Clinical Pearls & Morning Reports
Published November 20, 2019
Large clinical trials involving patients with type 2 diabetes have shown that inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of hospitalization for heart failure. The reduction in the risk of hospitalization for heart failure was observed early after randomization, which raised the possibility of mechanisms of action that differed from those usually postulated to explain the cardiovascular benefits of glucose-lowering therapies. McMurray et al. designed the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial to prospectively evaluate the efficacy and safety of the SGLT2 inhibitor dapagliflozin in patients with heart failure and a reduced ejection fraction, regardless of the presence or absence of diabetes. Read the Original Article here.
Q: What effects might explain the potential benefits of SGLT2 inhibitors in patients without diabetes who have established heart failure?
A: In addition to diuretic and related hemodynamic actions of SGLT2 inhibitors, effects on myocardial metabolism, ion transporters, fibrosis, adipokines, and vascular function have also been proposed. These actions, along with preservation of renal function, would also benefit patients with established heart failure, including those without diabetes, in whom SGLT2 inhibitors have not been tested.
Q: In the DAPA-HF trial, how did dapagliflozin compare with placebo with respect to the composite outcome of worsening heart failure or cardiovascular death among patients with heart failure and reduced ejection fraction?
A: In this trial, the risk of the primary composite outcome of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or death from cardiovascular causes was lower in the dapagliflozin group than in the placebo group. The primary composite outcome occurred in 386 patients (16.3%) in the dapagliflozin group and in 502 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). Event rates for all three components of the composite outcome favored dapagliflozin. The use of dapagliflozin also resulted in fewer symptoms of heart failure, as measured on the Kansas City Cardiomyopathy Questionnaire. Dapagliflozin was as effective in the 55% of patients without type 2 diabetes as in those with diabetes. This demonstration of the cardiovascular benefits of an SGLT2 inhibitor in patients without diabetes provides support for prior suggestions that such treatment has beneficial actions other than glucose lowering.
A: The lowering of the risk of the primary outcome was generally consistent across prespecified subgroups, although one comparison suggested possible heterogeneity, with less treatment benefit in patients in New York Heart Association (NYHA) functional class III or IV than in class II. However, findings with respect to other subgroups that also reflected more advanced disease (e.g., more reduced ejection fraction, worse renal function, and an increased N-terminal pro–B-type natriuretic peptide level) were not consistent with the finding regarding the NYHA class.
A: The authors used specific inclusion and exclusion criteria, which may have limited the generalizability of the findings. Less than 5% of the patients were black, and relatively few were very elderly with multiple coexisting illnesses. The baseline use of sacubitril–valsartan, which is more effective than renin–angiotensin system blockade alone at reducing the incidence of hospitalization for heart failure and death from cardiovascular causes, was low. However, the postulated mechanisms of action of SGLT2 inhibition and neprilysin inhibition are distinct, and in a post hoc subgroup analysis, the benefit of dapagliflozin was similar in patients treated with sacubitril–valsartan and in those who did not receive such treatment.