DAPA-HF study found beneficial cardiovascular results were consistent across subgroups regardless of diabetes status or medication combinations.
One of the most concerning cardiovascular complications for patients with diabetes is the development of heart failure (HF). Because of this, several diabetes medications have been studied to determine whether they are beneficial or harmful in treating patients with HF. For example, previous research has shown that thiazolidines and saxagliptin can worsen heart failure outcomes. However, three separate sodium-glucose cotransporter 2 (SGLT2) inhibitor trials, the Empagliflozin Cardiovascular Outcome (EMPA-REG OUTCOME), the Canagliflozin Cardiovascular Assessment Study Program (CANVAS), and the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI) trial, showed a relative risk reduction of heart failure hospitalization for patients with diabetes of 35%, 33%, and 27%, respectively. Such findings have led to researching the use of SGLT2 inhibitors in the standalone HF population. Recently a study was published, the DAPA-HF trial, providing evidence for improved mortality and morbidity benefits when using dapagliflozin in combination with standards of care treatment for patients with heart failure and reduced left ventricular fraction.
The DAPA-HF study was a multicentered (including over 20 countries), randomized, double-blinded, superiority trial comparing the use of dapagliflozin to placebo when added to the current standard of care models, in reducing the incidence of cardiovascular death or heart failure events including hospitalization or emergency heart failure visits. The study included men and women 18 years or older with a heart failure diagnosis of at least two years, a diagnosis of New York Heart Association (NYHA) functional classification of class II or above, and a documented left ventricular ejection fraction less than 40%. A total of 4744 patients were randomized in a one-to-one ratio to either the dapagliflozin or placebo group, receiving 10 mg of drug or placebo daily. Secondary outcomes highlighted comparisons between dapagliflozin and placebo rehospitalization rates secondary to heart failure, change in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS), and renal function. The study accessed comparison outcomes using hazardous ratios (HR) at 95% confidence intervals employing Cox proportional-hazards models.
The results of the study overwhelmingly favored the use of dapagliflozin across all subgroups of patients with HF. Researchers calculated the hazardous ratio comparing dapagliflozin versus placebo to be 0.74 (95% CI 0.65 – 0.85) for the primary composite endpoint, which included cardiovascular death and heart failure hospitalization (p < 0.0001). These results were consistent across subgroups regardless of diabetes status, medication combinations, or KCCQ-TSS baseline scores. Patients treated with dapagliflozin reported clinically significant improvements in HF symptoms following eight months of treatment, as defined as an increase in KCCQ-TSS scoring of 5 or more. Dapagliflozin, in comparison to the placebo, reduced blood pressure at eight months while producing a small increase in serum creatine, a well-documented side effect of SGLT2 inhibitors. Even so, dapagliflozin treatment groups had lower rates of renal adverse events than placebo groups. Finally, the major adverse event associated with the use of dapagliflozin was volume depletion, most evident in sub-groups receiving concurrent diuretic treatment.
This landmark trial illustrated the additive benefits of dapagliflozin in combination with current medication management for patients with HF and reduced ejection fraction. Importantly, the study provides evidence that dapagliflozin addition can reduce mortality and morbidity associated with HF, even when used in patients without diabetes. Improvements seen in both diabetic and non-diabetic subgroups suggest dapagliflozin’s original hypothesized mechanism of improvement through glucose-lowering effects may be untrue. Researchers are now proposing various theories for the mechanism of action behind the benefits, including an increased diuretic response, increased renal erythropoietin secretion, or activation of the sympathetic nervous system. Regardless of how the drug confers its benefits, the potential for quality of life improvement within this patient population is substantial. With dapagliflozin gaining FDA approval for the treatment of HF, standard treatment algorithms will likely change to reflect new evidence.
- Diabetic medications such as SGLT2 inhibitors have been shown to reduce mortality and morbidity in patients with HF and reduced ejection fraction.
- Dapagliflozin received FDA approval for the treatment of HF and reduced ejection fraction based on the DAPA-HF study.
- Results from the DAPA-HF study showed dapagliflozin versus placebo hazardous ratio of 0.74 across all subgroups.
Campbell, Patrick. “Dapagliflozin Receives Heart Failure Approval for Non-Diabetic Patients.” HCPLive®, May 6, 2020, www.mdmag.com/medical-news/farxiga-dapagliflozin-heart-failure-approval-for-nondiabetic-patients.
Docherty, et al. “Effects of Dapagliflozin in DAPA-HF According to Background Heart Failure Therapy.” OUP Academic, Oxford University Press, March 28, 2020, academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehaa183/5813081.
Stephen Rubano, PharmD. Candidate, USF Taneja College of Pharmacy