SGLT2 inhibitor improves CV outcomes in HFrEF patients independent of SBP

Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF)

Literature - Serenelli M, Böhm M, Inzucchi SE, et al. - Eur Heart J, doi: 10.1093/eurheartj/ehaa496.

Introduction and methods

HF patients with reduced ejection fraction (HFrEF) have reduced cardiac output, which can result in lower systolic blood pressure (SBP) and increased risk of adverse events [1-5]. Most beneficial therapies for HFrEF reduce SBP, but HFrEF patients with lower SBP have increased risk of adverse events compared to patients with a higher SBP. Also concerns about hypotension lead to underuse of beneficial medication, which worsen clinical outcomes [6,7]. SGLT2 inhibitors are recommended in diabetes patients with HF and have been shown to reduce the risk of HF hospitalization and lower baseline SBP in T2DM patients by 3-4 mm Hg [8,9].

This subanalysis of the Dapagliflozin and Prevention of Adverse Outcome in Heart Failure (DAPA-HF) trial in HFrEF patients assessed the effect of the SGLT2 inhibitor dapagliflozin on SBP and the efficacy and safety according to baseline SBP.

The DAPA-HF trial was a randomized, double-blind, placebo-controlled, event-driven, trial in HFrEF patients (NYHA Class II to IV, LVEF ≤40%, and NTproBNP ≥600 pg/mL [≥400 pg/mL if hospitalized due to HF in the last 12 months, or ≥900 pg/mL in patients with AF or atrial flutter irrespective of history of HF hospitalization]). Main exclusion criteria included SBP<95 mm Hg or symptoms of hypotension, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m² or rapidly declining kidney function, or T1DM. A total of 4744 patients were randomly assigned to receive, in addition to their standard medication, 10 mg dapagliflozin or placebo daily. The primary outcome was the composite of an episode of worsening HF (urgent visit due to HF or hospitalization) or CV death. In this subanalysis of the DAPA-HF trial, patients were subdivided into four baseline SBP groups: <110 mm Hg (n=1205), ≥110 to <120 mm Hg (n=981), ≥120 to <130 mm Hg (n=1149), and ≥130 mm Hg (n=1409). SBP was measured at 14, 60, 120, 240, and 360 days, and every 4 months thereafter.

Main results

  • Overall, the SBP changes from baseline to the first 8 months treatment with dapagliflozin were 1.92 ± 14.92 mmHg compared to -0.38 ± 15.27 mmHg in the placebo group; the between-treatment difference was -1.41 (95% CI: -2.27 to -0.52, P=0.0002).
  • SBP changes for the lowest SBP category (<110 mm Hg) after 8 months of treatment were -5.28 ± 12.97 mmHg for dapagliflozin and -6.05 ± 13.13 mmHg for placebo (between treatment difference 0.68, 95% CI: -2.27 to 0.91, P=0.40). For the highest SBP category (≥130 mm Hg) SBP changes were -9.03 ± 15.62 mm Hg for dapagliflozin and -7.48 ± 15.20 mm Hg for placebo (between-treatment difference -1.49, 95% CI -3.21 to 0.24, P=0.092). P for interaction across baseline SBP groups and treatment effect on SBP was 0.012.
  • The incidence of the primary outcome was highest in the placebo group with the lowest SBP. The HRs for the effect of dapagliflozin on CV death and HF hospitalization or urgent visit in relation to SBP were 0.76 (95% CI: 0.60-0.97) for those with SBP<110 mm Hg, 0.76 (95% CI:0.57-1.02) for those with SBP ≥110 to <120 mm Hg, 0.81 (95% CI: 0.61-1.08) for patients with SBP ≥120 to <130 mm Hg, and 0.67 (95% CI: 0.51-0.87) for patients with SBP ≥130 mm Hg compared to the corresponding SBP placebo groups (Pinteraction=0.78).
  • Treatment with dapagliflozin resulted in less CV and all-cause deaths, and HF worsening, compared to the corresponding placebo groups, irrespective of SBP (all Pinteraction>0.05).
  • There was a consistent effect of dapagliflozin across all four SBP groups on the composite outcome of first and recurrent HF hospitalization and CV death (Pinteraction=0.99).
  • When analysis was performed with SBP as a continuous variable, the effect of dapagliflozin was consistent across the entire spectrum of SBP for all endpoints compared to placebo.
  • The group of patients receiving dapagliflozin showed, after 8 months, an improvement in KCCQ-TTS, irrespective of SBP baseline (Pinteraction=0.06).
  • Dapagliflozin was well tolerated in the <110 mm Hg SBP group compared to the other SBP groups. Discontinuation of the treatment occurred in 13.4% of these patients compared to 12.1% of patients treated with a placebo (across all SBP categories: Pinteraction=0.34). There was a difference in treatment effect with dapagliflozin on adverse renal events across SBP subgroups, with more renal adverse events with dapagliflozin than placebo in those with SBP ≥130 mmHg (Pinteraction=0.015). Serious renal events however, occurred less with dapagliflozin compared to placebo across all four SBP groups (Pinteraction=0.23).


HFrEF patients in the DAPA-HF trial receiving 10 mg of dapagliflozin daily showed improved CV outcome compared to the placebo group, independent of SBP.


1. Rouleau JL, Roecker EB, Tendera M, et al. Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study. J Am Coll Cardiol 2004;43:1423–1429.

2. Anand IS, Rector TS, Kuskowski M, et al. Effect of baseline and changes in systolic blood pressure over time on the effectiveness of valsartan in the Valsartan Heart Failure Trial. Circ Heart Fail 2008;1:34–42

3. Meredith PA, Östergren J, Anand I, et al. Clinical outcomes according to baseline blood pressure in patients with a low ejection fraction in the CHARM (Candesartan in Heart failure: assessment of Reduction in Mortality and morbidity) program. J Am Coll Cardiol 2008;52:2000–2007.

4. Bohm M, Young R, Jhund PS, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J 2017;38:1132–1143.

5. Williams B, Mancia G, Spiering W, et al. ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021–3104.

6. Peri-Okonny PA, Mi X, Khariton Y, et al. Target doses of heart failure medical therapy and blood pressure: insights from the CHAMP-HF registry. JACC Heart Fail 2019;7:350–358.

7. Bozkurt B. Response to Ryan and Parwani: Heart failure patients with low blood pressure: how should we manage neurohormonal blocking drugs. Circ Hear Fail 2012;5:820–821.

8. Cosentino F, Grant PJ, Aboyans V, et al. ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255–323.

9. Yuliya L, Petter B, Udell JA, et al. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation 2017;136:1643-1658.

Find this article online at Eur Heart J.

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free