Renal Effects of SGLT2 Inhibitors and Potential Clinical Implications: Beyond the Heart

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have opened a new horizon in the management of heart failure (HF) with or without diabetes, given the considerable evidence supporting the effects of SGLT2 inhibitors on HF.1, 2) The relevance of SGLT2 inhibitors is steadily growing in patients with HF, indicating their potential as a mainstay of HF therapy in the near future. In addition, the potential role of SGLT2 inhibitors in protecting the renal function of patients with HF has received considerable attention.3) Recently, in addition to randomized trials assessing effectiveness, several real-world studies have emphasized the nephroprotective efficacy of SGLT2 inhibitors.4, 5, 6) From this standpoint, SGLT2 inhibitors could be of considerable interest to cardiologists and endocrinologists, as well as nephrologists.

Various pleiotropic effects of SGLT2 inhibitors have been recently reported, and multiple mechanisms have been proposed regarding the cardiovascular benefits of SGLT2 inhibitors. The most plausible mechanisms include blood pressure reduction, prevention of cardiac remodeling, and amelioration of cardiac energy metabolism.7) Furthermore, inhibition of SGLT2 can decrease the osmotic gradient between glomerular circulation and urinary tubules, resulting in glucosuria, natriuresis, and diuresis. SGLT2 inhibitors activate tubule-glomerular feedback by enhancing sodium delivery to macula densa cells, which induces the constriction of afferent glomerular arterioles and, in turn, reduces glomerular hyperfiltration, thereby decreasing subsequent albuminuria with beneficial effects on potential renal damage.8, 9)

In the present issue of IJHF, Kim et al. revealed that initiating SGLT2 inhibitors could reduce the dose of loop diuretics in outpatients with compensated HF.10) The authors found that 23.1% of patients experienced diuretic dose reduction during the 430 days of the mean follow-up period. The daily average dose of furosemide decreased from 16 to 8.5 mg, and the diuretic dose was almost 50% of its initial amount. Another interesting aspect of this study was that more than 80% of the registry data were from patients with HF exhibiting preserved ejection fraction. Based on these findings, it may be reasonable to consider empirical loop diuretic dose reduction when initiating an SGLT2 inhibitor in patients with HF in an outpatient clinical setting. However, these results should be interpreted with caution, given the potential limitations of the study. First, the study included a relatively small number of patients (especially patients with HF presenting reduced ejection fraction), and the cohort was based on outpatients who were relatively less sick. In addition, the study had a retrospective design and was performed at a single center. Furthermore, the study was a case series. Although it was possible to establish the decrease in diuretic dose during the follow-up period, there was no control group to compare the obtained findings. In addition, if authors could provide supportive data clarifying whether improvements in creatinine level or glomerular filtration rate could be attributed to the reduced diuretic dose or whether the diuretic dose is reduced following an improvement in natriuretic peptides (such as B-type natriuretic peptide [BNP] and its N-terminal fragment [NT-proBNP]), the study would have more robust implications. Data regarding the effect of diuretic dose reduction on renal or cardiovascular outcomes were lacking, and we expect these findings will be subsequently reported following additional analysis.

What are the clinical implications of the study by Kim et al.? These findings could be relevant in patients with decompensated HF exhibiting fluid overload. Resistance to loop diuretics is often encountered in such patients. Sequential nephron blockade agents, such as thiazides, can be combined with loop diuretics, and this method is often considered to overcome diuretic resistance, especially during decompensated HF. However, this combination regimen is not always effective and is often associated with an increased risk of electrolyte imbalance (such as hypokalemia and hyponatremia), hypotension, and renal injury. Based on the RECEDE-CHF trial,11) which reported a significant increase in diuresis over 24 h following the addition of empagliflozin to regular loop diuretics, the SGLT2 inhibitor could be a good alternative to thiazide-type diuretics in patients with HF presenting evidence of volume overload, accompanied by resistance to high-dose loop diuretics. However, the target patient group differed between these two studies (outpatient and hospital inpatient); therefore, additional studies are required to support this strategy.

The study by Kim et al. affords another take-home message that needs to be discussed. Recently, the importance of the “four-pillar (angiotensin receptor-neprilysin inhibitor [ARNI], beta-blocker, mineralocorticoid receptor antagonist [MRA], and SGLT2 inhibitor)” approach for treating heart failure with reduced ejection fraction (HFrEF) has been increasingly emphasized. However, which drugs should be applied first and how remains controversial. Based on the evidence of the diuretic effect of SGLT2 inhibitors, suitable recommendations have been presented by Packer et al.12) According to this formula, the first step in initiating treatment is recommended in the order of beta-blockers and SGLT2 inhibitors, followed by ARNI and MRA. Although physicians are well-aware of the importance of beta-blockers in patients with HFrEF, the application of these agents as first-line therapy is often not preferred, owing to limitations of fluid retention. The recommended strategy could offset the side effects and maximize the benefits of SGLT2 inhibitors, which appears to be a markedly reasonable and relatively easy approach in clinical practice.