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The DAPA-HF trial has already changed cardiology in opening up a new class of drugs to patients with heart failure (HF), whether or not they have diabetes. Now the trial is yielding clues as to how it benefits them. For now, it's doing so by process of elimination.

A new analysis suggests that dapagliflozin (Farxiga, AstraZeneca) didn't need help from loop diuretics to cut the risk for clinical events in patients with HF with reduced ejection fraction (HFrEF), a benefit seen across the spectrum of glycosylated hemoglobin levels and without compromising renal function, say DAPA-HF investigators.

Also, use of dapagliflozin and its clinical effects were not associated with changes in loop diuretic dosage.

Those findings and others suggest the drug helps in HFrEF at least partly by some other mechanism than its own diuretic effect, the researchers say.

Such insights will likely be important to case-by-case decisions on whether to use the drug, a sodium-glucose cotransporter 2 (SGLT2) inhibitor once reserved for patients with diabetes, given the recently broader landscape of HF treatment options.

As previously reported from DAPA-HF, with more than 4700 patients, those who received dapagliflozin showed significant reductions in the primary end point, a composite of cardiovascular (CV) death, HF hospitalization, and urgent HF visit requiring IV therapy over about 18 months. The 45% of patients with and 55% without type 2 diabetes enjoyed about equal benefit in the placebo-controlled trial for that end point, as well as for all-cause mortality.

SGLT2 inhibitors work in diabetes by promoting urinary glucose excretion. That had led some to speculate that its benefit in HFrEF comes primarily from a diuretic effect; the current findings largely put that question to rest.

"Our findings show that treatment with dapagliflozin was effective regardless of diuretic use or diuretic dose. They also show that dapagliflozin did not lead to an increase in renal adverse events or discontinuation of therapy in patients treated with a diuretic," trialist Alice M. Jackson, MB, ChB, told theheart.org | Medscape Cardiology.

"In fact, renal adverse events were generally less common in patients treated with dapagliflozin, across the diuretic categories," said Jackson, from the University of Glasgow, United Kingdom.

Jackson presented the new analysis June 5 at a Late-Breaking Science Session during HFA Discoveries, the online substitute for the annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology. The HFA sessions were conducted virtually this year due to the COVID-19 pandemic.

At baseline, 84% of patients were on conventional diuretics. The post hoc analysis broke out all patients by loop-diuretic dosage level: none; less than 40 mg furosemide equivalents (FE); 40 mg FE; or more than 40 mg FE. Clinical outcomes were similar across the four groups.

The DAPA-HF trial has already changed cardiology in opening up a new class of drugs to patients with heart failure (HF), whether or not they have diabetes. Now the trial is yielding clues as to how it benefits them. For now, it's doing so by process of elimination.

A new analysis suggests that dapagliflozin (Farxiga, AstraZeneca) didn't need help from loop diuretics to cut the risk for clinical events in patients with HF with reduced ejection fraction (HFrEF), a benefit seen across the spectrum of glycosylated hemoglobin levels and without compromising renal function, say DAPA-HF investigators.

Also, use of dapagliflozin and its clinical effects were not associated with changes in loop diuretic dosage.

Those findings and others suggest the drug helps in HFrEF at least partly by some other mechanism than its own diuretic effect, the researchers say.

Such insights will likely be important to case-by-case decisions on whether to use the drug, a sodium-glucose cotransporter 2 (SGLT2) inhibitor once reserved for patients with diabetes, given the recently broader landscape of HF treatment options.

As previously reported from DAPA-HF, with more than 4700 patients, those who received dapagliflozin showed significant reductions in the primary end point, a composite of cardiovascular (CV) death, HF hospitalization, and urgent HF visit requiring IV therapy over about 18 months. The 45% of patients with and 55% without type 2 diabetes enjoyed about equal benefit in the placebo-controlled trial for that end point, as well as for all-cause mortality.

SGLT2 inhibitors work in diabetes by promoting urinary glucose excretion. That had led some to speculate that its benefit in HFrEF comes primarily from a diuretic effect; the current findings largely put that question to rest.

"Our findings show that treatment with dapagliflozin was effective regardless of diuretic use or diuretic dose. They also show that dapagliflozin did not lead to an increase in renal adverse events or discontinuation of therapy in patients treated with a diuretic," trialist Alice M. Jackson, MB, ChB, told theheart.org | Medscape Cardiology.

"In fact, renal adverse events were generally less common in patients treated with dapagliflozin, across the diuretic categories," said Jackson, from the University of Glasgow, United Kingdom.

Jackson presented the new analysis June 5 at a Late-Breaking Science Session during HFA Discoveries, the online substitute for the annual scientific meeting of the Heart Failure Association (HFA) of the European Society of Cardiology. The HFA sessions were conducted virtually this year due to the COVID-19 pandemic.

At baseline, 84% of patients were on conventional diuretics. The post hoc analysis broke out all patients by loop-diuretic dosage level: none; less than 40 mg furosemide equivalents (FE); 40 mg FE; or more than 40 mg FE. Clinical outcomes were similar across the four groups.

  • 0.57 (0.36–0.92) for patients not on diuretics
  • 0.78 (0.68–0.90) for patients on any diuretic dosage
  • 0.74 (0.65–0.85) overall

Patients on diuretics, Jackson said during her formal online presentation, showed a "tendency toward slightly more volume depletion in those on dapagliflozin than in those on placebo, but the excess was small and not greater than approximately 3% in those taking 40 mg furosemide equivalent diuretic. And fortunately, this did not result in an increase in frequency in renal adverse events nor of discontinuation of study drug."

Rate of Volume Depletion* by Diuretic Group and Treatment Group in DAPA-HF
Diuretic CategoryPlacebo (%)Dapagliflozin (%)
No diuretic 8.5 4.3
<40 mg FE 5.3 5.5
40 mg FE 4.9 8.0
>40 mg FE 8.9 10.5
*interaction P = .012

Renal adverse events were similarly prevalent in the two treatment groups, as were such events leading to treatment discontinuation. But serious renal events were less common in the dapagliflozin group (1.6% vs 2.7%; P = .009), as was investigator-reported serious acute kidney injury (1.0% vs 1.9%; P = .007).

"Overall, renal events were infrequent," Jackson said, and "because of the small number of events, it is very difficult to draw conclusions about the impact of dapagliflozin on renal function according to diuretic-dose subgroups."

Still, she said, worsening renal function was less common on dapagliflozin in three of the four groups by diuretic dosage; the exception was the less than 40 mg FE group, "but the absolute difference in this group was only two events."

There seem to be dapagliflozin mechanisms "underneath the surface that need to be unraveled," Doehner said as discussant, processes that are favorable for the treatment of HFrEF in which "diuretics play no big role."

HFA Discoveries 2020 from the Heart Failure Association (HFA) of the European Society of Cardiology. Presented June 5, 2020.

From www.medscape.com

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