Emerging role of dapagliflozin as a standard treatment for patients with HFrEF

Prof. Javed Butler
University of Mississippi Medical Center
Jackson, US
Prof. Hung-Fat Tse
Department of Medicine
The University of Hong Kong
08 Sep 2021
The sodium-glucose co-transporter 2 (SGLT2) inhibitor, dapagliflozin, has been approved as an adjunct to standard therapy to reduce the risk of cardiovascular (CV) death and hospitalization for patients with heart failure with reduced ejection fraction (HFrEF). At an industry-sponsored webinar, Professor Javed Butler of the University of Mississippi Medical Center in Jackson, US, reviewed results of the phase III DAPA-HF trial that supported dapagliflozin’s HFrEF indication approval and advocated its earlier use in HFrEF patients. Meanwhile, in an interview with MIMS Doctor, Professor Hung-Fat Tse of the Department of Medicine, University of Hong Kong, discussed how these findings relate to local clinical practice.

Burden and unmet needs of HF management

“Heart failure [HF] remains a major global health problem,” said Butler. “Its prevalence and associated years lost to disability [YLD] have been steadily increasing in recent decades.”[AME Medical J 2020;5:1-6] 

Based on the Global Health Data Exchange registry, HF prevalence and HF-related YLD have increased by approximately 36 percent between 1990 and 2017. By 2030, HF prevalence and HF-related YLD are expected to increase by approximately 15 percent and 10 percent, respectively. [AME Medical J 2020;5:1-6] 

“HF poses a significant disease burden because patients are at increased risk of recurrent hospitalizations and even death,” he continued. “Even with current standard-of-care [SoC] HF treatments, nine out of 10 patients may remain symptomatic.” [JACC Heart Fail 2018;6:465-473] 

“Moreover, approximately a third of patients with HFrEF may be at high risk of hospitalization or CV death after several years, including those who appear to be stable,” stressed Butler. [Circulation 2004;110:2618-2626]

“Each episode of hospitalization for HF [HHF] further increases patients’ risk of mortality,” he added. “Since repeat HHF is a strong predictor of mortality for these patients, providing optimal therapy that helps prevent HHF should be of highest priority.” [Mil Med 2017;182:e1932-e1937]  

However, the CHAMP-HF (Change the Management of Patients with Heart Failure) registry reported persistence of significant gaps in the use and dose of guideline-directed medical therapy in patients with HFrEF, including nonprescription of recommended therapies or use of below-target doses of approved therapies due to intolerance. [J Am Coll Cardiol 2018;72:351-366]  

“There remains a residual risk of HHF or death despite the use of currently recommended HF therapies,” Butler pointed out. [Eur J Heart Fail 2016;37:2129-2200; N Engl J Med 2014;371:993-1004] “Thus, aside from optimizing currently available therapies, there is also an unmet need for newer HF treatments.”

DAPA-HF trial: Dapagliflozin in HFrEF with or without T2DM
First approved for use in patients with type 2 diabetes mellitus (T2DM), the SGLT2 inhibitor dapagliflozin has emerged as an important component of foundational quadruple therapy for HFrEF due to its HF benefits, which were demonstrated in patients with or without T2DM in the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) trial. [Cell Metab 2019;30:847-849; N Engl J Med 2019;381:1995-2008]    

DAPA-HF was an international, multicentre, parallel-group, randomized, double-blind trial that included 4,744 patients with New York Heart Association (NYHA) class II, III or IV HF and an ejection fraction ≤40 percent (HFrEF), with or without T2DM. The patients were randomly assigned to receive either dapagliflozin 10 mg or placebo, given orally once daily in addition to SoC. The primary composite endpoint was time to first occurrence of a worsening HF event (defined as HHF or an urgent visit resulting in intravenous therapy for HF) or CV death, and the median duration of follow-up was 18.2 months. [N Engl J Med 2019;381:1995-2008]  

Results showed that dapagliflozin was associated with a significant relative risk reduction (RRR) of 26 percent vs placebo for the primary endpoint (hazard ratio [HR], 0.74; 95 percent confidence interval [CI], 0.65 to 0.85; p<0.001). The statistically significant RRR of the primary endpoint was met early in the trial, at day 28 (HR, 0.51; 95 percent CI, 0.28 to 0.94; p=0.03). [N Engl J Med 2019;381:1995-2008; JAMA Cardiol 2021;6:499-507]  

Dapagliflozin’s benefit in the primary endpoint was observed regardless of whether patients had T2DM or not. Compared with placebo, dapagliflozin also significantly reduced the risks of worsening HF (HR, 0.70; 95 percent CI, 0.59 to 0.83; p=0.00003) and CV death (HR, 0.82; 95 percent CI, 0.69 to 0.98; p=0.029 in patients with or without T2DM. (Figure 1) It also significantly reduced the risk of all-cause mortality vs placebo (HR, 0.83; 95 percent CI, 0.71 to 0.97; p=0.022). [N Engl J Med 2019;381:1995-2008]


In terms of tolerability profile, comparable rates of adverse events related to volume depletion, renal dysfunction and hypoglycaemia were reported in the dapagliflozin and placebo arms. [N Engl J Med 2019;381:1995-2008]  

Based on DAPA-HF results, dapagliflozin was the first SGLT2 inhibitor approved by the FDA and in Hong Kong for treatment of adult patients with symptomatic chronic HFrEF (NYHA class II–IV). Currently in Hong Kong, dapagliflozin is the only SGLT2 inhibitor approved for this indication. [https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-typeheart-failure; Forxiga Hong Kong Prescribing Information]

Dapagliflozin as part of HFrEF SoC
“It is important to point out that a majority of patients in DAPA-HF were already on guideline-directed medical therapy and were receiving multiple medications for HFrEF at study baseline,” noted Butler. “In fact, at the start of the trial, >90 percent of patients were receiving a diuretic, a beta-blocker and an angiotensin drug [ie, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI)].” [N Engl J Med 2019;381:1995-2008]  

“The European Society of Cardiology [ESC] also acknowledged a sub-analysis of DAPA-HF, which demonstrated that dapagliflozin produced significant improvements in quality of life as assessed by the Kansas City Cardiomyopathy Questionnaire [KCCQ] in patients with HFrEF. This is of high clinical value,” he added. [Circulation 2020;141:90-99; Eur J Heart Fail 2020;22:1495-1503] 

“Based on the results of DAPA-HF and dapagliflozin’s consistent clinical benefits observed across a broad range of patients with HFrEF, dapagliflozin is now considered to be one of the four pillars in HFrEF management alongside other oral HFrEF therapies shown to reduce the risks of CV mortality and HHF [ie, ARNIs, ACEIs, ARBs, beta-blockers, and mineralocorticoid receptor antagonists (MRAs)],” emphasized Butler. [N Engl J Med 2019;381:1995-2008; Circulation 2020;141:100-111; Eur J Heart Fail 2020;22:1247-1258; Eur Heart J 2020;41:2379-2392; Cell Metab 2019;30:847-849]

In the 2021 American College of Cardiology (ACC) expert consensus on optimization of HF management, SGLT2 inhibitors are included as a component of first-line quadruple therapy for patients with HFrEF. (Figure 2) [J Am Coll Cardiol 2021;77:772-810]


According to the ACC, guideline-directed medical therapy should be started immediately in patients with HFrEF since delayed initiation, which is associated with treatment inertia, is specifically a challenge with starting SGLT2 inhibitor therapy (ie, dapagliflozin). [J Am Coll Cardiol 2021;77:772-810; Circ Heart Fail 2020;13:e008030] In addition, the ACC expert consensus recommends that, unless contraindicated, an SGLT2 inhibitor should be added for patients with chronic HFrEF who are already receiving ARNI/ACEI/ARB, beta-blocker and MRA therapies. This makes dapagliflozin the first SGLT2 inhibitor to be approved for HFrEF, a vital component of HFrEF management. [J Am Coll Cardiol 2021;77:772-810; Circ Heart Fail 2020;13:e008030]  

The clinical benefits of dapagliflozin have also been recognized by the ESC, which highlighted the clinical importance of its timely initiation in patients with HF, since reductions in important clinical events were seen within weeks of initiating treatment. As HFrEF is associated with severely impaired survival, timely initiation of a therapy with proven benefits on outcomes including mortality is crucial. [Eur J Heart Fail 2020;22:1495-1503]  

“The conventional sequence for initiating HFrEF therapy is by the order in which they were tested in clinical trials,” noted Butler. “Prescribers also tend to titrate each drug to the target dose used in clinical trials before adding another therapy. Unfortunately, this means delaying the initiation of therapies demonstrated to reduce morbidity and mortality.” [Circulation 2021;143:875-877]  

Dapagliflozin has emerged as a crucial component of HFrEF treatment. Results from DAFA-HF as well as recommendations from the ACC and ESC highlight the importance of early initiation of dapagliflozin in patients with chronic HFrEF who are already receiving ARNI/ACEI/ARB, beta-blocker and MRA treatment in order to improve outcomes by preventing HHF and reducing the risk of CV mortality.

HF burden and dapagliflozin use in Hong Kong

HF situation in Hong Kong

“Detailed surveillance data of HF are limited in Hong Kong,” reported Tse. “Nevertheless, HF remains an important cause of hospitalization and mortality locally.”  

“We previously conducted a retrospective observational study with the Hong Kong Heart Failure Registry of consecutive Chinese patients hospitalized for new-onset HF between 2005 and 2012,” he shared. “We found that 5 years after diagnosis, the all-cause mortality rate for patients with HF was 54 percent, while CV mortality rate was 20.7 percent.” [J Card Fail 2016;22:600-608]

This registry included a total of 1,940 patients, of whom 54.2 percent were female. The mean age of the study population was 78.2 ± 11.8 years. During this period, the rate of new hHF was 0.59 per 1,000 individuals. The most prevalent comorbidities were hypertension (69.8 percent), DM (35.9 percent) and coronary artery disease (29.3 percent), and 52.3 of patients had HF with preserved EF. [J Card Fail 2016;22:600-608]  

“The high all-cause mortality rate in our registry is likely due to most patients being elderly with multiple comorbidities,” suggested Tse. [J Card Fail 2016;22:600-608]  

Implications of dapagliflozin’s approval for HFrEF treatment
“The use of SGLT2 inhibitors is not yet common in patients with HFrEF in Hong Kong,” said Tse. “In our registry, about a third of patients with HF also had DM. However, based on our experience, only about 10 percent of patients with HFrEF and DM are on SGLT2 inhibitors.” [J Card Fail 2016;22:600-608]  

“Most patients in Hong Kong who have both HFrEF and T2DM are likely to be on dipeptidyl peptidase-4 [DPP-4] inhibitors since these drugs were approved before SGLT2 inhibitors,” he explained. “Dapagliflozin was only approved for DM in Hong Kong in 2014. However, with its recent HFrEF indication approved by the US FDA, we expect to see dapagliflozin’s increased use not only in patients with T2DM and HFrEF, but also in those with HFrEF in general.” [https://www.astrazeneca.com/media-centre/press-releases/2021/forxiga-approved-in-china-forheart-failure.html;Forxiga Hong Kong Prescribing Information]  

“Although currently recommended by the ACC as part of first-line treatment for patients with HFrEF, dapagliflozin prescription is limited by the reimbursement constraints within Hong Kong’s Hospital Authority,” said Tse. “Since the use of dapagliflozin for HFrEF currently entails an out-of-pocket expense for our patients, our current strategy is to discuss with patients the current guideline recommendations and advantages of dapagliflozin use.” [J Am Coll Cardiol 2021;77:772-810] 

“Dapagliflozin use may also result in weight loss, and this may be a concern in patients with low body mass index,” he noted. “Genitourinary infections are also a common adverse effect. Patients should be warned of this increased risk of infection and advised to take precautionary measures.” [Forxiga Hong Kong Prescribing Information]  

“Based on the safety and efficacy results of DAPA-HF and current guideline recommendations, the benefits of dapagliflozin in patients with HFrEF occur early. In the absence of contraindications and cost concerns, it is advisable to initiate treatment as early as possible to optimize patient outcomes,” said Tse. [N Engl J Med 2019;381:1995-2008; Eur J Heart Fail 2020;22:1495-1503; J Am Coll Cardiol 2021;77:772-810]

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