Reference: N Engl J Med . 2019 Nov 21
Heart failure, an entity with multiple causes, represents a significant source of morbidity, mortality, and healthcare expenditures (Nat Rev Cardiol. 2016 Jun). Patients with heart failure can be further categorized based on ejection fraction of the left ventricle, with reduced ejection fraction defined as being ≤40% (Circulation. 2013). Previously, multiple clinical trials have demonstrated that a treatment regimen that includes dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor used in the treatment of diabetes mellitus type 2, in addition to standard medical therapies for heart failure with reduced ejection fraction, resulted in improved clinical outcomes for patients with diabetes and heart failure (N Engl J Med 2017, N Engl J Med 2019). The study being reviewed adds to the available evidence on the safety and efficacy of the SGLT-2 inhibitor in patients with heart failure, with or without diabetes.
A recent randomized, placebo-controlled, multi-site trial compared the efficacy of dapagliflozin 10mg daily vs placebo in 4,744 adults (mean age 66 years, 77% men) with New York heart Association (NYHA) class II, III, or IV heart failure with ejection fraction ≤40% receiving standard heart-failure device therapy and/or standard drug therapy. After randomization, there were no statistically significant differences in baseline characteristics between the treatment and placebo groups. The primary outcome was a composite worsening of heart failure, defined as hospitalization or urgent visit resulting in IV therapy for heart failure, and cardiovascular death. Secondary outcomes were total number of hospitalizations for heart failure, change in symptom score on the Kansas City Cardiomyopathy Questionnaire (KCCQ), worsening renal function, progression into end stage renal disease (ESRD) or renal death, and all-cause mortality, 11% of patients discontinued treatment, but all were included in the analysis. Median follow-up was 18.2 months.
Comparing dapagliflozin vs placebo, the primary outcome occurred in 16.3% vs. 21.2% (p < 0.001, number needed to treat [NNT] 21), with worsening heart failure in 9.7% vs. 13.4% (p < 0.05, NNT 27) and cardiovascular death in 9.6% vs.11.5% (p < 0.05, NNT 53), respectively. In subgroup analysis, similar results were observed in both patients with and without diabetes. For secondary outcomes, all-cause mortality occurred in 11.6% of patients in dapagliflozin group compared to 13.9% of patients in the placebo group (p < 0.05, NNT 44). Dapagliflozin was also associated with improved KCCQ symptom scores compared to placebo (p < 0.001). There were no significant differences between groups for worsening renal function, adverse events of interest (including volume depletion, renal adverse events, fracture, amputation, or major hypoglycemia), or discontinuation due to adverse events.
The results of this study support the initiation of dapagliflozin in patients with heart failure with reduced ejection fraction, regardless of the diagnosis of diabetes mellitus (N Engl J Med. 2019). While promising, the study was not double-blind, and dosing of the patients’ other medications could be altered during the trial period. This could introduce bias into the results if there were significant differences in treatment adjustments between the groups. Further research on the use of SGLT-2 inhibitors in heart failure with reduced ejection fraction should explore its use in patients on static drug regimens. Additionally, the authors of this paper noted low usage in their sample population of sacubitril-valsartan, a therapy currently recognized to be more effective than that of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) alone. Future research which includes patients on optimized therapy, including SGLT-2 inhibitors, would further help elucidate the benefits of dapagliflozin as adjunctive therapy. Though more research on specific areas would be beneficial, the results of this study represent promising findings which support the addition of dapagliflozin to the pharmacologic management of patients with heart failure with reduced ejection fraction regardless of whether the patient has comorbid diabetes mellitus.
For more information, see the topic Heart Failure with Reduced Ejection Fraction in Dynamed.
This Resident Focus was written by Gunnar Magnuson a first year resident at Memorial Health University Medical Center Family Medicine residency program in Savannah, Georgia. Originally from Murfreesboro, Tennessee, he completed his undergraduate degree in health sciences from East Tennessee State University before attending medical school at the Edward Via College of Osteopathic Medicine in Auburn, Alabama. When not seeing patients, he enjoys family time with his wife and two dogs.