Using dapagliflozin to reduce symptoms in transthyretin cardiac amyloidosis: An n-of-1 trial series pilot study

Background The role of guideline-directed medical therapy for heart failure (HF) is unclear in transthyretin amyloid cardiomyopathy (ATTR-CM). Dapagliflozin has demonstrated beneficial effects across HF phenotypes, and retrospective studies suggest potential benefit in ATTR-CM; however, prospective data are lacking. This pilot study evaluated the effect and tolerability of dapagliflozin in patients with ATTR-CM to inform the design of a larger randomized trial. Methods Participants were followed for 30 weeks over three study periods: 8 weeks baseline without study medication, 12 weeks intervention with dapagliflozin 10 mg once daily, and 10 weeks withdrawal without study medication. The study was open-label and nonrandomized. Vital signs and NT-proBNP were assessed every second week, while Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS) and 6-minute walking test (6MWT) were assessed every 4 weeks. Results were analyzed using linear mixed-effects models. Results Seven of ten enrolled patients completed the trial. One participant discontinued because of genitourinary adverse effects, and two withdrew for reasons unrelated to the intervention. The estimated intervention-versus-baseline difference was −142 pg/mL (95% CI −324–41) for NT-proBNP, 24.3 m (95% CI −2.8 to 51.5) for 6MWT distance, and 0.4 points (95% CI −4.0 to 4.8) for KCCQ-TSS. Sitting SBP was 8.8 mmHg lower during intervention than during baseline (95% CI −13.2 to −4.4). No increase in hypotensive symptoms or cardiovascular adverse events was detected. Conclusions Dapagliflozin was generally well tolerated in this pilot study of patients with ATTR-CM. The estimated differences in NT-proBNP, 6MWT distance, and KCCQ-TSS were imprecise and did not provide conclusive evidence of treatment effects. SBP was lower during treatment, without a detected increase in hypotensive symptoms. These exploratory findings support further evaluation in an adequately powered randomized trial. Trial registration This study was registered with clinical trial number EudraCT no 2021-003674-32