SGLT2 inhibitors in heart failure

Case scenario

Malcolm (68 years old, male) visits your pharmacy with a new prescription for sacubitril/valsartan. He mentions he has recently been diagnosed with heart failure with reduced ejection fraction (HFrEF). You review his records and confirm he is still taking metformin/sitagliptin for type 2 diabetes. Malcolm explains that he has taken this for many years, and that his general practitioner has advised him that his blood glucose control needs to be better. He expresses frustration that the shortness of breath from his heart failure limits his ability to exercise and improve his diabetes. Malcolm hopes that starting this new medicine will improve this.

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Introduction

Heart failure is a clinical syndrome caused by the inability of the heart muscle to provide adequate cardiac output and/or the presence of increased cardiac pressure. This is due to either a structural or functional abnormality of the heart.¹ The clinical syndrome consists of symptoms such as breathlessness and fatigue and may be accompanied by signs of fluid accumulation such as peripheral oedema, elevated jugular venous pressure and pulmonary crackles.¹

In many cases, heart failure may be both preventable and treatable. Choice of treatment depends on the type of heart failure present, with management being primarily pharmacological.¹

Pharmacists play an essential role in optimising pharmacotherapy for heart failure patients, providing recommendations on safe and effective dose titration and appropriate pharmacological management, as well as providing education, counselling and support for adherence.²

Heart failure

Heart failure remains a global public health issue that affects at least 38 million people worldwide.² It is a major cause of hospitalisation in Australia and is associated with significant healthcare costs.³

Heart failure has a poor prognosis and results in markedly reduced quality of life.¹ Readmission to hospital is extremely common, with about 1 in 3 patients being readmitted in the first month, and up to 15% of patients dying within the first 6 months, after being discharged from hospital.⁴ By 12 months post-discharge, approximately 25% of heart failure patients will have died.⁵

Concerningly, due to population aging and increasing prevalence of comorbidities, heart failure hospitalisations could increase by as much as 50% in the next 25 years.¹

Categorisation of heart failure

Heart failure is categorised according to the measurement of the left ventricular ejection fraction (LVEF). Knowing the LVEF at time of diagnosis is crucial, as this guides treatment.¹ Heart failure is categorised as either^1,6,7:

• Heart failure with reduced ejection fraction (HFrEF), defined by an LVEF of ≤40% (historically known as systolic heart failure)
• Heart failure with mildly reduced ejection fraction (HFmrEF), defined by an LVEF range of 41–49% (historically known as heart failure with mid-range ejection fraction).
• Heart failure with preserved ejection fraction (HFpEF), defined by an LVEF of ≥50% (historically known as diastolic heart failure)

These classifications stem from original heart failure treatment trials showing significantly improved outcomes in patients with LVEF ≤40%, but not above.¹ This is due to the difference in pathophysiology of the two main phenotypes. In HFrEF, the primary issue is reduced cardiac contractility which reduces output, therefore therapies aimed at improving systolic function are effective for both survival and symptoms.⁸ However, HFpEF is characterised by myocardial stiffness, systemic inflammation and increased left ventricular filling pressures, all contributing to diastolic dysfunction.⁸ Therefore, the traditional heart failure therapies do not improve the prognosis or management in HFpEF as they do for HFrEF.¹

Pharmacological management of heart failure

HFrEF

For HFrEF, there are effective pharmacological therapies, supported by robust, high-quality evidence. These include what has now become known as ‘the four pillars’, and these collectively make up guideline-directed medical therapy for HFrEF. These include^9–11:

1. A beta blocker with demonstrated improvement of outcomes in heart failure (i.e. bisoprolol, nebivolol, carvedilol or metoprolol XL)
2. A mineralocorticoid receptor antagonist (also known as an ‘aldosterone antagonist’)
3. A renin angiotensin system inhibitor – either an angiotensin-converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or an angiotensin receptor neprilysin inhibitor (ARNI), with the latter being preferred by guidelines
4. A sodium-glucose cotransporter 2 inhibitor (SGLT2i).

This combination of medicines has been shown to be the most effective regimen at reducing all-cause death relative to placebo, delaying disease progression, decreasing symptoms and improving quality of life in HFrEF.^9,10 The reduction in risk of death is substantial, with a relative risk reduction in all-cause mortality of 73%.^12,13 This has been translated to an extension of life expectancy in HFrEF by 7.9 years in a 50-year-old patient, and by 5 years in a 70-year-old patient, compared with no treatment.¹²

All patients with HFrEF should be prescribed all four agents (unless contraindicated or not tolerated), with early initiation being associated with the best outcomes.^1,9,10 Other therapies are available as HFrEF progresses, however the ‘four pillars’ are the cornerstone of HFrEF treatment.¹⁰

HFmrEF

There is limited evidence to support specific recommendations for the pharmacological management of HFmrEF.¹ Some studies suggest that patients with HFmrEF may receive similar benefit from a beta blocker, a mineralocorticoid receptor antagonist and a renin angiotensin system inhibitor as in HFrEF, and SGLT2is have been shown to reduce the risk of cardiovascular death and hospitalisation for heart failure.¹⁴ The medicines used to treat HFrEF are often used to treat HFmrEF, however the confidence in prognostic benefits is much less.^1,14

HFpEF

For the treatment of HFpEF, no medicines have demonstrated a statistically significant benefit on mortality.¹ Recommended treatment consists of¹⁵:

1. An SGLT2i
2. Diuretics for fluid retention
3. Appropriate treatment of comorbidities, e.g. hypertension.

The use of an SGLT2i in HFpEF has not been shown to improve mortality to the same extent as for HFrEF. However, an SGLT2i is still recommended because major trials have shown they can still offer some benefits.^16,17

The EMPEROR-Preserved trial demonstrated a 21% lower relative risk in the composite of cardiovascular death or hospitalisation for heart failure with the use of empagliflozin in the treatment of HFpEF compared with placebo – a result driven primarily by a reduction in risk of hospitalisation rather than mortality.¹⁶ Importantly, this benefit was seen regardless of the diabetic status of the patient.¹⁶ This benefit was later reinforced by the DELIVER trial which showed a lower risk of its composite primary outcome of worsening heart failure or cardiovascular death with dapagliflozin use, compared to placebo for those with HFmrEF and HFpEF.¹⁸ As a result, SGLT2is have received a strong recommendation for the management of HFpEF in treatment guidelines.¹

Additionally, mineralocorticoid receptor antagonists are used in clinical practice because they have been associated with a reduction in risk of hospitalisation for HFpEF patients, as demonstrated by the TOPCAT trial.¹⁹

A focus on SGLT2is

Initially developed as a medicine used for type 2 diabetes, SGLT2is have become a crucial cardiovascular drug class, as demonstrated above by their role in the management of heart failure, and now have renal and cardiovascular indications irrespective of type 2 diabetic status. This is largely due to results of cardiovascular outcome trials mandated by the United States Food and Drug Administration (FDA) in 2008. These trials led to findings that have significantly changed clinical practice.²⁰ They arose from concerns of cardiovascular risks with certain medicines used for type 2 diabetes, evidence suggesting rosiglitazone may increase the risk of myocardial infarction, and in recognition of the high prevalence of cardiovascular disease in these patients.²⁰

SGLT2is lower blood glucose by inhibiting SGLT2 transporters in the proximal tubules of the kidneys to decrease glucose reabsorption, which increases the excretion of glucose in the urine.²¹ Sodium excretion also occurs because the SGLT2 receptor is close to, and works together with, a sodium/hydrogen exchanger, which is a major receptor responsible for sodium reuptake.²²

Although SGLT2is lower blood glucose, blood pressure and contribute to diuresis, their benefits in terms of renal and cardiovascular outcomes cannot be solely attributed to these properties, as similar clinical benefits are not seen with other agents that lower glucose, blood pressure or increase natriuresis to similar or greater extent.^23,24 The mechanism of action linked to these benefits is complex, and appears to also be a combination of anti-inflammatory and anti-fibrotic effects, a reduction in epicardial fat and a reduction in hyperinsulinaemia.²¹

Additional evidence also suggests a reduction in oxidative stress, less coronary microvascular injury and improved contractile performance.²³ Emerging clinical evidence may also suggest antiarrhythmic properties, which is particularly important given that ventricular arrhythmias and sudden cardiac death is a major cause of death in heart failure patients.²¹ Some trials have demonstrated a decrease in sudden cardiac death for patients using a SGLT2i.²¹

The EMPA-REG OUTCOME trial in 2015 was a landmark study, demonstrating that empagliflozin significantly reduced cardiovascular death among high-risk patients with type 2 diabetes, compared to placebo.²⁵ Importantly, it also suggested renal benefits, with less cases of acute renal failure in the empagliflozin group.²⁵ These findings were later confirmed by the EMPA-Kidney (empagliflozin) and DAPA-CKD (dapagliflozin) trials, which both showed reduced rates of death due to renal disease, slower decline in renal function and delayed time to needing dialysis.^26–28

The cardiovascular benefits of these medicines went on to be confirmed in further trials including the DAPA-HF (2019), EMPEROR Reduced (2020), EMPEROR Preserved (2021) and DELIVER (2022) trials.^16,18,29,30

Key practice points

• As SGLT2is contribute to sodium excretion and have a diuretic effect, it may be prudent to review and potentially decrease the dose of other diuretics in euvolaemic patients prior to commencement if appropriate.²⁴
• The cut-offs in estimated glomerular filtration rate (eGFR) for commencement of SGLT2is vary according to its indication^21,31,32:
  • For heart failure and chronic kidney disease: can be commenced when eGFR is greater than 25 mL/min (dapagliflozin) or 20 mL/min (empagliflozin). However, they may (and should) be continued if eGFR reduces below this level as heart failure and/or chronic kidney disease progresses due to continued benefits, until dialysis
    is started. 
  • For treating type 2 diabetes only: glucose-lowering effect is reduced (dapagliflozin) or likely absent (empagliflozin) when eGFR is less than 45 mL/min (dapagliflozin) or
    30 mL/min (empagliflozin). However, cardiovascular and renal benefits have been shown to continue as renal function falls.
• Upon commencement, it is normal to observe an initial increase in serum creatinine and a decrease in eGFR.^24,27 This often occurs during the first 2 weeks of therapy and then stabilises within about a month. Decreases in eGFR of up to 30% are considered normal and no change to therapy is required.^27,33 This initial ‘dip’ in eGFR is due to a reduction in glomerular hyperfiltration and glomerular pressure.^27,33,34 Glomerular hyperfiltration is a known mechanism contributing to chronic kidney disease, therefore this initial decline of up to 30% is tolerated in order to protect long-term renal function.^27,34
• Due to the increased risk of diabetic ketoacidosis, SGLT2is should not be used in patients who have type 1 diabetes unless prescribed and managed by an endocrinologist.³⁵
• For key counselling considerations see Table 1.

Knowledge to practice

The use of heart failure guideline-directed medical therapy in HFrEF can have a significant impact on patient outcomes. The combination of the ‘four pillars’ (a heart failure beta blocker, an mineralocorticoid receptor antagonist, a renin angiotensin system inhibitor and an SGLT2i) has the ability to improve life expectancy, delay disease progression, decrease heart failure symptoms and improve quality of life.^9,10 All patients with HFrEF should be prescribed all four agents unless a contraindication or intolerance exists preventing their use.³² 

In HFpEF, there are currently no medicines that demonstrate a statistically significant benefit on mortality. However, the use of SGLT2is has been shown to reduce risk of hospitalisation (regardless of diabetic status) and are recommended to be used by guidelines as part of its management, and in the managment of HFmrEF.^1,9,14

Conclusion

Heart failure remains a significant health burden, but modern medicines, particularly SGLT2is, can offer significant benefits. Pharmacists play a pivotal role in optimising therapy, ensuring adherence, and providing education to patients. By leveraging their expertise as medication experts, pharmacists can profoundly impact outcomes, improving survival and quality of life for individuals living with heart failure and associated comorbidities.

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Key points

• Heart failure is a clinical syndrome due to either a structural or functional abnormality of the heart. Heart failure has a poor prognosis and results in markedly reduced quality of life.
• Heart failure is categorised according to the measurement of left ventricular ejection fraction (LVEF) and this guides treatment.
• SGLT2is form part of guideline-directed medical therapy for HFrEF and are recommended for all patients with HFpEF and HFmrEF due to their known benefits.
• Pharmacists should familiarise themselves with the role of SGLT2is in heart failure and be able to counsel and provide appropriate guidance on their use and role in therapy.

References 

1. 1. 1. McDonagh T, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. 
      2. Atherton J, Sindone A, De Pasquale CG et al. National Heart Foundation of Australia 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;27:1123–208. 
      3. Health AIo, Welfare. Heart, stroke and vascular disease: Australian facts. Canberra: AIHW; 2024. At: www.aihw.gov.au/reports/heart-stroke-vascular-diseases/hsvd-facts/contents/about 
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      25. Zinman B, Wanner C, Lachin JM et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373(22):2117–28. 
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      33. DeSantis, A. Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycaemia in type 2 diabetes mellitus. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA [internet]. At: www.uptodate.com 
      34. Heerspink HJL, Cherney DZI. Clinical Implications of an acute dip in eGFR after SGLT2 inhibitor initiation. Clin J Am Soc Nephrol 2021;16(8):1278–80. 
      35. Queensland Health. Sodium-glucose co-transporter-2 (SGLT2) inhibitors for heart failure: patient information. 2022. At: https://www.health.qld.gov.au/__data/assets/pdf_file/0022/1154380/SGLT2-inhibitor-Patient-Information.pdf
      36. SALHN Diabetes Services. Patient Information:  SGLT2 Inhibitors – Medication for type 2 diabetes. 2024. At: www.sahealth.sa.gov.au/wps/wcm/connect/892bb44d-a530-4453-90db-6949461b60c8/Diabetes+SGLT2+inhibitors+-+Medication+for+type+2+diabetes+Consumer+Health+Information+-+SALHN.pdf?MOD=AJPERES&CACHEID=ROOTWORKSPACE-892bb44d-a530-4453-90db-6949461b60c8-oS7mcPn
      37. Jaarsma T, Hill L, Bayes-Genis A et al. Self-care of heart failure patients: practical management recommendations from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2021 Jan;23(1):157–174. 
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Our author

Cassie Potts (she/her) BPharm, GradCertChronCondMgt, FANZCAP (Cardiol), AdPhaM is a Senior Clinical Pharmacist with SA Pharmacy and has over 11 years of experience specialising in heart failure as part of the cardiology team at Flinders Medical Centre. She serves on the AdPha Cardiology Leadership Committee and currently practises within the intensive care unit at the Royal Adelaide Hospital.

Our reviewer

Hana Numan (she/her) BPharm (NZ), PGDipClinPharm (NZ), MPS (NZ)