a larger study of similar population, which showed treatment with dapagliflozin reduced rates of worsening heart failure or cardiovascular death from 21.2% to 16.3% over a median period of 18.2 months of treatment (P < 0.001).1 Components of the endpoint both favored dapagliflozin as well: cardiovascular death 9.6% vs. 11.5% and worsening heart failure in 10.0% vs. 13.7%.
The mechanisms by which dapagliflozin and other SGLT2 inhibitors benefit patients with heart failure are unclear. Certainly, improved blood sugar control in diabetic patients may limit cardiovascular morbidity and mortality, and urinary excretion of glucose may result in improved control of volume status. Studies also have shown SGLT2 inhibitors lead to a reduction in left ventricular mass in patients with coronary disease and diabetes, alterations in cardiomyocyte metabolism favoring ketone bodies, and reductions in intracellular sodium and calcium.
DEFINE-HF’s interesting twist was its focus on quality of life. Physicians and patients always have considered quality of life when making treatment decisions, although the database to guide these discussions has, at times, been thin. However, more recently, tools to assess quality of life, such as the KCCQ, have become available and implemented in clinical trials alongside “hard” endpoints such as mortality and hospitalization. In this particular case, the quality of life data aid the patient and physician in deciding whether to add yet another medication to already-extensive regimens. Most patients in this study were taking at least six medications on enrollment: ACE/ARB/ARNI, beta-blocker, aldosterone antagonist, loop diuretic, lipid-lowering agent, and one or more medications for diabetes. The cost and complexity of these regimens certainly weigh on patients’ minds and wallets. Talking with patients about mortality absolute risk reductions in the 2% range, as seen in DAPA-HF, may not be sufficient for some patients to add an additional medication, while a clinically significant improvement in quality of life may be more meaningful.
As we have seen in previous trials, the use of evidence-based heart failure therapies far exceeded that in clinical practice. The benefit of dapagliflozin may be more marked in patients unable to tolerate other evidence-based heart failure medications. Where on the pathway from normal glucose metabolism to insulin dependence were the nondiabetics in this study? The average age and high incidence of coronary disease and dyslipidemia leads me to suspect a sizable number of nondiabetics presented with impaired glucose tolerance, which may explain some of the benefit of dapagliflozin. For example, I am less certain a benefit would be seen in lean young adults with familial cardiomyopathy. I am interested to see if SGLT2 inhibitors are helpful for patients with heart failure with preserved ejection fraction, considering the lack of evidence-based treatment options demonstrating a benefit.
How will these data alter my management of systolic heart failure patients? For patients with type 2 diabetes mellitus and heart failure, dapagliflozin certainly should be part of their medication regimen, perhaps replacing less beneficial medications like sulfonylureas. For nondiabetic patients similar to the populations studied in DEFINE-HF and DAPA-HF, we will discuss dapagliflozin as an additional therapy beyond ACE/ARB/ARNI, beta-blockers, and aldosterone antagonists. For patients significantly different from the populations studied, such as lean young adults with familial cardiomyopathy, I would like to see additional data before routinely prescribing dapagliflozin. Finally, a practical point: Coordination of care with primary care physicians and endocrinologists will be even more important in the future, as we coordinate who prescribes and monitors which medication for which patient.
Financial Disclosure: Internal Medicine Alert’s Physician Editor Stephen Brunton, MD, is a retained consultant for Abbott Diabetes, Acadia, AstraZeneca, and Boehringer Ingelheim; and he serves on the speakers bureau of AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, and Novo Nordisk. Peer Reviewer Gerald Roberts, MD; Editor Jonathan Springston; Editor Jason Schneider; Editorial Group Manager Leslie Coplin; and Accreditations Manager Amy M. Johnson, MSN, RN, CPN, report no financial relationships relevant to this field of study.