Effectiveness and tolerability of SGLT2i treatment in ATTR-CM

In a longitudinal, observational study, SGLT2i therapy was well tolerated in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) and associated with slower clinical decline and reduced risks of all-cause mortality, CV death, and HF hospitalization .

This summary is based on the publication of Porcari A, Cappelli F, Nitsche C, et al./strong> - SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2024 Jun 18;83(24):2411-2422. doi: 10.1016/j.jacc.2024.03.429

Introduction and methods

Background

Transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal disease characterized by the deposition of amyloid fibrils, which consist of misfolded transthyretin (TTR) aggregates, in the myocardium. Currently, tafamidis is the only drug approved for the treatment of ATTR-CM, but its use is limited in many countries due to the high cost [1]. The role and value of standard HF therapies for patients with ATTR-CM have been long debated because HF clinical trials exclude patients with amyloid depositions. As such, ATTR-CM was an exclusion criterion in previous RCTs of SGLT2 inhibitors.

Aim of the study

The study aim was to investigate the effectiveness and tolerability of treatment with SGLT2 inhibitors in patients with ATTR-CM, as well as the association of this treatment with mortality and HF hospitalization.

Methods

In this multicenter, longitudinal, observational study, the authors collected data of 2356 consecutive ATTR-CM patients from 14 referral centers for amyloid cardiomyopathy in the UK, the US, Austria, and Italy in the period 2014–2022. Among these patients, 260 (11%) received SGLT2 inhibitor treatment. Using propensity score matching in a 1:1 ratio, 220 patients (85%) could be adequately matched to 220 control ATTR-CM patients who did not receive SGLT2 inhibitor treatment. Median follow-up time was 28 months (Q1–Q3: 18–45).

Outcomes

The primary endpoint was all-cause mortality. Secondary endpoints were CV death, unplanned hospitalization for worsening HF, and a composite outcome of CV death and HF hospitalization.

Main results

Effectiveness and tolerability

• At 12 months, patients treated with SGLT2 inhibitors exhibited a decreased rate of worsening HF symptoms, as assessed by NYHA functional class, compared with patients not on SGLT2 inhibitor therapy: The odds of having a deteriorating NYHA class at 12 months compared with having a stable or improved NYHA class were reduced by 53% in the SGLT2 inhibitor treatment group (OR: 0.47; 95%CI: 0.25–0.87; P=0.017).
• Similarly, patients receiving SGLT2 inhibitors showed a slower rate of increase in NT-proBNP levels at 12 months, after adjusting for baseline NT-proBNP levels, than untreated patients (mean change: 323 vs. 914 ng/L; P<0.001), a slower rate of eGFR decline at 12 months after adjusting for baseline eGFR (mean change: –2 vs. –6 mL/min/1.73 m²; P<0.001), and no change in systolic blood pressure (SBP) at 12 months after adjusting for baseline SBP levels (mean change: –3 vs. –7 mmHg; P=0.24).
• SGLT2 inhibitor treatment was associated with fewer new prescriptions of loop diuretics over 12 months (OR: 0.14; 95%CI: 0.04–0.47; P=0.001).
• During follow-up, SGLT2 inhibitors were discontinued in 10 of the 220 treated patients (4.5%).

Mortality and HF hospitalization

• Time-dependent Cox regression analysis with SGLT2 inhibitor use as the time-varying exposure indicated 29 patients (13.2%) receiving SGLT2 inhibitors died during follow-up compared with 82 untreated patients (24.7%) (4.0 vs. 10.8 deaths per 100 patient-years; HR: 0.57; 95%CI: 0.37–0.89; P=0.010).
• These results were consistent across TTR genotype (wild-type ATTR-CM vs. p.V142I-associated hereditary ATTR-CM; P for interaction=0.94), presence of diabetes (diabetes vs. no diabetes; P for interaction=0.29), and treatment with disease-modifying drugs, including tafamidis and patisiran (treated vs. untreated; P for interaction=0.46).
• A Kaplan-Meier analysis based on “baseline treatment status”—in which patients were classified as “on SGLT2 inhibitor treatment” at baseline and continued to be classified this way regardless of whether or not the treatment was discontinued, and vice versa—further confirmed the findings (log-rank P=0.001).
• The rate of CV death was lower in SGLT2 inhibitor–treated patients compared with untreated patients (2.4 vs. 8.4 deaths per 100 patient-years; HR: 0.41; 95%CI: 0.24–0.71; P<0.001), as were the rates of HF hospitalization (3.6 vs. 9.2 events per 100 patient-years; HR: 0.57; 95%CI: 0.36–0.91; P=0.014) and the composite outcome of CV death and HF hospitalization (5.5 vs. 13.9 events per 100 patient-years; HR: 0.47 ; 95%CI: 0.38–0.84; P=0.003).

Conclusion

In this longitudinal, observational study using propensity score matching, ATTR-CM patients treated with SGLT2 inhibitors had a decreased rate of worsening HF symptoms, an attenuated rise in NT-proBNP levels, a slower eGFR decline, and fewer new loop diuretic prescriptions at 12 months compared with patients who did not receive this treatment. During a median follow-up time of 28 months, SGLT2 inhibitor treatment was associated with reduced risks of all-cause mortality, CV death, HF hospitalization, and the composite outcome of CV death and HF hospitalization . Furthermore, SGLT2 inhibitor therapy was well tolerated (discontinuation rate: 4.5%) and not associated with significant SBP changes.

The authors note that “the effect sizes [in this study] are likely representing an overestimate of the true treatment effect, which is not uncommon in [propensity score]–matched analysis approaches, especially when the number of events is relatively low. Nonetheless, the results strongly support a benefit across the different endpoints.” In addition, “[i]n the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2 inhibitors in patients with ATTR-CM.”

Find this article online at J Am Coll Cardiol.

Reference

1. Kazi DS, Bellows BK, Baron SJ, et al. Cost-effectiveness of tafamidis therapy for transthyretin amyloid cardiomyopathy. Circulation. 2020;141:1214–1224.