How Dapagliflozin Works in HFpEF: Some Clues From CAMEO-DAPA

NEW ORLEANS, LA—Ever since sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to have beneficial effects in patients with heart failure, there have been questions about the underlying mechanisms: the small, randomized CAMEO-DAPA trial provides some answers.

Among patients who have heart failure with preserved ejection fraction (HFpEF), 24 weeks of treatment with dapagliflozin (Farxiga; AstraZeneca) reduced pulmonary capillary wedge pressure (PCWP), a measure of left-heart filling pressure, both at rest and during exercise, thus “improving the fundamental hemodynamic abnormality underlying this disorder,” according to Barry Borlaug, MD (Mayo Clinic, Rochester, MN).

Treatment also reduced right atrial (RA) and pulmonary artery (PA) pressures, body weight, and plasma volume, he reported to attendees of the American College of Cardiology/World Congress of Cardiology (ACC/WCC) 2023 meeting via livestream.

“These findings provide new insight into the mechanisms underlying the favorable clinical benefits of dapagliflozin in patients with HFpEF,” he concluded.

Exploring Mechanisms of Benefit

Dapagliflozin and another SGLT2 inhibitor, empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly), have been shown to improve clinical outcomes and quality of life in patients with HFpEF, which accounts for about half of all heart failure cases and has few proven treatments. But the mechanisms of cardiovascular benefit for SGLT2 inhibitors, which were initially developed to treat type 2 diabetes, have been debated.

Borlaug noted that a key feature of HFpEF is an elevation of left-heart filling pressures at rest and exercise, with this finding driving disability, worsening clinical status, and greater risks for adverse outcomes.

In CAMEO-DAPA, he and his colleagues hypothesized that 24 weeks of dapagliflozin would reduce left-heart filling pressures in the setting of HFpEF. They randomized 43 patients (mean age 67 years; 66% women) with HFpEF (LVEF ≥ 50%), NYHA class II/III symptoms, and an elevated PCWP, with 38 ultimately receiving treatment with either placebo or dapagliflozin 10 mg once daily.

At baseline, mean PCWP measured using invasive cardiopulmonary exercise testing, the primary endpoint, was 16 mm Hg at rest and 33 mm Hg at peak exercise. After 24 weeks of treatment, this measure was 3.5 mm Hg lower at rest in the dapagliflozin group relative to placebo (P = 0.029) and 6.1 mm Hg lower during exercise (P = 0.019).

There were overall declines in RA and PA pressures considering rest and exercise values together. During exercise, RA pressure was lower by an average of 4.2 mm Hg (P = 0.01) and PA pressure was lower by an average of 5.9 mm Hg (P = 0.022).

Dapagliflozin also provided greater reductions in plasma volume (258 mL lower than in the placebo group; P = 0.015) and body weight (3.5 kg lower; P = 0.006). Changes in PCWP were strongly associated with changes in body weight, with a weaker correlation with plasma volume.

More Than a Diuretic Effect?

Commenting for TCTMD, Maya Guglin, MD, PhD (Indiana University Health, Indianapolis), chair of the ACC Heart Failure and Transplant Council, said the results are “very, very expected and very intuitive.”

Since SGLT2 inhibitors have favorable effects in heart failure regardless of ejection fraction, it means there is a critical link in pathogenesis shared by HFpEF and HFrEF, she said. That common feature is congestion, which is associated with elevated pressures in the cardiac chambers. By increasing the concentration of glucose in the urine, and, in turn, the osmotic pressure of urine, SGLT2 inhibitors help facilitate the release of water from the body into the urine. “Therefore, they act as osmotic diuretics,” Guglin explained. “Whatever causes diuretic [effects] decreases congestion. Whatever decreases congestion is beneficial for heart failure.”

”There was never a question in my mind that this is their primary mechanism,” Guglin continued. “I know that people argue that there are different effects to it, but this study shows beautifully that hemodynamically they work as diuretics, they reduce congestion. Therefore, they benefit patients with heart failure because the intracardiac pressures decrease at rest but especially with exercise.”

During a panel discussion following his presentation, however, Borlaug indicated that there is likely more going on than just a diuretic effect, noting that the decline in PCWP was more tightly associated with a reduction in body weight than with plasma volume. He suggested possible effects on venous capacitance, stress blood volume, myocardial diastolic and lusitropic function, and systolic reserve.

“We think that these may also be contributing,” Borlaug said. “My guess is that it’s probably a combination of many different little things that are all adding together to lead to this 20% to 25% favorable improvement in filling pressures.”