# Sodium–Glucose Cotransporter 2 Inhibitor Combined with Conventional Diuretics Ameliorate Body Fluid Retention without Excessive Plasma Volume Reduction

## TL;DR

Combining SGLT2 inhibitors with diuretics helps reduce fluid retention without overly lowering plasma volume or stressing the body's systems.

## Contribution

The study shows that combining SGLT2 inhibitors with diuretics improves fluid balance without over-activating compensatory mechanisms.

## Key findings

- Copeptin levels decreased significantly in the combined treatment group compared to SGLT2 inhibitors alone.
- The combination treatment reduced interstitial and total body water more effectively than SGLT2 inhibitors alone.
- Plasma volume and hormonal systems were not excessively affected by the combination therapy.

## Abstract

We previously reported that sodium–glucose cotransporter 2 (SGLT2) inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake. However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. In this study, we examined the comparative effects of the SGLT2 inhibitor dapagliflozin (SGLT2i group, n = 53) and the combined use of dapagliflozin and conventional diuretics, including loop diuretics and/or thiazides (SGLT2i + diuretic group, n = 23), on serum copeptin, a stable, sensitive, and simple surrogate marker of vasopressin release and body fluid status. After six months of treatment, the change in copeptin was significantly lower in the SGLT2i + diuretic group than in the SGLT2i group (−1.4 ± 31.5% vs. 31.5 ± 56.3%, p = 0.0153). The change in the estimated plasma volume calculated using the Strauss formula was not significantly different between the two groups. Contrastingly, changes in interstitial fluid, extracellular water, intracellular water, and total body water were significantly lower in the SGLT2i + diuretic group than in the SGLT2i group. Changes in renin, aldosterone, and absolute epinephrine levels were not significantly different between the two groups. In conclusion, the combined use of the SGLT2 inhibitor dapagliflozin and conventional diuretics inhibited the increase in copeptin levels and remarkably ameliorated fluid retention without excessively reducing plasma volume and activating the renin–angiotensin–aldosterone and sympathetic nervous systems.