Trends in use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) in Australia in the era of increased evidence of their cardiovascular benefits (2014–2022)

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are two classes of glucose-lowering medicines [1]. SGLT2i prevents the kidneys from reabsorbing glucose to the systemic circulation, resulting in urinary glucose excretion; GLP-1RA stimulates glucose-dependent insulin secretion and suppresses glucagon secretion, leading to lower plasma glucose levels [1]. Due to their ability to reduce blood glucose, SGLT2i and GLP-1RA have been used to treat type 2 diabetes (T2D) for over a decade [2, 3].

Since 2015, clinical trials have also shown these medicines significantly reduce cardiovascular events among patients with T2D and established cardiovascular disease (CVD) or high cardiovascular risk (Table S1). SGLT2i reduces hospitalisations for heart failure by 27–35% and major adverse cardiovascular events (MACE) in patients with T2D and at high cardiovascular risk by 14–20% [1]. Similarly, GLP-1RA reduces MACE by 12% among people with T2D [4]. Due to the cardiovascular benefits of SGLT2i and GLP-1RA, recent clinical guidelines for diabetes treatment recommend the use of SGLT2i or GLP-1RA for people with concomitant T2D and other cardiovascular risk factors [5, 6].

More recent trials have shown protective effects of SGLT2i in other populations, regardless of T2D: SGLT2i significantly decreases re-hospitalisations and cardiovascular deaths among people with heart failure [7], and reduces end-stage kidney disease and renal deaths among people with chronic kidney disease [8]. SGLT2i is now recommended for people with early-stage heart failure [5, 9] and people with chronic kidney disease, regardless of T2D [10]. The Australian Pharmaceutical Benefits Scheme (PBS) also expanded SGLT2i therapeutic indications to include heart failure and chronic kidney disease in January and September 2022, respectively (Table S2). GLP-1RA have also shown significant effects in reducing body weight in people with overweight or obesity [11, 12], but they have not been indicated for treating weight loss in the PBS.

Despite advances in knowledge about the broader cardiovascular benefits of SGLT2i and GLP-1RA, there is limited evidence on trends in the uptake of these therapies among different clinical populations [13] and prescribers [14, 15], particularly in Australia. Prior studies show that SGLT2i and GLP-1RA use among people with T2D have substantially increased worldwide [3]. However, the use of these therapies is still suboptimal in many jurisdictions. A multinational study showed that only 15% of people with T2D were prescribed SGLT2i or GLP-1RA as an add-on therapy between 2017 and 2019 [3], with similar rates observed in Australia during 2012–2017 [2]. As T2D is largely managed in primary care, general practitioners (GPs) prescribe most of the SGLT2i and GLP-1RA [14, 15]. However, GPs have reported the need for further education and engagement with endocrinologists in managing T2D [16]. The role cardiologists, renal physicians and other specialities, in prescribing these medicines is expected to increase with expanding therapeutic indications.

We therefore used dispensing data from a nationally representative sample of Australians in the period 2014–2022 to: 1) quantify trends in SGLT2i or GLP-1RA use in people with evidence of T2D and/or cardiovascular conditions, and by the specialty of prescriber; 2) quantify changes in characteristics of new users of SGLT2i or GLP-1RA; and 3) describe the uptake of specific SGLT2i and GLP-1RA medicines among new users with evidence of cardiovascular conditions.

Our study provides a contemporary perspective on SGLT2i and GLP-1RA use in Australia in the context of increasing clinical evidence of cardiovascular benefits and expanding therapeutic indications for SGLT2i medicines for heart failure. Most new users of SGLT2i and GLP-1RA had evidence of treatment for CVD or CVD risk factors, including T2D. We also observed a rapid increase in the use of SGLT2i among those with evidence of cardiovascular conditions, but not T2D, as well as a rapid increase in prescribing by cardiologists, consistent with the expansion of indications for SGLT2i to include heart failure. In addition, empagliflozin became the most prescribed SGLT2i and dulaglutide or semaglutide the most prescribed GLP-1RA. Accordingly, new users of SGLT2i in 2022 tended to be older, more likely to be male, and have evidence of treatment for heart failure, but not T2D, than in earlier years. Changes in the characteristics of new users of GLP-1RA were less pronounced.

Overall, the increasing trends in SGLT2i and GLP-1RA use suggest that clinicians are applying the best available evidence. While the trends of increasing use found in our study are similar to those seen in Australian studies in earlier years [2, 22, 23], there was a much larger increase from 2016, coinciding with the first trials among people with T2D showing cardiovascular benefits of SGLT2i and GLP-1RA in late 2015 [1]. Moreover, our findings are similar to other countries which also reported increased use of these medicines over time, such as the United Kingdom [2, 24], Denmark [25], Canada [2, 26] and the United States (US) [14, 15, 27].

Notably, the majority of SGLT2i were prescribed by clinicians other than cardiologists, endocrinologists and nephrologists. This is also consistent with prescribing patterns in the US [14, 15] and Denmark [25]. The small percentage of SGLT2i and GLP-1RA prescribed by cardiologists prior to 2022 possibly relates to cardiologists’ lack of confidence in prescribing those agents which are perceived as diabetes drugs [28]. However, we observed a rapid increase in SGLT2i use since the addition of heart failure to PBS indications, alongside an increase in prescribing by cardiologists, and use of these medicines among people with possible evidence of heart failure. The increased prescribing by cardiologists likely also reflects recommendations of using SGLT2i in recent guidelines from cardiac societies [5, 9]. We also observed few SGLT2i dispensings prescribed by nephrologists, which is likely due to the absence of chronic kidney disease as a PBS indication for SGLT2i during the study period. However, no such rapid increase was observed for GLP-1RA, possibly due to the lack of evidence of cardiovascular benefits and reimbursement for people without T2D.

Encouragingly, we found that medicines with higher cardiovascular benefits such as empagliflozin [29] and dulaglutide or semaglutide [30, 31] were the most commonly initiated in the subgroup of new users with evidence of cardiovascular conditions. This was similar to findings among people with T2D with a history of myocardial infarction, stroke or heart failure in the US [15]. This indicates clinicians are up to date with guidelines and clinical evidence of the cardiovascular benefits of these medicines.

The lower proportion of new users with evidence of T2D in recent years shows a tendency for both SGLT2i and GLP-1RA to be used for indications beyond T2D. This was particularly interesting for GLP-1RA, as PBS indications in Australia currently do not support the use of GLP-1RA beyond T2D – inferring the possibility of off-label use for other indications such as weight loss. The higher percentage of female users of GLP-1RA in recent years could similarly be related to the clinical evidence of weight loss of GLP-1RA published in 2021 [11].

Given we used a 10% representative sample of the population, we estimate approximately 670,000 Australians received SGLT2i and/or GLP-1RA during the study period, the majority of whom had evidence of T2D or cardiovascular conditions. Approximately 1.16 million Australians have been diagnosed with T2D, with 60,000 new T2D diagnoses every year [32]. Around 1.15 million Australians are estimated to have one or more self-reported cardiovascular conditions, with over 100,000 having heart failure, and over 250,000 having concurrent diabetes [33]. While not all these people have an indication for the use of SGLT2i or GLP-1RA, based on these estimates there is potential for further optimising the use of SGLT2i and GLP-1RA relative to the large number of Australians with T2D and CVD (including heart failure) [33].

As the body of evidence of benefits of SGLT2i and GLP-1RA continues to grow and their indications expand (e.g. SGLT2i for chronic kidney disease [8, 34–36] and GLP-1RA for weight loss [11, 12]), it is important to continue monitoring patterns of use of these medicines and understanding barriers for their uptake. More research is needed to explore what factors are associated with the use of SGLT2i and GLP-1RA, such as use in clinically indicated populations and across different socio-demographic groups, to provide evidence for further strategies for improving SGLT2i and GLP-1RA use.

Our study has some limitations. First, PBS data do not capture private and public hospital inpatient prescriptions (e.g. for medicines not listed in the PBS such as liraglutide or PBS-listed medicines privately purchased), and so may underestimate SGLT2i and GLP-1RA use. Second, since no information regarding indication for prescribing is available in the PBS data, we derived proxies from dispensing of other medicines, which may be subject to misclassification. Third, there were shortages of some medicines of interest during the study period (Table S2), which may have affected usage patterns. Fourth, given the study period included the COVID-19 pandemic, changes in patient access to health services and prescriber access to educational activities may have affected SGLT2i and GLP-1RA use. However, this may not have a great impact on patient access to health services given there was no reduction in the number of Medicare Benefits Scheme claims (e.g. GP attendance) and PBS dispensings during the pandemic [37].

SGLT2i and GLP-1RA use increased substantially in accordance with the increasing evidence of cardiovascular benefits. The use of SGLT2i and GLP-1RA prescribed by cardiologists increased over time, and rapidly increased from 2022 when the therapeutic indication for heart failure was included in the PBS. In recent years, medicines with higher cardiovascular benefits such as empagliflozin and semaglutide accounted for a large percentage of new users with evidence of cardiovascular conditions. This study shows the diffusion of medicines aligns with new evidence and indications and suggests there is potential to further optimise the use of these evidence-based therapies in Australia.

We acknowledge Melisa Litchfield for her role in providing the data and gaining ethics approval. We thank the Australian Government Services Australia for supplying the data.

JL, SAP, JRG, MOF and JDOC conceived and designed the study. JL undertook analyses with feedback from MOF and JDOC. JL, MOF and JDOC interpreted the results. JL wrote the manuscript with critical comments and revised by SAP, JRG, KHP, AH, DB, ROD, MOF and JDOC. All authors read and approved the final manuscript.

Open Access funding enabled and organized by CAUL and its Member Institutions. This research is supported by the National Health and Medical Research Council (NHMRC) Ideas Grants (grant number: 2002889; grant number: 1183273) and NHMRC Medicines Intelligence Centre of Research Excellence (grant number: 1196900). Dr Falster is supported by a Future Leader Fellowship from the National Heart Foundation of Australia (grant number: 105609) and the Medicines Intelligence Centre of Research Excellence (grant number: 1196900).

The PBS 10% sample was provided by the Australian Government Services Australia under licence. Access to these data by other individuals or authorities is not permitted without the express permission of the approving human research ethics committees and data custodians.