Dapagliflozin Halves Hyperkalemia in Some HF Patients

Mitchel L. Zoler, PhD

October 29, 2020

For patients with heart failure with reduced ejection fraction (HFrEF), the addition of dapagliflozin (Farxiga) to a mineralocorticoid receptor antagonist (MRA) halved the incidence of moderate to severe hyperkalemia, a prespecified analysis of DAPA-HF data shows.

Dapagliflozin "attenuates the risk of moderate to severe hyperkalemia in MRA-treated patients with HFrEF," said Søren Lund Kristensen, MD, from the University of Glasgow, United Kingdom.

MRAs are a "foundational drug" for patients with HFrEF, but they are "unfortunately underutilized, especially in North America, and fear of hyperkalemia is the major concern. Any approach that minimizes the risk related to MRAs is attractive and may facilitate the use of this life-saving therapy," he told Medscape Medical News.

Data showing a link between the sodium glucose cotransporter 2 (SGLT2) inhibitor and a decrease in MRA-induced hyperkalemia — believed to be first evidence of such an association — were presented by Kristensen at Kidney Week 2020.

The 4744 DAPA-HF participants were randomly assigned to guideline-directed therapy with dapagliflozin or placebo. During a median follow-up of 18.2 months, there was a significant 26% reduction in the primary end point — worsening heart failure or cardiovascular death in patients with chronic heart failure with reduced ejection fraction — as reported last year in the New England Journal of Medicine.

Reassurance About Safety

At baseline, roughly 70% of the study participants were receiving treatment with an MRA, either spironolactone or eplerenone. This class of agents is known to potentially cause an elevation in serum potassium levels.

In that subgroup, the cumulative incidence of moderate to severe hyperkalemia, defined as a potassium level above 6.0 mmol/L, was lower in the dapagliflozin group than in the placebo group (1.0 vs 1.7 episodes per 100 patient-years). And the reduction in the incidence was significant in the dapagliflozin group (hazard ratio [HR], 0.50; P = .01).

For mild hyperkalemia — defined as a potassium level above 5.5 mmol/L — the incidence was not significantly different between the dapagliflozin and placebo groups (HR, 0.86; P = .14).

For DAPA-HF participants who were not receiving an MRA at baseline, there was no significant association between dapagliflozin and hyperkalemia.

"These are important data. They won't change practice, because we would use an SGLT2 inhibitor and an MRA in appropriate patients anyway, but it gives reassurance" about the safety of this combination, said Justin Ezekowitz, MBBCh, from the University of Alberta in Edmonton, Canada.

"The limitation of an analysis like this is that the study included patients at lower risk than many patients in general heart failure clinics, recently hospitalized patients, and patients with lower levels of estimated glomerular filtration rates [eGFRs]," Ezekowitz told Medscape Medical News. DAPA-HF participants had an average eGFR of about 66 mL/min per 1.73 m², and more than 40% had an eGFR below 60 mL/min per 1.73 m².

Mechanism of Action Unclear

The finding left both Kristensen and Ezekowitz uncertain about the possible mechanism of the effect.

SGLT2 inhibitors dampen glucose reabsorption in the proximal nephron, but preserve sodium–potassium exchange in the distal nephron, Kristensen explained. In addition, their slowing of the progressive decline in eGFR, causing mild diuresis, and their modest blood pressure effects should help "preserve kidney function and potassium homeostasis," he said.

This decrease in the incidence of hyperkalemia episodes is similar to that seen in PARADIGM-HF participants who were treated with an MRA plus the combination of sacubitril and valsartan (Entresto), an angiotensin receptor neprilysin inhibitor (ARNI) used for the treatment of HFrEF. In that analysis, the rate of more severe hyperkalemia was 37% higher in patients who received enalapril, an ACE inhibitor, than in those who received the ARNI combination.

The PARADIGM-HF finding is "puzzling," said Kristensen, because the ARNI combination suppresses aldosterone, an action that would be expected to raise potassium levels.

Hyperkalemia is known to be associated with ACE inhibitors, so finding that the sacubitril and valsartan combination has "a much lower risk helped clinicians switch" to this new option, said Ezekowitz.

It's not clear whether the mechanisms of dapagliflozin are the same as those of the ARNI combination, but "I would be surprised if they were," he added.

Kristensen agreed. ARNIs and SGLT2 inhibitors both help preserve kidney function, so this might be a shared mechanism, but the other ways by which dapagliflozin might reduce MRA-induced severe hypokalemia are likely not shared with the sacubitril and valsartan combination, he said.

DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin. PARADIGM-HF was sponsored by Novartis, the company that markets the sacubitril and valsartan combination. Glasgow University has received payments from AstraZeneca for work on the DAPA-HF trial performed by its staff. Kristensen has disclosed no relevant financial relationships.. Ezekowitz reports receiving consulting fees and research grants from Amgen, American Regent, Applied Therapeutics, Bayer, Cytokinetics, Merck, Novartis, Sanofi, and Servier.

Kidney Week 2020: American Society of Nephrology Annual Meeting: Abstract FR OR191. Presented October 23, 2020.

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