Efficacy and tolerability of sodium–glucose cotransporter-2 inhibitors in transthyretin amyloid cardiomyopathy: A systematic review and stratified meta-analysis

Aims: Although disease-modifying therapies have changed the management of transthyretin amyloid cardiomyopathy (ATTR-CM), supportive heart failure care remains crucial. Patients with ATTR-CM were excluded or underrepresented in randomized trials of sodium-glucose cotransporter-2 inhibitors (SGLT2i), leaving their role in this population uncertain. We performed a systematic review and stratified meta-analysis evaluating their efficacy, safety, and tolerability. Methods and results: PubMed/MEDLINE, Scopus, and the Cochrane Library/CENTRAL were searched up to 1 May 2026. The primary endpoint was ATTR-specific HR-based all-cause mortality. For studies enrolling both ATTR and AL amyloidosis, only separable ATTR subcohort estimates were extracted for the primary synthesis; AL estimates were excluded. Risk of bias was assessed using ROBINS-I and certainty of evidence using GRADE. Eighteen studies were included, comprising 12,039 SGLT2i-treated patients and 12,016 comparator patients across all analytic domains, although possible database overlap should be considered. The primary ATTR-specific HR-based synthesis showed an association between SGLT2i therapy and lower all-cause mortality (HR 0.65, 95% CI 0.56-0.76; I & sup2;=37.5%; 8 studies). HF-related events were directionally favourable but non-definitive (HR 0.73, 95% CI 0.50-1.06; I & sup2;=73.2%; 5 studies). Composite mortality/HF-related outcomes were associated with a lower risk (HR 0.69, 95% CI 0.55-0.85; I & sup2;=3.1%; 3 studies). Arrhythmic outcomes were only exploratory. SGLT2i therapy appeared well tolerated, with low pooled rates of definite discontinuation (6.9%), genitourinary events (4.7%), and AKI/renal adverse events (2.3%). Conclusion: Current non-randomized ATTR-specific evidence suggests that SGLT2i therapy in ATTR-CM/ATTR-HF is associated with lower all-cause mortality and acceptable safety and tolerability. Certainty remains low because of observational design, endpoint heterogeneity, heterogeneous background disease-modifying therapy, potential database overlap, and lack of patient-level amyloidosis subtype/stage stratification. Dedicated randomized trials are needed.