Are SGLT2 inhibitors cardioprotective in wild-type ATTR-CM patients?

The use of sodium glucose cotransporter-2 (SGLT2) inhibitors nearly halves the risk of all-cause mortality at 3 years in patients with wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) and type 2 diabetes (T2D), findings from an observational study suggest.

For the primary endpoint of risk of all-cause mortality, the Kaplan-Meier survival curve reflected a hazard ratio of 0.53 (95 percent confidence interval, 0.36–0.74; p<0.001) with SGLT2 inhibitor use in wild-type ATTR-CM patients, as opposed to those who were not on SGLT2 inhibitor therapy.

The risks were similar for the secondary endpoints of atrial fibrillation, end-stage renal disease, ventricular tachycardia/fibrillation, and stroke at 3 years between participants on SGLT2 inhibitor therapy compared with those who were not.

High mortality

“Wild-type ATTR-CM is a progressive restrictive cardiomyopathy characterized by deposition of misfolded transthyretin in the myocardium, resulting in high mortality. This disease burden and clinical trajectory is further worsened by concomitant T2D,” noted the group of researchers from the Division of Cardiovascular Disease at the University of Alabama at Birmingham in the US, in their poster presented at HSFA ASM 2024.

SGLT2 inhibitors have shown benefit for heart failure hospitalizations in T2D patients and have now been recommended for use across the spectrum of left ventricular ejection fraction.

“[However,] limited data exist regarding SGLT2 inhibitor use in wild-type ATTR-CM patients,” said the researchers. “[Hence, we conducted] a retrospective cohort study … using federated real-world electronic health record (EHR) data assimilated from large academic medical centres across the US.”

The researchers characterized 1,531 T2D patients as also having wild-type ATTR-CM. Of these, 596 (38.9 percent) were on SGLT2 inhibitors. After propensity score matching, each study group comprised 534 participants (mean age at index 75 years). The cohort was stratified based on SGLT2 inhibitor use at the time of diagnosis of wild-type ATTR-CM. [Parcha, V, et al, HFSA ASM 2024]

About 80 percent of the overall participants had hypertension, over half had ischaemic heart disease, and 50 percent had chronic kidney disease. Other comorbidities were neoplasms, obesity, chronic obstructive pulmonary disease, depression, cerebral infarction, asthma, and nicotine dependence. Roughly a third of participants were on background tafamidis.

More studies needed to validate cardioprotective effect

However, the findings may have been limited by the retrospective nature of the study, the investigators noted. “EHR-based, real-world data utilizing standardized codes was used to define study variables and outcomes, which are subject to coding errors and cannot quantify the severity of the outcomes.”

Moreover, residual confounding from unmeasured variables may have contributed to the observed associations with the outcomes despite propensity score matching, they added.

The researchers called for prospective randomized clinical trials to further evaluate the cardioprotective efficacy of SGLT2 inhibitors in wild-type ATTR-CM patients with T2D.