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HomeCardiologySGLT2 inhibitors in preserved ejection fraction heart failure — Meta-analysis

SGLT2 inhibitors in preserved ejection fraction heart failure — Meta-analysis

Sodium-glucose co-transporter-2 (SGLT2) inhibitors, beneficial in reduced ejection fraction heart failure, can also treat preserved ejection fraction, found a meta-analysis by the University of East Anglia (UEA) in the European Journal of Preventive Cardiology.

Lead researcher Prof Vass Vassiliou, from UEA’s Norwich Medical School and an honorary consultant cardiologist at the Norfolk and Norwich University Hospital, said: “Heart failure affects about one million people in the UK.

“There are two types. Heart failure with a reduction in ejection fraction happens when the heart is unable to pump blood round the body due to a mechanical issue. And heart failure with preserved ejection fraction happens when, despite the heart pumping out blood well, it is not sufficient to provide oxygen to all the parts of the body. Patients are equally split between the two types of heart failure.

“For many years there was not a single medicine that could improve the outcome in patients with the second type of heart failure, those with preserved ejection fraction. This type of heart failure had puzzled doctors, as every medicine tested showed no benefit.

“One class of heart medication, called SGLT2 inhibitors, was initially used for patients with diabetes. However, it was noticed that it also helped patients who had heart failure.

“Previous studies had shown this medication would be beneficial in heart failure with reduced ejection fraction. But we found that it can also help heart failure patients with preserved ejection fraction.”

SGLT2 inhibitors are more commonly known under their trade-names: Forxiga (Dapagliflozin), Invokana (Canagliflozin), and Jardiance (Empagliflozin). The research team undertook a meta-analysis of all studies published in the field and brought together data from almost 10,000 patients. They used statistical modelling to show the specific effect of these medicines.

Vassiliou said: “We found that patients taking SGLT2 inhibitors were 22% less likely to die from heart-related causes or be hospitalised for heart failure exacerbation than those taking placebo.

“This is very important because this is the first medication that can provide a benefit to this previously untreatable group of patients, in terms of heart-related deaths or hospitalisation … it will revolutionise the treatment offered to heart failure patients,”
he added.

The study was led by researchers at UEA in collaboration with the Norfolk and Norwich University Hospital, Imperial College London and Imperial College NHS Trust, and Cambridge University Hospitals.

Study details

Sodium glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction: a systematic review and meta-analysis.

Vasiliki Tsampasian, Hussein Elghazaly, Rahul Chattopadhyay, Omar Ali, Natasha Corballis, Panagiota Anna Chousou, Allan Clark, Pankaj Garg, Vassilios S Vassiliou.

Published in European Journal of Preventive Cardiology on 1 December 2021


While heart failure with preserved ejection fraction (HFpEF) is increasingly studied, the search for a single pharmacotherapeutic agent that will improve hard endpoints like hospitalisation and mortality still continues.

Given the various subphenotypes of HFpEF, this makes it difficult for a single agent to be universally beneficial. The recent publication of EMPEROR-PRESEVED3 was an instrumental time for an updated meta-analysis focused on sodium glucose co-transporter 2 inhibitors (SGLT2i) use in HFpEF. We systematically searched PubMed, Embase, Cochrane and Web of Science databases from inception to 27 August 2021. The key terms used for the search were ‘SGLT2’ or ‘Sodium-glucose cotransporter- 2 inhibitors’ or ‘canagliflozin’ or ‘dapagliflozin’ or ‘empagliflozin’ or ‘ertugliflozin’ and ‘heart failure’ with at least six months of follow-up. Our primary endpoint was cardiovascular death and hospitalisation for heart failure (HHF). From 9,493 articles, 167 studies underwent full-text screening, a total of five studies and 9,726 patients were included. Of those, 5,046 patients received an SGLT2i, and 4,680 placebo.

The hazard ratios and 95% CI given in each study were used for the meta-analysis. A random-effects model with inverse-variance weights was used to combine the effect measures from all studies on a logarithmic scale. Statistical heterogeneity was assessed using the I2 statistic. The statistical analyses were conducted using the Review Manager (RevMan) software (version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014).

The use of SGLT2 inhibitors was associated with a significant reduction in CV death or HHF (HR = 0.78, 95% CI: 0.69, 0.87; I2 0%) and in HHF (HR = 0.71, 95% CI: 0.61, 0.84; I2 0%) compared with placebo. There were no significant differences between the two groups of patients in terms of CV death (HR = 1.01, 95% CI: 0.80, 1.28; I2 23%) and all-cause mortality (HR = 1.01, 95% CI: 0.89, 1.14; I2 0%)

However, as some studies included patients with left ventricular ejection fraction (LVEF) 40–50%, not fulfilling the definition of HFpEF according to the recent ESC Heart Failure guidelines, we also undertook a focused pre-specified subanalysis for those studies with available data for patients with LVEF > 50%.

This comprised 5,928 patients and showed a 23% reduction in CV death or HHF (HR = 0.77, 95% CI: 0.66, 0.91; I2 22%) in the SGLT2 group. This value remained significant even after sensitivity analysis removing each study sequentially.

Effect of SGLT2 inhibitors vs placebo on the risk of cardiovascular death or hospitalisation for heart failure for the total population.

We confirm that the use of SGLT2i is associated with a substantial decrease in the risk of CV death or HHF in patients with heart failure and ejection fraction >40%. Importantly, in this first and largest meta-analysis reviewing LVEF >50%, we show that this benefit is maintained, albeit to a lesser degree, in the cohort of patients with LVEF ≥50%. SGLT2i become in this way the first medication with potential for prognostic benefit in HFpEF. However, overall mortality was not improved in HFpEF, indicating that the other comorbidities associated with HFpEF play a significant role. To draw robust conclusions safely regarding these efficacy outcomes, further large trials need to evaluate the effect of the SGLT2 inhibitors in a sufficient number of patients with HFpEF.

The various subphenotypes of HFpEF and its management have puzzled physicians for several years. The high rates of morbidity and mortality that it carries, along with the diagnostic and treatment challenges, have transformed it in one of the most challenging clinical entities. SGLT2i appear to provide some light and positivity, as their cardiometabolic profile impacts favourably on the complex pathophysiological mechanisms involved in HFpEF. However, the quest to untangle the complexity of treating HFpEF is certainly not over.

We show conclusively that for LVEF 40–50% included as HFpEF in previous studies (but no longer considered HFpEF in the guidelines) there is a strong benefit from SGLT2i translating to reduced cardiovascular mortality and HHF, but not overall mortality. This also extended to the LVEF >50% but with a smaller effect. Additionally, while the vast majority of the patients included in this meta-analysis were individuals with diabetes at baseline, the cardioprotective benefits of the SGLT2i have been shown to occur via mechanisms independent of baseline diabetes status.

Furthermore, the effect of SGLT2i in patients with reduced EF without diabetes is well-documented and EMPEROR-Preserved also included patients without diabetes, therefore their effect is applicable to patients without diabetes. Nonetheless, the DELIVER trial currently recruiting (NCT03619213), will provide additional data in HFpEF patients without diabetes. The journey for an optimal and effective medication for HFpEF still continues.

One may argue that with SGLT2i the target destination is now visible, and Ithaca is closer than it has even been.


European Journal of PreventatiVe Cardiology article – Sodium glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction: a systematic review and meta-analysis (Open access)


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