Copeptin adaptive response to SGLT2 inhibitors in patients with type 2 diabetes mellitus: The GliRACo study

Abstract

Introduction: In type 2 diabetes mellitus (T2DM), the antidiuretic system participates in the adaptation to osmotic diuresis further increasing urinary osmolality by reducing the electrolyte-free water clearance. Sodium glucose co-transporter type 2 inhibitors (SGLT2i) emphasize this mechanism, promoting persistent glycosuria and natriuresis, but also induce a greater reduction of interstitial fluids than traditional diuretics. The preservation of osmotic homeostasis is the main task of the antidiuretic system and, in turn, intracellular dehydration the main drive to vasopressin (AVP) secretion. Copeptin is a stable fragment of the AVP precursor co-secreted with AVP in an equimolar amount.

Aim: To investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients.

Methods: The GliRACo study was a prospective, multicenter, observational research. Twenty-six consecutive adult patients with T2DM were recruited and randomly assigned to empagliflozin or dapagliflozin treatment. Copeptin, plasma renin activity, aldosterone and natriuretic peptides were evaluated at baseline (T0) and then 30 (T30) and 90 days (T90) after SGLT2i starting. Bioelectrical impedance vector analysis (BIVA) and ambulatory blood pressure monitoring were performed at T0 and T90.

Results: Among endocrine biomarkers, only copeptin increased at T30, showing subsequent stability (7.5 pmol/L at T0, 9.8 pmol/L at T30, 9.5 pmol/L at T90; p = 0.001). BIVA recorded an overall tendency to dehydration at T90 with a stable proportion between extra- and intracellular fluid volumes. Twelve patients (46.1%) had a BIVA overhydration pattern at baseline and 7 of them (58.3%) resolved this condition at T90. Total body water content, extra and intracellular fluid changes were significantly affected by the underlying overhydration condition (p < 0.001), while copeptin did not.

Conclusion: In patients with T2DM, SGLT2i promote the release of AVP, thus compensating for persistent osmotic diuresis. This mainly occurs because of a proportional dehydration process between intra and extracellular fluid (i.e., intracellular dehydration rather than extracellular dehydration). The extent of fluid reduction, but not the copeptin response, is affected by the patient's baseline volume conditions.

Clinical trial registration: Clinicaltrials.gov, identifier NCT03917758.

Keywords: arginine-vasopressin; bioelectrical impedance vector analysis; extracellular fluid; osmotic homeostasis; renin-angiotensin-aldosterone system; sodium glucose co-transporter type 2 inhibitors.

FIGURE 1

Recruitment process flow-chart.

FIGURE 2

Correlation between plasma copeptin (p-copeptin) and plasma osmolality levels (p-Osm) the day before the start of SGLT2i (T0) and then at 30 (T30) and 90 (T90) treatment days (locally weighted scattered-pot smoother (LOESS) with a span of 80%).

FIGURE 3

Mean Biavectors from overhydrated (red ellipse) and normohydrated patients (black ellipse), recorded the day before the start of SGLT2i (T0), compared with the two-sample Hotelling’s T2 test (p < 0.0001).

FIGURE 4

Mean Biavectors’ displacement, between the day before the start of SGLT2i (T0) and 90 treatment days (T90), from overhydrated (red ellipse, p < 0.001) and normohydrated patients (black ellipse, not significant), compared with the paired one-sample Hotelling’s T2 test.

FIGURE 5

Schematic summary of the hypothesized response of osmoreceptors to water flow across cell membranes due to persistent osmotic diuresis during treatment with SGLT2i (AVP, arginine-vasopressin; EFW, electrolyte-free water; u-Osm, urine osmolality).