Association between sodium-glucose cotransporter 2 inhibitor therapy and outcome in 1,775 congenital heart disease patients – Application of an active comparator new user design

Background

Heart failure (HF) is highly prevalent in congenital heart disease (CHD), driving morbidity and mortality. Evidence supporting sodium–glucose cotransporter-2 inhibitors (SGLT2i) in CHD remains scarce, largely due to the absence of randomised trials in this specific patient group.

Purpose

To evaluate the prognostic association of SGLT2i use in CHD using an active comparator new user design (ACNUD).

Methods

Within a nationwide administrative database, CHD patients newly initiated on SGLT2i were identified and compared with active new users of mineralocorticoid receptor antagonists (MRAs). Propensity-score matching and multivariable time-dependent Cox regression were applied, adjusting for age, gender, CHD complexity, comorbidities, diabetes, prior emergency admissions, and concomitant HF therapy. The primary endpoint was all-cause mortality; the secondary endpoint was a composite of all-cause mortality or cardiac-related emergency admission.

Results

A total of 1,775 CHD patients received SGLT2i (median age 68 [IQR 57–79] years; 44% women) and were compared with 4,460 new MRA users (median age 67 [48-79] years; 50% female). SGLT2i recipients more frequently had diabetes (68% vs. 30%), obesity (56% vs. 36%), renal dysfunction (44% vs. 37%), and arterial hypertension, whereas heart failure and prior emergency admissions were more prevalent among MRA users (Table 1). Median follow-up was 445 [IQR 409–501] days and 1,565 [1,502–1,616] days in the SGLT2i and MRA group, respectively. In the SGLT2i cohort, 197 patients died and 697 experienced cardiac-related emergency admissions, compared with 1,200 deaths and 2,663 admissions among MRA users. After multivariable adjustment, SGLT2i therapy was associated with significantly lower all-cause mortality (HR 0.60; 95% CI 0.49–0.74; p<0.001) and reduced risk of the composite endpoint (HR 0.72; 95% CI 0.65–0.80; p<0.001) compared with new MRA users (Figure 1).

Independent predictors of mortality included increasing age, heart failure, renal dysfunction (HR 1.50, p<0.001), prior diuretic therapy, and cardiac glycoside use. Female gender, arterial hypertension (HR 0.58; all p<0.001), prior ARB therapy, beta-blocker use, and implantable cardioverter-defibrillator implantation were associated with lower mortality risk. For the composite endpoint, age, stroke, heart failure, diabetes, renal dysfunction (HR 1.29; p<0.001), and prior diuretic therapy were independently associated with increased risk, whereas ARB therapy and ICD implantation were protective.

Conclusions

In this nationwide CHD cohort analysed using an ACNUD, initiation of SGLT2i therapy was independently associated with improved survival and fewer cardiac-related emergency admissions compared with new MRA use. These findings demonstrate the feasibility of robust comparative effectiveness research in CHD and provide real-world evidence addressing the persistent lack of randomised trial data in this high-risk population.