We investigated the factors associating with the renoprotection of SGLT2i therapy in patients with HF and T2DM. The major finding of the present study was that lower plasma BNP level and the use of RASI at baseline were associated with the renoprotective effect of SGLT2i. Those with lower plasma BNP levels and the use of RASI had greater eGFR during the 12-month follow-up period over those without both of them irrespective of the eGFR levels and the HbA1c levels at baseline.
SGLT2i and BNP
Both EMPEROR-Reduced trial and DAPA-HF trial demonstrated that SGLT2i prevented the occurrence of worsening HF in patients with chronic HFrEF [9, 10]. The EMPEROR-Reduced trial further demonstrated that empagliflozin was associated with a lower risk of renal outcome and a slower progressive decline in renal function. Several large placebo-controlled trials using SGLT2i suggested that they might exert a beneficial effect on the renal outcome as a class effect [11–13]. On the contrary, the DAPA-HF trial, which used dapagliflozin, did not demonstrate the improvement of renal outcome [14].
The pattern of inconsistent findings in renal outcomes might be explained by the differences in the distribution of NYHA functional class in each trial. More patients with NYHA class II were enrolled in the EMPEROR-Reduced trial compared to the DAPA-HF trial. SGLT2i might have renoprotective effect particularly for those with less sick HF, as we also found in this study. In a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials, HFrEF patients with NYHA class II also had a lower risk of composite cardiovascular outcome compared to those with NYHA class III–IV symptoms [15]. These findings appear to be due to direct cardioprotective and nephroprotective effects, which may be related to actions on sodium balance, energy homeostasis, and mitigation of cellular stress [16]. The detailed mechanism remains uncertain, but the existence of renal congestion, indicated by the elevated BNP level, might suppress the improvement in renal function.
SGLT2i and RASI
RASI were the only classes of medication that have been shown to slow a decline in kidney function [4, 5]. The use of RASI was also associated with the renoprotective effect in the present study. Although few studies have investigated the combined effects of RASI and SGLT2i, several previous studies of SGLT2i have identified a minimal increase in plasma renin activity [17, 18]. SGLT2i can cause diuresis, natriuresis, and associated body fluid loss, resulting in renin activation. Although a reduction in plasma volume by SGLT2i would be expected to activate renin-angiotensin-aldosterone system, RASI may counterbalance this effect. Hence, RASI may have played an important role in renal protection in the present study.
Conversely, several studies in animal models or humans have confirmed unchanged activity in the renin-angiotensin-aldosterone system following the SGLT2i administration [19, 20]. An increase in GFR associating with long-term SGLT2i therapy is thought to be secondary to tubuloglomerular feedback, which is also a response of the macula densa to the increased salt delivery via inhibition of sodium transport proximally [21]. Furthermore, an increase in sodium chloride delivery to the macula densa may suppress the renin-angiotensin-aldosterone system. These different effects of SGLT2i may explain the inconsistent data regarding the responses of renin-angiotensin-aldosterone system to SGLT2i.
Consequently, the association between SGLT2i and systemic renin-angiotensin-aldosterone system activation is not straightforward. However, since plasma renin activity is significantly higher in patients with HF compared to healthy people [22], it is plausible that the renin-angiotensin-aldosterone system is activated in participants in the present study. This hypothesis may explain the finding that the use of RASI was associated with the renoprotective effect of SGLT2i in the present study.
Limitations
The sample size was small and the observation period was only one year. Given the low event number, the number of potential confounders included in the multivariate analyses was restricted. The one-year observation period may be insufficient to reveal changes in eGFR after SGLT2i administration. A large-scale multicenter study with a longer follow-up period is required. Although there was a difference in renal outcome between EMPEROR-Reduced trial and DAPA-HF trial, the multiple types of SGLT2i were used in the present study. Therefore, it remains unclear whether the renal beneficial effect is consistent across any SGLT2is. Lastly, the EMPEROR-Reduced trial revealed that SGLT2i reduced the risk of the composite renal endpoint, independently of diabetes status [23]. We also indicated that increases in eGFR during the observation period were independent of the HbA1c levels, whereas we did not include patients without T2DM in this study. Further studies are warranted to clarify the mechanism of SGLT2i on renal function and outcome.