Response to Comment on Mone et al. Empagliflozin Improves Cognitive Impairment in Frail Older Adults With Type 2 Diabetes and Heart Failure With Preserved Ejection Fraction. Diabetes Care 2022;45:1247–1251

We thank Drs. Liang and Gu (1) for their interest in our study published in Diabetes Care (2) and their kind words of appreciation. Our study is the first to directly assess the cognitive status of empagliflozin in elderly patients and its relevant impact in terms of quality of life (QoL). Our findings provide strong evidence that empagliflozin improves health-related QoL. Interestingly, most recent observations are fully in agreement with our results. Indeed, in the Empagliflozin in Patients Hospitalized for Acute Heart Failure (EMPULSE) trial, empagliflozin was shown to be beneficial in patients hospitalized for acute heart failure (HF) regardless of the degree of symptomatic impairment at baseline, improving symptoms, physical limitations, and QoL, with benefits seen as early as 15 days. Similarly, the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved), conducted in patients with HF with preserved ejection fraction (HFpEF), has revealed that empagliflozin significantly ameliorates health-related QoL, as assessed via the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) at 12, 32, and 52 weeks. Of note, the KCCQ-23 includes 23 items that map to various domains: QoL, symptom frequency, symptom burden and stability, physical limitations, social limitations, and self-efficacy. Consistent with these findings, the CHIEF-HF (Canagliflozin Impact on Health Status, Quality of Life, and Functional Status in Heart Failure) decentralized trial, conducted in a completely remote fashion without in-person interactions, revealed that the 12-week change in KCCQ-23 total symptom score was 4.3 points higher following sodium–glucose cotransporter 2 (SGLT2) inhibition compared with placebo; remarkably, the benefits were observed as early as 2 weeks after initiation of therapy, and similar effects were observed in patients with HFpEF, in those with HF with reduced ejection fraction, and in participants with and without diabetes.

Mechanistically supporting our view, we have recently demonstrated that empagliflozin attenuates endothelial dysfunction induced by high glucose by improving cell viability and reducing mitochondrial calcium overload and the generation of reactive oxygen species (3). Moreover, we have validated the functional role of empagliflozin in rescuing the microRNA signature of endothelial dysfunction in patients with HFpEF and diabetes (4). In the latter trial, we identified a distinctive profile of circulating microRNAs that were significantly regulated in HFpEF patients compared with healthy control subjects; the increased levels of microRNAs known as biomarkers of endothelial dysfunction were significantly attenuated after a 3-month treatment with empagliflozin, whereas no significant differences were detected in patients treated with metformin or insulin (4).

The main mechanisms proposed to explain the favorable pleiotropic systemic effects of SGLT2 inhibition include improved endothelial function, enhanced calcium handling and myocardial energetics, and decreased inflammation and oxidative stress (5). The latest guidelines on HF management (6) recommend SGLT2 inhibitors be designated class 1A in HF with reduced ejection fraction and class 2A in HF with ejection fraction >40%. As masterfully summarized by Eugene Braunwald (7), who has defined SGLT2 inhibitors as the statins of the 21st century, SGLT2 inhibition improves cardiovascular outcomes in patients with HF over a wide range of ejection fractions, regardless of whether the patients have diabetes. Thus, it seems that the best answer to the question “Do SGLT2 inhibitors improve QoL?” is “Yes, they do.”