SGLT2 inhibitors extend survival in amyloidosis patients with or without HF

Treatment with SGLT2 inhibitors can prolong the life of patients with amyloidosis with or without a diagnosis of heart failure (HF), a study has shown.

“SGLT2 inhibitor therapy is associated with significant survival benefits in amyloidosis patients with HF and may offer broader advantages across the amyloidosis spectrum, including [those] without HF,” the investigators said.

A total of 5,612 patients (mean age 74 years, 64 percent male) were included in this retrospective cohort study. Amyloidosis patients treated with SGLT2 inhibitors showed a higher survival probability at 5 years than those who did not receive such treatment (62.6 percent vs 39.1 percent; hazard ratio [HR], 0.54, 95 percent confidence interval [CI], 0.50–0.58; p<0.001). [Am J Med 2025;138:980-986]

Similarly, the use of SGLT2 inhibitors provided significant survival benefits in 1,490 patients without HF (HR, 0.57, 95 percent CI, 0.43–0.74; p<0.001).

In a subcohort of HF patients with transthyretin and amyloid light-chain amyloidosis, SGLT2 inhibitor use resulted in consistent benefits, including reduced mortality and favourable trends in acute myocardial infarction and stroke.

These findings supported those from previous studies, which demonstrated the benefits of SGLT2 inhibitors in HF that extend to patients with amyloid heart diseases. [J Card Fail 2024;30:1641-1646; Eur J Heart Fail 2024;26:938-947]

Mechanisms

“The notable SGLT2i benefits are likely conferred through multiple mechanisms that are beneficial to HF, including diuretic and anti-inflammatory effects,” the investigators said. [Am J Physiol Cell Physiol 2023;325:C661-C681] 

In recent studies, SGLT2 inhibitors have been shown to improve hemodynamics and induce a metabolic shift at the systemic level “by fostering ketones and fatty acids utilization as glucose-alternative substrates, thereby modulating major nutrient-sensing pathways that drive the ageing process. [Circulation 2022;146:1383-1405; Am J Physiol Cell Physiol 2023;325:C661-C681]

“Specifically, SGLT2 inhibitors may upregulate nutrient deprivation signalling and downregulate nutrient surplus signalling that promotes autophagy and prevents apoptotic cell death,” the investigators said. [Nat Rev Cardiol 2023;20:443-462]

In addition, SGLT2 inhibitors could reduce oxidative and endoplasmic reticulum stress, promote mitochondrial biogenesis, and lessen profibrotic pathways. Such mechanistic actions help boost senescent cells through autophagy promotion and cellular stress reduction, leading to improved overall cellular health and function. [Circulation 2022;146:1383-1405]

"These novel mechanisms make them a promising therapeutic option for patients with amyloidosis to improve lifespan, even in the absence of HF,” the investigators said. [Prog Cardiovasc Dis 2023;81:2-9] 

Kidney protection

Furthermore, previous trials have demonstrated the renoprotective effects of SGLT2 inhibitors despite an initial decline in glomerular filtration rates. [Kidney360 2024;5:771-782]

According to the investigators, it is possible that such dip in glomerular filtration rate following the use of SGLT2 inhibitors could trigger chronic kidney disease (CKD) coding.

However, “[t]he reassuring fact that increased CKD risk did not translate into an increase in all-cause mortality or other cardiovascular events supported this hypothesis, which implies the overall safety of this drug class in patients with amyloidosis,” they added.

The current retrospective cohort study utilized de-identified electronic health records from the TriNetX platform, which includes data from 101 healthcare organizations between 2009 and 2024.

The investigators compared two cohorts of amyloidosis patients with HF based on SGLT2 inhibitor use. Another cohort without an HF diagnosis was also examined. Baseline characteristics were balanced using propensity score matching.