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

Abstract

IntroductionIn 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.AimTo investigate the copeptin adaptive response to SGLT2i, as well as the induced changes in body fluid distribution in T2DM patients.MethodsThe 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.ResultsAmong 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.ConclusionIn 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 registrationClinicaltrials.gov, identifier NCT03917758.

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

“…However, after 5 to 7 days, although fractional lithium excretion was maintained and glycosuria persisted, the drugs had no significant effect on total urinary sodium excretion or volume. Several studies 37,39,40,44,46,72 have noted a decrease in free water clearance, accompanied by vasopressin activation; such an antiaquaretic counterregulatory response may be particularly likely in patients with diabetes. 83 Heart Failure With and Without Recent Acute Decompensation In patients with chronic heart failure receiving low doses of loop diuretics, the response to SGLT2 inhibition was characterized primarily by an increase in electrolyte-free water clearance.…”

“…As noted earlier, after SGLT2 inhibition, the reabsorption of sodium and chloride is enhanced in downstream nephron sites 20,33 as a result of upregulation of vasopressin, uromodulin, aldosterone, and α-ketoglutarate. 20,28,32,[36][37][38][44][45][46] Increases in aldosterone may in part explain the effect of SGLT2 inhibitors to mitigate the risk of hyperkalemia (without inducing hypokalemia) in patients with diabetes or heart failure. 47,48 Activation of Tubuloglomerular Feedback Increased delivery of chloride to the macula densa after SGLT2 inhibition activates tubuloglomerular feedback, leading to afferent arteriolar vasoconstriction or efferent arteriolar vasodilation and a decline in glomerular filtration pressure.…”

“…From our comprehensive review, we identified 27 studies that evaluated the effects of SGLT2 inhibitors on urinary sodium and water excretion in healthy volunteers or patients with type 2 diabetes, heart failure, or chronic kidney disease, for periods ranging from 3 days to 3 months (Table 1). 12,32,37,39,40,42,44,46,58,61,[63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] Typically, dietary sodium and use of diuretics were not controlled; sodium balance was not achieved; and some studies analyzed spot (rather than 24-hour) urine collections. 12,46,67,81 Trials that were double-blind and placebo-controlled are less subject to these confounding factors.…”

“…12,32,37,39,40,42,44,46,58,61,[63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81] Typically, dietary sodium and use of diuretics were not controlled; sodium balance was not achieved; and some studies analyzed spot (rather than 24-hour) urine collections. 12,46,67,81 Trials that were double-blind and placebo-controlled are less subject to these confounding factors.…”

“…On the basis of a comprehensive review, we identified 13 studies that evaluated the effects of SGLT2 inhibitors on extracellular water (Table 3). 44,46,67,72,73,79,99,103,108,[124][125][126][127][128] These reports performed measurements using diverse methods, typically without a control group, making it difficult to reliably discern a treatment effect. In 5 trials that were double blind and placebo controlled, SGLT2 inhibition modestly decreased extracellular fluid in patients with diabetes or heart failure after 1 to 2 weeks, but with little effect after 1 to 3 months.…”