SGLT2 inhibitors in heart failure: A prescription for optimised pharmacist care

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 health care costs.³

Heart failure has a poor prognosis and results in markedly reduced quality of life.¹ Re-admission to hospital is extremely common with about 1 in 3 patients being readmitted in the first month, and up to 15% of patients dying during 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 ageing and increasing prevalence of comorbidities, heart failure hospitalisations could increase by as much as 50% in the next 25 years.¹

Categorisation

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 dysfunction or 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 dysfunction or 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, the HFpEF phenotype 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

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 and a renin angiotensin system inhibitor as in HFrEF, and SGLT2i’s 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 or morbidity.¹ Recommended treatment consists of:¹⁵

1. An SGLT2i
2. Diuretics for fluid retention
3. Treatment of co-morbidities such as 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, SGLT2i’s 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 SGLT2i’s

SGLT2i’s 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.²⁰ 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.²¹

Although SGLT2i’s 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 more extents.^22,23

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 reduction in hyperinsulinaemia.²⁰

Additional evidence also suggests a reduction in oxidative stress, less coronary microvascular injury and improved contractile performance.²² 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.²⁰

Some trials have demonstrated a decrease in sudden cardiac death for patients using a SGLT2i.²⁰

Initially developed as a medicine used for diabetes, SGLT2i’s have now become a crucial cardiovascular drug class as demonstrated above by their role in the management of heart failure. 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.²⁴ 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.²⁴

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 SGLT2i’s contribute to sodium excretion and have a diuretic effect, it may be prudent to review and potentially slightly decrease the dose of other diuretics in euvolaemic patients prior to commencement if appropriate.²³
• The cut-offs in estimated glomerular filtration rate (eGFR) for commencement of SGLT2i’s 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 be continued if eGFR reduces below this level as heart failure and/or chronic kidney disease progresses, until dialysis is started.
• For type 2 diabetes: glucose-lowering effect is likely reduced or absent when eGFR is less than 45 mL/min (dapagliflozin) or 30mL/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.^23,27 This often occurs during the first 2 weeks of therapy and then stabilises within about a month. Decreases in GFR 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, SGLT2i’s should not be used in patients who have type 1 diabetes unless prescribed and managed by an endocrinologist.³⁵
• For key counselling considerations please see table below.

SGLT2i key counselling considerations

References: AMH²³ QLD Health³⁵, SA Health³⁶, Jaarsma et al³⁷, Heart Online³⁸

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 antagonists, 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 or morbidity. However, the use of SGLT2i’s 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.^1,9

Conclusion

Heart failure remains a significant health burden, but modern medicines, particularly SGLT2i’s, 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 co-morbidities.