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DAPA-HF: Dapagliflozin reduces HF events, CV death in T2DM and non-T2DM patients

Prof. John McMurray
Principal Investigator
University of Glasgow
Glasgow, United Kingdom
Prof. Marco Metra
Discussant
University of Brescia
Brescia, Italy
10 Oct 2019
Sodium-glucose co-transporter 2 (SGLT2) inhibitors were previously shown to reduce the risk of heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). However, it had remained uncertain whether the HF benefits of SGLT2 inhibitors could also be observed in those without T2DM. Results of the DAPA-HF trial, presented at the European Society of Cardiology (ESC) Congress 2019 and World Congress of Cardiology (WCC) 2019, showed for the first time that the SGLT2 inhibitor dapagliflozin reduced the risk of death and hospitalization in HF patients with reduced ejection fraction (rEF) regardless of diabetic status.

DAPA-HF: First SGLT2 inhibitor to show HF benefits in non-T2DM patients

DAPA-HF is an international, multicentre, parallel group, randomized, double-blind study that involved 4,744 patients with HFrEF with (n=2,139) or without diabetes (n=2,605). Notably, 1,096 patients were recruited from Asian sites (China, n=237; India, n=237; Japan, n=343; Taiwan, n=141; Vietnam, n=138). Key inclusion criteria were symptomatic HF with left ventricular ejection fraction (LVEF) ≤40 percent, and N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥600 pg/mL (≥400 pg/mL if hospitalized for HF within the last 12 months; ≥900 pg/mL if atrial fibrillation/flutter present). [Eur J Heart Fail 2019, doi: 10.1002/ejhf.1548]

The patients were randomized to receive dapagliflozin 10 mg once daily or placebo, in addition to standard-of-care therapy. The study’s primary composite endpoint was a worsening HF episode (hospitalization or the equivalent, ie, an urgent HF visit) or cardiovascular death, analyzed as time‐to‐first event. (Figure 1) [Eur J Heart Fail 2019, doi: 10.1002/ejhf.1548]

DAPA-HF1.0

“Patient characteristics were well balanced in both groups at baseline,” noted principal investigator Professor John McMurray of the University of Glasgow, Glasgow, UK. “Patients in the study had been receiving adequate HF medications. For example, 93–94 percent of patients were on diuretics, while 93–94 percent were on angiotensin-converting enzyme [ACE] inhibitors/angiotensin II receptor blockers [ARBs]/angiotensin receptor-neprilysin inhibitor [ARNI].” (Table) [Eur J Heart Fail 2019, doi: 10.1002/ejhf.1548]

DAPA-HF2

Study results

After a median follow-up of 18.2 months, a significant 26 percent relative risk reduction and 4.9 percent absolute risk reduction was observed with dapagliflozin vs placebo in the primary endpoint (16.3 percent vs 21.2 percent; hazard ratio [HR], 0.74; 95 percent confidence interval [CI], 0.65 to 0.85; p=0.00001; number needed to treat, 21). (Figure 2)

DAPA-HF3

“Importantly, these benefits were observed regardless of T2DM status [HR for T2DM patients, 0.75; 95 percent CI, 0.63 to 0.90; HR for patients without T2DM, 0.73; 95 percent CI, 0.60 to 0.88],” highlighted McMurray.

In 11 percent of the patients who had been on ARNI at baseline, a trend of benefit was observed with dapagliflozin for the primary endpoint (HR, 0.75; 95 percent CI, 0.50 to 1.13).

Analysis of individual components of the primary endpoint showed significant reductions with dapagliflozin vs placebo in rates of worsening HF events (ie, HF hospitalization or urgent HF visit) (10.0 percent vs 13.7 percent; HR, 0.70; 95 percent CI, 0.59 to 0.83; p<0.001) as well as CV death (9.6 percent vs 11.5 percent; HR, 0.82; 95 percent CI, 0.69 to 0.98; p=0.03). (Figure 3)

DAPA-HF4

CI = confidence interval; CV = cardiovascular; DAPA = dapagliflozin; HR = hazard ratio; RRR = relative risk reduction

Adapted from McMurray J, et al, ESC 2019.

More patients receiving dapagliflozin vs placebo had HF symptom improvements as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) (mean change from baseline to 8 months: +6.1 vs +3.3; p<0.001) (≥5 points improvement: 58 percent vs 51 percent; odds ratio [OR], 1.15; 95 percent CI, 1.08 to 1.23; p<0.001) (≥5 points deterioration: 25 percent vs 33 percent; OR, 0.84; 95 percent CI, 0.78 to 0.90; p<0.001).

Moreover, the risk of all-cause mortality was reduced by 17 percent with dapagliflozin vs placebo (HR, 0.83; 95 percent CI, 0.71 to 0.97; p=0.022). Worsening of renal function was noted in 1.2 percent vs 1.6 percent of the patients (HR, 0.71; 95 percent CI, 0.44 to 1.16; p=0.17).

The adverse event (AE) profile was generally comparable between the dapagliflozin and placebo groups. No significant differences were noted for volume depletion (7.5 percent vs 6.8 percent; p=0.4) and renal dysfunction (6.5 percent vs 7.2 percent; p=0.36). Major hypoglycaemia, as well as lower limb amputation and fracture, were infrequent in both groups. 

“Patients in both groups rarely required treatment discontinuation due to AEs [4.7 percent with dapagliflozin vs 4.9 percent with placebo; p=0.79],” noted McMurray.

Conclusion

“DAPA-HF is the first trial investigating the use of an SGLT2 inhibitor in the treatment of HF in adult patients with HFrEF with or without T2DM, on top of standard of care [eg, ACE inhibitors, ARBs, beta-blockers, ARNI, mineralocorticoid receptor antagonists],” said McMurray. “When added to standard therapy, dapagliflozin provided statistically significant and clinically meaningful reduction in the risk of worsening HF events and CV death. The safety profile of dapagliflozin in this trial was consistent with its previously established safety profile, with a low treatment discontinuation rate.”

“Dapagliflozin offers a new approach to the treatment of HFrEF,” he added. “It is the first treatment shown to reduce mortality in HF over the last 5 years, and the first beneficial HF treatment in the last 10 years that is not acting through neurohumoral mechanisms. In the DAPA-HF trial, dapagliflozin demonstrated what we would want a new HF drug to do: reduce hospital admission, increase survival, improve symptoms.”

Discussant review: DAPA-HF marks new era of HF treatment

The DAPA-HF trial enrolled patients with or without diabetes who had persisting symptoms, reduced LVEF and an elevated NT-proBNP level – similar to those enrolled in contemporary HFrEF registries and recent HFrEF randomized trials, such as the globally diverse PARADIGM-HF trial and ATMOSPHERE trial. [N Engl J Med 2014;371:993-1004; N Engl J Med 2016;374:1521-1532]

“The results of the DAPA-HF trial mark a new era of HF treatment,” said discussant Professor Marco Metra of the University of Brescia, Brescia, Italy. “Notably, the curves of the primary endpoint and worsening HF events diverged early. The HRs of the primary and key secondary endpoints in DAPA-HF were comparable to, if not better than, those in major positive trials of HFrEF pharmacological therapy in recent years. The quality-of-life improvements in the DAPA-HF trial were greater than that in the PARADIGM-HF trial [difference in KCCQ score, +2.8 vs +1.64].” [N Engl J Med 2014;371:993-1004]

Further questions

“It remains uncertain whether the HF benefits of dapagliflozin in HFrEF patients as seen in DAPA-HF can be translated into other HF phenotypes, such as HF patients with preserved ejection fraction,” suggested Metra. “There are also ongoing HF outcome trials on dapagliflozin as well as other SGLT2 inhibitors, which will confirm if the HF benefits can be reproduced with other SGLT2 inhibitors.” [Eur J Heart Fail 2019, doi: 10.1002/ejhf.1531]

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