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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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Vaping - Friend or Foe?

Rob Walker - 10 Oct, 2019

Where are we with vaping? Are e-cigarettes the shining knight to rid the world of cigarettes or dangerous products wrapped up in clever marketing with the ‘unintended consequence’ of luring young people into the world of smoking? Vaping is a subject we have been covering in our Autumn Hot Topics courses, and there has been plenty to discuss and digest over the past six weeks or so! A spate of serious lung injuries and a few deaths in the US, India announcing it will ban e-cigarettes completely, Public Health England standing by its view that they are a much safer alternative to smoking, and inflammatory headlines from news outlets adding fuel to the fire. As doctors it is a bit of a minefield, and a difficult area to navigate with our patients. However, a couple of excellent articles in the BMJ over the last four weeks have been useful to put this all in context (BMJ 2019;366:l5445 and BMJ 2019;366:l5591).

Smoking is BAD. This can be easily forgotten when we discuss the risks of vaping. Most of us will have had family members or friends that have been affected by smoking related illnesses. It took the death of my uncle from lung cancer at a young age to shift my family from a group of predominantly heavy smokers, to mostly non-smokers. So the first question is whether vaping is safer than smoking cigarettes? This BMJ editorial sets out that ‘there is now strong consensus that vaping is substantially less harmful than smoking’ and that is still the line taken by PHE. But what about all those people in the US with serious lung injuries? The BMJ article helps put this in context for us. Yes, these incidents are a serious wake-up call to the potential risks of vaping with 450 cases of severe pulmonary disease and six deaths; however, the outbreak appears confined to the US, where products are not well regulated, and the majority (although not all) of the cases were linked to people adding non-regulated products to the liquid solution, particularly THC. Vaping has been around for about a decade so if acute pulmonary injury was a common adverse effect we would expect to have seen cases elsewhere in the world by now. The BMJ editorial suggests that the circumstances of this outbreak point to faulty devices or contaminants, rather than a problem with vaping per-se. 

So, if current smokers want to quit smoking and are considering vaping, one key message is to use standard devices and not to contaminate or add other products; if they do, the short term risks appear low. But what about long term risks? This is the issue I think many of us are concerned about, and one we do not have an answer to. Most e-cigarettes emit numerous potentially toxic substances but we are likely to need another 10-20 years of epidemiological data before any conclusions can start to be drawn on this question. And it is an important question given recent RCT evidence from the UK (N Engl J Med 2019). This study showed that e-cigs were superior to standard nicotine replacement therapy (NRT), almost doubling the rate of smoking cessation at 1 year (18% in e-cig group vs 9.9% in NRT group). However, in the e-cig group 80% of the successful quitters were still using e-cigarettes at 1 year vs only 9% still using NRT at 1 year. If this is translated more widely with large numbers of quitters remaining on e-cigarettes and long term risks with e-cigarettes do emerge, this strategy may prove to have consequences.

But what about the exposure of vaping to children and young adults? Is vaping the ‘cool’ thing to do? Is this getting a generation of teenagers hooked on a different nicotine based product that will ultimately prove to be harmful, or could it lead to some of them taking up cigarette smoking? This is an area I’m sure many of us have considerable worries over. India has recently announced a total ban on e-cigarettes to stop a ‘youth epidemic’, although one can’t help feel that this decision was largely influenced by India being one of the biggest global producers of tobacco. So what data do we have? This second BMJ article discussed concerns in the US, with data showing a continued increase in vaping in high school students - up to 25% had reported vaping in the previous 30 days (up from 20%). The availability of fruity flavours and trendy devices has been widely attributed to this rise, and has led the the US announcing a ban on most flavoured products. In the UK the latest data from PHE (data up to 2018) shows that although experimentation with vaping in children and young adults is slowly increasing, the absolute rates of regular use remain low with 1.7% of 11-18 year olds vaping at least weekly, with the majority of these users being smokers already; regular (weekly) vaping in those that have never smoked in this age group remains very low at 0.2%, although this rate is rising; but as PHE state ‘The extent to which these young people would have tried smoking if vaping had not been available is unclear’.

So how do we deal with this uncertainty? My view is that we need to resist what seems to be an increasing trend in society by trying to deconstruct complex issues into a simple binary decision of ‘friend’ or ‘foe’. Medicine is never that simple, and we need to disregard the one sided inflammatory news headlines, embrace uncertainty and help our patients make informed choices given the information we currently have. Is vaping safe Doc? Not an easy question, but I hope the background above will allow you to have a more informed discussion with your patient next time…And remember, if you’ve had any thoughts or reflections on this, add these to your CPD log for appraisal, which you can do by clicking the ‘add reflective note’ button at the bottom of this blog through your NB Dashboard.

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Log in to your NB Dashboard and use the 'Add Reflective Note' button at the bottom of a blog entry to add your note.