Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were well tolerated and showed “favorable” outcomes for transthyretin cardiomyopathy (ATTR-CM) patients in a new U.S./European observational study. The research, published Monday online ahead of the June 18 issue of the Journal of the American College of Cardiology, found that the 220 ATTR-CM patients treated with an SGLT2i saw improved renal function, lowered heart failure hospitalization and reduced all-cause mortality versus 220 propensity-matched control subjects. ATTR-CM has been an exclusion criteria for randomized clinical trials of SGLT2i, noted the authors, led by Aldostefano Porcari, MD, from University College London; University of Trieste, Italy; and the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart, also in Trieste. The findings join the mounting evidence that supports a need for randomized SGLT2i therapy trials in ATTR-CM – a disease that had been considered “very rare” until the recent creation of noninvasive diagnostic pathways that have “proven otherwise” – Porcari and team said. ‘Favorable effects’ The researchers assessed data from 2,356 consecutive ATTR-CM patients treated in one of 14 referral centers for amyloid cardiomyopathy across the U.S., U.K., Austria and Italy between 2014 and 2022, identifying 220 ATTR-CM patients treated with SGLT2i, who were propensity score-matched with 220 ATTR-CM patients not treated with SGLT2i. At baseline, the 440 study subjects had a mean age of 77 years, 89.8% were male (89.1% for the propensity matched and 90.5% for the treatment group), and the majority were in New York Heart Association (NYHA) class II (66.8% vs. 65.9%, respectively). In the treatment group, 82.3% had wild type ATTR vs. 17.7% with hereditary ATTR (compared with 79.1% vs. 20.9% in the control arm), while 58.2% were hypertensive (compared to 57.3% in control). Baseline systolic blood pressure for 126 mm Hg overall (129 mm Hg for the control and 122 mm Hg for the treatment arm). All patients had their transthyretin (TTR) gene sequenced and were followed up with 6 to 12 monthly consultations. The most commonly prescribed SGLT2i drug was dapagliflozin (67.3%), followed by empagliflozin (32.3%) and canagliflozin (0.4%), and treatment was mainly prompted by heart failure with reduced ejection fraction (HFrEF) and diabetes. At 12 months, the SGLT2i treatment group fared better when it came to NYHA scoring. The odds of deteriorating NHYA functional class compared to stable or improved NYHA functional class at 12 months were reduced by 53% with SGLT2i treatment (odds ratio [OR]: 0.47; 95% confidence interval [CI]: 0.25-0.87; P = 0.017). Patients treated with SGLT2i also had slower increase rates of plasma N-terminal pro–B-type natriuretic peptide (NT-proBNP) at 12 months (P < 0.001). After adjustment for baseline NT-proBNP, values were a mean of 4,148 ng/L in the 220 treated patients vs. 5,032 ng/L in the 220 control individuals , with a median change over 12 months of +32 ng/L in treatment arm vs. +914 ng/L in control. SGLT2i treatment was also associated with a slower rate of decline in estimated glomerular filtration rate at 12 months, with a median change from baseline of -2 mL/min/1.73 m2 in the treatment group vs. -6 mL/min/1.73 m2 in control (P < 0.001). SGLT2i-treated patients also saw fewer new initiations of loop diuretic agent therapy. Among the 69 patients not already treated with a loop diuretic at baseline, new initiations occurred for 4 of 23 patients in the SGLT2i arm vs. 17 of 46 in control. SGLT2i treatment reduced new initiations of loop diuretic agents over 12 months by 86% (OR: 0.14; 95% CI: 0.04-0.47; P = 0.001), said the authors. Over 28 months, SGLT2i therapy was associated with lower all-cause mortality (hazard ratio [HR]: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). The effect of reduced HF hospitalization, and cardiovascular and all-cause mortality, came regardless of ejection fraction. Although the authors conceded that “the effect sizes are likely representing an overestimate of the true treatment effect,” they pointed out that this “is not uncommon in [propensity score]-matched analysis approaches, especially when the number of events is relatively low.” They went on to stress that: “The results strongly support a benefit across the different endpoints.” Porcari and colleagues added that the treatment was “well tolerated,” with only 4.5% of patients discontinuing therapy. Unmet ATTR-CM need The only drug currently approved for ATTR-CM is tafamidis, said Porcari and team. However, recent acknowledgement that the disease is more widely prevalent than previously thought is now “stimulating development of several highly promising disease-modifying therapies,” they said. The latest findings in the current study join mounting evidence of the potential benefit of conventional HF medications in ATTR-CM, they added, including a recent retrospective study in more than 2,000 ATTR-CM patients. It showed that beta blockers and mineralocorticoid receptor antagonists (MRA) lowered all-cause mortality in the indication. “In HF, in recent years, new therapeutic pathways beyond neurohormonal modulation have recently been associated with clinical and prognostic benefits,” the authors said. “In phase 3 randomized clinical trials, treatment with [SGLT2i] was associated with fewer HF hospitalizations and decreased progression of kidney disease and cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF); more recently, these findings have been extended to patients with HF and mildly reduced or preserved ejection fraction. However, patients with ATTR-CM were excluded from these SGLT2i clinical trials.” Porcari and colleagues went on to call for randomized trials to be conducted to determine the optimum dose and timing of SGLT2i therapy in ATTR-CM patients, with or without diabetes mellitus, and to identify factors associated with treatment interruption. In the absence of randomized trials, they said data from the current study “may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM.” Randomized trial unlikely to happen In an accompanying editorial, Sean P. Pinney, MD, from the Icahn School of Medicine at Mount Sinai, New York, and Maria Rosa Costanzo, MD, from the Midwest Cardiovascular Institute, Naperville, Illinois, agreed that the effect size is “probably overestimated.” And while they sided with the authors on the fact that a randomized trial of SGLT2i in this population could shed more light on its role as ATTR-CM treatment, the editorialists stressed: “the truth is that such a study is not likely to happen.” They added: “However, it should be recognized that the data presented by Porcari et al originates from some of the largest and most experienced centers caring for patients with cardiac amyloidosis. Although it cannot be concluded that this report is the final word on the matter, we must recognize that it may likely be the one that includes the greatest number of patients. “[…] For now, a reasonable conclusion to draw is that treating patients with ATTR-CM with an SGLT2i appears safe and may meaningfully reduce the risk of HF events including mortality. These are results we can all live with because they highlight an important tool that can benefit patients with limited treatment options.” Sources: Porcari A, Cappelli F, Nitsche C, et al. SGLT2 Inhibitor Therapy in Patients With Transthyretin Amyloid Cardiomyopathy. J Am Coll Cardiol 2024;83:2411-2422. Pinney SP, Costanzo MR. As Good as it Gets: SGLT2 Inhibitors in Cardiac Amyloidosis. J Am Coll Cardiol 2024; 83: 2423-2425. Image Credit: Gorodenkoff – stock.adobe.com