Sodium-glucose transporter 2 (SGLT2) inhibitors are safe and well-tolerated in people with heart failure (HF) related to adult congenital heart disease (ACHD) and associated with reduced hospitalization rates in these patients, new research suggested.
"There's hope now that there's a pharmacotherapy that can really impact the course of these patients," study author Anastasia D. Egorova, MD, PhD, senior medical specialist, Leiden University Medical Center, Leiden, the Netherlands, told theheart.org | Medscape Cardiology.
The findings were published online on March 25, 2024, in the Journal of the American College of Cardiology.
Patients with congenital heart disease typically receive surgical interventions at a young age, although they're not "cured," and many develop HF as a "natural course" later on, said Egorova.
"We're only now starting to see the full dimension of this because a lot of congenital heart patients are surviving into advanced age."
HF is often under-recognized in patients with ACHD, partly because they have more difficulty identifying their symptoms than those with acquired HF, said Egorova. "They've had cardiac limitations their entire life; it's not like a sudden onset of heart failure like you would see after a myocardial infarction."
These patients have also been excluded from clinical trials, creating "an evidence gap" for their management, she said.
New Drug Class
SGLT2 inhibitors are a relatively new class of drugs that have been shown to reduce the risk of worsening HF and cardiovascular-related death in patients with conventional HF. The authors noted a sharp increase in SGLT2 inhibitor prescriptions across four European ACHD centers since 2021.
But robust data supporting the use of SGLT2 inhibitor in the treatment of ACHD-related HF are lacking. "We have been reluctant to prescribe conventional heart failure medications" in this population, said Egorova.
The new multicenter, retrospective cohort study included 174 patients with ACHD receiving SGLT2 inhibitors, mean age 48.7 years. Most had quite complex disease; 51.1% had severe congenital heart disease, according to the European Society of Cardiology classification system.
Systemic ventricular function was at least moderately reduced in 69.5% of patients, and sub-pulmonary ventricular function was at least mildly reduced in 52.1%.
HF was the primary indication for SGLT2 inhibitor in the vast majority (93.1%) of participants followed by type 2 diabetes (6.3%), then chronic kidney disease (0.6%). Most patients were started on dapagliflozin or empagliflozin at the standard dose of 10 mg once per day.
Over two thirds of patients (68.8%) were on at least three HF drugs at baseline. An angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor was prescribed for 83.1% of patients.
The primary study outcome was safety and tolerability of SGLT2 inhibitors, which was evaluated by assessing side effects, discontinuation of therapy, mortality, and safety indices from 2 weeks to 3 months after starting SGLT2 inhibitor, including weight, blood pressure, and sodium, potassium, glucose, and creatinine levels.
Confirmed Safety
Over a median follow-up of 7.7 months, 10.3% of patients developed side effects, and 6.9% discontinued the therapy.
These results "are reflective of larger studies of SGLT2 inhibitors for conventional HF," said Egorova. "So, we're confirming an established safety profile and reassuring patients and doctors that we're not seeing many unexpected side effects."
However, one patient did develop Fournier's gangrene (necrotizing fasciitis) requiring surgical debridement and discontinuation of SGLT2 inhibitor. This is "a very rare" but "dramatic" complication, "which usually happens in patients with other risk factors, which was the case here," said Egorova.
Three patients (1.7%) experienced recurrent urinary tract infections that were treated successfully with oral antibiotics. There were no significant changes in weight, serum sodium, potassium, or glucose. Although diastolic blood pressure didn't change significantly, there was a significant decrease in systolic blood pressure.
A statistically significant creatinine increase compared to baseline was found in one patient in whom the SGLT2 inhibitor was discontinued.
During the follow-up, about 2.3% of patients died of causes unrelated to SGLT2 inhibitors.
In total, 23.5% were hospitalized for HF; 70% in the 12 months preceding initiation of SGLT2 inhibitor therapy and 30% during follow-up. Egorova noted HF-related admissions are a "super bad marker" in those with congenital heart issues.
The HF hospitalization rate in the 6 months following SGLT2 inhibitor prescription was threefold lower than the 6 months before treatment (relative hospitalization rate = 0.30; 95% CI, 0.14-0.62; P = .001). There was no significant reduction in the arrhythmia admission rate.
Revolutionary Results
"This gives us hope," said Egorova. "A lot of times, we approach congenital heart disease patients from the perspective that they've been surgically repaired, surgically corrected as far as possible, and pharmacotherapy can do nothing or very little for them. So, this gives us a more positive perspective, that for even the sickest patients who have had previous HF-related admissions, there's a drug that can change their course."
This, she added, is "revolutionary" for this patient group.
Although this was a limited cohort, the drug appeared to work equally in patients with dominant right ventricular morphology and those with dominant left ventricular morphology, and in those with more and less congenital defect complexities, said Egorova.
She and her colleagues will now try to better understand the mechanism of how this inhibition works, which could open the door to new management strategies. Another important step is to confirm the results in larger studies.
In an accompanying editorial, Luke J. Burchill, MBBS, PhD, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, and colleagues said the study "represents progress in the nascent field of ACHD HF research," but larger prospective randomized controlled trials are needed to confirm potential clinical benefits.
Much is still unknown about the cardioprotective effects of SGLT2 inhibitors, the editorialists wrote. "Reduced HF hospitalizations may signal potential benefit for ACHD HF patients, but there remain fundamental questions regarding the mechanisms by which SGLT2 inhibitor affect this change. For instance, what is the influence of comorbidities on SGLT2 inhibitor treatment response?"
They stressed the importance of a uniform definition of ACHD-related HF that considers diverse anatomic subgroups and establishes a much-needed evidence base surrounding how to accurately diagnose and classify ACHD-related HF.
The editorial noted the first natural SGLT inhibitor, phlorizin, was isolated from the bark of an apple tree back in 1835, and through scientific inquiry spanning almost two centuries, "we have arrived at this moment where the bark of an apple tree has been transformed into a novel treatment for ACHD-related HF."
The Department of Cardiology of the Leiden University Medical Center received unrestricted research and educational grants from Boston Scientific Corporation, Medtronic, and Biotronik. Egorova received support from the Leiden University Medical Center research council Cardio-Vascular cluster Themes for Innovation funding and consultancy and speaker fees from Boston Scientific Corporation and Medtronic Inc. Burchill had no relevant conflicts of interest.