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Dapagliflozin Improves Cardiovascular Outcomes in Patients With Heart Failure and Reduced Ejection Fraction
Study Overview
Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.
Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.
Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.
Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.
Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.
Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.
Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
Commentary
Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.1 This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.2,3
While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.
DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.
There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.
Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.
Applications for Clinical Practice
SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.
—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
Study Overview
Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.
Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.
Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.
Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.
Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.
Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.
Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
Commentary
Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.1 This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.2,3
While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.
DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.
There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.
Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.
Applications for Clinical Practice
SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.
—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO
Study Overview
Objective. To evaluate the effects of dapagliflozin in patients with heart failure with reduced ejection fraction in the presence or absence of type 2 diabetes.
Design. Multicenter, international, double-blind, prospective, randomized, controlled trial.
Setting and participants. Adult patients with symptomatic heart failure with an ejection fraction of 40% or less and elevated heart failure biomarkers who were already on appropriate guideline-directed therapies were eligible for the study.
Intervention. A total of 4744 patients were randomly assigned to receive dapagliflozin (10 mg once daily) or placebo, in addition to recommended therapy. Randomization was stratified by the presence or absence of type 2 diabetes.
Main outcome measures. The primary outcome was the composite of a first episode of worsening heart failure (hospitalization or urgent intravenous therapy) or cardiovascular death.
Main results. Median follow-up was 18.2 months; during this time, the primary outcome occurred in 16.3% (386 of 2373) of patients in the dapagliflozin group and in 21.2% (502 of 2371) of patients in the placebo group (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.65-0.85; P < 0.001). In the dapagliflozin group, 237 patients (10.0%) experienced a first worsening heart failure event, as compared with 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59-0.83). The dapagliflozin group hadlower rates of death from cardiovascular causes (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69-0.98) and from any causes (11.6% vs 13.9%; HR, 0.83; 95% CI, 0.71-0.97), compared to the placebo group. Findings in patients with diabetes were similar to those in patients without diabetes.
Conclusion. Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
Commentary
Inhibitors of sodium-glucose cotransporter 2 (SGLT-2) are a novel class of diabetic medication that decrease renal glucose reabsorption, thereby increasing urinary glucose excretion. In several large clinical trials of these medications for patients with diabetes, which were designed to meet the regulatory requirements for cardiovascular safety in novel diabetic agents, investigators unexpectedly found that SGLT-2 inhibitors were associated with a reduction in cardiovascular events, driven by a reduction in heart failure hospitalizations. The results of EMPA-REG OUTCOME, the first of these trials, showed significantly lower risks of both death from any cause and hospitalization for heart failure in patients treated with empagliflozin.1 This improvement in cardiovascular outcomes was subsequently confirmed as a class effect of SGLT-2 inhibitors in the CANVAS Program (canagliflozin) and DECLARE TIMI 58 (dapagliflozin) trials.2,3
While these trials were designed for patients with type 2 diabetes who had either established cardiovascular disease or multiple risk factors for it, most patients did not have heart failure at baseline. Accordingly, despite a signal toward benefit of SGLT-2 inhibitors in patients with heart failure, the trials were not powered to test the hypothesis that SGLT-2 inhibitors benefit patients with heart failure, regardless of diabetes status. Therefore, McMurray et al designed the DAPA-HF trial to investigate whether SGLT-2 inhibitors can improve cardiovascular outcomes in patients with heart failure with reduced ejection fraction, with or without diabetes. The trial included 4744 patients with heart failure with reduced ejection fraction, who were randomly assigned to dapagliflozin 10 mg once daily or placebo, atop guideline-directed heart failure therapy, with randomization stratified by presence or absence of type 2 diabetes. Investigators found that the composite primary outcome, a first episode of worsening heart failure or cardiovascular death, occurred less frequently in patients in the dapagliflozin group compared to the placebo group (16.3% vs 21.2%; HR, 0.74; 95% CI, 0.65-0.85; P < 0.001). Individual components of the primary outcome and death from any cause were all significantly lower, and heart failure–related quality of life was significantly improved in the dapagliflozin group compared to placebo.
DAPA-HF was the first randomized study to investigate the effect of SGLT-2 inhibitors on patients with heart failure regardless of the presence of diabetes. In addition to the reduction in the above-mentioned primary and secondary endpoints, the study yielded other important findings worth noting. First, the consistent benefit of dapagliflozin on cardiovascular outcomes in patients with and without diabetes suggests that the cardioprotective effect of dapagliflozin is independent of its glucose-lowering effect. Prior studies have proposed alternative mechanisms, such as diuretic function and related hemodynamic actions, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, vascular function, and the preservation of renal function. Future studies are needed to fully understand the likely pleiotropic effects of this class of medication on patients with heart failure. Second, there was no difference in the safety endpoints between the groups, including renal adverse events and major hypoglycemia, implying dapagliflozin is as safe as placebo.
There are a few limitations of this trial. First, as the authors point out, the study included mostly white males—less than 5% of participants were African Americans—and the finding may not be generalizable to all patient populations. Second, although all patients were already treated with guideline-directed heart failure therapy, only 10% of patients were on sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes. Also, mineralocorticoid receptor blockers were used in only 70% of the population. Finally, since the doses were not provided, whether patients were on the maximal tolerated dose of heart failure therapy prior to enrollment is unclear.
Based on the results of the DAPA-HF trial, the Food and Drug Administration approved dapagliflozin for the treatment of heart failure with reduced ejection fraction on May 5, 2020. This is the first diabetic drug approved for the treatment of heart failure.
Applications for Clinical Practice
SGLT-2 inhibitors represent a fourth class of medication that patients with heart failure with reduced ejection fraction should be initiated on, in addition to beta blocker, ACE inhibitor/angiotensin receptor blocker/neprilysin inhibitor, and mineralocorticoid receptor blocker. SGLT-2 inhibitors may be especially applicable in patients with heart failure with reduced ejection fraction and relative hypotension, as these agents are not associated with a significant blood-pressure-lowering effect, which can often limit our ability to initiate or uptitrate the other main 3 classes of guideline-directed medical therapy.
—Rie Hirai, MD, Fukui Kosei Hospital, Fukui, Japan
—Taishi Hirai, MD, University of Missouri Medical Center, Columbia, MO
—Timothy Fendler, MD, St. Luke’s Mid America Heart Institute, Kansas City, MO
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.
1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347-357.