SGLT2 Inhibitors in Acute Heart Failure The Earlier The Better DICTATE AHF

Ileana Piña interviews Zachary Cox, PharmD, about the DICTATE-AHF trial on the initiation of the SGLT2 inhibitor, dapagliflozin, early in acute heart failure decompensation.
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Ileana L. Piña, MD, MPH: Hello, and welcome. I'm Ileana Piña, professor of medicine at Thomas Jefferson University, and the chair of Quality. I am here at the European Society meetings with a large amount of excitement and many new trials that are being presented. That's exactly why we have my friend here, Dr Cox, who comes from Vanderbilt, to talk to us bit about DICTATE-AHF.
If it starts with a D, then we know it's dapagliflozin. Tell me, why did we think a sodium-glucose cotransporter 2 (SGLT2) [inhibitor] would do anything in acute heart failure? We're terrible at acute decompensation. We're awful. Why did you put it together that way?
DICTATE-AHF: Dapagliflozin in Acute Heart Failure
Zachary L. Cox, PharmD: Thank you so much for the opportunity to talk with you. When we looked at the space of acute heart failure, as you just laid out, we know that starting an SGLT2 inhibitor in the ambulatory setting or at hospital discharge and continuing it chronically has widespread benefit across patients, regardless of ejection fraction.
However, what we didn't know was that when starting it acutely on the first day of heart failure hospitalization, (1) does it provide any acute efficacy, and (2) is it safe? There have been concerns that it may not be safe and concerns that there may be increased risk for hypoglycemia or ketoacidosis in an acute hospital setting.
Piña: What mechanism are you targeting? We don't even know why all the benefits of the SGLT2s happen. We know about glucosuric effects, and we know that the curves split apart very quickly. But what's the drug really doing in an acute setting?
Cox: That's a great question because although we don't know all the mechanisms that probably lead to the chronic benefits, for acute efficacy, we looked at the benefits across diuresis, natriuresis, and diuretic response, looking for any additive benefit acutely for a diuretic decongestive outcome and then safety across all the other outcomes.
Piña: Interesting. We're going for the diuretic. What happened? Tell me a little bit more about what patients you recruited.
Cox: We took 240 patients across six hospital sites in the US, randomized them within 24 hours of presenting to the hospital, to either starting dapagliflozin 10 mg daily or structured usual care. Both groups had structural usual care, meaning that their intravenous (IV) diuretic regimen was protocolized and titrated to 3-5 L of urine output a day. We continued that until hospital day 5 or discharge if sooner, with 30-day follow-up for safety events.
Piña: The diuretic that you protocolized could have been bumetanide or furosemide; it didn't matter?
Cox: That's correct. The IV loop diuretic was protocolized as was when the addition of thiazide could happen.
Piña: You followed the DOSE trial protocol - that if it was insufficient, then you could add the hydrochlorothiazide.
Cox: That's exactly right.
Diuretic Efficiency and Safety Findings
Piña: Your goal was not a diuretic, rather your goal was the diuresis however you got there. Tell us the key findings.
Cox: The primary efficacy outcome that we looked at was diuretic efficiency. That's been calculated in many different ways, but we looked at change in weight over the study period, divided by the cumulative loop diuretic dose that was required to get this change in weight, which has been shown in many different cohorts to be prognostically significant. For safety, we had a blinded endpoint committee look at prespecified outcomes across diabetes, worsening renal function, across cardiovascular safety.
Piña: Did you look at things like hyperkalemia or hypokalemia?
Cox: We looked at severe electrolyte deficiencies. We also looked at genitourinary tract infections and really tried to provide the entire spectrum of potential concerns.
Piña: That was a busy safety committee.
Cox: It was. They had many events to look at. We also asked them to look at not only events but severity: Was this a severe event that prolonged hospitalization?
Piña: Tell me what happened.
Cox: We're pleased to say that, first, starting dapagliflozin on the first day was very safe. It did not worsen any cardiovascular endpoints nor worsen hypotension or severity of hypotension. It's also safe across all diabetes endpoints.
Piña: Did it change blood pressure at all? Did it have a vasodilatory affect at all?
Cox: There was no significant difference in mean blood pressure? There was no increased incidence of hypoglycemia or severity of this compared to usual care. There were no new urinary tract infections and no incidence of diabetic ketoacidosis.
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