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BOSTON -- Sodium-glucose cotransporter-2 (SGLT2) inhibitors were linked to long-term reductions in mortality risk among patients with pulmonary arterial hypertension (PAH), according to an observational cohort study.

At 1 year follow-up, 8.1% of patients with PAH who were prescribed SGLT2 inhibitors had died, compared with 15.5% of patients who did not take SGLT2 inhibitors (7.4% absolute risk reduction, RR 0.52, 95% CI 0.473-0.58, P<0.0001), reported Irakli Lemonjava, MD, of the Jefferson Einstein Hospital in Philadelphia, at the CHEST annual meeting hosted by the American College of Chest Physicians.

At 3 years, the absolute risk difference between the two groups increased to 9.2% (13% vs 22.5%, RR 0.579, 95% CI 0.535-0.627, P<0.0001) and at 5 years, the absolute risk difference was 10.4% (14.6% vs 25%, RR 0.583, 95% CI 0.542-0.628, P<0.0001).

Regarding his retrospective study's findings, "I think we cannot make any major conclusions and it does not change anything in the management for now in PAH patients," Lemonjava cautioned. "But we think it's interesting data," and should lead to further investigation in clinical trials, he told attendees.

"SGLT 2 inhibitors are known to have glucose-reducing properties, but recently there is evidence that they have cardio- and renoprotective effects, as well," he explained.

For example, the DELIVER trial found that an SGLT2 inhibitor reduced risk of cardiovascular death among patients with heart failure with preserved or mildly reduced ejection fraction.

"We thought investigating their role in a condition which is characterized by so much hemodynamic and metabolic disturbances would be interesting," he said. "PAH is a disease where fibrosis and inflammation, in addition to vascular remodeling, are an important part of it." However, any potential role of these medications in patients with PAH is currently unknown.

"I think [the study] is very innovative," session moderator Zeenat Safdar, MD, MSc, of the Houston Methodist Lung Center in Texas told MedPage Today. But, "the mechanism of action is open to speculation," she said.

SGLT2 inhibitors have diuretic and anti-inflammatory effects that may contribute to improved outcomes in patients with PAH, particularly for those who have left-sided heart disease or other cardiorespiratory comorbidities, session moderator Syed Rehan Quadery, MD, of the Mater Misericordiae University Hospital in Dublin, Ireland, told MedPage Today.

Those effects are probably "partly responsible for the improvement in survival in this cohort of patients," he speculated. In addition, the SGLT2 inhibitor empagliflozin [Jardiance] was recently shown in a hypoxic-PAH mouse model to have on pulmonary arterial smooth muscle cells via inhibition of the NOTCH3 signaling pathway, Quadery noted.

Safdar said that many of her patients with PAH are on SGLT2 inhibitors for obesity. "They're losing weight and improving their heart failure. They're getting better," she said. "But is this medication actually having an effect on the disease pathology, on endothelial cells? ... It is food for thought."

To investigate the impact of SGLT2 inhibitors on mortality in patients with PAH, Lemonjava and colleagues used real-world data from the large, global TriNetX platform. They identified a group of patients (n=6,238) over the age of 18 with ICD codes indicating PAH and RxNorm codes for SGLT2 inhibitors, including canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin, and ertugliflozin (Steglatro). Researchers used propensity score matching to identify a second group of patients (n=6,243) with PAH who received no SGLT2 inhibitors but had similar demographic characteristics and comorbidities to the first group.

The study was subject to important limitations, Lemonjava pointed out. The database relied on physician documentation and reporting, which may have been subject to bias. Also, propensity matching may have resulted in residual confounding, and did not take into consideration factors such as medication compliance or effects of lifestyle.

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