Reversal of beneficial CV effects of SGLT2i in HF after short withdrawal period

Blinded withdrawal of long-term randomized treatment with empagliflozin or placebo in patients with heart failure

News - Aug. 27, 2023

Presented at the ESC Congress 2023 by: Milton Packer, MD - Dallas, TX, USA

Introduction and methods

It is usually recommended that the foundational HF medications need to be taken indefinitely by patients who can tolerate these medications. However, it has never been studied whether these drugs are still effective after many years.

After the EMPEROR-Reduced and EMPEROR-Preserved trials, a protocol-mandated, blinded withdrawal of randomized study medication was performed at the end of the planned double-blind therapy. A total of 6799 patients were prospectively withdrawn from treatment. Of these patients, 3981 patients completed a 30 day withdrawal period with in-person off-treatment assessment (n=1961 in the empagliflozin group, and n=2020 in the placebo group). The primary endpoint was the composite of CV death or HF hospitalization.

Main results

  • After a 30-day withdrawal period with empagliflozin, there was an increased risk of CV death or HF hospitalization compared with 90 days prior to withdrawal (HR before withdrawal vs. after withdrawal of empagliflozin: 1.75; 95%CI: 1.20-2.64), whereas withdrawal of placebo had no effect on the composite outcomes (HR: 1.12; 95%CI: 0.76-1.66). (Time period by treatment interaction: p=0.068).
  • 90 days prior to withdrawal, empagliflozin reduced the risk of CV death or HF hospitalization compared with placebo (HR: 0.76; 95%CI: 0.60-0.96). After treatment withdrawal, there was an increase in these events in the empagliflozin group compared with the placebo group (HR: 1.18; 95%CI: 0.78-1.80).
  • Withdrawal of empagliflozin led to a decline in the placebo-corrected adjusted mean (±SE) KCCQ-CSS score of -1.6±0.4 (P<0.001) compared with withdrawal of placebo. In comparison, empagliflozin led to a +1.3±0.4 increase in KCCQ-CSS in the first 12 weeks of treatment. Together, this suggests a reversal of the beneficial effect on KCCQ-CSS that was seen in the first 12 weeks of treatment of approximately the same magnitude after treatment withdrawal. .
  • Withdrawal of empagliflozin increased the fasting blood glucose levels (+4.0±1.3; P<0.01), body weight (+0.5±0.1; P<0.001), serum uric acid levels (+0.6±0.0; P<0.001), serum bicarbonate (+0.3±0.1; P<0.001), eGFR (+2.7±0.3; P<0.001), systolic blood pressure (+2.3±0.5; P<0.001), and NT-proBNP (+1.07[95%CI:1.03-1.11]; P<0.001) compared with withdrawal of placebo. These changes were the inverses as was seen in the first 4 weeks of the trial 1-3 years earlier.


Withdrawal of empagliflozin in patients with HFrEF or HFpEF increased the risk of CV death or HF hospitalization. “Regardless of the mechanisms, our findings indicate that tolerance does not develop during long-term treatment with empagliflozin in patients with heart failure and, very importantly, that cessation of treatment even for short periods of time may have deleterious clinical consequences.”, according to Milton Packer.

- Our reporting is based on the information provided at the ESC Congress 2023 -

The results of this study were simultaneously published in Circulation Watch a video with Milton Packer on this study

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