SGLT2 inhibitors: between the zeal of the clinical studies and the challenges of the day-to-day practice

Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have demonstrated efficacy in reducing cardiovascular deaths and hospitalisations associated with heart failure patients. Despite well-established benefits observed in clinical trials, their real-world application remains underexplored. The purpose of this quality improvement project was to investigate and address the gap between evidence-based guidelines and the practical application of SGLT2i therapy in patients with heart failure with reduced ejection fraction (HFrEF).

The medical records were assessed in retrospect for HFrEF-related admissions at our cardiac centre. The main target of assessment was the dapagliflozin prescriptions in eligible patients. After the first cycle of data collection and analysis, several interventions, in the form of targeted teaching, empowering pharmacists, and utilising digital tools, were employed to improve compliance with prescriptions. After the implementation of our measures, a further cycle of data collection and analysis was carried out.

In the first cycle, 31% of 225 HFrEF patients, aged 74 ± 15 years, received dapagliflozin or had plans for its initiation. Prescription rates were influenced by age (mean 69 vs. 76 years, p<0.001) and admission under cardiology (70% vs. other specialties, p<0.001), while gender and diabetes had no impact. In the second cycle, 52% of 172 HFrEF, aged 74 ± 14 years, received dapagliflozin or had plans for its initiation. Prescription rates correlated with age (71 vs. 79 years, p<0.001) and admission under cardiology (59% vs. other specialties, p=0.002), with male patients more likely to be initiated on dapagliflozin (p=0.005).

Our quality improvement project sheds light on the challenges and opportunities in implementing dapagliflozin therapy for patients with HFrEF in a real-world clinical setting. The interventions introduced led to a substantial improvement in prescription rates, indicating the potential for positive change. There is a need for ongoing efforts to bridge the gap between evidence-based guidelines and clinical practice.

Introduction

Dapagliflozin is a well-established treatment for type 2 diabetes mellitus (T2DM) that belongs to a class of medications called sodium-glucose cotransporter type 2 inhibitors (SGLT2i). It exerts its hypoglycaemic effect through reversibly inhibiting SGLT2 in the renal proximal convoluted tubule to reduce glucose re-absorption and increase urinary glucose excretion.

Several well-designed randomised-controlled trials were conducted to assess the cardiovascular safety and efficacy of dapagliflozin, when administered at a dose of 10 mg once daily, in reducing cardiovascular events and related hospitalisations associated with heart failure (HF) regardless of the presence of T2DM.

In the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) study, treatment with dapagliflozin decreased mortality and hospitalisations, as well as improved the quality of life, for patients with heart failure with reduced ejection fraction (HFrEF).¹ In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial, dapagliflozin was associated with a reduction in the primary outcome of worsening HF or cardiovascular mortality in patients with HF with mildly reduced or preserved ejection fraction.²

The exact mechanisms by which dapagliflozin produces its cardioprotective benefits are uncertain, and more research is underway. This impact is independent of its hypoglycaemic effect. Therefore, it has become an essential therapy option for decreasing cardiovascular risk.

Real-world utilisation of SGLT2i in HF

In a pivotal study conducted by Pierce et al. in the US, the utilisation of SGLT2i within the context of HFrEF management was rigorously examined. This retrospective cohort investigation sought to elucidate the alignment between clinical practice and established guidelines, which advocate for SGLT2i therapy to ameliorate cardiovascular mortality and HF-related events. Astonishingly, the study’s findings reveal a striking discrepancy between guideline-endorsed strategies and their implementation in real-world scenarios. Specifically, only 20.2% of eligible patients were prescribed SGLT2i upon their hospital discharge, signalling a substantial gap in the translation of evidence-based care into clinical practice.³

Amid this overarching narrative, the study delved deeply into the intricate web of demographic and clinical factors that impact SGLT2i prescription rates. Predictably, patients with concomitant T2DM displayed a heightened likelihood of receiving SGLT2i prescriptions (26.2% for those with T2DM vs. 15.5% without, p<0.001), underscoring T2DM’s pivotal role in driving SGLT2i initiation. Moreover, the study illuminated that patients prescribed SGLT2i were more prone to concurrently receiving other guideline-recommended therapies, such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin-receptor blockers (ARB), and mineralocorticoid-receptor antagonists (MRA). A noteworthy observation emerged, however: a mere fraction of patients (less than 10%) benefited from comprehensive therapeutic approaches involving quadruple medical therapy, encompassing SGLT2i, ACEi/ARB/ARNI (angiotensin-receptor/neprilysin inhibitor), beta blocker, and MRA prescriptions upon hospital discharge.³

While the study unveiled promising trends in the escalating quarterly rates of SGLT2i prescription over the study duration, it simultaneously underscored significant variations across diverse healthcare institutions. Importantly, this variability persisted even after meticulous adjustment for patient and hospital characteristics, highlighting the multi-faceted influence of clinician and institutional practices. Potential drivers of this divergence encompassed factors such as awareness of guideline recommendations, clinician comfort levels with SGLT2i therapy, formulary constraints, and nuanced insurance coverage. In essence, Pierce et al.’s study sheds light on the urgency of bridging the gap between evidence-based guidelines and clinical reality, accentuating the critical need to optimise and standardise SGLT2i utilisation in HFrEF management for the ultimate betterment of patient outcomes.³

In this work, we present a sample of real-life compliance to the guidelines for dapagliflozin therapy prescription in patients with an established diagnosis of HF. We specifically assessed the adherence to the National Institute for Health and Care Excellence (NICE) guidance for adult patients with HFrEF, which states that “Dapagliflozin is recommended as an option for treating symptomatic chronic heart failure with reduced ejection fraction in adults, if it is used as an add-on to optimised standard care”.⁴

After auditing compliance with the therapy, we introduced easily applicable, reproducible measures that could be incorporated in day-to-day practice, and we assessed the effectiveness of these measures in improving adherence to the established guidelines for prescribing dapagliflozin in eligible patients with HFrEF.

Method

Data collection

The medical records were assessed in retrospect for both elective as well as emergency admissions to the medical, cardiology, and the cardiothoracic surgery wards at our tertiary referral centre for cardiology in the UK for the month of August 2022.

The records were initially screened for the presence of HFrEF as a primary diagnosis or comorbidity. HFrEF is defined when the left ventricular ejection fraction (LVEF) is lower than 40%. The records with HFrEF as a diagnosis/comorbidity were assessed further for dapagliflozin prescriptions, or a documented plan in the discharge letter to initiate dapagliflozin by the heart failure team in the community or by the patients’ general practitioner, taking into consideration the presence or absence of contraindications (severe renal failure with estimated glomerular filtration rate [eGFR] <15 ml/min/1.73 m², type 1 diabetes, and critical peripheral vascular disease). After the implementation of our proposed measures to improve dapagliflozin prescription in eligible patients, a further round of data collection and analysis was completed in a similar manner for the month of May 2023.

Implementation of change

Several interventions were employed to implement change. First, doctors in training were targeted via dedicated consultant teaching, which looked at the management of HF as a whole, but specifically highlighted SGLT2i as a novel intervention in HF practice. Second, heart failure specialist nurses were empowered to educate patients at the bedside, who were newly diagnosed with HFrEF, including daily carbohydrate intake, red flags and sick days. At a trust level, two medical grand rounds were held aiming at updating the wider medical body on updates in HF management. We also leveraged our digital capacity by advertising on trust-wide screensavers.

Statistical analysis

Statistical data analysis was performed using RStudio 1.4.1106 running R 4.0.5. Categorical data are presented as n/N (%) and continuous data as mean ± standard deviation (SD). Fisher’s exact and Chi-square tests were used to analyse categorical variables’ contingency tables, while continuous non-parametric data were compared using Wilcoxon rank-sum test.

Results

First cycle

A total of 1,653 admissions were assessed. In 225 (13.6%) (mean age 74 ± 16 years, 70% male) patients, HFrEF was the primary diagnosis or a comorbidity for the hospital admission. A total of 16 patients (7.1%) were excluded from further analysis as they were placed on an end-of-life pathway during the course of admission. There were 15 patients with a documented contraindication for dapagliflozin (six patients had severe renal failure with eGFR <15 ml/min/1.73 m², six patients had type 1 diabetes at risk of ketoacidosis, three patients had critical peripheral vascular disease) who were also excluded from further analysis (table 1).

In the 194 (mean age 74 ± 15 years, 74% male) patients who had HFrEF as a diagnosis, no contraindications for dapagliflozin and were not on an end-of-life pathway; only 60 (31%) patients had either dapagliflozin prescribed or a clear documented plan to initiate it in the community. The mean age of patients who were prescribed SGLT2i versus patients who were not prescribed SGLT2i was 69 versus 76 years, respectively (p<0.001). Patients who were prescribed dapagliflozin were more likely to be admitted under the care of the cardiology team, in contrast to other specialties (70% cardiology vs. 8.3% cardiothoracic surgery vs. 10% medical subspecialties vs. 12% medicine of the elderly, p<0.001). Neither the gender nor the presence of T2DM as a comorbidity impacted the dapagliflozin prescription rates. In patients who were admitted under the care of the cardiology team, neither gender, age nor the presence of T2DM had an impact on the rates of dapagliflozin prescriptions (table 2).

Second cycle

A total of 1,417 patient admissions were assessed. There were 172 (12.1%) (mean age 74 ± 15 years, 72% male) admissions where HFrEF was the main diagnosis or co-existed as a morbidity. There were 24 (14%) patients excluded from further analysis as they were placed on an end-of-life pathway. A total of 12 (8%) patients had a clearly documented contraindication for dapagliflozin (five patients had critical peripheral vascular disease, five patients had severe renal failure with eGFR <15 ml/min/1.73 m², and two patients had type 1 diabetes), and, thus, were excluded from further analysis (table 1).

There were 136 (mean age 74 ± 14 years, 74% male) patients who were eligible for dapagliflozin and had no documented contraindication. A total of 71 (52%) had dapagliflozin prescription on discharge or a clear plan to initiate it in the community. Patients on dapagliflozin were younger (71 vs. 79 years, p<0.001) and were admitted under the care of the cardiology team (59% vs. 23% cardiothoracic surgery, 7% medical subspecialties, and 11% medicine of the elderly, p=0.002). The patients’ gender had no effect on the prescription rates. T2DM also did not impact the dapagliflozin prescription rates. In patients who were admitted under the care of the cardiology team, male patients were more likely to be initiated on dapagliflozin (p=0.005) (table 3).

There was no statistical difference in any of age, gender, the presence of T2DM or the discharge team between the two rounds/cycles of assessment that could have contributed to the statistically significant difference in the rates of dapagliflozin prescription (table 4).

Discussion

DAPA-HF trial

The DAPA-HF trial, a pivotal randomised, placebo-controlled study, investigated the cardiovascular benefits of dapagliflozin in patients with HFrEF, regardless of their diabetic status. The trial revealed a remarkable 26% reduction in the risk of the primary composite outcome, which included incidents of worsening HF (hospitalisations or urgent visits with intravenous therapy) and death from cardiovascular causes. Notably, the dapagliflozin group exhibited a 4.5% absolute risk reduction in this composite outcome compared with placebo.¹

This ground-breaking study also underscored the broader therapeutic potential of dapagliflozin beyond cardiovascular outcomes. Patients treated with dapagliflozin experienced a clinically meaningful improvement in symptoms of HF, with a statistically significant reduction in the total symptom score on the Kansas City Cardiomyopathy Questionnaire. The observed benefits extended across the diabetic spectrum, with similar efficacy demonstrated in patients with and without T2DM, reaffirming dapagliflozin’s substantial impact on HF management. Moreover, the trial’s rigorous evaluation of patients with advanced HF and chronic kidney disease revealed dapagliflozin’s favourable safety and efficacy profile in this high-risk population. These findings provide compelling evidence of SGLT2i, such as dapagliflozin, as a potent therapeutic avenue for improving HF outcomes, transcending their traditional role in diabetes care.¹

Potential global impact of SGLT2i in HF

In one research study reported by Talha et al., the potential benefits of implementing SGLT2i therapy across different levels of LVEF in HF management was examined. Drawing from estimates of HF prevalence and LVEF distribution, the research anticipates that optimal SGLT2i utilisation could prevent a substantial seven to eight million worsening HF events and cardiovascular deaths globally over a three-year period. This encompasses a significant impact, with approximately 5.2 million events potentially averted in patients with reduced LVEF (HFrEF) and an additional 2.3 million in those with mid-range or preserved LVEF (HFmrEF and HFpEF).⁵

In the analysis of outcomes, the study projects that applying SGLT2i in patients with LVEF ≤40% could translate to averting or postponing between 2.98 and 5.13 million total HF hospitalisations, 4.07 and 5.58 million HF hospitalisations coupled with cardiovascular (CV) deaths, and 4.51 to 5.99 million worsening HF events and CV deaths over a three-year span. For patients with LVEF >40%, the estimated benefits encompass 1.56 to 2.09 million total HF hospitalisations, 1.83 to 2.40 million HF hospitalisations and CV deaths, and 2.10 to 2.56 million worsening HF events and CV deaths within the same time frame. The study underscores the potential global impact of SGLT2i incorporation, highlighting its crucial role in HF management across diverse regions and resource settings.⁵

Clinical inertia

Clinical inertia, a well-documented phenomenon, poses a significant challenge in the optimal prescribing of evidence-based medications for HFrEF. Despite compelling evidence showcasing reduced mortality rates and improved quality of life associated with guideline-recommended therapies, many patients with HFrEF are not prescribed these medications. The intricate landscape of clinical inertia in HFrEF prescribing is illuminated by a recent qualitative study, conducted by Trinkley et al., that engaged both cardiology and primary-care clinicians. This study delved into the underlying factors contributing to clinical inertia, shedding light on its multi-faceted nature across various levels of healthcare delivery.⁶

In the context of HFrEF prescribing, clinical inertia manifests through delayed intervention or treatment initiation, even in stable patients where evidence supports the need for treatment intensification. The study revealed that clinicians often hesitate to adjust medication regimens, fearing disruption or ‘rocking the boat’. Misconceptions about evidence-based recommendations, uncertainties about medication safety, and differing perspectives between generalists and specialists, further compound the issue. Addressing clinical inertia in HFrEF prescribing demands targeted interventions that enhance clinician education, patients’ education on their condition and available therapy options, which, in turn, promote informed decision-making, and align policy-level incentives with patient-centered care.⁶

Novel scores like the QUAD score have been previously proposed as a solution to address clinical inertia, particularly in optimising medical therapy for HF patients. If these scores were widely implemented in clinical practice, they could serve as a standardised benchmark for evaluating the effectiveness of treatment optimisation in such patients.⁷

Our experience with implementing change

Our primary challenge was building a multi-disciplinary coalition of doctors, pharmacists and allied healthcare professionals with the sense of urgency to deliver the change. Second, engaging all stakeholders at an organisational level including non-cardiology specialties was a challenge. We tackled this challenge with educational rounds to educate and empower those not so familiar with SGLT2i use. Finally, we anticipate that the ongoing challenge will be to sustain the momentum of change after the initial sense of urgency, via short-term goals and long-term audits of concordance.⁸

Limitations of our study

Our quality improvement project has inherent limitations that warrant consideration. First, it is based on a single-centre approach, conducted at a tertiary referral centre for cardiology in the UK. As such, the findings may not be universally applicable to diverse healthcare settings, and regional variations in clinical practices might impact generalisability. The retrospective design of the project also introduces limitations, relying on medical records, with the potential for incomplete or inaccurate information. In addition, while many patients had a documented plan in the hospital discharge letters to initiate dapagliflozin after discharge, we could not confirm if those prescriptions were issued. This design also restricts our ability to establish causation, allowing only the identification of associations. The project also assessed data for specific periods, and evolving clinical practices during the study period could influence outcomes. Despite evaluating a substantial number of hospital admissions, the sample size of patients eligible for dapagliflozin therapy was relatively small, potentially affecting statistical power. Our project focused specifically on HFrEF patients, and caution is advised when applying these findings to a broader HF population. In addition, the design of our project did not otherwise highlight newly diagnosed patients, or other HF pillar treatments that were newly prescribed during the course of admission, but rather specifically addressed a single pillar of treatment, SGLT2i. While interventions were introduced to improve compliance, the project design may not fully capture the long-term impact of these measures on clinician behaviour and prescription patterns.

Conclusion

Patients with HFrEF who are admitted under the cardiology team are more likely to receive dapagliflozin following best practices to reduce cardiovascular risk. However, we have demonstrated that the overall rate of prescription remains low in real-life practice. While there are many factors that could contribute to this inertia, the exact reasons are not entirely clear. Given the potential global impact of SGLT2i in HF, it is crucial to raise our efforts to overcome this inertia.

A good starting point would be to facilitate informative discussions with our colleagues from different cardiology subspecialties, as well as non-cardiology specialists, in addition to primary-care physicians, to highlight the impact of this class of drugs on HF patient outcomes. This, in addition to establishing pathways to encourage the appropriate initiation of this life-saving therapy, with full support from HF specialists, would definitely be a step in the right direction.

Key messages

• Despite the compelling evidence of clinical trials, real-life utilisation of sodium-glucose cotransporter t2 inhibitors (SGLT2i) remains low in real-life practice
• Education is key to overcome inertia in prescribing guideline-directed medical therapy in heart failure
• A multi-disciplinary approach is vital to overcome challenges associated with implementation of change in real-world practice

Conflicts of interest

None declared.

Funding

None.

Study approval

This study falls outside the scope of the UK policy framework for health and social care research and was registered with University of Southampton NHS foundation Trust as a service evaluation. It is a retrospective analysis of routinely collected anonymised data. The study was carried out in accordance with the code of ethics of the world medical association (Declaration of Helsinki).

Data availability

The data underlying this article will be shared upon reasonable request to the corresponding author.

References

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2. Solomon SD, McMurray JJV, Claggett B et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089–98. https://doi.org/10.1056/NEJMoa2206286

3. Pierce JB, Vaduganathan M, Fonarow GC et al. Contemporary use of sodium-glucose cotransporter-2 inhibitor therapy among patients hospitalized for heart failure with reduced ejection fraction in the US. JAMA Cardiol 2023;8:652–61. https://doi.org/10.1001/jamacardio.2023.1266

4. National Institute for Health and Care Excellence. Dapagliflozin for treating chronic heart failure with reduced ejection fraction. TA679. London: NICE, 2021. Available from: https://www.nice.org.uk/guidance/TA679

5. Talha KM, Butler J, Greene SJ et al. Potential global impact of sodium-glucose cotransporter-2 inhibitors in heart failure. Eur J Heart Fail 2023;25:999–1009. https://doi.org/10.1002/ejhf.2864

6. Trinkley KE, Dafoe A, Malone DC et al. Clinician challenges to evidence-based prescribing for heart failure and reduced ejection fraction: a qualitative evaluation. J Eval Clin Pract 2023;29:1363–71. https://doi.org/10.1111/jep.13885

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