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Importance: Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes.
Objective: To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes.
Design, Setting, and Participants: Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019.
Interventions: Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy.
Main Outcomes and Measures: The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%.
Results: Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes.
Conclusions and Relevance: In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status.
Trial Registration: ClinicalTrials.gov Identifier: NCT03036124.
|Family Medicine (FM)/General Practice (GP)|
|General Internal Medicine-Primary Care(US)|
How many agents with differing mechanisms can we give to our patients with heart failure? Will adverse interactions become apparent when it is too late? Can pharmaceutical trials ever have negative results after all the money put into them? Are we bad doctors if we do not prescribe all of them? Have we forgotten that the beta-blockers are the only agents that have improved ejection fraction and should be the first agents considered after making our patients euvolemic?
Provocative results from an RCT subgroup analyses suggesting that SGLPT2i can be helpful in HFrEF regardless of diabetes status. While some analyses were pre-specified, others were post-hoc. So, although caution is needed in interpreting these results, they are consistent with other recent studies suggesting CV and renal benefits from this drug class.
Interesting study. Needs further studies to put into practice.
Excellent study that highlights the impact of a novel treatment for heart failure. The outcomes for this group are clearly relevant to a broad audience and have the potential to be practice-changing. Importantly, most patients were already on guideline-driven therapy, so the study wasn`t treating under-treated patients.
I'm not sure this adds that much to the previously published results.
This is an interesting and potentially promising intervention based on a post hoc analysis of dapagliflozin in worsening heart failure and cardiovascular death among patients with heart failure, with and without diabetes.
This is most definitely right in center court for primary care physicians.