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SGLT2 inhibitors for heart failure – hope or hype?

Simon Curtis - 3 Oct, 2019

This month has seen the publication of the DAPA-HF trial in the NEJM, a trial which has got diabetologists, cardiologists (and the pharma company…) very excited as it adds weight to a growing evidence base that SGLT2 inhibitors improve outcomes in chronic heart failure. ‘Really? A diabetes drug for heart failure?’ I hear you cry… Yes, really. When the study outcome was announced, the researchers claimed that the results show that dapagliflozin ‘is truly a treatment for heart failure and not just a drug for diabetes’. So, is this a cause of hope for our growing population of patients with chronic heart failure, or just pharma-sponsored hype? Whatever side of that argument you are on, the rapidly evolving story of the SGLT2 inhibitors from simple oral hypoglycaemic drugs to agents for cardiovascular and renal protection is an interesting one.

Diabetes, renal and cardiovascular disease are of course intimately connected co-morbidities, but it is the CVD component which most often provides the sting in the diabetes tale. We have known for a while now that SGLT2 inhibitors improve cardiovascular outcomes in patients at high risk of cardiovascular events from key studies such as the EMPA-REG and CANVAS trials. These trials led to the change in international guidelines, such as joint US and European guidance, that SGLT2 inhibitors (or GLP-1 agonists) with proven cardiovascular benefit should be used in people with established cardiovascular disease. 

A seemingly serendipitous finding that emerged from these studies was a significant reduction in heart failure admissions, a finding re-confirmed in the more recent DECLARE-TIMI trial. A year ago, an important systematic review of SGLT2 inhibitor trials in type 2 diabetes suggested that the most important cardiovascular benefit of these drugs may well be the improved heart failure outcomes. The reduction in major adverse cardiovascular events was moderate and confined to patients with established atherosclerotic CVD, but SGLT2 inhibitors had ‘robust’ benefits on reducing heart failure admissions and progression of renal disease. The CREDENCE trial this year has also shown efficacy for canagliflozin in reducing progression of diabetes kidney disease. This all led to a breathily over excited Lancet editorial suggesting that SGLT2 inhibitors ‘cover it all’ by reducing major cardiovascular events, heart failure and renal disease progression by working on the ‘pumps, pipes and filter’ and that there is ‘compelling evidence’ that they should be considered first line after metformin for most people with type 2 diabetes. 

What is different about the new DAPA-HF trial is that this is the first major trial looking at dapagliflozin in patients with chronic heart failure with reduced ejection fraction without diabetes. Over a median of 18 months, a primary composite outcome of worsening heart failure or cardiovascular death was reduced in absolute terms from 21% to 16%. For a trial of this type, those are impressive figures. This improvement was seen both in patients with and without diabetes, suggesting that dapagliflozin has potential as a heart failure drug independent of diabetes. Interestingly, the improvement in heart failure outcomes is rapid suggesting that it is caused by improved haemodynamics, perhaps by a reduction in both pre-load through the diuresis effect but also through modification of sympathetic activity. How exactly SGLT2 inhibitors are working in heart failure is not certain, but the patient orientated outcomes have been replicated in sufficient studies to suggest it is a genuine class effect. 

So, does this mean we should be considering this drug for our heart failure patients? In the absence of diabetes, not yet and it is a case of ‘watch this space’ as we see if this finding is replicated in other studies and makes it into national guidance. Furthermore DAPA-HF was just looking at heart failure with reduced ejection fraction, further studies are going on (EMPEROR and DELIVER trials) looking at SGLTs in heart failure with preserved ejection fraction. We also need to be aware of the limitations and contraindications of these drugs, such as the increased incidence of UTIs and genital mycotic infections and the MHRA warnings regarding euglycaemic diabetic ketoacidosis and peripheral arterial disease. Many patients with chronic heart failure also have chronic kidney disease and these drugs currently cannot be initiated if the eGFR is < 60ml/min. However, following the CREDENCE trial that guidance may be about to change as canagliflozin is now licensed in the US at lower levels of eGFR.

So in conclusion, for patients with chronic heart failure without diabetes we need more research, and licensing and guidelines to change, before prescribing SGLT2 inhibitors. However, for our patients with chronic heart failure and diabetes the evidence now seems strong that we should be considering a SGLT2 inhibitor after metformin in this group of patients provided that they do not have contraindications. 

But I have a feeling that this story has a few more twists and turns in it yet...Come along to our Diabetes for Primary Care course in November and Sarah and Sue will give you the latest!

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