By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: The authors of a small, placebo-controlled study of 24 weeks of dapagliflozin therapy in patients with heart failure with preserved ejection fraction reported reductions in pulmonary capillary wedge pressure, which may explain the reductions in heart failure hospitalizations or cardiovascular death in larger randomized outcome trials.
SOURCE: Borlaug BA, Reddy YNV, Braun A, et al. Cardiac and metabolic effects of dapagliflozin in heart failure with preserved ejection fraction: The CAMEO-DAPA trial. Circulation 2023;148:834-844.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors in randomized, controlled trials have demonstrated a reduction in the risk of heart failure hospitalization or cardiovascular death, and improved quality of life in patients with heart failure with preserved ejection fraction (HFpEF).1 The mechanism of these effects is unclear. Thus, Borlaug et al hypothesized the SGLT2 inhibitor dapagliflozin would reduce pulmonary capillary wedge pressure (PCW) at rest and exercise, the hallmarks of hemodynamic abnormalities in HFpEF.
They prospectively randomized patients with HFpEF to 10 mg/day of dapagliflozin or placebo in a double-blind fashion. Ambulatory patients with a diagnosis of HFpEF (an EF 50% or greater) who demonstrated dyspnea on exertion and recorded an exercise PCW 25 mmHg or higher were enrolled. Researchers excluded patients with primary cardiomyopathies, pericardial disease, left-sided valve disease, ischemic heart disease, anemia, lung disease, or kidney disease.
At baseline and after 24 weeks of therapy, the patients underwent blood tests, echocardiograms, blood and plasma volume measurements, and right heart catheterization at rest and exercise. The primary endpoint was the change in PCW at rest and during maximum exercise from baseline to 24 weeks. Secondary endpoints included changes in pulmonary and right heart pressures, plasma volume, total blood volume, red cell volume, and body weight.
Among the 38 patients who completed the baseline measurements, 37 completed the entire study (21 dapagliflozin, 17 placebo, mean age = 68 years, 66% women, 71% obese). At baseline, mean PCW was about 16 mmHg at rest and 33 mmHg at peak exercise in both groups. At 24 weeks, the difference in PCW at rest between dapagliflozin and placebo was -3.5 mmHg (P = 0.029) and at maximum exercise was -5.7 mmHg (P = 0.027). Right atrial pressure at peak exercise was about 19 mmHg in both groups at baseline and decreased more in the dapagliflozin group (mean difference, -4.1 mmHg; P = 0.011) at 24 weeks.
Similarly, mean pulmonary artery pressure at peak exercise was about 49 mmHg in both groups at baseline and decreased more in the dapagliflozin group (-5.7 mmHg; P = 0.024). Also, dapagliflozin reduced body weight by -3.5 kg vs. placebo (P = 0.006) and plasma volume by -285 mL (P = 0.014). Total blood volume and red cell volume did not change significantly.
The authors concluded dapagliflozin reduces both resting and exercise PCW and favorably affects pulmonary artery and right heart filling pressures, plasma volume, and body weight in patients with HFpEF.
COMMENTARY
SGLT2 inhibitors are considered first-line therapy for HF of any variety, but specifically for HFpEF, based largely on two randomized, controlled trials, which revealed a reduction in HF hospitalizations and cardiovascular death, but not either alone.2 Several effects of these drugs have been postulated as mechanisms of these observations — namely, natriuretic effects, improved myocardial function, enhanced nutrient deprivation signaling (i.e., weight loss), and reductions in PCW. Elevated PCW at rest and exercise is believed to be the gold standard for confirming the diagnosis of HFpEF.3
Thus, Borlaug et al selected patients with elevated PCW during exercise for exploring the role of reducing PCW via SGLT2 inhibitor administration for patients with HFpEF. Interestingly, resting PCW was normal (lower than 15 mmHg) in 37% of the patients in the Borlaug et al study. Apparently, resting PCW is inadequate for identifying HFpEF patients. Based on plasma volume measurements, 18% of the study patients had mild congestion at baseline. During the 24-week study, researchers intensified diuretic therapy for 18% of placebo patients and 24% of dapagliflozin-treated patients. This was numerically nonsignificant but could be of clinical significance and would diminish the magnitude of plasma volume loss attributable to dapagliflozin.
The hemodynamic effects of dapagliflozin compared to placebo are statistically significant but modest. Although Borlaug et al claimed changes in exercise PCW similar to those observed in their study have been associated with improved symptoms, it is hard to imagine a peak exercise PCW that goes from 33.5 mmHg to 27 mmHg would significantly affect symptoms.
Unfortunately, there are no data presented on patient symptoms in this study. Also, the changes in PCW and plasma volume correlated significantly with weight loss, prompting one online commentator to opine that SGLT2 inhibitors are just expensive diuretics.
Other curious findings, considering the proposed mechanism of action of the SGLT2 inhibitors, are the fact there was no change in glomerular filtration rate, systolic blood pressure, exercise capacity, peak VO2, or peak arterial lactate. Final NTproBNP levels were not significantly different, but the reduction on dapagliflozin was. Also, the final hematocrit was not different, but the increase on dapagliflozin was. Finally, changes in rest and exercise do not necessarily support myocardial mechanistic alteration, because reductions in PCW could be related to a reduction in plasma volume. At this point, there is no stopping the SGLT2 inhibitor treatment in heart failure train, but the precise mechanism of any beneficial effects remains uncertain.
REFERENCES
1. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451-1461.
2. Tomasoni D, Fonarow GC, Adamo M, et al. Sodium-glucose co-transporter 2 inhibitors as an early, first-line therapy in patients with heart failure and reduced ejection fraction. Eur J Heart Fail 2022;24:431-441.
3. Eisman AS, Shah RV, Dhakal BP, et al. Pulmonary capillary wedge pressure patterns during exercise predict exercise capacity and incident heart failure. Circ Heart Fail 2018;11:e004750.
The authors of a small, placebo-controlled study of 24 weeks of dapagliflozin therapy in patients with heart failure with preserved ejection fraction reported reductions in pulmonary capillary wedge pressure, which may explain the reductions in heart failure hospitalizations or cardiovascular death in larger randomized outcome trials.
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