Combination therapy with SGLT2-inhibitors and tafamidis in transthyretin cardiomyopathy

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease associated with high morbidity and mortality. Tafamidis is the only US Food and Drug Administration-approved disease-modifying therapy. Sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) have shown promise in heart failure and may offer additive benefit when combined with tafamidis, although this remains unclear.

Using the TriNetX global research network, we identified adults with ATTR-CM treated with tafamidis between 2019 and 2022. Patients were stratified by concomitant use of SGLT2-Is (empagliflozin, dapagliflozin, or canagliflozin). Primary outcome was all-cause mortality; secondary outcomes included all-cause hospitalizations, acute myocardial infarction (AMI), stroke, heart failure hospitalizations, arrhythmias, and end-stage renal disease at 1- and 3-year follow-up.

After matching, 409 patients remained in each cohort. Combination therapy with SGLT2-Is and tafamidis was associated with significantly lower all-cause hospitalizations (1-year: OR 0.67, p = 0.005; 3-year: OR 0.67, p = 0.006) and AMI (1-year: OR 0.44, p = 0.001; 3-year: OR 0.56, p = 0.004). No significant mortality reduction was observed at either time point. No significant differences were observed for any of the other secondary outcomes.

In patients with ATTR-CM treated with tafamidis, adjunctive SGLT2-I use was associated with lower rates of hospitalization and AMI, without a significant mortality benefit. These findings support further prospective evaluation of combination therapy.