Copeptin and Body Fluid Responses to the Combined Use of an SGLT2 Inhibitor and Conventional Diuretics in Patients with CKD: The DAPA-BODY Trial

Background: We previously reported that SGLT2 inhibitors exert sustained fluid homeostatic actions through compensatory increases in osmotic diuresis-induced vasopressin secretion and fluid intake (Physiol Rep 2020, AJP Renal 2022). However, SGLT2 inhibitors alone do not produce durable amelioration of fluid retention. Methods: 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 surrogate marker of vasopressin release, and body fluid status measured by bioimpedance device (InBody S10). Results: After six months of treatment, the change in copeptin was significantly lower in the SGLT2i+diuretic group than in the SGLT2i group (SGLT2i 31.5±56.3% vs. SGLT2i+diuretic -1.4±31.5%, p=0.0153). The change in the estimated plasma volume calculated using the Strauss formula (-1.7±5.2% vs. -2.6±5.3%, p=0.2563) and brain natriuretic peptide (26.3±84.5% vs. 4.0±60.8%, p=0.1716) were not significantly different between the two groups. Contrastingly, changes in interstitial fluid (-1.7±5.4% vs. -8.8±12.5%, p=0.0013), extracellular water (-1.7±5.4% vs. -8.8±12.5%, p=0.0013), intracellular water (-2.1±5.1% vs. -5.8±9.3%, p=0.0183), and total body water (-2.1±4.8% vs. -6.2±9.0%, p=0.0089) were significantly lower in the SGLT2i+diuretic group than in the SGLT2i group. Changes in renin (16.3±102.8% vs. 26.6±91.0%, p=0.3765) and aldosterone (9.8±48.0% vs. 20.3±52.0% p=0.2560), and absolute epinephrine levels (21.3±13.8 pg/mL vs. 21.0±10.4 pg/mL, p=0.4854) were not significantly different between the two groups. 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. Funding: Private Foundation Support