What’s New? Brief Reports on Clinical Research
Written by Pablo Carrión Montaner, Hospital de Sabadell, Spain
Cardiac amyloidosis due to transthyretin (ATTR-AC) is an emerging disease that has come to light thanks to technological advances in non-invasive imaging tests. It has been shown to be a relatively common cause of heart failure; up to 10% of patients with heart failure with preserved ejection fraction have an underlying diagnosis of amyloidosis.
It is a disease systematically excluded from heart failure studies, so we do not know the impact of quadruple therapy on this population. To date, the only drug that has shown clinical benefit in this disease is Tafamidis, through a phase III randomized controlled clinical trial (Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy).
Several descriptive studies have shown a mortality benefit in patients with ventricular dysfunction (LVEF < 40%) treated with beta-blockers and mineralocorticoid receptor antagonists, which has opened the focus towards a potential benefit of heart failure treatment in this population. To date, there is little scientific evidence on the use of SGLT2 inhibitors in ATTR-AC.
The objective of this study was to obtain data on the efficacy and tolerability of SGLT2 inhibitors in the context of cardiac amyloidosis, a condition that, as mentioned, was an exclusion criterion in their major clinical trials.
This was a retrospective multicenter study that analyzed data from 2356 patients from 14 national reference centers for cardiac amyloidosis in the United Kingdom, United States, Austria, and Italy during the period 2014-2022, of which 260 (11%) received SGLT2 inhibitors (mainly dapagliflozin 10 mg/day). After assessing the groups according to treatment, 14 significantly different variables were identified to which age and NT-proBNP were added, obtaining as propensity the probability of being treated with SGLT2 inhibitors for each patient in order to compare them with a counterpart from the untreated group.
The study included 220 patients treated with SGLT2 inhibitors (mean age 77 ± 2 years; 82.3% wild-type amyloidosis and 17.7% with various hereditary forms; mean LVEF 45.8% ± 11%) and 220 adequately propensity-matched control individuals. At 12 months of follow-up, treatment with SGLT2 inhibitors was associated with less deterioration of NYHA functional class (OR 0.47; 95% CI: 0.25-0.87; p=0.017), NT-proBNP, and estimated glomerular filtration rate, and a reduction in the use of loop diuretics. No significant effect was observed on blood pressure, a clinically relevant aspect in the advanced stages of this disease, which prevents adherence to these disease-modifying drugs.
With a median follow-up of 28 months (Q1-Q3: 18-45 months), the use of SGLT2 inhibitors was significantly associated with a reduction in all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; p=0.01), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; p<0.001), heart failure hospitalization (HR: 0.57; 95% CI: 0.36-0.91; p=0.014), and the composite endpoint of cardiovascular mortality and heart failure hospitalization (HR: 0.57; 95% CI: 0.38-0.84; p=0.003). All results were independent of the type of amyloidosis, LVEF, the presence or absence of diabetes, and concomitant use of specific disease-modifying treatments.
The rate of discontinuation of SGLT2 inhibitors was low (4.5%), mainly due to recurrent urinary tract infections.
In conclusion, in this propensity-guided analysis, treatment with SGLT2 inhibitors in patients with cardiac amyloidosis was well-tolerated and was early associated with favorable effects on heart failure symptoms and signs, renal function, and the need for diuretics use, and was significantly associated with a reduced risk of hard endpoints such as heart failure hospitalization, cardiovascular mortality and total mortality.
As limitations, the authors describe that the results of this study differ from those reported in clinical trials in patients undergoing treatment with SGLT2 inhibitors. This overestimation of the effect is likely due to it being a retrospective study adjusted by propensity score, which does not allow for adjustment of all confounding factors. Nonetheless, this is a retrospective study with the inherent limitations. Thus, it should be considered as a hypothesis generator and ideally, these results should be confirmed with prospective randomized studies.
However, in the absence of randomized clinical trials, these data may have great relevance for all clinicians managing patients with ATTR-AC in their daily practice.
References:
- Porcari A, Cappelli F, Nitsche C, et al. SGLT2 inhibitor therapy in patients with transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol. 2024;83:2411-22.