Effect of SGLT2 inhibitors on body composition, fluid status and renin–angiotensin–aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy

Inhibitors of the sodium-coupled glucose transporter 2 (SGLT2) are a promising and increasingly prescribed class of oral antidiabetic drugs. SGLT2-inhibitors increase urinary excretion of glucose by inhibiting its reabsorption via SGLT2 in the proximal tubule of the kidney, thus lowering blood glucose levels [1]. Besides their antidiabetic effect, loss of body weight has been observed consistently [2‐4]. However, it is uncertain which body compartments and tissues change after the initiation of SGLT2 inhibition. In theory, body weight loss under treatment with SGLT2 inhibitors could be either due to loss of fat mass by a negative effect on the energy balance or due to loss of sodium and extracellular volume by a diuretic effect or due to a combination of both. Previous investigations of changes in body composition under SGLT2 inhibitors mainly relied on calculated indices or x-ray absorptiometry [5‐7]. In contrast, quantitative measurements of body composition have only lately been performed in a few cohorts [8‐11]. Early changes of body composition during the first days after initiation of SGTL2 inhibitors have not been investigated yet.

In addition to the antihyperglycemic effect, treatment with SGLT2 inhibitors was associated with reduction of hospitalization and mortality due to heart failure [12‐16]. Up to now, the underlying mechanisms remain ill-defined, further studies investigating this connection are carried out [17] and different theories have been discussed [18‐20]. Due to concomitant natriuresis of SGLT2 inhibitors, a direct diuretic effect with reduction of extracellular volume is conceivable. The early separation of the Kaplan–Meier curves for heart failure hospitalization and mortality in patients treated with empagliflozin [12] suggests an immediate effect on congestive symptoms and strikingly resembles that of thiazide diuretic chlorthalidone as observed in the ALLHAT Treatment Group in 2007 [21]. Bioimpedance spectroscopy analysis as a quantitative measurement method can contribute to further define changes of body composition under treatment with SGLT2 inhibitors and to identify changes in fluid status that could be responsible for these favorable effects in heart failure.

In this study, we analyzed the course of body composition and fluid status as measured by bioimpedance spectroscopy in a cohort of patients with type 2 diabetes after initiation of therapy with SGLT2 inhibitors empagliflozin or dapagliflozin during the first week and a follow up period of 6 months. Additionally, body composition and fluid status of patients with arterial hypertension and established diuretic therapy with hydrochlorothiazide, and control groups without SGLT2 inhibitors or diuretic medication were analyzed.

We found that the reduction of body weight during treatment with the SGLT2 inhibitors empagliflozin and dapagliflozin is caused by changes in volume status with decrease of extracellular water during the first days of intake, and by decrease of adipose tissue mass during the following weeks and months. The body weight reduction in our study was − 2.6 kg after 6 months and in the same range as reported previously with a body weight reduction of − 1.9 to − 2.3 after 14 to 24 weeks after initiation of a SGLT2 inhibitor [3, 5, 6, 28].

In our study, the reduction of body weight after 6 months was due to a loss of adipose tissue mass, while lean tissue mass did not change significantly. This is consistent with results from similar studies that used x-ray absorptiometry or calculated indices of adipose tissue mass [5‐7]. Other studies involving bioimpedance spectroscopy also found that weight loss under SGLT2 inhibition after 12–104 weeks was mainly via reduction of adipose mass [8‐10]. It has been discussed that the loss of adipose mass under SLGT2 inhibition can be attributed to an energy loss due to increased glycosuria [28‐30] and increased lipid utilization [31]. Interestingly, besides body fat, epicardial fat was reduced under medication with SGLT2 inhibitors, providing another possible mechanism of reduction of cardiovascular mortality by SGLT2 inhibitors [32, 33].

As the probably most obvious mechanism of cardiovascular risk reduction under SGLT2 inhibition, a diuretic effect as a consequence of increased glucosuria and natriuresis, can be expected [20]. A novel and important finding of the present study is that changes in body fluid status are transient after initiation of SGLT2 inhibitor treatment with empagliflozin or dapagliflozin. Extracellular water was reduced rapidly and significantly after 3 days, but had returned to baseline value when measured after three and 6 months. In a cohort of post-transplant diabetes mellitus, Schwaiger et al. [11] also found a decrease of extracellular fluid after 4 weeks and extracellular water returned to baseline value in the further course. In Japanese patients treated with ipragliflozin, Iizuka et al. [8] found a reduction of total body water by − 0.43 kg at 4 weeks, and a rising tendency at 12 weeks (− 0.37 kg), compared to baseline, respectively, with changes of body fluid mainly caused by extracellular water and no significant changes of intracellular water; however, changes of volume status during the first days of SGLT2 inhibition were not measured and follow up period was shorter, thus missing data on initial as well as long term changes in body fluid status. In our cohort, extracellular water was consistently decreased after 1 and 3 months (− 0.4 L/1.73 m² at day 30 and − 0.2 L/1.73 m² at day 90, compared to baseline, respectively), and showed a return to initial value in the long term follow up (− 0.01 L/1.73 m² at day 180 compared to baseline).

As one consequence of the diuretic effect of SGLT2 inhibitors, a reduction of arterial blood pressure can be expected. In our cohort, along with the course of OH and ECW, systolic and diastolic office blood pressure tended to decrease after 3 days, but there were no significant differences after 3 and 6 months, compared to baseline, respectively. However, in our study, blood pressure was measured only as a single office blood pressure. In studies that considered ambulatory blood pressure monitoring, SGLT2 inhibitors have been shown to reduce blood pressure measured after 3 and 6 months of intake [34‐37].

In accordance to our finding of transient decreased OH and ECW, increase of urine volume after initiation of SGLT2 inhibitors has also been found to be transient and was caused rather by natriuresis than by osmotic diuresis due to glycosuria [29, 38]. After initiation of SGLT2 inhibition, an initial, but no long-term elevated natriuresis has been shown, and compensatory mechanisms such as increased sodium reuptake through following tubular transporters and activation of RAAS, have been investigated [38, 39]. Systemic RAAS has been shown to be activated transiently in patients with type 2 diabetes after beginning of SGLT2 inhibitors [39], whereas intrarenal RAAS is not activated after SGLT2 inhibition [40]. SGLT2 inhibitors have been recommended as combination therapy to RAAS inhibitors, especially in diabetic kidney disease [41]. In our study, despite preexisting medication with RAAS inhibitors in nearly all patients, changes of fluid status were accompanied by a trend towards elevated plasma renin activity and serum aldosterone concentration after 30 days, suggesting an increased activity of RAAS, with normalization after 6 months. Our results therefore confirm active counteracting mechanisms of fluid regulation after inhibition of SGLT2 as discussed previously [39].

SGLT2 inhibitors have been suspected to promote the occurrence of stroke due to volume depletion [42, 43], with the Kaplan–Meier curves suggesting elevated risk of stroke during the first time after initiation of SGLT2 inhibition [44]. In the long term, however, stroke incidence is not elevated paralleling the normalization of volume depletion [45]. Another concern about the diuretic effect of SGLT2 inhibitors is that they could promote renal failure. Indeed, parallel to the reduction of ECW after 3 days and 1 month in our cohort, a decline of GFR was observed after initiation of SGLT2 inhibitors [46]. However, in the long term course, SGLT2 inhibitors have even been associated with a slower progression of chronic kidney disease [30, 46]. In our cohort, ongoing fluid loss or reduction of extracellular water as a risk of stroke or prerenal kidney injury was not observed with SGLT2 inhibition, supporting the safety of prescribing SGLT2 inhibitors, as long as counter-regulating mechanisms of fluid status are operative.

At baseline, participants of our study were normally hydrated as both, OH and ECW were in reference ranges. Comparison to a group of hypertensive patients with medication with hydrochlorothiazide as a diuretic agent showed no differences in fluid status of patients with chronic intake of SGLT2 inhibitors, hydrochlorothiazide, or no diuretic medication. This suggests that there is also no ongoing loss of extracellular water under treatment with the diuretic hydrochlorothiazide similar to SGLT2 inhibitors due to counter-regulation. In contrast to our study cohort, patients with heart failure are at risk for fluid overload and extracellular water accumulation, leading to hydropic decompensation and hospitalization [47]. Treatment with SGLT2 inhibitors has been shown to reduce this risk [12] and was found to be safe and efficient in patients with type 2 diabetes and different stages of cardiovascular disease [48]. SGLT2 inhibition could lead to a sustained correction of fluid accumulation in patients starting with an elevated level of overhydration and extracellular water. This is supported by the finding that patients at risk for heart failure, who were treated with empagliflozin, had a reduced need for loop diuretics [14]. In a cohort of chronic kidney disease patients with fluid retention, decrease of extracellular fluid under medication with dapagliflozin was smaller than under medication with furosemide, but larger than under medication with tolvaptan [49]. Our data therefore are compatible with the notion that the protective effect of SGLT2 inhibitors from heart failure is related to their effect on extracellular volume and overhydration. This effect could even be enhanced in patients with overhydration at baseline.

Overall, the diuretic effect of SGLT2 inhibitors seems to be most effective during the initial period of SGLT2 inhibition [38], and we showed that it causes changes in fluid status and could therefore be responsible for fast acting beneficial effects on heart failure; reduction of adipose tissue that we confirmed in the follow up period of SGLT2 inhibition indicates that additional mechanisms for risk reduction in heart failure could gain importance in the long term course, such as lipid utilization [31], reduction of epicardial fat [32, 33], and effects on vascular endothelial function [50].

The limitations of this study are the small number of patients and healthy participants without heart failure or proteinuria, conditions known to be associated with overhydration and edema. The strengths of the study are the direct measurements with the output of quantitative data of volume status and body composition by using bioimpedance spectroscopy. To our knowledge, it is the first study concentrating on the changes of fluid status and body composition during the first days after initiation of SGLT2 inhibitor treatment and during a follow up period of 6 months. Even in our small cohort, significant changes in the intraindividual course of the parameters of interest could be detected, indicating robustness of the observed changes.

In conclusion, our study shows that body weight reduction under the intake of SGLT2 inhibitors is caused by a decrease of adipose tissue mass after 6 months of intake and by a transient decrease of extracellular water after 3 days and 1 month, which is counterbalanced by upregulation of renin–angiotensin–aldosterone system. Our data argue against an ongoing fluid loss under treatment with SGLT2 inhibitors, which is also not seen in chronic thiazide treatment.