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Dr. Marc Ferrini
In type 2 diabetic patients, sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of cardiovascular death or hospitalization for heart failure by 23%, with a similar benefit in patients with and without atherosclerotic cardiovascular disease, with and without a history of heart failure (HF) (1). Although we do not know how these drugs work, a glucose independent mechanism seems likely, supporting the hypothesis of the efficacy of these drugs in HF patients, regardless of the presence of diabetes.
DAPA-HF, presented by Pr. John McMurray at the European Society of Cardiology Congress in Paris and recently published (2), is the first HF outcomes trial with an SGLT2 inhibitor in adults with HF and reduced ejection fraction (HFrEF), including those with and without diabetes, on top of standard care.
4744 patients with symptomatic HFrEF (NYHA class II-IV), left ventricular ejection fraction <40% and elevated N-terminal pro-B-type natriuretic peptide concentration were randomly assigned to once daily dapagliflozin 10 mg or 5 mg or matching placebo. Type 2 diabetes was present in 45% of the patients. People with type 1 diabetes or those with severe renal disease were excluded. Contemporary therapy included a renin-angiotensin system inhibitor in 94%, a β-blocker in 96%, a mineralocorticoid receptor antagonist (MRA) in 71%, and sacubitril/valsartan in (only) 11%.
The relative risk for the primary outcome (a composite of time to first cardiovascular (CV) death or HF hospitalization or urgent HF visit requiring intravenous therapy) was reduced by 26% compared with standard care alone (hazard ratio [HR], 0.74; 95% CI, 0.65 - 0.85; p = .00001). The number needed to treat was 21.
Dapagliflozin lowered the risk for worsening HF events by 30% (10% vs 13.7%; HR, 0.70; 95% CI, 0.59 - 0.83), HF hospitalizations by 30% (9.7% vs 13.4%; HR, 0.70; 95% CI, 0.59 - 0.83), and CV death by 18% (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69 - 0.98).
In addition, the risk for all-cause death was reduced by 17% (HR, 0.83; 95% CI, 0.71 - 0.97).
Rates of adverse events were low, without any difference between the two groups: identical rate of treatment discontinuation (4.7% vs 4.9%) and fewer serious adverse events with dapagliflozin (38% vs 42%; P < .01).
These amazing results, showing a large benefit additive to background usual HF therapies, with a similar magnitude regardless of the presence or the absence of diabetes, demonstrate the role of Dapagliflozin in managing patients with HF.
Probably yes in the future, no for the moment.
It is impossible to extrapolate the results in this very selected population (low rate of elderly and of black people; few patients on sacubitril–valsartan treatment; quite low severity of HF…) to the whole spectrum of HF population. More trials with the other SGLT2 inhibitors are expected and their results will be reviewed by regulators and guideline writers. (3)
Nevertheless, cardiologists must be aware and become familiar with these new drugs that open a new era in HF medical treatment.
Good news: an ongoing trial on empagliflozin heart failure finishes soon and the FDA has granted fast-track designation to dapagliflozin to reduce the risk for CV death or the worsening of HF in adults with HFrEF or those who have HF with preserved EF.
To be continued!
1/ Zelniker TA et al.
SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials
Lancet 2019; 393: 31–39
2/ McMurray J JV et al.
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction
New Engl J Med September 19, 2019 DOI: 10.1056/NEJMoa1911303
3/ Fang JC.
Heart-Failure Therapy — New Drugs but Old Habits?
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