Heart Failure
Joey Sweeney, PharmD, BCPS
In May, FDA approved dapagliflozin to treat patients with New York Heart Association (NYHA) class II–IV heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization. The drug, initially approved as a treatment for type 2 diabetes, is the first sodium-glucose cotransporter 2 (SGLT2) inhibitor approved for this indication.
AstraZeneca, which makes dapagliflozin under the brand name Farxiga, received a Priority Review designation, which ensured FDA would act upon the application within 6 months. FDA granted this expedited application because, if approved, the drug would significantly improve outcomes in patients experiencing this serious condition.
Clinical trial
Dapagliflozin’s approval was based on a Phase III, double-blind, placebo-controlled trial of 4,744 patients. The study lasted for about 18 months. The researchers excluded patients who recently received treatment with an SGLT2 inhibitor or had type 1 diabetes, hypotension, or a low estimated glomerular filtration rate (eGFR). Heart failure patients with reduced kidney function were also excluded from the study.
Death from cardiovascular causes was 1.9% lower in the treatment group compared with placebo, while all-cause mortality was 2.3% lower. A first worsening heart failure composite (morbidity index) was 4.9% lower in the treatment group.
The primary composite outcome was statistically favorable for men in the dapagliflozin group. Women also benefited from dapagliflozin therapy, but the statistical significance was unclear. In addition, patients with NYHA class II heart failure clearly benefited from dapagliflozin therapy. However, class III and IV patients’ hazard ratios did cross 1, calling into question the statistical significance of benefit for these groups.
Curiously, the placebo group exhibited higher rates of volume depletion (0.5% more) and serious adverse renal events (1.1% more), although this was not statistically significant. The researchers noted no statistically significant differences between the groups on adverse effects and safety outcomes. This seems counterintuitive, but perhaps dapagliflozin is exceptionally safe or that statistical chance favorably benefited the treatment group.
Characteristics of patients at baseline—including age, sex, body-mass index, race, region, NYHA functional classification, heart rate, systolic blood pressure, left ventricular ejection fraction, medical history, eGFR, heart failure and glucose-lowering medications, and others—do not show any obviously significant differences between the placebo and treatment groups.
Interestingly, dapagliflozin was similarly effective in both patients with and without diabetes. The authors propose that glucose lowering is likely not the mechanism responsible for the drug’s heart failure benefits.
Although dapagliflozin appears safer than placebo, providers should still monitor fluid status before and during initiation of dapagliflozin therapy. For patients with diabetes on concurrent glucose-lowering therapies, it is also a good idea to continue keeping a close eye on blood sugar.
Limitations
It is unknown if the low baseline use of sacubitril-valsartan, which is more efficacious in treating heart failure because it inhibits both neprilysin (sacubitril) and the angiotensin system (valsartan), would eclipse dapagliflozin’s benefit. The authors postulate this would not be the case, but additional studies are needed to confirm the suspicion.
Generalizability of the data may also be limited, given the inclusion and exclusion criteria of the study and that less than 5% of patients were Black.
Despite these limitations, dapagliflozin is a welcome addition to the cardiologist’s repertoire against heart failure. The SGLT2 inhibitor will reduce deaths and hospitalizations associated with the condition while having benign adverse drug effects on patients. Dapagliflozin’s approval may launch a new era in the battle against heart failure.