Endocrine Abstracts

Introduction: Glucose-induced osmotic diuresis and free water loss induced by the SGLT2 inhibitor empagliflozin effectively increase sodium levels in patients with a chronic syndrome of inappropriate antidiuresis (SIAD) where arginine vasopressin (AVP) levels are inappropriately increased in relation to osmolality. The hormone apelin opposes the actions of AVP in salt and water homeostasis and administering exogenous apelin increases sodium levels in rats with SIAD. In patients with type 2 diabetes mellitus and heart failure, apelin levels increased after a 6-month treatment with dapagliflozin. We aimed to investigate whether an increase in plasma apelin level may contribute to the therapeutic efficacy of empagliflozin in chronic SIAD.

Methods: Post-hoc secondary analysis of a double-blind, crossover, placebo-controlled trial performed from 12/2017 to 08/2021 at the University Hospital Basel, Switzerland, investigating the effect of a 4-week treatment with empagliflozin 25 mg/day as compared to placebo in 14 outpatients with chronic SIAD. The primary objective was to investigate the effect of empagliflozin on apelin levels. Secondary objectives included the effect of empagliflozin on copeptin levels and on the apelin/copeptin ratio. Absolute changes in apelin, copeptin and their ratio were compared using a paired Wilcoxon signed-rank test. The relationship between apelin and sodium levels was investigated by computing Spearman correlation coefficients.

Results: Fourteen patients, 50% female, with a median [IQR] age of 72 years [65–77] were included in the analysis. Median apelin levels were 956 pmol/l [853, 1038] at baseline. Median [IQR] apelin absolute changes were 102 [1, 166] pmol/l and 82 [-47, 199] pmol/l (P= 0.677) at the end of the placebo and empagliflozin phase respectively. Baseline apelin levels did not correlate with baseline sodium levels (ρ = 0.34, P= 0.282), nor did their absolute changes at week 4 (ρ = -0.007, P= 0.974). Median copeptin levels were 2.6 [2.2, 4.5] pmol/l at baseline and increased by 0.2 [-0.1, 0.6] pmol/l and 0.6 [0.3, 0.9] pmol/l (P= 0.069) over the placebo and empagliflozin phase, respectively. Median apelin/copeptin ratio was 369 [147, 503] at baseline and increased by 8 [-97, 36] and decreased by 4 [-72, 32] (P= 0.266) during the placebo and empagliflozin phase, respectively.

Conclusion: Treatment with empagliflozin in patients with chronic SIAD did not lead to significant changes in either apelin or copeptin levels, or the apelin/copeptin ratio. Our findings suggest that the efficacy of empagliflozin in SIAD is not due to an alteration in plasma apelin concentration.