Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypoglycemic and diuretic effects by inhibiting the absorption of sodium and glucose from the proximal tubule. Currently available data indicate that SGLT2 inhibitors transiently enhance urinary sodium excretion and urinary volume. When combined with loop diuretics, SGLT2 inhibitors exert a synergistic natriuretic effect. The favorable diuretic profile of SGLT2 inhibitors may confer benefits to volume management in patients with heart failure but this natriuretic effect may not be the dominant mechanism for the superior long-term outcomes observed with these agents in patients with heart failure. The first part of this review explores the causes of transient natriuresis and the diuretic mechanisms of SGLT2 inhibitors. The second part provides an overview of the synergistic effects of combining SGLT2 inhibitors with loop diuretics, and the third part summarizes the mechanisms of cardiovascular protection associated with the diuretic effects of SGLT2 inhibitors.
Highlights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of hypoglycemic drugs that have been shown to improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM) (Zinman et al, 2015; Neal et al, 2017; Wiviott et al, 2019)
As shown in the DAPA-HF (McMurray et al, 2019) and EMPEROR-reduced trials (Packer et al, 2020), SGLT2 inhibitors notably reduce the risk of worsening heart failure (HF) or death from cardiovascular causes in patients with HF and a reduced ejection fraction (HFrEF)
SGLT2 inhibitors have a unique diuretic mechanism thought to be one of the reasons for cardiovascular benefits in patients with HF; we summarise the following cardiovascular protective mechanisms associated with diuresis caused by SGLT2 inhibitors (Figure 2)
Summary
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a relatively new class of hypoglycemic drugs that have been shown to improve cardiovascular outcomes in type 2 diabetes mellitus (T2DM) (Zinman et al, 2015; Neal et al, 2017; Wiviott et al, 2019). As shown in the DAPA-HF (McMurray et al, 2019) and EMPEROR-reduced trials (Packer et al, 2020), SGLT2 inhibitors notably reduce the risk of worsening heart failure (HF) or death from cardiovascular causes in patients with HF and a reduced ejection fraction (HFrEF). Among these inhibitors, dapagliflozin significantly reduced the risk of the primary composite endpoint in patients with or without diabetes (McMurray et al, 2019). Compared to loop diuretics, SGLT2 inhibitors uniquely prevent sodium and glucose reabsorption in the renal proximal tubule, which result in increased sodium chloride delivery to the macula densa, thereby leading to physiological changes in nervous system function, fluid balance, and energy metabolism that
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