Sodium glucose cotransporter 2 inhibitors for all HFrEF patients: can we afford it? A cost-effectiveness analysis of dapagliflozin

The global burden of heart failure (HF) remains tremendous, with an estimated 26 million people affected worldwide, leading some to describe it as a global epidemic.1 HF is still related to high morbidity and mortality and is responsible for a large part of the total health expenditure on cardiovascular diseases. In recent decades, outstanding successes have been achieved in the treatment of chronic heart failure with reduced ejection fraction (HFrEF). For several pharmacotherapies, excellent evidence is available for substantial improvement of morbidity and mortality in these patients. Thus, a combination of beta-blockers, renin–angiotensin system inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]) and mineralocorticoid receptor antagonists (MRAs) has been established as standard therapy in all national and international guidelines. After several years without positive data for new pharmacotherapies, the impressive results of the PARADGIM-HF trial in 20142 led to the inclusion of the angiotensin receptor neprilysin inhibitor (ARNi) sacubitril-valsartan into the guidelines as a treatment for HFrEF. In recent years, various studies have produced results that have brought a completely new drug class into the focus as a possible therapy for chronic HF, the sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2 inhibitors were originally developed as anti-diabetes agents and the initial diabetes outcome trials surprisingly showed that their use was related to reduced rates of incident HF. Currently, a large body of evidence from randomised controlled trials and observational studies demonstrates a significant decrease in hospitalisations due to HF with SGLT2 inhibitors compared with placebo or other anti-diabetes drugs in type 2 diabetes.3 This stimulated the initiation of studies specifically dedicated to investigate the effects of SGTL2 inhibitors in HF. Recently, the DAPA-HF trial demonstrated numerous beneficial effects of dapagliflozin in addition to standard therapy in adults with chronic HFrEF (e.g. improved health status and survival or reduced need for hospitalisation).4 Of note, these findings were similar in patients with and without diabetes. A methodically excellent paper from an Australian working group, that has been published recently in the European Journal for Preventive Cardiology, provides initial data that will help to answer this question.5 Savira and colleagues assessed the cost-effectiveness of dapagliflozin in addition to standard care compared with standard care alone in patients with HFrEF. For this purpose they developed a decision analytic Markov model to simulate the progression of chronic HF based on a hypothetical population of 1000 participants considering the clinical characteristics of the participants in the DAPA-HF trial4 (i.e. a mean age 66 years, a left ventricular ejection fraction of 40% or less with New York Heart Association class II, III and IV symptoms, and receiving standard care for HF, without severe kidney dysfunction or kidney failure and without type 1 diabetes or hypotension). The main outcome in this study was ‘the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained’. ICER is a summary measure representing the economic value of an intervention, compared with an alternative treatment and is calculated by dividing the difference in total costs (incremental cost) by the difference in the chosen measure of health outcome or effect (incremental effect) to provide a ratio of ‘extra cost per extra unit of health effect’ – for the more expensive therapy versus the alternative. The measure of health effect used in this study was QALY, which is frequently used in this context.6 In decision-making, ICERs are useful for the value of a new intervention that is more expensive than previous therapies but generates an improved health effect.6,7 Using this approach, the authors calculated that – over a lifetime horizon – the addition of dapagliflozin would prevent 88 acute HF hospitalisations and yield an additional 416 years of life and 288 QALYs. Based on Australian sources additional costs of A$3,692,440 were calculated, meaning an ICER of A$12,482 per QALY gained. The authors carried out various sensitivity analyses, showing very well the robustness of the estimate; that is, the major findings remained stable if other assumptions for the risk of HF progression were made. The calculated costs of approximately €7600 (A$12,482) per QALY gained are well below the threshold of approximately €22,300 to €33,500 (£20,000 to £30,000) per QALY that is commonly considered as cost-effective for a (new) technology or treatment by the UK’s National Institute for Health and Care Excellence (NICE).8 Taking into account the still poor prognosis of chronic HF, one could even apply the much higher threshold of approximately €55,750 (£50,000) for life-extending treatments at the end of life that is proposed by NICE.8 This clearly demonstrates that dapagliflozin might be a highly cost-effective supplementary option in HF treatment. An especially important finding is that cost-effectiveness has been demonstrated regardless of whether diabetes was present or not. No differences were found between patients with and without diabetes. It even seemed to be the case that over a lifetime horizon dapagliflozin was more cost-effective in individuals without than in those with diabetes. This finding may be due to the longer life expectancy of individuals without diabetes and the resulting higher number of potentially prevented hospital admissions, but this certainly needs further investigation. This paper is the first one reporting the cost-effectiveness of dapagliflozin in the setting of HF. The authors provide solid first evidence demonstrating that the use of dapagliflozin in addition to standard care might be cost-effective compared with standard care alone among patients with HFrEF, regardless of the diabetic status. These findings might have important implications for the therapeutic role of dapagliflozin beyond its glucose-lowering effect. The data presented are particularly of interest since in May 2020 the US Food and Drug Administration (FDA) approved dapagliflozin as the first SGLT2 inhibitor for adults with HFrEF and NYHA classes II–IV.9 This approval provides affected patients an additional treatment option that is related to improved quality of life, reduced need for hospitalisation and better survival. On the other hand, this also raises the question as to which patients this therapy should be recommended for. Current evidence might indicate that it could be beneficial for a large proportion of HFrEF patients. However, it still seems too early for such a general recommendation. These questions can certainly not be answered by the data presented alone. In this respect, relevant limitations must also be considered (e.g. the restriction on dapagliflozin as well as on the inclusion criteria and outcome variables of the DAPA-HF trial, the Australian healthcare perspective). It is still necessary to investigate the cost-effectiveness of SGTL2 inhibitors in HF treatment for other healthcare systems; for example, in Europe or the USA. Furthermore, a direct comparison of SGLT2 inhibitors with other ‘new’ HF pharmacotherapies, in particular with the ARNi sacubitril-valsartan, would also be of interest as well as analyses for other HF forms, particular patients with a preserved left ventricular ejection fraction in which diabetes is frequently present and still no evidence-based pharmacotherapy is available. The current study perfectly complements the strong evidence for the beneficial clinical effects of SGTL2 inhibitors in HF patients. Dapagliflozin not only influences many prognostic, health-related and clinical parameters, but also seems to be a cost-effective therapy in this setting. The findings will certainly stimulate further research, which is now essentially needed to evaluate further the role of SGLT2 inhibitors in HF therapy. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author(s) received no financial support for the research, authorship, and/or publication of this article.