Authors’ reply
We thank Patoulias and colleagues for their interest in our manuscript.1 The authors of the letter raise a very important issue in the treatment of patients with chronic heart failure (CHF); namely, the risk for sarcopenia and the potential unfavorable effect of sodium-glucose cotransporter 2 (SGLT-2) inhibitors on skeletal muscle mass (SMM). Sarcopenia, which has recently been newly defined as a functional disability involving weakness of muscle strength and a reduction in whole-body SMM,2 is recognized as a general predictor of all-cause mortality and frailty, and is also linked with a reduced peak oxygen consumption and shorter exercise time, particularly in patients with CHF.3 The available data show a weight-lowering effect of empagliflozin, dapagliflozin, ipragliflozin, luseogliflozin, and canagliflozin administered for 24 to 52 weeks with or without metformin.4-5 This effect was associated with a reduction in total, visceral, and epicardial fat, which is recognized as one of the cardioprotective properties of flozins, and with a mainly nonsignificant influence on SMM, but with improvement in the endocrine function of the skeletal muscle (eg, reduction in blood concentration of myostatin) and metabolic functions (eg, decrease in insulin resistance). However, so far, the favorable effect of SGLT-2 inhibitors on body composition was shown only in patients with type 1 and 2 diabetes mellitus (DM), but not in those with CHF. In light of this, the question raised by Patoulias and colleagues is of great clinical importance, especially as SGLT-2 inhibitors have become one of 5 first-line classes of drugs dedicated to treatment of patients with CHF, both with and without DM.5 In our study, we found an almost 10-fold higher risk of all-cause readmission in patients with a visceral fat level (VFL) score greater than 15, suggesting that VFL acts as the main body composition target of SGLT-2 inhibitors in CHF patients. Such assumption corroborates the outcomes of the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure) and EMPEROR-Reduced (Empagliflozin Outcom Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) trials.5 Unfortunately, in our investigation, none of the CHF patients were treated with SGLT-2 inhibitors, which can be explained by the study enrollment period (May 2016–February 2018), high costs of treatment with SGLT-2 inhibitors, their relatively short availability on the Polish market (about 6 years) as well as the fact that they had only recently been included in the standard therapy of CHF.5
While preparing this reply, we also reanalyzed our database. We discovered, among other things, that CHF patients with type 2 DM seemed more likely to benefit from therapy with SGLT-2 inhibitors compared with nondiabetic individuals. For example, they had a significantly higher body mass index (BMI), waist circumference, waist-to-hip ratio, waist-to-height ratio, fat mass (FM), and VFL, as well as a lower percentage of SMM in whole body weight (SMM%). On the other hand, there were no significant differences between CHF patients with and without type 2 DM in the Mini Nutritional Assessment score and SMM expressed in kilograms. These differences in nutritional statuses of the patients were associated with a significantly higher Borg Dyspnea Scale score and significantly shorter distance during a 6-minute walk test in patients with DM compared with nondiabetic individuals, but without significant differences in Barthel scale score or handgrip strength. Among the parameters of nutritional status assessment in CHF patients, a higher SMM% was associated with a higher rate of all-cause mortality, higher VFL increased the risk of all-cause readmission, and a lower percentage of FM in whole body mass (FM%) was associated with a shorter length of hospital stay.1 Of note, absolute SMM and FM expressed in kilograms, which would seem to be better indicators of a potential weight-reducing effect of SGLT-2 inhibitors than the relative biomarkers (SMM% and FM%), did not influence patients’ prognoses. As a result of the limitations of the body composition assessment method mentioned in our study (the use of only 2 frequencies in the bioelectrical impedance analysis and calculation of body composition parameters based on algorithms provided by the manufacturer of the device),1 the relative increase in SMM% and decrease in FM% found in our study can also be interpreted as having resulted from water retention (more severe CHF advancement), which, in turn, might suggest greater importance of the diuretic compared with the weight-decreasing effect of SGLT-2 inhibitors in CHF patients. Therefore, the mechanism of SGLT-2 inhibitors in CHF patients requires further study, especially in the context of the still undetermined clinical importance of the so-called “obesity paradox” or “BMI paradox.” Also, the role of adipose tissue distribution, body composition, and the prognostic effect of their potential modification by treatment with SGLT-2 inhibitors in patients with CHF should be further investigated.
Jacek Budzyński, Anna Wawrzeńczyk (Department of Vascular and Internal Diseases, Nicolaus Copernicus University in Toruń, Toruń, Poland, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland; Department of Angiology, Jan Biziel University Hospital No. 2 in Bydgoszcz, Bydgoszcz, Poland)
None declared.
Budzyński J, Wawrzeńczyk A. Sodium-glucose cotransporter 2 inhibitors and heart failure decompensation: considerations on body composition and skeletal mass. Authors’ reply. Pol Arch Intern Med. 2021; 131: 16169. doi:10.20452/pamw.16169
- 1.
- Wawrzeńczyk A, Kowalczyk G, Szukay B, et al. Nutritional status and body composition of patients hospitalized due to exacerbated heart failure. Pol Arch Intern Med. 2021; 131: 16132.Crossref
- 2.
- Cruz-Jentoft AJ, Bahat G, Bauer J, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019; 48: 16-31.Crossref
- 3.
- Suzuki T, Palus S, Springer J. Skeletal muscle wasting in chronic heart failure. ESC Heart Fail. 2018; 5: 1099-1107.Crossref
- 4.
- Nagai Y, Fukuda H, Kawanabe S, et al. Differing effect of the sodium-glucose cotransporter 2 inhibitor ipragliflozin on the decrease of fat mass vs. lean mass in patients with or without metformin therapy. J Clin Med Res. 2019; 11: 297-300.Crossref
- 5.
- McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021; 42: 3599-3726.