SGLT2 inhibitors for Heart failure with preserved ejection fraction

The rise and rise of the SGLT2 inhibitors over the past few years has been so jaw-dropping that a recent editorial in the European Heart Journal even compared their development to that of ‘aspirin, penicillin, and statins’, describing them as ‘the, or one of the, major pharmacological advances in cardiovascular medicine in the 21^st century’. 

Excitement began to build when the EMPA-REG trial found that rates of hospitalisation for heart failure were 35% lower with empagliflozin compared to placebo. This was a big surprise! The study had been run to establish the cardiovascular safety of empagliflozin, which is a requirement for new diabetes medications following the experience with rosiglitazone causing an increased risk of death from cardiovascular disease. People had not expected to find empagliflozin would actually have a cardiovascular benefit. 

Large scale randomised trials, such as DAPA-HF, were quickly organised and confirmed that SGLT2 inhibitors reduced the risk of all-cause mortality and hospitalisation due to heart failure for people with heart failure and reduced ejection fraction (HFrEF). 

However, other medications that improve prognosis in people with HFrEF, such as ACE inhibitors, beta-blockers or ARNIs, have not had this same effect in people with heart failure who have a preserved ejection fraction (HFpEF). Indeed, no medications have been shown to offer a meaningful improvement in survival for this group. Patients and clinicians alike struggle with this serious diagnosis for which we have such limited treatment, especially given it accounts for around half of all people with heart failure. 

So are the SGLT2 inhibitors the drug to finally break this mould? In a previous NB blog just under a year ago, Rob Walker, discussed the results of the EMPEROR-Preserved study. In EMPEROR-Preserved, those with heart failure and a left ventricular ejection fraction (LVEF) between 40 and 50% benefitted from empaglifozin, but the benefits of the medication seemed to disappear as the ejection fraction increased and those with an LVEF > 60% had similar outcomes to the control group. It looked as though it might be another situation where a drug could help people with HFrEF but not those with HFpEF. 

But not so fast! 

The DELIVER study was reported at this summer’s European Society of Cardiology Congress and has changed the landscape again. DELIVER randomised over 6,000 people with HFpEF to treatment with dapagliflozin or placebo. Over a median follow-up of just over 2 years, there was close to 20% reduction in the risk of hospitalisation from heart failure or death with dapagliflozin (HR 0.82, 95%CI 0.73 to 0.92). These results were very consistent across sub-groups of ejection fraction, even people with a LVEF > 60%. 

At the Congress we also saw the results of a meta-analysis of five randomised controlled trials of SGLT2 inhibitors in patients with HFpEF, including EMPEROR-Preserved and DELIVER. SGLT2 inhibitors caused a 10% reduction in cardiovascular death (HR 0.88, 95%CI 0.77 to 1.00) and a 25% reduction in first hospitalisation for heart failure (HR 0.74, 95%CI 0.67 to 0.83). The number need to treat to prevent one death or heart failure hospitalisation was 25. Importantly, there was no increased risk of serious adverse events such as DKA, hypoglycaemia or amputation in the SGLT2 inhibitor groups. 

It seems we might finally have a treatment for HFpEF that can improve survival and heart failure outcomes. Licensing for SGLT2 inhibitors is already changing in the USA to reflect this and it will be a surprise if NICE do not follow suit in the near future. This is good news for patients with HFpEF, a common condition with a high hospitalisation and mortality rate, that we may now start to see outcomes improve.