Psychopathological characteristics in patients with arginine vasopressin deficiency (central diabetes insipidus) and primary polydipsia compared to healthy controls.

OBJECTIVE: Distinguishing arginine vasopressin deficiency (AVP-D; central diabetes insipidus) from primary polydipsia (PP), commonly referred to as psychogenic polydipsia, is challenging. Psychopathologic findings, commonly used for PP diagnosis in clinical practice, are rarely evaluated in AVP-D patients, and no comparative data between the two conditions currently exist. DESIGN: Data from two studies involving 82 participants [39 AVP-D, 28 PP, and 15 healthy controls (HC)]. METHODS: Psychological evaluations were conducted using standardized questionnaires measuring anxiety [State-Trait Anxiety Inventory (STAI)], alexithymia [Toronto Alexithymia Scale (TAS-20)], depressive symptoms (Beck's Depression Inventory-II (BDI-II), and overall mental health [Short Form-36 Health Survey (SF-36)]. Higher STAI, TAS-20, and BDI-II scores suggest elevated anxiety, alexithymia, and depression, while higher SF-36 scores signify better overall mental health. RESULTS: Compared to HC, patients with AVP-D and PP showed higher levels of anxiety (HC 28 points [24-31] vs AVP-D 36 points [31-45]; vs PP 38 points [33-46], P < .01), alexithymia (HC 30 points [29-37] vs AVP-D 43 points [35-54]; vs PP 46 points [37-55], P < .01), and depression (HC 1 point [0-2] vs AVP-D 7 points [4-14]; vs PP 7 points [3-13], P < .01). Levels of anxiety, alexithymia, and depression showed no difference between both patient groups (P = .58, P = .90, P = .50, respectively). Compared to HC, patients with AVP-D and PP reported similarly reduced self-reported overall mental health scores (HC 84 [68-88] vs AVP-D 60 [52-80], P = .05; vs PP 60 [47-74], P < .01). CONCLUSION: This study reveals heightened anxiety, alexithymia, depression, and diminished overall mental health in patients with AVP-D and PP. The results emphasize the need for careful interpretation of psychopathological characteristics to differentiate between AVP-D and PP.

Effect of dulaglutide in promoting abstinence during smoking cessation: 12-month follow-up of a single-centre, randomised, double-blind, placebo-controlled, parallel group trial.

Background: Smoking cessation is challenging, despite making use of established smoking cessation therapies. Preclinical studies and one clinical pilot study suggest the antidiabetic drug glucagon-like peptide-1 (GLP-1) analogue to modulate addictive behaviours and nicotine craving. Previously, we reported the short-term results of a randomised, double-blind, placebo-controlled trial. Herein we report long-term abstinence rates and weight developments after 24 and 52 weeks. Methods: This single-centre, randomised, double-blind, placebo-controlled, parallel group trial was done at the University Hospital Basel in Switzerland. We randomly assigned (1:1) individuals with at least a moderate nicotine dependence willing to quit smoking to either a 12-week treatment with dulaglutide 1.5 mg or placebo subcutaneously once weekly in addition to standard of care smoking cessation therapy (varenicline 2 mg/day and behavioural counselling). After 12 weeks, dulaglutide or placebo injections were discontinued and the participants were followed up at week 24 and 52. The primary outcome of self-reported and biochemically confirmed point prevalence abstinence rate, and secondary outcome of secondary outcome of weight change were assessed at weeks 24 and 52. All participants who received one dose of the study drug were included in the intention to treat set and participants who received at least 10/12 doses of the study drug formed the per protocol set. The trial was registered at ClinicalTrials.gov, NCT03204396. Findings: Of the 255 participants who were randomly assigned between June 22, 2017 and December 3, 2020, 63% (80/127) (dulaglutide group) and 65% (83/128) (placebo group) were abstinent after 12 weeks. These abstinence rates declined to 43% (54/127) and 41% (52/128), respectively, after 24 weeks and to 32% (41/127) and 32% (41/128), respectively, after 52 weeks. Post-cessation weight gain was prevented in the dulaglutide group (-1.0 kg, standard deviation [SD] 2.7) as opposed to the placebo group (+1.9 kg, SD 2.4) after 12 weeks. However, at week 24, increases in weight from baseline were observed in both groups (median, interquartile range [IQR]: dulaglutide: +1.5 kg, [-0.4, 4.1], placebo: +3.0 kg, [0.6, 4.6], baseline-adjusted difference in weight change -1.0 kg (97.5% CI [-2.16, 0.16])), and at week 52 the groups showed similar weight gain (median, IQR: dulaglutide: +2.8 kg [-0.4, 4.7], placebo: +3.1 kg [-0.4, 6.0], baseline-adjusted difference in weight change: -0.35 kg (95% CI [-1.72, 1.01])). In the follow-up period (week 12 to week 52) 51 (51%) and 48 (48%) treatment-unrelated adverse events were recorded in the dulaglutide and the placebo group, respectively. No treatment-related serious adverse events or deaths occurred. Interpretation: Dulaglutide does not improve long-term smoking abstinence, but has potential to counteract weight gain after quitting. However, 3 months of treatment did not have a sustained beneficial effect on weight at 1 year. As post-cessation weight gain is highest in the first year after quitting smoking, future studies should consider a longer treatment duration with a GLP-1 analogue in abstinent individuals. Funding: Swiss National Science Foundation, the Gottfried and Julia Bangerter-Rhyner Foundation, the Goldschmidt-Jacobson Foundation, the Hemmi-Foundation, the University of Basel, the Swiss Academy of Medical Sciences.

Arginine or Hypertonic Saline-Stimulated Copeptin to Diagnose AVP Deficiency.

BACKGROUND: Distinguishing between arginine vasopressin (AVP) deficiency and primary polydipsia is challenging. Hypertonic saline-stimulated copeptin has been used to diagnose AVP deficiency with high accuracy but requires close sodium monitoring. Arginine-stimulated copeptin has shown similar diagnostic accuracy but with a simpler test protocol. However, data are lacking from a head-to-head comparison between arginine-stimulated copeptin and hypertonic saline-stimulated copeptin in the diagnosis of AVP deficiency. METHODS: In this international, noninferiority trial, we assigned adult patients with polydipsia and hypotonic polyuria or a known diagnosis of AVP deficiency to undergo diagnostic evaluation with hypertonic-saline stimulation on one day and with arginine stimulation on another day. Two endocrinologists independently made the final diagnosis of AVP deficiency or primary polydipsia with use of clinical information, treatment response, and the hypertonic-saline test results. The primary outcome was the overall diagnostic accuracy according to prespecified copeptin cutoff values of 3.8 pmol per liter after 60 minutes for arginine and 4.9 pmol per liter once the sodium level was more than 149 mmol per liter for hypertonic saline. RESULTS: Of the 158 patients who underwent the two tests, 69 (44%) received the diagnosis of AVP deficiency and 89 (56%) received the diagnosis of primary polydipsia. The diagnostic accuracy was 74.4% (95% confidence interval [CI], 67.0 to 80.6) for arginine-stimulated copeptin and 95.6% (95% CI, 91.1 to 97.8) for hypertonic saline-stimulated copeptin (estimated difference, -21.2 percentage points; 95% CI, -28.7 to -14.3). Adverse events were generally mild with the two tests. A total of 72% of the patients preferred testing with arginine as compared with hypertonic saline. Arginine-stimulated copeptin at a value of 3.0 pmol per liter or less led to a diagnosis of AVP deficiency with a specificity of 90.9% (95% CI, 81.7 to 95.7), whereas levels of more than 5.2 pmol per liter led to a diagnosis of primary polydipsia with a specificity of 91.4% (95% CI, 83.7 to 95.6). CONCLUSIONS: Among adult patients with polyuria polydipsia syndrome, AVP deficiency was more accurately diagnosed with hypertonic saline-stimulated copeptin than with arginine-stimulated copeptin. (Funded by the Swiss National Science Foundation; CARGOx ClinicalTrials.gov number, NCT03572166.).

Risk constellation of hospital acquired pressure injuries in patients with a spinal cord injury/ disorder - focus on time since spinal cord injury/ disorder and patients' age.

STUDY DESIGN: Prospective cohort study. OBJECTIVES: The aim of this study was to evaluate how time since spinal cord injury/disorder (SCI/D) and patients' age influence risk constellation for hospital acquired pressure injuries (HAPI) in patients with a SCI/D. SETTING: Acute care and rehabilitation clinic specialized in SCI/D. METHODS: We collected patients' characteristics and 85 risk factors for HAPI development in adults with SCI/D with at least one HAPI during their inpatient stay between August 2018 and December 2019. We analyzed patients' characteristics and HAPI risk factors using descriptive statistics according to time since SCI/D ( < 1 year, 1-15 years, > 15 years) and patients' age (18-35 years, 35-65 years, > 65 years). RESULTS: We identified 182 HAPI in 96 patients. Comparing patients with SCI/D < 1 year with the other groups, autonomic dysreflexia (p < 0.001), abnormal body temperature (p = 0.001), hypertensive episode (p = 0.005), and pneumonia (p < 0.001) occurred more frequently; mean hemoglobin (p < 0.001), albumin (p = 0.002) and vitamin D levels (p = 0.013) were significantly lower, and patients with time since SCI/D < 1 year scored fewer points (10-12) on the Braden Scale (p < 0.001). Comparing groups per patients' age, only the SCIPUS score was higher in patients > 65 years compared to the other two groups (p = 0.002). CONCLUSIONS: Different risk factor constellation seem to be underlying HAPI development with more differences in patients time since SCI/D than patients' age. Awareness of these differences in risk factor constellation depending on time since SCI/D in these patients might lead to different HAPI prevention strategies. SPONSORSHIP: The study team didn't receive any additional sponsorship.

Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial.

BACKGROUND: Disruptions of the hypothalamic-pituitary axis can cause an arginine vasopressin deficiency, also known as central diabetes insipidus. Patients with this condition are at high risk of additional oxytocin deficiency owing to the close anatomical proximity of oxytocin-producing neurons; however, no conclusive evidence for such a deficiency has been reported. We aimed to use 3,4-methylenedioxymethamphetamine (MDMA, also known as ecstasy), a strong activator of the central oxytocinergic system, as a biochemical and psychoactive provocation test to investigate oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus). METHODS: This single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial included patients with arginine vasopressin deficiency (central diabetes insipidus) and healthy controls (matched 1:1 by age, sex, and BMI) and was conducted at the University Hospital Basel, Basel, Switzerland. We used block randomisation to assign participants to receive either a single oral dose of MDMA (100 mg) or placebo in the first experimental session; patients received the opposite treatment at the next session, with a wash-out period of at least 2 weeks between the two sessions. Participants and investigators assessing the outcomes were masked to assignment. Oxytocin concentrations were measured at 0, 90, 120, 150, 180, and 300 min after MDMA or placebo. The primary outcome was the area under the plasma oxytocin concentration curve (AUC) after drug intake. The AUC was compared between groups and conditions using a linear mixed-effects model. Subjective drug effects were assessed throughout the study using ten-point visual analogue scales. Acute adverse effects were assessed before and 360 min after drug intake using a 66-item list of complaints. This trial is registered with ClinicalTrials.gov, NCT04648137. FINDINGS: Between Feb 1, 2021, and May 1, 2022, we recruited 15 patients with arginine vasopressin deficiency (central diabetes insipidus) and 15 healthy controls. All participants completed the study and were included in the analyses. In healthy controls, median plasma oxytocin concentration was 77 pg/mL (IQR 59-94) at baseline and increased by 659 pg/mL (355-914) in response to MDMA, resulting in an AUC of 102 095 pg/mL (41 782-129 565); in patients, baseline oxytocin concentration was 60 pg/mL (51-74) and only slightly increased by 66 pg/mL (16-94) in response to MDMA, resulting in an AUC of 6446 pg/mL (1291-11 577). The effect of MDMA on oxytocin was significantly different between groups: the AUC for oxytocin was 82% (95% CI 70-186) higher in healthy controls than in patients (difference 85 678 pg/mL [95% CI 63 356-108 000], p<0·0001). The increase in oxytocin in healthy controls was associated with typical strong subjective prosocial, empathic, and anxiolytic effects, whereas only minimal subjective effects were observed in patients, in agreement with the lack of increase in oxytocin concentrations. The most frequently reported adverse effects were fatigue (eight [53%] healthy controls and eight [53%] patients), lack of appetite (ten [67%] healthy controls and eight [53%] patients), lack of concentration (eight [53%] healthy controls and seven [47%] patients), and dry mouth (eight [53%] healthy controls and eight [53%] patients). In addition, two (13%) healthy controls and four (27%) patients developed transient mild hypokalaemia. INTERPRETATION: These findings are highly suggestive of clinically meaningful oxytocin deficiency in patients with arginine vasopressin deficiency (central diabetes insipidus), laying the groundwork for a new hypothalamic-pituitary disease entity. FUNDING: Swiss National Science Foundation, Swiss Academy of Medical Sciences, and the G&J Bangerter-Rhyner Foundation.

Effect of dulaglutide in promoting abstinence during smoking cessation: a single-centre, randomized, double-blind, placebo-controlled, parallel group trial.

Background: Quitting smoking is difficult due to barriers such as craving for cigarettes and post-cessation weight gain. Recent experimental data suggest a role of glucagon-like peptide-1 (GLP-1) in the pathophysiology of addiction in addition to appetite regulation and weight control. We hypothesized that a pharmacological intervention with the GLP-1 analogue dulaglutide during smoking cessation may improve abstinence rates and reduce post-cessation weight gain. Methods: This is a single-centre, randomized, double-blind, placebo-controlled, parallel group, superiority study conducted in the University Hospital Basel in Switzerland. We included adult smokers with at least moderate cigarette dependence who wanted to quit. Participants were randomly assigned to a 12-week treatment with dulaglutide 1.5 mg once weekly or placebo subcutaneously in addition to standard of care including behavioural counselling and oral varenicline pharmacotherapy of 2 mg/day. The primary outcome was self-reported and biochemically confirmed point prevalence abstinence rate at week 12. Secondary outcomes included post-cessation weight, glucose metabolism, and craving for smoking. All participants who received one dose of study drug were included in the primary and safety analyses. The trial was registered on ClinicalTrials.gov (NCT03204396). Findings: Between June 22, 2017, and December 3, 2020, 255 participants were enrolled and randomly assigned to each group (127 in the dulaglutide group and 128 in the placebo group). After 12 weeks, 63% (80/127) participants on dulaglutide and 65% (83/128) on placebo treatment were abstinent (difference in proportions -1.9% [95% Confidence interval (CI) -10.7, 14.4], p-value (p) = 0.859). Dulaglutide decreased post-cessation weight (-1 kg [standard deviation (SD) 2.7]), while weight increased on placebo (+1.9 kg [SD 2.4]). The baseline-adjusted difference in weight change between groups was -2.9 kg (95% CI -3.59, -2.3, p < 0.001). Haemoglobin A1c (HbA1c) level declined on dulaglutide treatment (baseline-adjusted median difference in HbA1c between groups -0.25% [interquartile range (IQR) -0.36, -0.14], p < 0.001). Craving for smoking declined during treatment without any difference between the groups. Treatment-emergent gastrointestinal symptoms were very common in both groups: 90% (114/127) of participants on dulaglutide and 81% (81/128) on placebo). Interpretation: Dulaglutide had no effect on abstinence rates but prevented post-cessation weight gain and decreased HbA1c levels. GLP-1 analogues may play a role in future cessation therapy targeting metabolic parameters such as weight and glucose metabolism. Funding: Swiss National Science Foundation, the Gottfried Julia Bangerter-Rhyner Foundation, the Goldschmidt-Jacobson Foundation, the Hemmi-Foundation, the University of Basel, the Swiss Academy of Medical Sciences.

Hypothalamic-pituitary-adrenal axis activity in patients with primary polydipsia compared to healthy controls.

OBJECTIVE: Primary polydipsia is characterized by excessive fluid intake which may suppress vasopressin levels. It is speculated that suppressed vasopressin levels lead to a dysregulated hypothalamic-pituitary-adrenal (HPA) axis as vasopressin co-modulates the HPA axis. However, data are contradictory. The aim of this study was to investigate markers of the HPA axis in patients with primary polydipsia compared to healthy controls. DESIGN: Exploratory analysis combining data from two different prospective observational studies. PATIENTS: We included 34 patients with primary polydipsia (68% females, median aged 29.5 years (interquartile range, IQR: 26.0, 38.8) and 20 healthy controls (55% females, median age 24.0 years [IQR: 22.0, 27.2]). MEASUREMENTS: The main outcome was difference in HPA axis activity assessed using circadian serum and salivary cortisol, 24-h urinary free cortisol and cortisol levels before and after adrenocorticotropic hormone (ACTH) stimulation; vasopressin suppression was assessed measuring fasting copeptin levels between patients with primary polydipsia and healthy controls using Wilcoxon rank-sum test. RESULTS: No difference was seen in circadian serum cortisol levels (p = .9), urinary free cortisol levels (p = .17) and serum cortisol in response to ACTH stimulation (p = .77) between groups. Circadian salivary cortisol levels were significantly lower in patients with primary polydipsia compared to healthy controls with an estimated difference of -3.7 nmol/L (95% CI: -5.5, -1.8 nmol/L, p < .001). Fasting copeptin levels were significantly lower in patients with primary polydipsia compared to healthy volunteers (p < 0.01). CONCLUSION: Our results suggest no difference in HPA axis activity between patients with primary polydipsia and healthy controls. The observed difference in salivary cortisol levels may be linked to a dilution effect in saliva rather than an altered stress axis considering the other findings.

Treatment Effect of the SGLT2 Inhibitor Empagliflozin on Chronic Syndrome of Inappropriate Antidiuresis: Results of a Randomized, Double-Blind, Placebo-Controlled, Crossover Trial.

BACKGROUND: The syndrome of inappropriate antidiuresis (SIAD) is characterized by a reduction of free water excretion with consecutive hypotonic hyponatremia and is therefore challenging to treat. The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion, likely leading to increased electrolyte free water clearance. METHODS: In this randomized, double-blind, placebo-controlled, crossover trial, we compared 4-week treatment with empagliflozin 25 mg/d to placebo in outpatients with chronic SIAD-induced hyponatremia. At baseline and after both treatment cycles, patients underwent different assessments including neurocognitive testing (Montreal Cognitive Assessment [MoCA]). The primary end point was the difference in serum sodium levels between treatments. RESULTS: Fourteen patients, 50% female, with a median age of 72 years (interquartile range [IQR], 65-77), completed the trial. Median serum sodium level at baseline was 131 mmol/L (IQR, 130-132). After treatment with empagliflozin, median serum sodium level rose to 134 mmol/L (IQR, 132-136), whereas no increase was seen with placebo (130 mmol/L; IQR, 128-132), corresponding to a serum sodium increase of 4.1 mmol/L (95% confidence interval [CI], 1.7 to 6.5; P =0.004). Exploratory analyses showed that treatment with empagliflozin led to improved neurocognitive function with an increase of 1.16 (95% CI, 0.05 to 2.26) in the MoCA score. Treatment was well tolerated; no serious adverse events were reported. CONCLUSION: The SGLT2 inhibitor empagliflozin is a promising new treatment option for chronic SIAD-induced hyponatremia, possibly improving neurocognitive function. Larger studies are needed to confirm the observed treatment effects. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03202667. PODCAST: This article contains a podcast at.

Effect of a 3-Week Treatment with GLP-1 Receptor Agonists on Vasoactive Hormones in Euvolemic Participants.

CONTEXT: Glucagon-like-peptide-1 receptor agonists (GLP-1 RAs) exert cardiovascular benefits by reducing plasma glucose, body weight, and blood pressure. The blood pressure-lowering effect may be mediated by angiotensin II (ANG II) suppression and consecutive natriuresis. However, the role of ANG II and other vasoactive hormones on GLP-1 RA treatment has not been clearly defined. OBJECTIVE: This work aimed to investigate the effect of a 3-week treatment with the GLP-1 RA dulaglutide on vasoactive hormones, that is, renin, ANG II, aldosterone, mid-regional proatrial natriuretic peptide (MP-proANP), and natriuresis in euvolemic participants. METHODS: Randomized, double-blinded, placebo-controlled, crossover trials were conducted at University Hospital Basel, Switzerland. A total of 54 euvolemic participants, including 20 healthy individuals and 34 patients with primary polydipsia, received a subcutaneous injection of dulaglutide (Trulicity) 1.5 mg and placebo (0.9% sodium chloride) once weekly over a 3-week treatment phase. RESULTS: After a 3-week treatment phase, dulaglutide showed no effect on plasma renin, plasma ANG II, or plasma aldosterone levels in comparison to placebo. Natriuresis remained unchanged or decreased on dulaglutide depending on the measured parameter. Dulaglutide significantly decreased plasma MR-proANP levels (treatment effect: 10.60 pmol/L; 95% CI, -14.70 to -7.90; P < .001) and systolic blood pressure (median: 3 mm Hg; 95% CI, -5 to 0; P = .036), whereas heart rate increased (median: 5 bpm; 95% CI, 3-11; P < .001). CONCLUSION: In euvolemic participants, a 3-week treatment of dulaglutide reduced systolic blood pressure independently of plasma renin, ANG II, or aldosterone levels and urinary sodium excretion. The reduction in MR-proANP might be secondary to reduced arterial pulse pressure.

Risk factors for hospital acquired pressure injury in patients with spinal cord injury during first rehabilitation: prospective cohort study.

STUDY DESIGN: Prospective observational cohort study. OBJECTIVES: First, describe pressure injury (PI) and associated risk factors in individuals with spinal cord injury/disorder (SCI/D) during first rehabilitation. Second, evaluate a prediction model for hospital acquired PI (HAPI) development. SETTING: Acute care and rehabilitation clinic specialized in SCI/D. METHODS: Patients ≥18 years of age with SCI/D were included during first rehabilitation between 08/2018 and 12/2019. We performed a systematic literature search to identify risk factors for PI development. Patients were classified according to HAPI developed. Between group differences of patients' characteristics and risk factors were analyzed using descriptive statistics. Logistic predictive models were performed to estimate HAPI development and receiver operator characteristic (ROC) curve was used to test the model. RESULTS: In total, 94 patients were included, 48 (51.1%) developed at least one HAPI and in total 93 were observed, mainly stage I and stage II HAPI according to the European Pressure Ulcer Advisory Panel. We found nine significantly associated risk factors: completeness of SCI/D, pneumonia, sedative medications, autonomic dysreflexia, Braden ≤12 points, SCIPUS ≥9 points, lower admission SCIM and lower admission FIM-cognition, longer length of stay (LOS) (p ≤ 0.0005). In a predictive model, none of the risk factors was associated with HAPI development (AUC = 0.5). CONCLUSION: HAPIs in patients with SCI/D during first rehabilitation are a frequent and complex condition and associated with several risk factors. No predictive model exists but with the identified risk factors of this study, larger studies can create a tailored and flexible HAPI risk prediction model.

A randomized controlled trial of the GLP-1 receptor agonist dulaglutide in primary polydipsia.

BackgroundPrimary polydipsia, characterized by excessive fluid intake, carries the risk of water intoxication and hyponatremia, but treatment options are scarce. Glucagon-like peptide 1 (GLP-1) reduces appetite and food intake. In experimental models, GLP-1 has also been shown to play a role in thirst and drinking behavior. The aim of this trial was to investigate whether GLP-1 receptor agonists reduce fluid intake in patients with primary polydipsia.MethodsIn this randomized, double-blind, placebo-controlled, 3-week crossover trial, 34 patients with primary polydipsia received weekly dulaglutide (1.5 mg, Trulicity) in one treatment segment and placebo (0.9% sodium chloride) in the other. During the last treatment week, patients attended an 8-hour evaluation visit with free access to water. The primary endpoint was total fluid intake during the evaluation visits. Treatment effects were estimated using linear mixed-effects models. In a subset of 15 patients and an additional 15 matched controls, thirst perception and neuronal activity in response to beverage pictures were assessed by functional MRI.RESULTsPatients on dulaglutide reduced their fluid intake by 490 mL (95% CI: -780, -199; P = 0.002), from 2950 mL (95% CI: 2435, 3465) on placebo to 2460 mL (95% CI: 1946, 2475) on dulaglutide (model estimates), corresponding to a relative reduction of 17%. Twenty-four-hour urinary output was reduced by -943 mL (95% CI: -1473, -413; P = 0.001). Thirst perception in response to beverage pictures was higher for patients with primary polydipsia than for controls, and lower for patients on dulaglutide versus placebo, but functional activity was similar among groups and treatments.CONCLUSIONSGLP-1 receptor agonists reduce fluid intake and thirst perception in patients with primary polydipsia and could therefore be a treatment option for these patients.Trial registrationClinicaltrials.gov NCT02770885.FundingSwiss National Science Foundation (grant 32473B_162608); University Hospital and University of Basel; Young Talents in Clinical Research grant from the Swiss Academy of Medical Sciences and the Gottfried & Julia Bangerter-Rhyner Foundation; Top-up Grant from the PhD Programme in Health Sciences, University of Basel.

Can treatment response to SGLT2-inhibitors in syndrome of inappropriate antidiuresis be predicted by copeptin, natriuretic peptides and inflammatory markers?

PURPOSE: The syndrome of inappropriate antidiuresis (SIAD) is the main cause of hyponatremia and the SGLT2-inhibitor empagliflozin is a promising new treatment option. A biomarker predicting treatment response could optimize treatment success. MATERIALS AND METHODS: Secondary analysis of a trial including 84 hospitalized patients with SIAD-induced hyponatremia. Patients were randomized to four days of treatment with empagliflozin 25 mg/d (n = 43) or placebo (n = 41) with both groups receiving fluid restriction <1000 ml/d. Baseline levels of copeptin, the natriuretic peptides MR-proANP and NT-proBNP and C-reactive protein (CRP) were evaluated as predictors for treatment response defined as absolute sodium change, using linear regression models. Additionally, urinary sodium was assessed as predictor for non-response to fluid restriction alone by constructing the receiver-operating characteristic (ROC) curve. RESULTS: No clinically relevant predictive value for treatment response to empagliflozin could be found for copeptin, MR-proANP, NT-proBNP or CRP. A urinary sodium cut-off of >76 mmol/l led to a specificity of 91.7% [95% confidence interval (CI): 75%, 100%] and sensitivity of 51.9% [33.3%, 70.4%] to predict non-response to fluid restriction alone. CONCLUSIONS: Based on our data, no biomarker could be identified as predictor for treatment response to empagliflozin. Urinary sodium was confirmed as a good marker for non-response to fluid restriction in SIAD patients. Clinical trial registration: ClinicalTrials.gov (Number: NCT02874807).

Oxytocin levels in response to pituitary provocation tests in healthy volunteers.

OBJECTIVE: Oxytocin, secreted into circulation through the posterior pituitary, regulates lactation, weight, and socio-behavioral functioning. Oxytocin deficiency has been suggested in patients with hypopituitarism; however, diagnostic testing for oxytocin deficiency has not been developed. The aim of this study was to investigate known pituitary provocation tests to stimulate plasma oxytocin. DESIGN: Sixty-five healthy volunteers underwent either the hypertonic saline or arginine infusion test, known to stimulate copeptin, or the oral macimorelin test, known to stimulate growth hormone. Plasma oxytocin was measured before and once plasma sodium level ≥ 150 mmol/L for the hypertonic saline, after 60 min for the arginine infusion, and after 45 min for the oral macimorelin test (expected peak of copeptin and growth hormone levels, respectively). Primary outcome was a change from basal to stimulated oxytocin levels using paired t-tests. RESULTS: As expected, copeptin increased in response to hypertonic saline and arginine infusion (P < 0.001), and growth hormone increased to oral macimorelin (P < 0.001). Oxytocin increased in response to hypertonic saline infusion from 0.4 (0.2) to 0.6 pg/mL (0.3) (P = 0.003) but with a high variance. There was no change to arginine infusion (P = 0.4), and a trend to lower stimulated levels to oral macimorelin (P = 0.05). CONCLUSION: Neither the arginine infusion nor the oral macimorelin test stimulates plasma oxytocin levels, whereas there was an increase with high variance upon hypertonic saline infusion. As a predictable rise in most participants is required for a reliable pituitary provocation test, none of the investigated pituitary provocation tests can be recommended diagnostically to identify patients with an oxytocin deficiency.

Prevalence and outcome of dysnatremia in patients with COVID-19 compared to controls.

OBJECTIVE: The pandemic of coronavirus disease (COVID-19) has rapidly spread globally and infected millions of people. The prevalence and prognostic impact of dysnatremia in COVID-19 is inconclusive. Therefore, we investigated the prevalence and outcome of dysnatremia in COVID-19. DESIGN: The prospective, observational, cohort study included consecutive patients with clinical suspicion of COVID-19 triaged to a Swiss Emergency Department between March and July 2020. METHODS: Collected data included clinical, laboratory and disease severity scoring parameters on admission. COVID-19 cases were identified based on a positive nasopharyngeal swab test for SARS-CoV-2, patients with a negative swab test served as controls. The primary analysis was to assess the prognostic impact of dysnatremia on 30-day mortality using a cox proportional hazard model. RESULTS: 172 (17%) cases with COVID-19 and 849 (83%) controls were included. Patients with COVID-19 showed a higher prevalence of hyponatremia compared to controls (28.1% vs 17.5%, P < 0.001); while comparable for hypernatremia (2.9% vs 2.1%, P = 0.34). In COVID-19 but not in controls, hyponatremia was associated with a higher 30-day mortality (HR: 1.4, 95% CI: 1.10-16.62, P = 0.05). In both groups, hypernatremia on admission was associated with higher 30-day mortality (COVID-19 - HR: 11.5, 95% CI: 5.00-26.43, P < 0.001; controls - HR: 5.3, 95% CI: 1.60-17.64, P = 0.006). In both groups, hyponatremia and hypernatremia were significantly associated with adverse outcome, for example, intensive care unit admission, longer hospitalization and mechanical ventilation. CONCLUSION: Our results underline the importance of dysnatremia as predictive marker in COVID-19. Treating physicians should be aware of appropriate treatment measures to be taken for patients with COVID-19 and dysnatremia.

Effects of glucagon-like peptide-1 receptor agonists on fluid intake in healthy volunteers.

PURPOSE: Glucagon-like peptide-1 (GLP-1) receptor agonists (RA) reduce appetite and energy intake. Recent findings from animal studies suggest a role of GLP-1 in drinking and water homeostasis. We aimed to elucidate whether GLP-1 RA reduce fluid intake in healthy volunteers. METHODS: Double-blind, randomized, placebo-controlled, crossover study. 20 healthy volunteers received dulaglutide 1.5 mg and placebo (0,9% sodium chloride) subcutaneously once weekly for 3 weeks. At the end of each treatment period, participants attended an 8-h evaluation visit, during which they were requested to eat two standardized meals and to drink water ad libitum. The primary outcome was the total fluid intake (ml) during the evaluation visit. RESULTS: Mean [SD] age of participants (60% female) was 27 [9.2] years. All but four participants drank less on dulaglutide versus placebo treatment despite identical food intake. The median [IQR] difference of fluid intake on dulaglutide compared to placebo treatment was -100 ml [-400-0]. Median [IQR] total fluid intake was 1300 ml [888-1600] versus 1600 ml [1000-1720], on dulaglutide and placebo treatment, p = 0.06. Median [IQR] 24-h urine output was reduced in dulaglutide versus placebo-treated participants: 1250 ml [975-2080] versus 1680 ml [1400-2040], p = 0.04. Median serum sodium levels were 140 mmol/L on both visits and no difference in thirst perception was noted. CONCLUSIONS: GLP-1 RA such as dulaglutide seem to modulate fluid balance in humans. This leads us to speculate that GLP-1 RA may be an interesting therapeutic options for patients with excessive drinking behavior e.g., primary polydipsia.

Low arginine vasopressin levels in patients with diabetes insipidus are not associated with anaemia.

OBJECTIVE: Arginine vasopressin (AVP) is released upon osmotic stimulation or hypovolaemia in order to maintain water balance. A recent study showed a role of AVP in haematopoiesis by stimulating red blood cell precursors, suggesting a higher risk of anaemia in patients with AVP deficiency. The objective was to explore the effect of low AVP levels in patients with central diabetes insipidus (cDI) and primary polydipsia (PP) on haemoglobin and the prevalence of anaemia. METHODS: A total of 164 patients with either cDI (70, 43%) or PP (94, 57%) and 30 healthy volunteers from two prospective diagnostic studies performed in Switzerland, Germany and Brazil were studied. A standardized clinical and biochemical (eg copeptin, full blood count) assessment was performed. Haemoglobin and haematocrit levels and prevalence of anaemia (defined as haemoglobin values of <120 g/L in women and <130 g/L in men) were analysed. RESULTS: Mean copeptin values were 2.63 pmol/L (±1.08) and 3.91 pmol/L (±4.28) in patients with cDI and PP and 24.76 pmol/L (±5.75) in healthy volunteers, P = .02. The prevalence of anaemia was low in all participants with 7.1%, 2.2% and 10% in cDI, PP and in healthy volunteers, P = .15. Mean haemoglobin values were similar in all groups: 139 g/L (±15.85), 140 g/L (±13.16) and 139 g/L (±13.05) in patients with cDI, PP and healthy volunteers, P = .90, as were mean haematocrit values with 41% in all groups (P = .85). CONCLUSION: Chronic low AVP levels in patients with cDI and PP do not affect haemoglobin levels and prevalence of anaemia.

A Randomized Trial of Empagliflozin to Increase Plasma Sodium Levels in Patients with the Syndrome of Inappropriate Antidiuresis.

BACKGROUND: Treatment options to address the hyponatremia induced by the syndrome of inappropriate antidiuresis (SIAD) are inadequate. The sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin promotes osmotic diuresis via urinary glucose excretion and therefore, might offer a novel treatment option for SIAD. METHODS: In this double-blind, randomized trial, we recruited 88 hospitalized patients with SIAD-induced hyponatremia <130 mmol/L at the University Hospital Basel from September 2016 until January 2019 and assigned patients to receive, in addition to standard fluid restriction of <1000 ml/24 h, a once-daily dose of oral empagliflozin or placebo for 4 days. The primary end point was the absolute change in plasma sodium concentration after 4 days of treatment. Secondary end points included predisposing factors for treatment response and safety of the intervention. RESULTS: Of the 87 patients who completed the trial, 43 (49%) received treatment with empagliflozin, and 44 (51%) received placebo. Baseline plasma sodium concentrations were similar for the two groups (median 125.5 mmol/L for the empaflozin group and median 126 mmol/L for the placebo group). Patients treated with empagliflozin had a significantly higher increase of median plasma sodium concentration compared with those receiving placebo (10 versus 7 mmol/L, respectively; P=0.04). Profound hyponatremia (<125 mmol/L) and lower baseline osmolality levels increased the likelihood of response to treatment with empagliflozin. Treatment was well tolerated, and no events of hypoglycemia or hypotension occurred among those receiving empagliflozin. CONCLUSIONS: Among hospitalized patients with SIAD treated with fluid restriction, those who received empagliflozin had a larger increase in plasma sodium levels compared with those who received placebo. This finding indicates that empagliflozin warrants further study as a treatment for the disorder.

Seasonality of Hypoosmolar Hyponatremia in Medical Inpatients - Data from a Nationwide Cohort Study.

CONTEXT: Hyponatremia is the most prevalent electrolyte disturbance in hospitalized patients. Previous studies have shown a seasonal variation of profound hyponatremia with higher prevalence during warmer months. OBJECTIVE: This study aimed at analyzing the seasonal prevalence and sex- and age-specific differences of hyponatremia in medical inpatients. DESIGN: Nationwide cohort study from January 2009 and December 2015 using prospective administrative data. SETTING: Medical inpatients. PATIENTS: Diagnosis of hypoosmolar hyponatremia. MAIN OUTCOME MEASURES: The primary outcome was the monthly alteration in hyponatremia prevalence. Secondary outcomes were the association of outdoor temperature with hyponatremia prevalence and differences among sex and age groups. RESULTS: Of 2 426 722 medical inpatients, 84 210 were diagnosed with hypoosmolar hyponatremia, of whom 61% (n = 51 262) were female. The highest overall prevalence of hyponatremia was observed in July (4.5%, n = 8976); the lowest in December (2.7%, n = 6530). The overall prevalence of hyponatremia in women compared with men was higher by 58% (odds ratio [OR], 1.58; 95% confidence interval [CI], 1.56-1.60). The sex-specific difference was most pronounced in the warmest month of July (mean temperature 20.1°C (OR, 1.76; 95% CI, 1.68-1.84). We observed the strongest association between seasonality and hyponatremia in elderly (>80 years) female inpatients admitted during the month of July (OR, 2.40; 95% CI, 2.20-2.62]). CONCLUSION: The prevalence of diagnosed hypoosmolar hyponatremia in medical inpatients increases during summer months with higher outdoor temperature. Elderly female inpatients were most susceptible to the seasonal rise in hyponatremia prevalence.

Arginine-stimulated copeptin measurements in the differential diagnosis of diabetes insipidus: a prospective diagnostic study.

BACKGROUND: Differential diagnosis of diabetes insipidus is challenging. The most reliable approach is hypertonic saline-stimulated copeptin measurements. However, this test is based on the induction of hypernatraemia and requires close monitoring of plasma sodium concentrations. Arginine-stimulated copeptin measurements might provide an alternative, simple, and safe test. METHODS: In this prospective diagnostic study, we recruited a development cohort from University Hospital Basel, Basel, Switzerland, and a validation cohort from five centres in Basel, Aarau, Luzern, Bern, and St Gallen, Switzerland, and the University Hospital Würzburg, Würzburg, Germany. For both cohorts, patients were eligible for inclusion if they were aged 18 years or older, were newly referred with polyuria (>50 mL/kg bodyweight per day) or had a known diagnosis of central diabetes insipidus or primary polydipsia. We also recruited a comparator cohort of healthy controls in parallel to each cohort, comprising adults (aged 18 years and older, with normal drinking habits, and no history of polyuria) and children who underwent arginine stimulation to diagnose growth hormone deficiency (children were only included in the comparator cohort to the development cohort as proof of concept). Patients and healthy controls underwent arginine stimulation with measurement of plasma copeptin at baseline and 30, 45, 60, 90, and 120 min. The primary objective in the development cohort was to determine the diagnostic accuracy of plasma copeptin concentrations to discriminate between diabetes insipidus and primary polydipsia, and in the validation cohort was to confirm those results. Adverse effects of the test were monitored in all participants, with tolerability of the test rated using a visual analogue scale (VAS) that ranged from no (0) to maximum (10) discomfort. This trial is registered with ClinicalTrials.gov, number NCT00757276. FINDINGS: Between May 24, 2013, and Jan 11, 2017, 52 patients were enrolled in the development cohort (12 [23%] with complete diabetes insipidus, nine [17%] with partial diabetes insipidus, and 31 [60%] with primary polydipsia) alongside 20 healthy adults and 42 child controls. Between Oct 24, 2017, and June 27, 2018, 46 patients were enrolled in the validation cohort (12 [26%] with complete diabetes insipidus, seven [15%] with partial diabetes insipidus, and 27 [59%] with primary polydipsia) alongside 30 healthy adult controls (two patients in this cohort were excluded from the main analysis because of early vomiting during the test). In the pooled patient and control datasets, median arginine-stimulated copeptin concentrations increased in healthy adult controls (from 5·2 pM [IQR 3·3-10·9] to a maximum of 9·8 pM [6·4-19·6]) and in participants with primary polydipsia (from 3·6 pM [IQR 2·4-5·7] to a maximum of 7·9 pM [5·1-11·8]), but only minimally in those with diabetes insipidus (2·1 pM [IQR 1·9-2·7] to a maximum of 2·5 pM [1·9-3·1]). In the development cohort, a cutoff of 3·5 pM at 60 min provided the highest diagnostic accuracy of 94% (95% CI 84-98). The accuracy of this cutoff in the validation cohort was 86% (95% CI 73-94). By pooling the data from both cohorts, an optimal accuracy of 93% (95% CI 86-97) was reached at a cutoff of 3·8 pM copeptin at 60 min (sensitivity 93%, 95% CI 86-98; specificity 92%, 95% CI 84-100). The test was safe and well tolerated, with median VAS scores of 3·5 (IQR 2-4) in patients with diabetes insipidus, 3 (2-4) in those with primary polydipsia, 1 (1-3) in healthy adults, and 1 (0-5) in healthy children in the pooled participant dataset. INTERPRETATION: Arginine-stimulated copeptin measurements are an innovative test for diabetes insipidus with high diagnostic accuracy, and could be a simplified, novel, and safe diagnostic approach to diabetes insipidus in clinical practice. FUNDING: Swiss National Science Foundation and University Hospital Basel.

Influence of Outdoor Temperature and Relative Humidity on Incidence and Etiology of Hyponatremia.

CONTEXT: Hyponatremia is the most common electrolyte disturbance in hospitalized patients. Known risk factors are heart or renal failure, excessive drinking, or the use of diuretics. The incidence of hyponatremia may also be influenced by climate. OBJECTIVE: Analyzing the influence of outdoor temperature and relative humidity on the incidence and etiology of hyponatremia. DESIGN: Cohort A: cross-sectional study from January 2011 to December 2016. Cohort B: prospective observational study from June 2011 to August 2013. SETTING: Emergency departments of two tertiary centers. PATIENTS: Cohort A: patients with plasma sodium ≤145 mmol/L (n = 222,217). Cohort B: consecutive patients (n = 294) with profound hyponatremia (plasma sodium ≤125 mmol/L). MAIN OUTCOME MEASURE: The effects of outdoor temperature and relative humidity on the incidence of mild (sodium 126 to 134 mmol/L) and profound hyponatremia (sodium ≤125 mmol/L) were investigated via logistic regression models. The effects of outdoor temperature and relative humidity on hyponatremia etiology were evaluated. RESULTS: In cohort A, 9.9% had mild and 1.08% had profound hyponatremia. Outdoor temperature was significantly associated with the incidence of profound but not mild hyponatremia (P < 0.01, P = 0.3). Relative humidity was not associated with the incidence of hyponatremia. In cohort B, diuretic-induced hyponatremia occurred more frequently with higher outdoor temperatures, whereas other etiologies showed no clear variation with outdoor temperature or relative humidity. CONCLUSIONS: Higher outdoor temperature, but not relative humidity, seems to be associated with the incidence of profound hyponatremia. Our data suggest that diuretics should be used with caution during hot weather.