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PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
PARIS – Treatment with the SGLT2 inhibitor dapagliflozin produced a statistically significant 27% drop in cardiovascular death or heart failure events in patients with existing heart failure with reduced ejection fraction and no diabetes, results that in a stroke changed the status of dapagliflozin from fundamentally a drug that treats diabetes to a drug that treats heart failure.
“Dapagliflozin offers a new approach to the treatment of heart failure with reduced ejection fraction” (HFrEF), John McMurray, MD, said at the annual congress of the European Society of Cardiology.
The results he reported from the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) trial showed statistically significant benefits when adding dapagliflozin to guideline-directed therapy for a list of outcomes that include a 17% drop in all-cause death compared with placebo, an 18% fall in cardiovascular death, and a 25% relative reduction in total heart failure hospitalizations plus cardiovascular deaths during a median follow-up of just over 18 months. The primary endpoint of the reduction in cardiovascular death, first heart failure hospitalization, or an urgent heart failure visit fell by 25% in the enrolled patients with diabetes (45% of the study population, all with type 2 diabetes), and by 27% in the remaining patients who had no diabetes, showing that the presence of diabetes had no impact on the heart failure benefit from dapagliflozin (Farxiga). The absolute reduction in the primary endpoint was about 5%, with a number needed to treat of 21 to prevent one primary endpoint during 18 months of treatment.
Dr. McMurray’s report of the primary endpoint as well as the finding that the drug was as effective in patients without diabetes as in those with diabetes were both met with loud applause by the packed congress audience.
The efficacy results also showed that 58% of patients on dapagliflozin had a clinically meaningful (5 point or greater) increase in their quality of life score on the Kansas City Cardiomyopathy Questionnaire after 8 months on treatment compared with a 51% rate in the placebo patients, a statistically significant difference.
The safety results showed no new signals for a drug that already has regulatory approval but was being used in a novel population. The rate of major hypoglycemia was virtually nonexistent, 0.2%, and identical in both treatment arms. All adverse events occurred at roughly equal rates in the dapagliflozin and placebo groups, with a 5% rate of adverse events leading to study discontinuation in both arms, and a serious adverse event rate of 38% in the dapaglifolzin patients and 42% in the placebo patients. The rate of worsening renal function was less than 2% in both arms and not statistically different.
“This is as close to a home run as you see in heart failure treatment,” commented Douglas L. Mann, MD, professor of medicine at Washington University, St. Louis, and a heart failure clinician and researcher.
DAPA-HF “is a landmark trial. It took a diabetes drug and used it in patients without diabetes, a concept that would have been considered outlandish 5 years ago. Scientifically it’s huge,” commented Deepak L. Bhatt, MD, professor of medicine at Harvard Medical School in Boston.
The DAPA-HF results were another step in the remarkable journey toward heart failure intervention taken by the SGLT2 (sodium glucose cotransport 2) inhibitor class of drugs that includes dapagliflozin as well as canagliflozin (Invokana) and empagliflozin(Jardiance), a path that began 4 years ago with the report of empagliflozin’s unexpected efficacy for reducing cardiovascular death and heart failure hospitalizations in a large cardiovascular-safety study, EMPA-REG OUTCOME (N Engl J Med. 2015 Nov 26;373[22]:2117-28). Subsequent reports showed similar effects benefiting heart failure and survival for canagliflozin and dapagliflozin, and now with DAPA-HF the evidence extended the benefit to heart failure patients regardless of whether they have diabetes. Additional studies now in progress are exploring the same question for empagliflozin and canagliflozin.
The results from DAPA-HF are likely a class effect for all these SGLT2 inhibitors, suggested Dr. McMurray in a video interview, a view shared by several other experts. He cautioned clinicians against using dapagliflozin to treat patients with heart failure with reduced ejection fraction (HFrEF) but without diabetes until this indication receives regulatory approval, and even then using dapagliflozin or other SGLT2 inhibitors this way may take some getting used to on the part of cardiologists and other clinicians.
“The results put dapagliflozin in the same league as [standard HFrEF drugs], but using it will require a shift in thinking. Most physicians will initially say “aren’t SGLT2 inhibitors used for treating diabetes?” Dr. Bhatt said.
“I’m sure most cardiologists are not familiar with the SGLT2 inhibitors; we’ll have to educate them,” conceded Dr. McMurray, professor of medical cardiology at the University of Glasgow. However, other aspects of dapagliflozin and this drug class in general may make the SGLT2 inhibitors particularly attractive and spur their use once labeling changes.
The adverse-event profile seen in DAPA-HF looked very “clean,” said Dr. Mann, especially compared with the other medical classes recommended in guidelines for patients with HFrEF: the angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and mineralocorticoid-receptor antagonists such as spironolactone, and the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril-valsartan (Entresto). As used in DAPA-HF dapagliflozin also had the advantages of not needing dose titration or laboratory follow-up, as do several of these other drug classes.
“I think dapagliflozin will have a huge uptake [for treating HFrEF], because it will be easy for primary care physicians to prescribe. It will be easier to use than traditional heart failure medications.” Once approved for heart failure use, Dr. Mann predicted a standard dosing regimen for HFrEF patients of an ACE inhibitor, ARB or ARNI, a beta-blocker, a mineralocorticoid-receptor antagonist, and an SGLT2 inhibitor. He suggested that this large and cumbersome collection of medications could conceivably be simplified into a polypill.
He also saw a suggestion in the DAPA-HF results that combining dapagliflozin with the ARB valsartan might have similar efficacy to dapaglifozin plus sacubitril-valsartan, which might also help simplify heart failure treatment. In the trial, 11% of patients received sacubritril-valsartan, and the primary-endpoint reduction compared with placebo in this subgroup was 26%, compared with 25% for patients treated with an ACE inhibitor or ARB. Currently, labeling for sacubitril-valsartan calls for starting a patients on an ACE inhibitor or ARB, titrating them to a stable and effective dosage, and then stopping this regimen to switch to the ARNI. If dapagliflozin is also added, then a simpler approach would be to just start a patient on valsartan, optimize the dosage, and then start dapagliflozin and achieve the same benefit as from sacubitril-valsartan plus dapagliflozin. While an attractive scenario, it needs validation, Dr. Mann said in an interview.
One additional, notable finding from DAPA-HF was that the primary endpoint benefit appeared much stronger in patients with New York Heart Association class II heart failure at entry, two-thirds of the study population, compared with patients with class III or IV HFrEF. Compared with placebo the primary endpoint fell by 37% among the class II patients, a statistically significant difference, but by just 10% in the class III and IV patients, a reduction that was not significant compared with placebo. This too needs more study, commented Dr. Mann, as does the ways by which dapagliflozin and the other SGLT2 inhibitors benefit heart failure patients. Currently the ways by which dapagliflozin produced these results remain unknown.
DAPA-HF randomized a total of 4,744 patients at 410 sites in 20 countries. About 10% of enrolled patients were in the United States.
DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF. Dr. McMurray had no other relevant disclosures. Dr. Mann has been a consultant to Bristol-Myers Squibb, LivaNova, Novartis, and Tenaya Therapeutics. Dr. Bhatt has received research funding from AstraZeneca, and he has served as a consultant to or received research funding from several other companies.
REPORTING FROM THE ESC CONGRESS 2019
Key clinical point: Dapagliflozin produced multiple, statistically significant benefits in heart failure patients on top of guideline-directed therapy.
Major finding: The study’s primary endpoint fell by a statistically significant 27% with dapagliflozin compared with placebo in patients without diabetes.
Study details: DAPA-HF, a multinational study with 4,744 patients at 410 sites.
Disclosures: DAPA-HF was sponsored by AstraZeneca, the company that markets dapagliflozin (Farxiga). AstraZeneca paid Glasgow University to cover Dr. McMurray’s salary during the time he spent working as principal investigator of DAPA-HF.