On 1 January 2022, the PBS listing for Forxiga (dapagliflozin) was extended for patients with symptomatic heart failure with LVEF ≤40% as add-on therapy to optimal standard treatment.1 This extended availability is in line with recent evidence of the benefit of the sodium-glucose co-transporter 2 (SGLT2) inhibitor in patients with heart failure with or without diabetes.2
PBS clinical criteria for dapagliflozin in symptomatic heart failure
The new PBS Authority Required (Streamlined) listing for dapagliflozin is for symptomatic (NYHA class II-IV) heart failure and LVEF ≤40%. Its use must be an add-on to standard treatment (which must include a beta-blocker and ACE inhibitor/ARB/ARNI unless contraindicated or not tolerated), and the patient must not be receiving another SGLT2 inhibitor. Notably, there is no requirement for the patient to have diabetes.
The listing corresponds with the push by leading heart failure specialists toward integrating SGLT2 therapy into standard treatment regimens. Cardiologist and director of Sydney Concord Hospital’s Heart Failure Unit and Department of Cardiac Rehabilitation, Professor Andrew Sindone, explains that SGLT2 inhibitors have quickly become an integral part of heart failure treatment, unless contraindicated. “There are now what I describe as four main pillars for managing heart failure: a drug that acts on the renin-angiotensin system (an ACE inhibitor, ARB or ARNI –preferably an ARNI), a beta-blocker, an MRA and an SGLT2 inhibitor,” he says.
DAPA-HF: Dapagliflozin reduces risk of worsening heart failure and CV death in symptomatic heart failure with LVEF ≤40%2
The PBS listing comes in the wake of the DAPA-HF trial,2 the first study investigating the efficacy of an SGLT2 inhibitor in patients with symptomatic heart failure (with LVEF ≤40%) with or without diabetes.2 The trial showed that dapaglifozin reduced the risk of worsening heart failure and death from CV causes in the patient population.2
A total of 4,744 patients with NYHA class II, III, or IV heart failure and LVEF ≤40% were randomised to either dapagliflozin (10 mg daily; n=2,373) or placebo (n=2,371), in addition to recommended therapy for heart failure.2
The primary outcome (a composite of worsening heart failure – hospitalisation or an urgent visit resulting in intravenous heart failure therapy – or cardiovascular death) occurred in 16.3% of patients in the dapagliflozin group and 21.2% in the placebo group (HR, 0.74; 95% CI, 0.65–0.85; P<0.001).
In terms of secondary outcomes, first worsening heart failure event occurred in fewer patients treated with dapagliflozin (10% versus 13.7% for placebo; HR 0.70; 95% CI, 0.59–0.83), and death from cardiac causes occurred in fewer dapagliflozin-treated patients compared to those randomised to placebo (9.6% versus 11.5% respectively; HR, 0.82; 95% CI, 0.69–0.98). Death from any cause occurred in fewer dapagliflozin-treated patients (11.6% of versus 13.9% for placebo. HR, 0.83; 95% CI, 0.71–0.97; nominal p=0.0217). 2
Dapagliflozin was also associated with a 2.3 point increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) health status score at 8 months compared to placebo (p<0.0001),3 reflecting an improvement in patient reported quality of life.3
Subgroup analyses showed that, in addition to diabetes status, the benefit of dapaglifozin was consistent across the age spectrum, diuretic use, use of ARNI therapy (although baseline use of ARNI was low), baseline health status and baseline medication use.3
There was no difference between the groups in the frequency of adverse events related to volume depletion, renal dysfunction and hypoglycaemia. The authors note, “There was no notable excess of any [adverse] event in the dapaglifozin group.”2
Patients with a medical history of diabetes mellitus represented 41.8% of the patient population in both the dapagliflozin and placebo groups. The authors explain, “Findings in patients with diabetes were similar to those in patients without diabetes.”2
The study authors conclude, “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.”2
Dapaglifozin helps achieve the primary goals in HF management: Prof. Sindone
“I’ve got three jobs [when treating my patients]: make the patient feel better, make them live longer, and keep them out of hospital. This [dapaglifozin] ticks all three of those boxes: It leads to a reduction in mortality and a reduction in hospitalisation, and subgroup analyses showed an improvement in quality of life.3 So it does what we want a drug to do. And it’s a clinically meaningful benefit – not just a statistically significant benefit,” notes Prof. Sindone.
“I’ve been putting patients with heart failure on SGLT2 inhibitors since DAPA-HF showed its benefits, and patients come back saying they feel so much better. Heart failure does have a worse quality of life than many other diseases, so this really is meaningful,” adds Prof. Sindone.
The emerging role of SGLT2 inhibitors in heart failure
With the data illustrating benefits of SGLT2 inhibitors in heart failure, Prof. Sindone says there’s no question that these agents should be an integral part of therapy. “I would not like to deny my patients a medication with a potential benefit in reducing mortality and heart failure hospitalisations,” he says.
Major international guidelines for the management of heart failure4-6 have recently been updated and now recommend SGLT2 inhibitors as standard treatment for patients with heart failure with reduced ejection fraction, in combination with an ACE inhibitor/ARB/ARNI, beta-blocker, and MRA, unless contraindicated.
“All four types of drugs should be used in heart failure patients,” explains Prof. Sindone. “That’s what the international guidelines say, and the new Australian guidelines will have guidance in line with this” he says. Prof. Sindone is co-author of the NHF/CSANZ Australian clinical guidelines for the management of heart failure,7 which have recently been updated and due for release shortly.
Clinical practice points on the use of SGLT2 inhibitors
“There are no additional precautions [with the use of dapaglifozin] when used in patients with heart failure to when it’s used in diabetes,” says Prof. Sindone. “If the patient gets diarrhoea, a respiratory tract infection or a urinary tract infection, we advise them to stop the treatment while they’re feeling unwell and restart when they’re feeling fine again,” he says. “I tell my patients they will pass more urine, and that’s what we want. It doesn’t mean they need to drink more fluid,” he adds.
Prof. Sindone notes that the patient’s kidney function may slightly decrease upon initiation of dapaglifozin therapy. “The kidney function will go down a little bit (around 13%) in the first eight weeks, but don’t get stressed. So many doctors stop therapy when this happens, but it’s actually a sign that the patient is responding to the medication due to tubuloglomerular feedback. You just need to wait it out and the renal function will bounce back,” he advises.
For non-congested or euvolaemic patients, Prof. Sindone may reduce concomitant diuretics if there is a risk of dehydration. “If the patient is on hydrocholorothiazide – either alone or in combination with an antihypertensive agent – I stop the hydrochlorothiazide,” he notes, adding that this agent has not been shown to offer any benefit in heart failure.
With respect to advice on potential adverse effects, Prof. Sindone says, “There’s the chance of thrush in women and uncircumcised men, so I advise patients to treat with the usual topical antifungals if this occurs. Also, if someone is having surgery with a general anaesthetic, they should stop the SGLT2 inhibitor three days before the surgery and restart the day after surgery once they are eating or drinking.”
Prof. Sindone notes that adjustments may be needed for concomitant diabetic medication when an SGLT2 inhibitor is initiated. “You need to modify any other antidiabetic agent with the potential to cause hypoglycaemia, for example insulin and sulphonylureas. If the patient is on a sulphonylurea, I discontinue this and initiate the SGLT2 inhibitor. If they are on a DPP4 inhibitor and their glucose control is good, I swap patients over to the SGLT2 inhibitor,” he explains.
A new era of heart failure management heralded with the arrival of SGLT2 inhibitors and ARNIs
Prof. Sindone says that it’s an exciting time in heart failure – an area of medicine that for years saw little progress in outcomes until relatively recently. Much of the excitement surrounds the gains being achieved by introducing SGLT2 inhibitors and ARNIs into heart failure therapy.
The benefits of these newer treatment regimens was recently quantified in a comparative analysis of clinical trial data looking at the outcomes afforded by “comprehensive” therapy (ARNI, beta-blocker, MRA, and SGLT2 inhibitor) versus “conventional” therapy (ACE inhibitor/ARB and beta-blocker) in patients with chronic heart failure with reduced ejection fraction.9 The analysis found that comprehensive therapy resulted in an additional 2.7–8.3 additional years free from cardiovascular death or first hospitalisation for heart failure and 1.4–6.3 additional years of survival compared to conventional therapy, depending on the patient’s age, with younger patients (55 years) benefiting the most.
PBS, Pharmaceutical Benefit Scheme; HF, heart failure; LVEF, left ventricular ejection fraction; CV, cardiovascular; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor II blocker; ARNI, angiotensin receptor neprilysin inhibitor, MRA, mineralocorticoid receptor antagonist; SGLT2, sodium-glucose co-transporter-2; NYHA, New York Heart Association, NHF/CSANZ, National Heart Foundation/Cardiac Society of Australia and New Zealand.
This article was sponsored by Astra Zeneca. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the Forxiga product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.
- Forxiga PBS listing. Available at www.pbs.gov.au
- McMurray JJV et al. Dapaglifozin in patients with heart failure and reduced ejection fraction. N Engl J Med 381;21: 1995–2008.
- Ponikowski P et al. Dapaglifozin in patients with heart failure and reduced ejection fraction – DAPA-HF. Available at https://www.acc.org/latest-in-cardiology/clinical-trials/2019/08/30/21/33/dapa-hf
- Vaduganathan M et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. The Lancet 2020; 396(10244): 121–128.
- Maddox TM et al. 2021 Update to the 2017 ACC Expert consensus decision pathway for optimization of heart failure treatment: Answers to 10 pivotal issues avout heart failure with reduced ejection fraction: A report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021; 77(6):772–810.
- McDonald M et al. CCS/CHFS Heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction. Can J Cardiol 2021; 37: 531–546.
- McDonagh T et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chornic heart failure. Eur Heart J 2021; 42(36): 3599–3726.
- Atherton JJ et al. National Heart Foundation of Australian and Cardiac Society of Australia and New Zealand: Guidelines for the prevention, detection and management of heart failure in Australia 2018. Heart Lung Circ 2018;27:1123–1208.
- Vaduganathan M et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020; 396 (10244): 121–128.