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Dapagliflozin's Heart Failure Benefits Consistent, Regardless of Iron Status at Baseline

An analysis of DAPA-HF provides insight into the effects of dapagliflozin use on the trial's primary outcome based on iron status at baseline and also sheds light on the impact of dapagliflozin use on iron status at 12 months.

New data from an analysis of the DAPA-HF trial suggests the effects of dapagliflozin (Farxiga) on heart failure outcomes were consistent, irrespective of iron status at baseline, but also suggest dapagliflozin use could influence iron levels in patients with iron deficiency.

Conducted on behalf of the DAPA-HF investigators and committees, results of the study demonstrate was greater among those with iron deficiency, but dapagliflozin provided a consistent reduction in the study’s primary outcome, regardless of iron status at baseline. Results also indicate use of dapagliflozin was associated with reductions in transferrin saturation and ferritin as well as increases in total iron-binding capacity and soluble transferrin receptor.

“The prevalence and incidence of iron deficiency were high among patients with HFrEF in DAPA-HF, and participants with iron deficiency had worse outcomes than those who were iron-replete. Dapagliflozin appeared to increase iron use but improved outcomes, irrespective of iron status at baseline,” wrote investigators.

The first trial examining use of an SGLT2 inhibitor for heart failure in patients with and without diabetes, the presentation of the original results of DAPA-HF at the European Society of Cardiology 2019 annual congress was a landmark moment for heart failure management, and medicine as a whole. Results of the trial, which randomized 4744 patients and had a median follow-up of 18.2 months, indicated the primary composite outcome occurred in 16.3% in the dapagliflozin group and in 21.2% in the placebo group (HR, 0.74 [95% CI 0.65-0.85]; P<0.00001).

In the present study, investigators sought to assess how baseline iron status might influence risk of outcomes and the effects of dapagliflozin. Of the 4744 patients randomized in the DAPA-HF trial, 3009 had ferritin and transferrin saturation measurements. Among those with available measurements, 43.7% (n=1314). For the purpose of analysis, investigators defined iron deficiency as a ferritin level less than 100 ng/mL or a transferrin saturation below 20% and a ferritin level 100-299 ng/mL. Investigators also pointed out additional biomarkers of iron metabolism were measured at baseline and 12 months after randomization.

Upon analysis, results indicated the rate of the primary composite outcome was 16.6 per 100 person-years among those with iron deficiency and 10.4 per 100 person-years among those without iron deficiency (P <.0001). Further analysis demonstrate the effects of dapagliflozin was consistent among those with iron deficiency and those without iron deficiency ((HR, 0.74 [95% CI, 0.58-0.92] vs HR, 0.81 [95% CI, 0.63-1.03]; P for interaction=.59), with similar results observed in subanalyses assessing individual components of the primary outcome.

Analysis of iron markers indicated reductions in transferrin saturation, ferritin, and hepcidin, along with an increase in total iron-binding capacity and soluble transferrin receptor in the dapagliflozin group compared with placebo. Using the ferritin and transferrin saturation criteria, investigators found the OR for developing iron deficiency by 12 months with dapagliflozin use compared to placebo therapy was 1.74 (95% CI, 1.34-2.25; P <.001).

“The presence of iron deficiency should not be considered a barrier to the use of dapagliflozin in patients with heart failure and reduced ejection fraction,” investigators noted, when explaining the clinical implications of the present study. “Regular monitoring of iron status should be performed in patients with heart failure and reduced ejection fraction, and guideline recommendations followed with regards to intravenous iron replacement when indicated.”

This study, “Iron Deficiency in Heart Failure and Effect of Dapagliflozin: Findings From DAPA-HF,” was published in Circulation.