Sodium-glucose co-transporter 2 inhibitors – new frontier in the treatment of heart failure

Introduction

Sodium-glucose co-transporter 2 (SGLT-2) inhibitors are a novel class of oral hypoglycaemic agents. The first sodium-glucose linked transporter inhibitor phlorizin was isolated from the root bark of apple trees in 1835¹. This is known to be the first natural substance with sodium-glucose linked transporter (SGLT) inhibitory activity. However, in spite of its inhibitory effects against sodium-glucose cotransporters, it was deemed unsuitable for further development as an anti-diabetic medication. This was primarily in view of its low therapeutic selectivity as it tends to inhibit both sodium-glucose linked transporter-1 (SGLT-1) (primarily localized in small intestine) and sodium-glucose linked transporter 2 (almost exclusively present in proximal convoluted tubule in kidneys). Through SGLT-1 inhibition, phlorizin can cause several gastrointestinal side effects, such as diarrhoea, dehydration, and malabsorption². Phloretin, a metabolite of phlorizin, also strongly inhibits the ubiquitous glucose transporter 1 (GLUT1), which then may obstruct glucose uptake in various tissues³.

In spite of these drawbacks, due to its strong inhibitory activity against SGLT-2, phlorizin served as a model for the development of novel SGLT-2 inhibitors which demonstrated considerably higher potency and selectivity against SGLT-2 compared to SGLT-1⁴. In 2012, dapagliflozin was the first SGLT-2 inhibitor to be approved in the UK for use in patients with type 2 diabetes mellitus⁵. There are currently four SGLT-2 inhibitors (dapagliflozin, canagliflozin, empagliflozin and ertugliflozin) licensed for use in the UK for treatment of patients with type 2 diabetes mellitus.

Effects of SGLT-2 inhibitors on the cardiovascular system:

1. SGLT-2 is a low affinity, high-capacity sodium-glucose cotransporter that is expressed almost exclusively in the kidneys and is responsible for glucose reabsorption in the proximal tubule segment 1 (S1), wherein it reabsorbs more than 90% of the filtered glucose load. SGLT-2 inhibition therefore reduces hyperglycaemia by promoting glycosuria.
2. The renal Na+/hydrogen exchanger 3 (NHE3) is present at the apical surface of renal epithelial cells, where it mediates sodium reabsorption; its action is responsible for a majority of the sodium reuptake that follows glomerular filtration. SGLT-2 inhibitors inhibit NHE3 thereby augmenting natriuresis^6,7. SGLT-2 inhibitor mediated natriuresis and glycosuria therefore lowers cardiac preload and reduces pulmonary congestion and systemic oedema. These effects appear to play a role in the reduction of hospitalisations for heart failure observed in the cardiovascular outcome trials in patients with type 2 diabetes mellitus.
3. Finally, SGLT-2 inhibitors have been shown to improve outcomes in patients with established atherosclerotic cardiovascular disease^8,9. The proposed underlying mechanisms driving this benefit could include a reduction in inflammation¹⁰ and oxidative stress¹¹, improvement in endothelial function¹¹ and lowering of HbA1c, blood pressure and body weight^12,13.

Clinical benefit of SGLT-2 inhibitors on the cardiovascular system

The treatment of diabetes has predominantly focused on reducing hyperglycaemia with the belief that optimising glycaemic control may reduce cardiovascular (CV) risk. However, following concerns around the cardiovascular safety of some of these anti-diabetic drugs, in particular the thiazolidinediones (rosiglitazone and pioglitazone)^14,15, the American and European regulatory bodies released a joint guideline in 2008 calling for more rigorous pre-approval demonstration of cardiovascular safety of novel anti-hyperglycaemic drugs^16,17. Since then, there has been a significant growth in the number of cardiovascular outcome trials for the new generation anti-hyperglycaemic drugs which includes the dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon like peptide-1 (GLP-1) receptor agonists and SGLT- 2 inhibitors.

These trials have not only confirmed the safety of these anti-diabetic drugs, but quite remarkably, they also identified two drug classes, SGLT-2 inhibitors and GLP-1 receptor agonists, which reduce major adverse cardiovascular events including cardiovascular death^9,18. These findings are revolutionising the care of patients with type 2 diabetes mellitus, and in the case of the SGLT-2 inhibitors, have been found to be beneficial in non-diabetic patients with heart failure as well^19,20. This review will briefly summarise the landmark trials demonstrating the beneficial cardiovascular effects of SGLT-2 inhibitors and the most recent ongoing trials.

Safety trials

The three initial cardiovascular outcome trials, EMPA-REG OUTCOME (empagliflozin)²¹, CANVAS (canagliflozin)²² and DECLARE-TIMI 58 (dapagliflozin)⁸ were multicentre randomised, double-blind, placebo-controlled trials, designed to examine the cardiovascular safety of oral SGLT-2 inhibitors in type 2 diabetes mellitus patients with either established cardiovascular disease or high cardiovascular risk. These trials recruited a high proportion of patients with established cardiovascular disease (100%, 66% and 41% for EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 respectively).  Around 10-14% of the trials’ participants had a history of heart failure. Remarkably, the results showed that there was a significant reduction in hospitalisation for heart failure which was consistent across all the three trials. In addition, there was a 38% reduction in cardiovascular death (HR 0.62; 95% CI, 0.49- 0.77; p<0.001) and 32% reduced risk of overall mortality (HR 0.68; 95% CI 0.57-0.82, p<0.001) noted with empagliflozin. There were no significant safety concerns with any of these SGLT-2 inhibitors with a slightly higher risk of genital infection noted with empagliflozin (6.8% vs 1.8%) and dapagliflozin (0.9% vs 0.1%) compared to placebo. In CANVAS, there was a higher rate of amputation of toes, feet or leg with canagliflozin than with placebo (HR 1.97; 95% CI, 1.41 to 2.75, p<0.05). The highest absolute risk of amputation occurred amongst patients with a prior history of peripheral vascular disease although the relative risk of amputation was similar between the treatment and control arms.

Trials in heart failure with reduced ejection fraction (HFrEF)

Following the initial SGLT-2 inhibitor cardiovascular outcome trials that demonstrated significant reductions for incident heart failure in people with type 2 diabetes, two recent trials—EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; with empagliflozin)²⁰ and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; with dapagliflozin)^19,23 evaluated the efficacy of SGLT2 inhibitors to treat patients with heart failure with reduced ejection fraction, with or without type 2 diabetes.

In addition to major clinical events, DAPA-HF also used the Kansas City Cardiomyopathy Questionnaire (KCCQ) patient-reported outcome measure to assess HF symptom burden from the patients’ perspective. A clinically meaningful ≥5-point improvement from baseline to 8 months was reported in 58.3% of dapagliflozin-treated patients versus 50.9% of placebo-treated patients (OR 1.15; 95% CI [1.08–1.23]; p<0.001). The number needed to treat for one patient experiencing a ≥5-point KCCQ improvement was 14.

Prespecified subgroup analysis from DAPA-HF demonstrated that compared with placebo, dapagliflozin improved symptoms and reduced the risk of worsening heart failure and cardiovascular death irrespective of the underlying aetiology of heart failure²⁵. Similarly, a number of subgroup analyses from DAPA-HF, both prespecified and post-hoc, demonstrated similar effects of dapagliflozin compared with placebo across the range of baseline KCCQ scores²⁶, underlying systolic blood pressure²⁷, BMI²⁸, or NT-pro-BNP concentration²⁹.

Clinical implications and guidelines

Although originally investigated as agents for glucose management, SGLT-2 inhibitors are now recognised to impact a wider range of systems, primarily in the cardio-renal axis, many of which are independent of glycaemic control. The results from the DAPA-HF and EMPEROR-Reduced trials have the potential to impact future heart failure management by strengthening the rationale for the use of SGLT-2 inhibitors in patients with heart failure with reduced ejection fraction. These results establish SGLT-2 inhibitors in addition to angiotensin converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitors, beta-blockers and mineralocorticoid receptor antagonists as the new standard of care in HFrEF.  In light of these trials, clinical guidelines and recommendations have been updated:

1. In 2019, prior to the availability of results from DAPA-HF, the European Society of Cardiology (ESC) updated its guidelines on diabetes, prediabetes and cardiovascular disease, and recommended that canagliflozin, dapagliflozin or empagliflozin should be considered in patients with type 2 diabetes mellitus and cardiovascular disease, or those at very  high/high cardiovascular risk, to reduce cardiovascular events (class of recommendation Ia)³⁰.
2. Empagliflozin was also recommended in patients with type 2 diabetes mellitus and cardiovascular disease to reduce the risk of death (class of recommendation Ia) and all SGLT-2 inhibitors were recommended in patients with Type 2 diabetes mellitus to lower the risk of hospitalisation for heart failure (class of recommendation Ia)³⁰
3. An ESC/Heart Failure Association (HFA) position paper published in 2019 stated that, because the three SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) had consistently demonstrated a substantial reduction in the risk of hospitalisation for heart failure across the spectrum of cardiovascular risk and regardless of a history of heart failure, they should be recommended to prevent hospitalisation for heart failure in patients with type 2 diabetes mellitus and high cardiovascular risk.
4. More recently, an ESC/HFA position paper on the role of SGLT-2 inhibitors in the treatment of heart failure recommended that SGLT-2 inhibitors be used in all patients with heart failure with reduced ejection fraction as soon as possible in addition to beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitors and mineralocorticoid receptor antagonists³¹.
5. The clear and significant impact of dapagliflozin on cardiovascular and total mortality in addition to the significant reduction in hospitalisation for heart failure suggests that dapagliflozin is the SGLT-2 inhibitor of choice in patients with heart failure with reduced ejection fraction³². In its updated guidance, National Institute for Health and Care Excellence (NICE) recently recommended dapagliflozin as an add-on option to optimal medical therapy for patients who have heart failure with reduced ejection fraction³³. Similarly, the United States Food and Drug Administration (FDA) also approved dapagliflozin for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure³⁴.

Recent trials of SGLT-2 inhibitors in HFrEF

The Empagliflozin compared with placebo on Exercise Ability and Heart Failure Symptoms, in patients with chronic heart failure with Reduced ejection fraction (EMPERIAL-Reduced; NCT03448419) study investigated the impact of empagliflozin on exercise capacity in 312 patients with HFrEF over 12 weeks³⁵.  The trial did not meet its primary endpoint, with no significant differences reported in the 6-minute walk test between the empagliflozin and placebo arms. Although the results are not published in full, early reports suggest improvements in KCCQ total symptom score in the empagliflozin group compared to placebo³⁶.

The Dapagliflozin Effect on Exercise capacity using a 6-minute walk test in patients with heart failure with Reduced ejection fraction (DETERMINE-reduced; NCT03877237) trial, investigating the impact of dapagliflozin compared to placebo on exercise capacity and quality of life in 313 patients with HFrEF, was completed in March 2020. The co-primary endpoints of this study were KCCQ total symptom score, the KCCQ physical limitation score and 6-minute walk test following 16 weeks of treatment. The results are pending.

SGLT-2 inhibitors in heart failure with preserved ejection fraction (HFpEF)

Presently the data supporting use of SGLT-2 inhibitors in HFpEF is not compelling. Post hoc subgroup analyses of the CANVAS³⁷ and DECLARE TIMI-58³⁸ trials showed a trend towards reduced hospitalisations with canagliflozin and dapagliflozin, respectively. The subgroup analysis of DECLARE TIMI 58 indicated a similar order of magnitude for benefit (HR 0.76, CI 0.62- 0.94) for HFpEF patients compared with HFrEF (HR 0.64, CI 0.43 – 0.95) for reduction in heart failure hospitalisation, albeit neither cardiovascular nor all-cause mortality. However, the subgroup analysis did not reach statistical significance and neither study was powered to detect such a difference in this small sub population (<1% of the study population in CANVAS and 4.7% of trial participants in DECLARE TIMI-58 had a documented history of HFpEF). Therefore, the results of these post hoc subgroup analyses should be interpreted with caution.

The Empagliflozin compared with placebo on Exercise ability and heart failure symptoms, in patients with chronic heart failure With Preserved ejection fraction (EMPERIAL-Preserved; NCT03448406) trial investigated the impact of empagliflozin on exercise capacity in 312 patients with HFpEF³⁵, and found no significant difference between the empagliflozin and placebo groups in terms of 6-minute walk test or KCCQ total symptom scores after 12 weeks³⁶.

Two major trials of SGLT-2 inhibitors in HFpEF are currently on-going. The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved; NCT03057951) trial will follow a similar study design to the EMPEROR-Reduced trial and has randomised 5,988 patients with heart failure with preserved ejection fraction to empagliflozin or placebo(39). The primary outcome for this study is a composite of cardiovascular death and heart failure hospitalisation. The study is due to complete in 2021. The Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure (DELIVER; NCT03619213) trial has recruited more than 6,200 patients with heart failure with preserved ejection fraction, who will be randomised to dapagliflozin or placebo in addition to current standard therapy. The study is due to complete in mid-2021. Compared to EMPEROR-Preserved the composite primary outcome of DELIVER trial also includes urgent heart failure visits to outpatient or emergency departments in addition to cardiovascular death and heart failure hospitalisation. Finally, the Dapagliflozin Effect on Exercise Capacity using a 6-minute Walk test in patients with heart failure with Preserved ejection fraction (DETERMINE-Preserved; NCT03877224) trial, a randomised controlled trial investigating the impact of dapagliflozin compared with placebo on exercise capacity and quality of life in 504 patients with HFpEF, completed in 2020 and the results are awaited.

Trials of SGLT-2 inhibitors in hospitalised patients with acute heart failure

It also remains unclear if initiating SGLT-2 inhibitors in the hospital setting in patients presenting with acute heart failure confers similar treatment benefits. Three trials, one recently published and two ongoing, examine this question.

Sotagliflozin is a dual SGLT-1/SGLT-2 inhibitor and thus differs from the SGLT-2 inhibitors studied to date. The Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF)⁴⁰ trial initially aimed to recruit 4,000 patients with type 2 diabetes mellitus and heart failure with reduced ejection fraction or heart failure with preserved ejection fraction in the immediate post-hospitalisation setting. In May 2020, the study was discontinued early because of financial concerns. The trial investigators managed to randomise a total of 1,222 patients to receive either sotagliflozin (n=608) or placebo (n=614) and follow up was over a median duration of 9 months. Although the study was stopped early, the rate of primary endpoint events (composite of CV death, HF hospitalization, or urgent visit for HF) was significantly lower in the sotagliflozin group than in the placebo group (51.0 vs. 76.3 events per 100 patient-years; hazard ratio, 0.67; 95% CI, 0.52 to 0.85; p<0.001). This achieved significance by 28 days of follow-up. Pre-specified subgroup analysis indicated no heterogeneity of treatment effect in those with or without LVEF <50%, but the small sample size (21% of participants had LVEF ≥50%) and early trial termination makes it difficult to be conclusive here. Therefore, in patients with diabetes and recent worsening heart failure, sotagliflozin therapy, initiated before or shortly after discharge, resulted in a significantly lower total number of deaths from cardiovascular causes, hospitalizations and urgent visits for heart failure than placebo.

Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure -Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68; NCT04363697) is a multicentre, randomized, double-blind, placebo-controlled trial to evaluate the effect of in-hospital initiation of dapagliflozin on clinical outcomes in patients with HFrEF who have been stabilised during admission for acute heart failure. The study is aiming to randomise 2,400 patients and is due to complete by May 2023. The primary outcome for this study is time to first occurrence of CV death or worsening heart failure.

The effect of Empagliflozin in patients hospitalised for acute heart failure (de novo or decompensated chronic HF) who have been stabilised (EMPULSE; NCT04157751) trial is a multicentre, randomised, double-blind, 90-day superiority trial to evaluate the effect on clinical benefit, safety and tolerability of once daily oral empagliflozin 10 mg compared to placebo. The aim is to recruit 500 patients into the study, which is due to complete in June 2021. The primary outcome is a composite of death, number of heart failure events (including hospitalisations for heart failure, urgent heart failure visits and unplanned outpatient visits), time to first heart failure event and change from baseline KCCQ-TSS score after 90 days of treatment.

With dapagliflozin now approved for use in patients with HFrEF, it remains to be established if any of the SGLT-2 inhibitors will have a similar symptomatic and prognostic benefit in hospitalised patients with acute heart failure and in patients with HFpEF, for whom there are currently no therapies that clearly improve long-term outcomes.

Disclosures

None.

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