SGLT-2 inhibitors first came into the market in 2013. FDA approved farxiga in January 2014. SGLT-2 inhibitors, as a class, have consistently shown to reduce cardiac outcomes in patients with type 2 diabetes, who also have clinical or subclinical heart failure.
The New England Journal of Medicine published the results of DAPA-HF, a major randomized clinical trial, in September 2019. Investigators evaluated the potential heart benefits of farxiga in patients without diabetes. A group of 5000 adults with heart failure stages 2–4 and an ejection fraction of <40% were randomized to receive farxiga or placebo. Participants were followed and analyzed at 18 months.
During this relatively short interval, farxiga improved the following outcomes significantly: 25% reduction in the primary endpoint (worsening of heart failure ± cardiovascular death), 30% reduction in worsening of heart failure, 18% reduction in cardiovascular death and a 17% reduction in mortality from any cause.
Surprisingly, these benefits were similar between patients with and without diabetes, indicating that the mechanism of heart failure protection of the SGLT-2 inhibitor is independent of hyperglycemia. The rates of adverse events were similar among adults receiving farxiga or a placebo.
DAPA-HF trial adds strong evidence for the use of SGLT-2 inhibitors in heart failure management, independent of diabetes status. I anticipate more extensive use of these medications by the cardiologists. It is fascinating to see how a class of drugs designed and utilized initially for diabetes is crossing over into the cardiology world.
N E J M
In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.
In this phase 3, placebo-controlled trial, we randomly assigned 4,744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy.
Primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (HR, 0.74; P<0.001).
A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (HR, 0.70; 95% CI, 0.59 to 0.83).
Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (HR, 0.82; 95% CI, 0.69 to 0.98);
276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (HR, 0.83; 95% CI, 0.71 to 0.97).
Findings in patients with diabetes were similar to those in patients without diabetes.
The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.
Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes.
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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.
Most patients in these trials did not have heart failure at baseline, so the benefit of treatment with an SGLT2 inhibitor largely reflected the prevention of incident 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.
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.
We 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.
In this randomized, placebo-controlled trial involving patients with heart failure and a reduced left ventricular ejection fraction, 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.
Each of the three components of the composite outcome was less common in the dapagliflozin group, as were the total numbers of hospitalizations for heart failure and deaths from cardiovascular causes.
The use of dapagliflozin also resulted in fewer symptoms of heart failure, as measured on the Kansas City Cardiomyopathy Questionnaire. The observed benefits, which were substantial and clinically significant, occurred early after randomization and were seen in patients who were receiving other recommended therapies for heart failure.
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. Thus, our findings potentially extend the therapeutic role of dapagliflozin beyond patients with diabetes.
The lowering of the risk of the primary outcome was generally consistent across the other prespecified subgroups, although one comparison suggested possible heterogeneity, with less treatment benefit in patients in 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 NT-proBNP level) were not consistent with the finding regarding the NYHA class.
Our population was distinct from the patients in previous trials of SGLT2 inhibitors, since our patients were at much higher risk for hospitalization for heart failure and for death from cardiovascular causes than many of the patients in the previous trials. Most of the patients in our trial were already being treated with a loop diuretic and a mineralocorticoid receptor antagonist, and we did not know whether dapagliflozin would cause the initial diuresis seen in other patient groups.
We did not know whether such an effect might lead to volume depletion and worsening of renal function, since many of our patients had chronic kidney disease. As it turned out, neither of these adverse effects was common (each occurring in <8% of the patients, with no between-group difference), and serious renal adverse events were generally uncommon and significantly less frequent in the dapagliflozin group.
Overall, few patients stopped dapagliflozin or placebo because of any adverse effect (<5% of the patients in either treatment group). Major hypoglycemia was rare, as was diabetic ketoacidosis, and both of these adverse events occurred only in patients with diabetes.
This trial has some limitations. We used specific inclusion and exclusion criteria, which may have limited the generalizability of our 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.
Among patients with heart failure and a reduced ejection fraction, those who received the SGLT2 inhibitor dapagliflozin had a lower risk of worsening heart failure or death from cardiovascular causes and better symptom scores than those who received placebo, regardless of the presence or absence of diabetes.