Dapagliflozin for heart failure

Field: Medicine (Health Sciences)

The sodium-glucose cotransporter-2 (SGLT2) inhibitor group of drugs are now assuming an importance in the improvement of cardiovascular outcomes in a similar way that the introduction of HMG-CoA reductase inhibitors (statins) did in the 1990s. SGLT2 proteins on the surface of the renal tubule cells are responsible for 90% of glucose re-absorption from the glomerular filtrate with inhibition increasing the loss of both glucose and sodium in the urine. The modern SGLT2 group of drugs have been developed from phlorizin a non- selective SGLT inhibitor extracted from the root bark of the apple tree and first tested in people in 1933.1 SGLT2 inhibitors are now a standard therapy for glycaemic control in people with diabetes and have also demonstrated reductions in major cardiovascular events in those with type 2 diabetes. We now also have good outcome data for the use of an SGLT2 inhibitor in those with defined heart failure but who do not have diabetes. In these patients, however, the mechanism of action is possibly beyond one of only glucose lowering. NICE published on 24 February 2021 their technology appraisal (TA 679) on the use of dapagliflozin for treating chronic heart failure with reduced ejection fraction (HFrEF).2 The recommendations were based on the acceptance by the committee that there remains an unmet need for new treatment options as many patients still have heart failure symptoms such as breathlessness despite current treatment being regarded as having been optimised. NICE recommends dapagliflozin in symptomatic patients but only as an add-on to optimised standard care. Its use should be on the advice of a heart failure specialist in primary, secondary or community care with monitoring done by the most appropriate health care professional. Optimised standard care is stated to be an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-2 receptor blocker (ARB) with a beta blocker and mineralocorticoid receptor antagonist (MRA) if tolerated. NICE also specifically mentions an alternative regimen of sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), with a beta blocker and, if tolerated, an MRA. A full submission on the use of dapagliflozin in adults for the treatment of symptomatic chronic heart failure with reduced ejection fraction is additionally due to be published by the Scottish Medicines Consortium on 12 April 2021.3 The Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial randomised 4744 patients with New York Heart Association class II, III or IV heart failure with an ejection fraction of <40% to receive 10mg dapagliflozin or placebo in addition to recommended therapy. The baseline recommended therapies were well matched between the two groups with 96% on a beta blocker and similar levels receiving renin angiotensin system blockers. Just over 10% were taking an ARNI. The primary outcome was a composite of worsening heart failure indicated as a hospitalisation or an urgent visit resulting in intravenous therapy for heart failure or cardiovascular death.4 Over a median period of 18.2 months the primary outcome occurred in 16.3% in the dapagliflozin group and 21.2% in the placebo group. The hazard ratio (HR) was 0.74 with 95% CI 0.65–0.85; p<0.001. The results for death from cardiovascular causes were 9.6% and 11.5% between the dapagliflozin group and placebo groups respectively. The HR was 0.82 with 95% CI 0.69–0.98. There was also a significant difference in total symptom score as measured by the Kansas City Cardiomyopathy Questionnaire score (p<0.01). The clinical benefit was seen early after randomisation. An important finding was that dapagliflozin was as effective in the 55% of patients without diabetes as in those with diabetes. The baseline mean eGFR was 66ml/min/1.73m2 in the dapagliflozin group with 40.6% having a rate of <60ml/min/1.73m2. Worsening renal function occurred in <8% in both groups. Serious renal adverse events occurred in 1.6% of the dapagliflozin group with 2.7% in the placebo group (p=0.009). In 2018 NICE published their national clinical guideline NG 106 – Chronic heart failure in adults: diagnosis and management.5 Their pharmacological recommendation for first-line treatment in those with reduced ejection fraction was to offer ACE inhibitor and a beta blocker with a licence for heart failure. They indicated that when deciding which drug to start first, clinical judgement should be used. Beta blockers should be introduced in a ‘start low, go slow’ manner. The ACE inhibitor therapy should be initiated at a low dose and titrated upwards at short intervals with two weeks suggested. An ARB licensed for heart failure can be used as alternative for those unable to tolerate an ACE inhibitor. An MRA is the next therapeutic choice if the patient continues to have symptoms of heart failure. Based on the NICE technology appraisal guidance, sacubitril/valsartan is also recommended as an option for treating symptomatic chronic heart failure if the patient is already taking a stable dose of an ACE inhibitor or an ARB. However, the guidance is clear that this treatment should only be started by a heart failure specialist with access to a multidisciplinary heart failure team. This ‘team’ is defined within the clinical guideline.5 The NICE TA 679 committee noted that dapagliflozin was innovative and a step change in the treatment of HFrEF. The recommendation for its use was on the basis that the cost effectiveness estimates were felt to be an acceptable use of NHS resources. The committee's preferred incremental cost-effectiveness ratio (ICER) for dapagliflozin was £7264 per quality-adjusted life year gained.2 As part of the economic analysis ACE/ARBs, diuretics, beta blockers and MRAs were felt not to be direct comparators to dapagliflozin, unlike sacubitril/valsartan. On an indirect comparison dapagliflozin, being less costly, was felt to be at least as effective at reducing the risk of death from cardiovascular causes. The comment of the clinical experts informing the committee was that the choice of sacubitril/valsartan or dapagliflozin would depend individually on the patient's symptoms and comorbidities. With the publication of NICE's TA 679, we now have two different patient populations in which dapagliflozin can be used with the benefit going beyond glucose lowering. It is currently used in primary care to improve glycaemic control but not commenced if the eGFR is <60ml/min/1.73m2 and discontinued if this falls below 45ml/min/1.73m2.6 Before commencing therapy the primary care physician should consider any factors within the patient's history that would predispose to ketoacidosis. Awareness of possible volume depletion during intercurrent illness is important, with strict adherence to ‘sick day rules’.7 In relation to heart failure there is clear guidance on obtaining advice prior to commencing dapagliflozin in the community. A different approach is required in relation to renal function prior to starting therapy and what to do if it falls: in the DAPA-HF trial the eGFR went down to 30ml/min. For those with both heart failure and diabetes, additional glucose-lowering treatment should be considered if the eGFR falls below 45ml/min. The 10mg heart failure dose cannot be used in type 1 diabetes whereas the 5mg dose can be used as an adjunct to insulin for glycaemic control. The most recent European Society of Cardiology (ESC) guideline on heart failure was published in 20168 with the next update planned for this year. The 2016 guideline indicated that the SGLT2 inhibitor empagliflozin should be considered in patients with type 2 diabetes in order to prevent or delay the onset of heart failure or prolong life. An expert consensus report of the Heart Failure Association of the ESC published in 2019 acknowledged at that time that no specific recommendations for the use of SGLT2 inhibitors in patients with established heart failure could be made.9 Any new trial evidence published after the consensus statement would be considered for the 2021 guideline update. A full list of the 18 ongoing randomised trials of SGLT2 inhibitors in patients with heart failure is included within this published paper. The lead author for the DAPA-HF paper has recently published an argument to reconsider our standard approach to sequencing drugs in patients with HFrEF.10 Are guideline development groups, however, willing to adopt a new approach to heart failure management? In the article it is argued that the current approach is to commence the drugs in the sequence in which they showed benefit in clinical trials over the last 40 years, which assumes that the most effective and best tolerated drugs were tested first. In fairness, NICE NG 106 does offer the starting choice between ACE inhibitors and beta blockers based on clinical choice.5 At present we are recommended to titrate each drug to the target dose used in the clinical trials before moving to the next class of drugs on the basis that drugs are only effective when titrated to the target dose. Low starting dose can, however, reduce the risk of cardiovascular death with target dose only slightly more effective. Even within the clinical trials, patients were still on lower than target doses of the recommended treatments. Some classes of drugs were not used at all. If target doses need to be reached before moving on to the next drug in the sequence this can take up to six months to prescribe all the recommended drugs. Even with a comprehensive and dedicated approach, this time scale is often in clinical practice extended. This approach may deny the patient benefit, for this period of time, therapies that have been shown to reduce morbidity and mortality soon after initiation. The suggested alternative is to start with the simultaneous initiation of a beta blocker and an SGLT2 inhibitor on the basis that the latter will reduce the risk of hospitalistion for heart failure and could also mitigate the short-term risk of worsening heart failure when a beta blocker is commenced. Within one to two weeks the next step would be the addition of sacubitril/valsartan, with care if there is hypotension, and after a further one to two weeks an MRA would be added if the serum potassium is normal and renal function is not impaired. This sequencing would be more suitable for outpatients with up-titration pursued after the initial four-week period. In the ideal situation, however, therapy should always be individualised to each patient's own individual circumstances. This approval for the use of a new therapy for symptomatic heart failure is an important step in our clinical management of this condition. It is important, however, that there are clear and robust clinical processes in place to commence the drug and monitor its use. Documenting and differentiating the indication for dapagliflozin in different disease categories is paramount, yet continuing to individualise its clinical use. Dr Begg has previously received lecture and advisory board fees from AstraZeneca. References are available in Practical Diabetes online at https://wchh.onlinelibrary.wiley.com.