Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes

Key Points

Question  Is the effect of dapagliflozin in patients with heart failure and reduced ejection fraction consistent in patients with and without type 2 diabetes mellitus?

Findings  In this exploratory analysis of a randomized clinical trial that included 4744 patients, dapagliflozin, compared with placebo, added to recommended therapy significantly reduced the risk of the primary composite outcome of a first episode of worsening heart failure (hospitalization for heart failure or an urgent heart failure visit requiring intravenous therapy) or cardiovascular death in patients with diabetes (hazard ratio, 0.75) and in patients without diabetes (hazard ratio, 0.73). In patients without diabetes, the hazard ratio was 0.74 in individuals with a glycated hemoglobin of at least 5.7% and the hazard ratio was 0.67 in those with a glycated hemoglobin less than 5.7%.

Meaning  Dapagliflozin was effective at reducing cardiovascular morbidity and mortality in patients with heart failure and reduced ejection fraction independent of diabetes status.

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

Quiz Ref IDInhibitors of the sodium-glucose cotransporter 2 (SGLT2), initially developed as a treatment for individuals with type 2 diabetes, prevent reabsorption of filtered glucose and lower blood glucose levels by increasing urinary excretion.^1-3 In trials of participants with type 2 diabetes, these drugs led to a reduction in incident heart failure, which occurred early after randomization and appeared to be independent of baseline and time-dependent changes in glycated hemoglobin, suggesting this benefit may not necessarily be due to glucose lowering and might also be found in individuals without diabetes.^4-8 In parallel, experimental evidence emerged suggesting that SGLT2 inhibitors may have cardioprotective actions independent of blood glucose level.^9-11Quiz Ref ID The Dapagliflozin And Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial included patients with heart failure and reduced ejection fraction with and without type 2 diabetes. Dapagliflozin reduced the risk of worsening heart failure events and cardiovascular death and improved symptoms.^12,13 The key question arising from the DAPA-HF trial is how the effects of dapagliflozin compared in patients with and without diabetes, and whether the findings of this trial support the hypothesis that SGLT2 inhibition might be an effective treatment for patients with heart failure, including those without diabetes. In this exploratory analysis, the efficacy of dapagliflozin, along with metabolic and hemodynamic changes and adverse events, were analyzed in patients with heart failure with reduced ejection fraction with and without diabetes and across the range of baseline glycated hemoglobin levels in DAPA-HF.

The design and conduct of this double-blind, randomized, placebo-controlled trial are published and the protocol and statistical analysis plan (SAP) are available in Supplement 1 and Supplement 2.^12,13 The trial was approved by the ethics committee at each study site and all patients provided written informed consent. The trial was reviewed by an independent data monitoring committee.^12,13

Adults aged at least 18 years with New York Heart Association (NYHA) class II, III, or IV symptoms; an ejection fraction of 40% or less; and an elevated level of plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) were eligible for inclusion.^12,13 Patients were required to receive standard drug and device therapy for heart failure. The aim of the study was to enroll patients with heart failure and reduced ejection fraction. Individuals with type 2 diabetes were to continue to receive their glucose-lowering treatments, but these could be adjusted as required.

Exclusion criteria included recent treatment with or intolerance of an SGLT2 inhibitor, symptoms of hypotension or a systolic blood pressure of less than 95 mm Hg, type 1 diabetes mellitus, and an estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m² of body surface area (or rapidly declining kidney function).^12,13 Race and ethnicity were recorded in this study based on US Food and Drug Administration recommendations and investigators were asked to report participants’ race and ethnicity according to the categories in this guidance.^14,15

Investigators recorded whether patients had a history of diabetes at the enrollment visit (visit 1). Patients also underwent measurement of their glycated hemoglobin level in a central laboratory at visit 1 and again at the randomization visit (visit 2), which occurred 14 (±7) days later. For this prespecified subgroup analysis, patients were categorized as having diabetes if they had a history of diabetes or their glycated hemoglobin was at least 6.5% (≥48 mmol/mol) at visits 1 and 2. Patients with a glycated hemoglobin level less than 5.7% (<39 mmol/mL) at visits 1 and 2 were considered to have a normal glycated hemoglobin. For the purposes of this trial, patients with a glycated hemoglobin of at least 5.7% and less than 6.5% were considered to have prediabetes.^12,13

Patients were randomized to receive 10 mg of dapagliflozin once daily or matching placebo, in accordance with the sequestered fixed randomization schedule, using balanced blocks to ensure an approximate 1:1 ratio of the 2 treatments (Figure 1).^12,13 The randomization codes were generated in blocks of 4 using a computer-generated random number generator. The blocks were not revealed to the investigators and randomization was performed via an interactive voice/web response system. Randomization was stratified based on a diagnosis of type 2 diabetes or a glycated hemoglobin level of at least 6.5% (≥48 mmol/mol) at the enrollment visit (visit 1).

Patients were evaluated 14 and 60 days after randomization, with additional study visits at 4 months and at 4-month intervals thereafter. The full schedule of assessments is provided in the protocol (Supplement 1). Dose reduction (to 5 mg daily of dapagliflozin or matching placebo) or temporary discontinuation was permitted in the instance of any episode of an acute, unexpected decline in eGFR; volume depletion; or hypotension (or to avoid these), with a subsequent increase in dose (or restarting treatment) advised if possible.

The primary outcome for the trial was the composite of a first episode of worsening heart failure or cardiovascular death. An episode of worsening heart failure was defined as an unplanned hospital admission because of worsening heart failure or an urgent hospital visit requiring treatment for worsening heart failure with intravenous therapy.¹⁶ The first of the secondary outcomes was the composite of hospital admission for worsening heart failure or cardiovascular death. The additional secondary outcomes were the total number of hospital admissions for heart failure (including repeat admissions) and cardiovascular deaths; change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score (range, 0-100; higher scores indicate fewer symptoms; ≥5-point change considered clinically meaningful)¹⁷; the incidence of a composite worsening kidney function outcome, consisting of a 50% or greater sustained (ie, ≥28 days) decline in eGFR, kidney failure (defined as a sustained [ie, ≥28 days] eGFR <15 mL/min/1.73m², sustained dialysis treatment, or kidney transplant) or kidney-related death; and death from any cause.^12,13 The clinical outcomes described were adjudicated by a blinded end point committee.¹⁶

Diabetes status at baseline was one of the prespecified exploratory analysis subgroups. The SAP stated that the primary outcome, the cardiovascular death component of this composite, and the first secondary outcome would be analyzed in the prespecified subgroups (Supplement 2). The SAP also stated that outcomes would be analyzed among patients without diabetes according to whether their glycated hemoglobin level was less than 5.7% (normal) or greater than or equal to 5.7% (prediabetes). Analysis of the change from baseline to each visit for glycated hemoglobin, eGFR, body weight, and blood pressure were prespecified exploratory outcomes.

We conducted additional, post hoc analyses of outcomes according to glycated hemoglobin levels, examining this as a categorical variable (tertiles) in patients without diabetes and a continuous variable in all patients. We also conducted a post hoc analysis of change in hematocrit.

The prespecified analyses of adverse events included serious adverse events, adverse events associated with discontinuation of study treatment, adverse events of interest (ie, volume depletion, kidney events, major hypoglycemia, bone fractures, diabetic ketoacidosis, amputations), and laboratory findings of note. Other adverse events were not routinely collected in view of the extensive prior reporting of these adverse events for dapagliflozin. Doubling of serum creatinine was a prespecified exploratory end point.

The statistical assumptions underlying DAPA-HF are published and the SAP is available in Supplement 2.^12,13 Data from all randomized patients were included in this intention-to-treat analysis of the primary and secondary outcomes. Baseline characteristics were summarized as means and SDs, medians and interquartile ranges (IQRs), or percentages.

Patients without diabetes were divided into 2 categories based on their baseline glycated hemoglobin level: less than 5.7% (normal) or greater than or equal to 5.7% (prediabetes). In a post hoc analysis, patients without diabetes were also divided into 3 groups by tertile of glycated hemoglobin at baseline: less than or equal to 5.6%, 5.7% to 5.9%, and greater than or equal to 6.0%. The effect of treatment according to continuous glycated hemoglobin as a fractional polynomial was examined in an additional post hoc analysis.

Longitudinal measures, such as glycated hemoglobin level and body weight, were analyzed using a mixed model for repeated measurements (adjusted for baseline values, visit, randomized treatment, and interaction of treatment and visit with a random intercept and slope per patient). The least squares mean differences between treatment groups were estimated with 95% CIs and plotted for each group. The same approach was used in the post hoc analysis of hematocrit.

Time-to-event data were evaluated using Kaplan-Meier estimates and Cox proportional hazards models as prespecified in the SAP (Supplement 2). In a post hoc sensitivity analysis, we included trial site as an explanatory variable in the Cox models. The proportionality assumption was tested by Schoenfeld residuals and was met (P > .05 for all outcomes). Effect modification of treatment effect by baseline diabetes status was assessed by a likelihood ratio test. Total events (including repeat hospital admissions) were analyzed using a semiparametric proportional rates model to test the treatment effect and to quantify the treatment difference.¹⁸

The KCCQ total symptom score was analyzed as a composite rank-based end point, incorporating patient vital status (dead or alive) at 8 months and change in score from baseline to 8 months in patients who were alive, using the rank analysis of covariance method, with a corresponding win ratio used to estimate the magnitude of treatment effect (additional details are available in the SAP in Supplement 2).¹⁹ Adverse events were analyzed in patients who were randomized and received at least 1 dose of dapagliflozin or placebo and compared using a Fisher exact test.

These exploratory analyses were performed using Stata, version 15 (StataCorp), and SAS, version 9.4 (SAS Institute). All P values provided are 2-sided, and P <.05 was considered nominally statistically significant.

Of the 4744 patients included, 2605 (55%) did not have diabetes. Of the remaining 2139 patients, 1983 (92.7%) had a history of diabetes at screening and an additional 156 (7.3%) were found to have previously undiagnosed diabetes (ie, a glycated hemoglobin ≥6.5% at visit 1 [enrollment] and visit 2 [randomization]). Of the 2605 patients without diabetes, 1748 (67.1%) had a glycated hemoglobin level of at least 5.7% at visit 1 or visit 2 and 839 (32.2%) had a glycated hemoglobin level less than 5.7% at both visit 1 and visit 2. In addition, 12 patients had only a single glycated hemoglobin measurement of less than 5.7% and 6 patients were missing both baseline glycated hemoglobin measurements (these 18 patients were included in the normal glycated hemoglobin group).

The baseline characteristics of patients with and without diabetes were well balanced between patients assigned to receive dapagliflozin or placebo within each patient group (Table 1). Patients without diabetes were significantly less likely to be black and to have an ischemic etiology than participants with diabetes (Table 1). Mean body mass index, heart rate, systolic blood pressure, and NT-proBNP level were significantly lower in participants without diabetes compared with those with diabetes. Mean eGFR was significantly higher in participants without diabetes compared with those with diabetes. The mean glycated hemoglobin level in patients without diabetes was 5.8%, compared with 7.4% in those with diabetes. The median (IQR) duration of diabetes was 7.41 (2.73-13.5) years.

At baseline, median (IQR) KCCQ total symptom scores were significantly higher (indicating better health) in patients without diabetes than in those with diabetes (79.2 [61.5-91.7] vs 75.0 [56.3-91.7]; P < .001; Table 2). A total of 1995 patients (93.3%) with diabetes and 2447 (93.9%) without diabetes took a renin-angiotensin system blocker and 1529 patients (71.5%) with diabetes and 1841 (70.7%) without diabetes took a mineralocorticoid receptor antagonist.

Patients without diabetes had a lower rate of the prespecified primary end point, the composite of a first episode of worsening heart failure or cardiovascular death, than patients with diabetes (eg, 17.7% vs 25.5% in the placebo groups) (Table 2, Figure 2, and Figure3A). Among participants without diabetes, the rate of the primary end point was lower in those with a baseline glycated hemoglobin less than 5.7% than in those with a level greater than or equal to 5.7% (eg, 16.9% vs 18.0% in the placebo groups) (Figure 3A). In contrast, the overall change in the KCCQ total symptom score did not differ significantly: increase of 3.1 (95% CI, 2.1-4.2) from baseline to 8 months in the placebo group in participants without diabetes compared with 3.5 (95% CI, 2.1-4.9) in those with diabetes (Table 2).

The effects of dapagliflozin on the primary composite outcome, each of the individual mortality and hospital admission outcomes, and on urgent visits for worsening heart failure requiring intravenous treatment are shown in Table 2 and eFigure 1 in Supplement 3. The primary composite outcome occurred in 171 of 1298 patients (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]) among patients without diabetes and in 215 of 1075 patients (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group among patients with diabetes (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80; Table 2). The effect of dapagliflozin on all other outcomes did not differ significantly between patients with and without diabetes, as was the case for the kidney composite outcome (which was not improved significantly by dapagliflozin overall). In post hoc sensitivity analyses, adjusting for trial site gave similar results (eTable in Supplement 3).

Among patients without diabetes at baseline, the numbers of patients with the primary end point were 118 (13.7%) in the dapagliflozin group and 160 (18.0%) in the placebo group among those with a glycated hemoglobin of at least 5.7% (hazard ratio, 0.74 [95% CI, 0.59-0.94]) and 53 (12.1%) in the dapagliflozin group and 71 (16.9%) in the placebo group among patients with a glycated hemoglobin less than 5.7% (hazard ratio, 0.67 [95% CI, 0.47-0.96]) (P value for interaction = .72; Figure 3A). A post hoc analysis of patients without diabetes divided into 3 groups by baseline glycated hemoglobin is shown in eFigure 2 in Supplement 3. An additional post hoc analysis that used glycated hemoglobin as a continuous measure demonstrated benefit of dapagliflozin across the range of levels (P value for interaction for the primary end point = .97; Figure 3B). Cardiovascular death and all-cause death outcomes can be found in eFigure 3 in Supplement 3.

Between baseline and 8 months, the mean KCCQ total symptom score increased by 2.2 (95% CI, 0.7-3.7) points more in the dapagliflozin group than in the placebo group in patients without diabetes and by 3.5 (95% CI, 1.6-5.4) points more in patients with diabetes (P value for interaction = .18; Table 2).

In individuals without diabetes, significantly more patients in the dapagliflozin group than in the placebo group reported an increase of at least 5 points (the minimally important difference) in the KCCQ total symptom score (57.7% vs 51.7%; odds ratio, 1.12 [95% CI, 1.03-1.22]; P < .01) and significantly fewer reported a decrease of at least 5 points (26.0% vs 31.3%; odds ratio, 0.88 [95% CI, 0.81-0.97]; P < .01). In individuals with diabetes, significantly more patients in the dapagliflozin group than in the placebo group also reported an increase of at least 5 points (58.9% vs 49.9%; odds ratio, 1.20 [95% CI, 1.09-1.31]; P < .001) and significantly fewer reported a decrease of at least 5 points (24.5% vs 34.8%; odds ratio, 0.78 [95% CI, 0.71-0.87]; P < .001) (P value for interaction for improvement = .294; P value for interaction for deterioration = .075).

Changes in laboratory measures, weight and blood pressure, and hematocrit, adjusting for baseline value, are shown in Figure 4, Figure 5, and Figure 6 and eFigure 4 in Supplement 3. The placebo-corrected change in glycated hemoglobin between baseline and 4 months in patients without diabetes was 0.003% (95% CI, −0.022 to 0.028), compared with −0.261% (95% CI, −0.354 to −0.169) in patients with diabetes, with a significant interaction between diabetes status at baseline and the effect of dapagliflozin, compared with placebo, on glycated hemoglobin over the duration of the trial (P value for interaction <.001) (Figure 4A). There was an initial decrease in eGFR with dapagliflozin in both groups, although the between-treatment difference had attenuated by 4 months (placebo-corrected change in participants without diabetes, −1.9 mL/min/1.73m² [95% CI, −2.6 to −1.2]; participants with diabetes, −2.4 mL/min/1.73m² [95% CI, −3.3 to −1.6]), with no interaction between diabetes status and the effect of dapagliflozin (Figure 4B).

Weight declined in both patient groups (eg, placebo-corrected decrease in those without diabetes, −0.7 kg [95% CI, −0.9 to −0.4] at 4 months vs −0.8 kg [95% CI. −1.1 to −0.5] in those with diabetes), but there was no interaction between diabetes status and the effect of dapagliflozin (Figure 5A). Similarly, systolic blood pressure declined in both patient groups (placebo-corrected decrease at 4 months, −1.8 mm Hg [95% CI, −2.8 to −0.8] in those without diabetes vs −1.6 mm Hg [95% CI, −2.8 to −0.4] in those with diabetes), but there was no interaction between diabetes status and the effect of dapagliflozin (Figure 5B).

In a post hoc analysis, hematocrit increased with dapagliflozin in both patient groups, with plateau reached after approximately 4 months (placebo-corrected change, 2.3% [95% CI, 2.0-2.5] in participants without diabetes vs 2.8% [95% CI, 2.5-3.1] in patients with diabetes), with an interaction between diabetes status and the effect of dapagliflozin (P value for interaction <.001) (Figure 6).

In patients without diabetes, NT-proBNP decreased by 144 pg/mL (95% CI, 13-276) in the dapagliflozin group and increased by 84 pg/mL (95% CI, −89 to 257) in the placebo group between baseline and 8 months (between-treatment difference, −278 pg/mL [95% CI, −485 to −71]; P = .009). The corresponding changes in participants with diabetes were a decrease of 257 (95% CI, 100-415) pg/mL in the dapagliflozin group and an increase of 121 (95% CI, −64 to 306) pg/mL in the placebo group (between-treatment difference, −333 pg/mL [95% CI, −562 to −104]; P = .004) (P value for interaction = .73).

The study medication was stopped in 144 patients (11.1%) in the dapagliflozin group and 141 (10.8%) in the placebo group among patients without diabetes and 105 (9.8%) in the dapagliflozin group and 117 (11.0%) in the placebo group among patients with diabetes. Doubling of serum creatinine occurred in 22 patients (1.7%) without diabetes in the dapagliflozin group and 36 patients (2.8%) in the placebo group (P = .08); among participants with diabetes, doubling of serum creatinine occurred in 21 patients (2.0%) in the dapagliflozin group and 41 (3.9%) in the placebo group (P = .01).

The most common adverse events of interest were those related to volume depletion and kidney impairment (Table 3). The incidence of these adverse events did not differ significantly between dapagliflozin and placebo in either patient group. Three patients (0.06%) experienced definite or probable diabetic ketoacidosis in the trial (all were patients with diabetes randomized to receive dapagliflozin). Eight patients (0.17%) experienced major hypoglycemia in the trial, and all 8 had diabetes (4 randomized to receive dapagliflozin and 4 randomized to receive placebo). Overall, 25 patients (0.5%) had an amputation (1 [0.1%] in the dapagliflozin group and 3 [0.2%] in the placebo group among patients without diabetes and 12 [1.1%] in the dapagliflozin group and 9 [0.8%] in the placebo group among patients with diabetes).

Quiz Ref IDThe key finding from these exploratory analyses of patients with heart failure with reduced ejection fraction was that the effect of the SGLT2 inhibitor dapagliflozin on the primary and principal secondary outcome did not differ in individuals with and without diabetes. Furthermore, among the individuals without diabetes, the reduction in the primary outcome with dapagliflozin was consistent in those with a glycated hemoglobin greater than or equal to 5.7% and less than 5.7% (ie, in those with prediabetes and those with a normal glycated hemoglobin).^20,21 These data provide evidence that the benefits of SGLT2 inhibition are not limited to people with diabetes or prediabetes and are applicable to patients with heart failure with reduced ejection fraction, irrespective of glycemic status.

Quiz Ref IDDapagliflozin reduced glycated hemoglobin in patients with type 2 diabetes but had no effect on this measure in patients without diabetes. However, the effects of dapagliflozin on weight, blood pressure, hematocrit, eGFR, and NT-proBNP were directionally similar in those with and without diabetes, although significantly more pronounced in the former group for hematocrit.

These findings suggest the benefits of dapagliflozin were independent of plasma glucose lowering. Other mechanisms of action for SGLT2 inhibitors have been proposed, including a diuretic effect.^22,23 While this mechanism was not measured directly in the present trial, the early decreases in systolic blood pressure, weight, and eGFR and the increase in hematocrit were consistent with a diuretic action. However, very little is known about the effects of SGLT2 inhibitors on urinary sodium and water excretion when added to conventional diuretic therapy, especially in patients with heart failure, and particularly in those without diabetes.^22,24-26 There are other potential explanations for the decrease in eGFR and increase in hematocrit, including augmentation of tubulo-glomerular feedback and increase in kidney erythropoietin secretion.^27-29 The time course of the changes in eGFR and hematocrit observed were quite different, with the initial decrease in eGFR reversing after 14 days, whereas hematocrit increased progressively over the first 4 months, plateauing thereafter.

Other diuresis-independent actions, including effects on ion transporters, fibrosis, adipokines, sympathetic nervous system activity, and vascular function, have also been proposed, although clinical evidence supporting these is sparse.^3,10,30,31 SGLT2 inhibitors may reduce left ventricular mass and an effect on cardiac remodeling could explain the decrease in NT-proBNP observed with dapagliflozin.^3,9,10,32 Prevention of decline in kidney function is also likely to be beneficial in heart failure.

Quiz Ref IDThe rate of adverse events related to volume depletion was low and not significantly different between participants with and without diabetes. Other prespecified adverse events were infrequent in both groups of patients, and discontinuation of study drug was also uncommon in the 2 groups. Neither major hypoglycemia nor diabetic ketoacidosis occurred in any patient without diabetes. Although there was no statistically significant effect on the prespecified kidney outcome, this occurred in few patients treated with dapagliflozin. However, doubling of serum creatinine (a prespecified exploratory outcome) was less common in patients who received dapagliflozin, both in patients with and without diabetes.

This study has several limitations. First, although this analysis was prespecified, the results reported in this study are based on subgroup analysis. Second, some analyses were post hoc, including those that evaluated outcomes according to glycated hemoglobin levels by tertiles in patients without diabetes and as a continuous variable in all patients and those that evaluated changes in hematocrit levels. Third, additional information that might have helped explain the effects of SGLT2 inhibitors in heart failure was not collected. Fourth, the diagnosis of previously unknown diabetes was based on 2 consecutively elevated glycated hemoglobin levels (≥6.5%), and an alternative diagnostic approach (eg, an oral glucose tolerance test and fasting plasma glucose measurement) might have recategorized some patients.^18,19 Fifth, to fit with the scheduled assessments in the trial, “prediabetes” was pragmatically defined as 1 glycated hemoglobin level measurement of at least 5.7% at visit 1 or visit 2 (ie, not having 2 consecutively normal levels [<5.7%] or having known or previously undiagnosed diabetes).

In this exploratory analysis of a randomized clinical trial of patients with heart failure with reduced ejection fraction, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status.

Corresponding Author: John J. V. McMurray, MD, Professor, British Heart Foundation Cardiovascular Research Centre, University of Glasgow, 126 University Pl, Glasgow G12 8TA, United Kingdom (john.mcmurray@glasgow.ac.uk).

Accepted for Publication: February 6, 2020.

Published Online: March 27, 2020. doi:10.1001/jama.2020.1906

Correction: This article was corrected on April 6, 2021, to correct weight decline in those with diabetes being mislabeled as weight decline in those without diabetes at 8 months, reference 16 rather than reference 18 being cited in footnote “b” in Table 2, and the absolute difference in cardiovascular death or hospitalization for heart failure among patients with diabetes not being presented as a percentage in Table 2.

Author Contributions: Drs McMurray and Jhund had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Petrie and Verma contributed equally.

Concept and design: Petrie, Inzucchi, Boehm, de Boer, Køber, Kosiborod, Langkilde, Martinez, Ponikowski, Sjöstrand, Solomon, Greasley, Boulton, McMurray.

Acquisition, analysis, or interpretation of data: Petrie, Verma, Docherty, Inzucchi, Anand, Belohlavek, Chiang, Chopra, Desai, Diez, Drozdz, Dukat, Ge, Howlett, Katova, Kitakaze, Ljungman, Merkely, Nicolau, O'Meara, Pham, Schou, Tereschchenko, Køber, Kosiborod, Langkilde, Ponikowski, Sabatine, Sjöstrand, Solomon, Johanson, Greasley, Boulton, Bengtsson, Jhund, McMurray.

Drafting of the manuscript: Petrie, Docherty, Dukat, Boulton, Jhund, McMurray.

Critical revision of the manuscript for important intellectual content: Petrie, Verma, Docherty, Inzucchi, Anand, Belohlavek, Boehm, Chiang, Chopra, de Boer, Desai, Diez, Drozdz, Dukat, Ge, Howlett, Katova, Kitakaze, Ljungman, Merkely, Nicolau, O'Meara, Pham, Schou, Tereschchenko, Køber, Kosiborod, Langkilde, Martinez, Ponikowski, Sabatine, Sjöstrand, Solomon, Johanson, Greasley, Boulton, Bengtsson, McMurray.

Statistical analysis: Docherty, Jhund, McMurray.

Obtained funding: Katova, Langkilde, Johanson, McMurray.

Administrative, technical, or material support: Petrie, Inzucchi, de Boer, Dukat, Ge, Howlett, Ljungman, Merkely, Schou, Køber, Langkilde, Johanson, Boulton, McMurray.

Supervision: Petrie, Anand, Chiang, Diez, Drozdz, Dukat, Ge, Kitakaze, Nicolau, Pham, Tereschchenko, Køber, Kosiborod, Langkilde, Martinez, Ponikowski, Sjöstrand, Solomon, Jhund, McMurray.

Conflict of Interest Disclosures: Dr Petrie reported receiving lecture fees from AstraZeneca and Eli Lilly during the conduct of the study and personal fees from Novo Nordisk, AstraZeneca, NAPP Pharmaceuticals, Takeda Pharmaceutical, Alnylam, Bayer, Resverlogix, and Cardiorentis and grants and personal fees from Boehringer Ingelheim and Novartis outside the submitted work. Dr Verma reported receiving personal fees from AstraZeneca, Sun Pharmaceuticals, and Toronto Knowledge Translation Working Group during the conduct of the study and grants and personal fees from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, and Merck; grants from Bristol-Myers Squibb; and personal fees from Eli Lilly, Janssen, Novartis, Novo Nordisk, Sanofi outside the submitted work. Dr Docherty reported his employer, the University of Glasgow, being paid by AstraZeneca (sponsor of DAPA-HF) for his involvement in the DAPA-HF trial and receiving personal fees from Eli Lilly outside the submitted work. Dr Inzucchi reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, VTV Therapeutics, Sanofi/Lexicon, and Novo Nordisk outside the submitted work. Dr Anand reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from Amgen, ARCA, Boston Scientific Corporation, Boehringer Ingelheim, LivaNova, and Zensun outside the submitted work. Dr Belohlavek reported receiving personal fees from AstraZeneca during the conduct of the study and grants from the Ministry of Health/Grant Agency for Health Research of the Czech Republic and personal fees from Novartis, Boehringer Ingelheim, Amgen, Medpace, and Pfizer outside the submitted work. Dr Boehm reported receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Servier, Medtronic, Vifor, and Novartis outside the submitted work. Dr Chiang reported receiving honorarium for lectures from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. Dr de Boer reported receiving grants from Abbott, Bristol-Myers Squibb, and Novo Nordisk; personal fees from Abbott; and grants and personal fees from Novartis, Roche, and AstraZeneca outside the submitted work. Dr Desai reported receiving personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Merck, Regeneron, and Relypsa and grants and personal fees from AstraZeneca, Alnylam, and Novartis outside the submitted work. Dr Diez reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Howlett reported receiving grants and personal fees from AstraZeneca Canada and Boerhinger Ingelheim/Eli Lilly during the conduct of the study and grants and personal fees from Servier Canada, Novartis, Pfizer, and Bayer; personal fees from Otsuka, Alnylam, and Akcea; grants from Medtronic; and serving on the medical advisory board for Caridiol outside the submitted work. Dr Katova reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Kitakaze reported receiving grants and personal fees from AstraZeneca during the conduct of the study and grants from the Japanese government, the Japan Heart Foundation, and the Japan Agency for Medical Research and Development; grants and personal fees from Asteras, Sanofi, Pfizer, Ono, Novartis, Tanabe-Mitubishi, and Takeda; and personal fees from Daiichi-sankyo, Bayer, Bheringer, Kowa, Sawai, Merck Sharp & Dohme, Shionogi, Kureha, Japan Medical Data, Taisho-Toyama, and Toa Eiyo outside the submitted work. Dr Ljungman reported receiving personal fees and financial reimbursement to the institution from AstraZeneca during the conduct of the study and personal fees from Novartis and Pfizer outside the submitted work. Dr Merkely reported receiving personal fees from AstraZeneca and Servier outside the submitted work. Dr Nicolau reported receiving grants from AstraZeneca during the conduct of the study and personal fees from Amgen, Daiichi-Sankyo, and Servier; grants from AstraZeneca, Bristol-Meyers-Squibb, CLS Behring, Dalcor, Jansen, Novo Nordisk, and Vifor; and grants and personal fees from Bayer, Novartis, and Sanofi outside the submitted work. Dr O'Meara reported consultation and speaker fees being paid to the Montreal Heart Institute Research Center from Amgen, Merck, and Novartis; receiving consultation and speaker fees from AstraZeneca, Bayer, and Boehringer Ingelheim; serving on a steering committee and as a national leader for clinical studies with fees paid to Montreal Heart Institute Research Center from American Regent, AstraZeneca, Cytokinetics, Merck, and Novartis; and clinical trial participation from Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi. Dr Schou reported receiving personal fees and nonfinancial support from AstraZeneca and personal fees from Novo Nordisk and Bohringer Ingelheim outside the submitted work. Dr Tereschchenko reported receiving personal fees from AstraZeneca during the conduct of the study and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, Servier, and Amgen outside the submitted work. Dr Køber reported receiving grants from AstraZeneca to the institution for participation in Dapa-HF steering committee during the conduct of the study and personal fees from speakers honorarium from AstraZeneca and Novartis outside the submitted work. Dr Kosiborod reported receiving grants and personal fees from AstraZeneca and Boehringer Inelheim and personal fees from Sanofi, Amgen, Novo Nordisk, Merck, Eisai, Janssen, Bayer, GlaxoSmithKline, Glytec, Intarcia, Novartis, Applied Therapeutics, Amarin, and Eli Lilly outside the submitted work. Dr Langkilde reported receiving being a full-time employee of and shareholder in AstraZeneca during the conduct of the study. Dr Martinez reported receiving personal fees from AstraZeneca during the conduct of the study. Dr Ponikowski reported receiving personal fees and fees to his institution from participation as an investigator in clinical trials from AstraZeneca during the conduct of the study and from Boehringer Ingelheim, Servier, Novartis, Berlin-Chemie, Bayer, Renal Guard Solutions, Pfizer, Respicardia, Cardiorentis, and Cibiem; grants, personal fees, and fees to his institution from Impulse Dynamics; and fees to his institution from Vifor, Corvia, and Revamp Medical outside the submitted work. Dr Sabatine reported receiving grants and personal fees from AstraZeneca during the conduct of the study; grants and personal fees from Amgen, Intarcia, Janssen Research and Development, Medicines Company, MedImmune, Merck, and Novartis; personal fees from Anthos Therapeutics, Bristol-Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, Ionis; and grants from Daiichi-Sankyo, Bayer, Pfizer, Poxel, Eisai, GlaxoSmithKline, Quark Pharmaceuticals, and Takeda outside the submitted work; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Abbott, Aralez, Roche, and Zora Biosciences. Dr Sjöstrand reported receiving personal fees from and being a full-time employee and shareholder of AstraZeneca outside the submitted work. Dr Solomon reported receiving grants from AstraZeneca during the conduct of the study and grants from Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Sanofi Pasteur, and Theracos and personal fees from Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Bristol-Myers Squibb, Cardior, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GlaxoSmithKline, Ironwood, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, and Tenaya outside the submitted work. Dr Johanson reported receiving personal fees from AstraZeneca during the conduct of the study and outside the submitted work. Dr Greasley reported being an employee of and shareholder in AstraZeneca. Dr Boulton reported being an employee of and shareholder in AstraZeneca outside the submitted work. Dr Bengtsson reported receiving personal fees from AstraZeneca outside the submitted work. Dr Jhund reported his employer being paid by AstraZeneca for his time working on the study and receiving personal fees from and his employer being paid by Novartis; grants and personal fees from Boehringer Ingelheim; personal fees from Cytokinetics and Vifor Pharma outside the submitted work; and being the director of Global Clinical Trials Partners Ltd. Dr McMurray reported receiving grants and his employer being paid by AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study and grants and his employer being paid by Novartis, Amgen, Bristol-Myers Squibb, Bayer, Abbvie, Dal-Cor, Kidney Research UK, and Cardurion and grants from British Heart Foundation outside the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by AstraZeneca. Dr McMurray was supported by a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217.

Role of the Funder/Sponsor: Representatives of AstraZeneca were involved with the executive committee in the design and conduct of the study. Site monitoring and data management were carried out by AstraZeneca. Data analysis was carried out at Glasgow University. Interpretation of the data and preparation of the manuscript was carried out by the executive committee, including representatives of AstraZeneca. Review and approval of the of the manuscript, as well as the decision to submit the manuscript for publication, was taken by all authors, including representatives of AstraZeneca. AstraZeneca had no veto of the right to publish or control over which journal to submit.

Meeting Presentation: This paper was presented at the American College of Cardiology Meeting; March 28, 2020.

Data Sharing Statement: See Supplement 4.