The effect of glucose dynamics on plasma copeptin levels upon glucagon, arginine, and macimorelin stimulation in healthy adults : Data from: Glucacop, Macicop, and CARGO study.

PURPOSE: Non-osmotic stimulation tests using glucagon, arginine, or macimorelin were recently evaluated for their ability to assess posterior pituitary function. Glucagon and arginine, but not macimorelin, stimulated copeptin secretion (a surrogate marker of vasopressin) and, therefore, provide novel tests to assess the posterior pituitary. The exact underlying mechanism behind their stimulatory effect remains elusive. METHODS: This analysis combined data from three diagnostic studies conducted at the University Hospital Basel, Switzerland. In total, 80 healthy adults underwent the glucagon (n = 22), arginine (n = 30), or macimorelin (n = 28) stimulation tests. The primary objective was to investigate glucose course upon glucagon, arginine, and macimorelin stimulation tests and its effect on plasma copeptin release. RESULTS: Upon glucagon stimulation, the median [IQR] glucose level at baseline was 5.0 [4.6, 5.2] mmol/l, peaked at 8.1 [7.2, 9.4] mmol/l after 30 min and decreased to a minimum of 3.8 [3.5, 4.5] mmol/l after 120 min. The median copeptin increase upon glucagon stimulation was 7.7 [2.6, 28.0] pmol/l. Upon arginine, the glucose level at baseline was 4.9 [4.8, 5.5] mmol/l, peaked at 6.0 [5.2, 6.4] mmol/l after 30 min and decreased to a minimum of 4.3 [3.8, 4.8] mmol/l after 60 min. The median copeptin increase upon arginine stimulation was 4.5 [2.9, 7.5] pmol/l. Upon macimorelin, glucose levels showed no notable dynamics over the 120 min, and no major change in copeptin was observed. In the pooled dataset, a decrease in glucose levels was significantly correlated with copeptin increase (ρ = 0.53, p < 0.01). CONCLUSION: A similar course in plasma glucose was observed in the copeptin-stimulating test, i.e., after glucagon and arginine, while macimorelin had no effect on glucose and copeptin levels. We hypothesize that a drop in glucose levels observed upon glucagon and arginine might stimulate copeptin.

Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome.

Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1ß expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44-66), 26% were female and median BMI was 37 kg/m2 (IQR 34-39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by - 200 pg/mL (95%CI - 334 to - 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: - 8.8 pg/mL (95%CI - 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI - 236 to - 113; p < 0.001). Anti-inflammatory treatment with both, IL-1 antagonism and corticosteroids reduced FGF21 levels at short-term in individuals with the metabolic syndrome.Trial registration: ClinicalTrials.gov Identifiers NCT02672592 and NCT00757276.

The role of IL-1 in the regulation of copeptin in patients with metabolic syndrome.

Arginine vasopressin (AVP) was suggested to contribute to cardiovascular risk and type 2 diabetes in patients with metabolic syndrome. The proinflammatory cytokine interleukin (IL)-1 is able to induce AVP secretion and plays a causal role in cardiovascular mortality and type 2 diabetes. We investigated in two studies whether copeptin levels - the surrogate marker for AVP - are regulated by IL-1-mediated chronic inflammation in patients with metabolic syndrome. Study A was a prospective, interventional, single-arm study (2014-2016). Study B was a randomized, placebo-controlled, double-blind study (2016-2017). n = 73 (Study A) and n = 66 (Study B) adult patients with metabolic syndrome were treated with 100 mg anakinra or placebo (only in study B) twice daily for 1 day (study A) and 28 days (study B). Fasting blood samples were drawn at day 1, 7, and 28 of treatment for measurement of serum copeptin. Patients with chronic low-grade inflammation (C-reactive protein levels ≥2 mg/L) and BMI >35 kg/m2 had higher baseline copeptin levels (7.7 (IQR 4.9-11.9) vs 5.8 (IQR 3.9-9.3) pmol/L, Pinflamm = 0.009; 7.8 (IQR 5.4-11.7) vs 4.9 (IQR 3.7-9.8) pmol/L, PBMI = 0.008). Copeptin levels did not change either in the anakinra or in the placebo group and remained stable throughout the treatment (P = 0.44). Subgroup analyses did not reveal effect modifications. Therefore, we conclude that, although IL-1-mediated inflammation is associated with increased circulating copeptin levels, antagonizing IL-1 does not significantly alter copeptin levels in patients with metabolic syndrome.

IL (Interleukin)-1 Receptor Antagonist Increases Ang (Angiotensin [1-7]) and Decreases Blood Pressure in Obese Individuals.

IL (Interleukin)-1 antagonism decreases blood pressure in obese individuals. The underlying mechanisms are unknown. Based on experimental data, we hypothesized an effect of IL-1 antagonism via modulation of the renin-angiotensin-aldosterone system. In this explorative study, we examined shorter- (2 days) and longer-term effects (4 weeks) of IL-1 antagonism (anakinra/Kineret) on renin-angiotensin system peptide profiles and on hemodynamic parameters assessed by noninvasive measurement in obese (body mass index ≥30 kg/m2) individuals from 2 interventional trials (a prospective interventional trial [n=73] and a placebo controlled-double blinded interventional trial [n=67]). A total of 140 patients were included. Systolic blood pressure decreased after short-term (absolute difference -5.2 mm Hg [95% CI, -8.5 to -1.8]; P=0.0006) and after longer-term treatment with anakinra (absolute difference -3.9 mm Hg [95% CI, -7.59 to -0.21]; P=0.04), with no change in blood pressure in the placebo group. Upon IL-1 antagonism, equilibrium levels of Ang II (angiotensin II), Ang I, aldosterone, and renin remained unchanged. In contrast, Ang (1-7) peptide levels increased after 4 weeks (between-group difference 16.35 pmol/L [95% CI, 1.22-30.17], P=0.03), as well as the Ang (1-7)/Ang II ratio (between-group difference 0.42 [95% CI, 0.17-0.67], P=0.02) in comparison to placebo. Consistently, the stroke systemic vascular resistance index significantly decreased in the anakinra group (between-group difference of -62.65 dyn/sec per cm-5 per m2 [95% CI, -116.94 to -18.36], P=0.008, consistent with a 25% decrease). IL-1 antagonism increased the vasodilatory Ang (1-7) peptide after 4 weeks of treatment in obese individuals, paralleled by a decrease in peripheral vascular resistance. These findings point to an IL-1 mediated blood pressure-lowering mechanism via modulation of Ang (1-7). Registration- URL: https://www.clinicaltrials.gov. Unique identifiers: NCT02227420 and NCT02672592.

Comparison of 1 mg versus 2 mg Dexamethasone Suppression Test in Patients with Obesity.

In this study, we compared the 2 mg dexamethasone suppression test (DST) with the gold-standard 1 mg DST in obese patients in order to reduce the false-positive rate for Cushing's syndrome (CS). The primary endpoint was the comparison of serum cortisol levels after 1 mg versus 2 mg DST in patients with a BMI >30 kg/m2 and at least one additional feature of the metabolic syndrome. Secondary endpoints were comparison of salivary cortisol and ACTH levels, respectively. Fifty-four obese patients were included. Median serum cortisol levels after 1 mg DST and 2 mg DST were similar [28 nmol/l (20; 36) vs. 28 nmol/l (20; 38), p=0.53]. Salivary cortisol was 8.2 nmol/l (4.7; 11.7) after the 1 mg DST vs. 6.7 nmol/l (4.2; 9.5) after the 2 mg test, p=0.09. ACTH levels were higher after the 1 mg DST compared to the 2 mg DST [10.0 pg/ml (7.6; 10.7) vs. 5.0 pg/ml (5.0; 5.1), p<0.0001]. The false positive rate after the 1 mg DST was 14.8% (n=8) and was reduced to 11.1% (n=6) after the 2 mg DST. All non-suppressors (n=8) had type 2 diabetes and most of them took a medication interacting with cytochrome P450 3A4 (CYP3A4). In individuals with obesity, the 2 mg DST was not superior to the 1 mg DST in regard to serum cortisol levels. However, in some patients, particularly with poorly controlled diabetes or medication interacting with CYP3A4 and without adequate suppression after the 1 mg DST, the 2 mg DST might prove helpful to reduce the false-positive rate for CS. ClinicalTrials.gov Number: NCT02227420.

Interleukin-1 Antagonism Decreases Cortisol Levels in Obese Individuals.

Context: Increased cortisol levels in obesity may contribute to the associated metabolic syndrome. In obesity, the activated innate immune system leads to increased interleukin (IL)-1ß, which is known to stimulate the release of adrenocorticotropin hormone (ACTH). Objectives: We hypothesized that in obesity IL-1 antagonism would result in downregulation of the hypothalamo-pituitary-adrenal axis, leading to decreased cortisol levels. Design and Participants: In this prospective intervention study, we included 73 patients with obesity (body mass index [BMI] ≥30 kg/m2) and at least one additional feature of the metabolic syndrome. Outcome Measures: The primary end point was change in morning cortisol from baseline to after the administration of the IL-1 receptor antagonist (anakinra/Kineret®, total dose 3 × 100 mg). Secondary end points were effects on salivary cortisol and ACTH. Results: Median age was 56 years, 50.7% of patients were female, and median BMI was 36.3 kg/m2. Median morning serum cortisol levels (nmol/L) decreased significantly after IL-1 antagonism [from baseline, 452 to 423; absolute difference, -38.7; 95% confidence interval (CI), -64 to -13.4; P = 0.0019]. Similar effects were found for salivary cortisol levels (-2.8; 95% CI, -4.4 to -1.3; P = 0.0007), ACTH levels (-2.2; 95% CI; -4.2 to -0.1; P = 0.038), systolic blood pressure (-5.2, 95% CI, -8.5 to -1.8; P = 0.0006), and heart rate (-2.9; 95% CI, -4.7 to -1.0; P = 0.0029). Conclusion: IL-1 antagonism in obese individuals with features of the metabolic syndrome leads to a decrease in serum cortisol, salivary cortisol, and ACTH levels along with a reduction in systolic blood pressure and heart rate.

Plasma Apelin Concentrations in Patients With Polyuria-Polydipsia Syndrome.

CONTEXT: Apelin and arginine vasopressin are antagonists in the regulation of body fluid and osmotic homeostasis. There are no data about apelin levels in patients with polyuria-polydipsia syndrome (PPS). OBJECTIVE: To investigate plasma apelin levels and plasma apelin to copeptin ratios in patients with PPS and healthy volunteers using copeptin as a surrogate marker for arginine vasopressin. DESIGN, PARTICIPANTS, AND SETTING: We included 41 patients with PPS in this post hoc analysis of a prospective study performed in tertiary care hospitals in Switzerland and Germany and 113 healthy volunteers as a control group. OUTCOME MEASURES: Plasma apelin and copeptin levels were measured in 15 patients with complete central diabetes insipidus (DI), seven patients with complete nephrogenic DI, 19 patients with primary polydipsia (PP), and 113 healthy volunteers. RESULTS: Plasma apelin levels were highest in patients with complete nephrogenic DI (413 pmol/L; interquartile range, 332-504 pmol/L; P = .01) and lower in patients with PP (190 [172-215] pmol/L; P < .001) or complete central DI (209 [174-241] pmol/L; P = .02) as compared to healthy volunteers (254 [225-311] pmol/L). Plasma apelin to copeptin ratio in patients with PP (53 [38-92] pmol/pmol; P > .9) was similar to healthy volunteers (57 [37-102] pmol/pmol). In contrast, the apelin to copeptin ratio was higher in patients with complete central DI (89 [73-135] pmol/pmol; P = .02) and lower in patients with complete nephrogenic DI (7 [6-10] pmol/pmol; P < .001) compared to healthy volunteers. CONCLUSION: In PP, normal plasma apelin to copeptin ratio attests a normal water homeostasis. In contrast, in patients with central or nephrogenic DI, the increased or decreased apelin to copeptin ratio, respectively, reflects a disturbed osmotic and body fluid homeostasis.

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS: In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS: From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION: Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING: Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Copeptin concentrations during psychological stress: the PsyCo study.

OBJECTIVE: The prognostic/diagnostic biomarker copeptin, an arginine vasopressin surrogate, reflects physical stress. Whether copeptin concentration increases upon psychological stress is unknown. We investigated psychological stress effects on copeptin secretion in healthy volunteers and patients with central diabetes insipidus (DI). DESIGN: A prospective observational study was conducted to study the relation between copeptin concentration and psychological stress. METHODS: A total of 20 healthy adults (ten female) and eight patients with central DI (four female) underwent the Trier Social Stress Test including, in order, 30-min waiting period, 10-min anticipation period, 10-min test period and 40-min recovery. Serum copeptin and cortisol concentrations and self-rated stress component feelings were determined in the pre-/post-anticipation period, post-test period and twice post-recovery. RESULTS: In healthy volunteers, the median (25th-75th percentile) copeptin concentration peaked immediately during the post-test period at 5.1 (3.2-7.0) pmol/l, vs 3.7 (2.6-5.4) pmol/l at baseline. Over the measurement course, copeptin concentration significantly elevated (coefficient; 95% CI) (0.14; 0.06-0.23, P=0.002). The important predictors of increase in copeptin concentration were feelings of tension (0.06; 0.04-0.08, P<0.001) and avoidance (0.07; 0.04-0.10; P<0.001). Copeptin and cortisol levels were associated (0.43; 0.13-0.72, P<0.005). Patients with DI had lower baseline concentrations (1.55 (1.2-3.1) pmol/l) when compared with healthy volunteers, P=0.006. Patients with DI showed no increase upon psychological stress (peak 2.15 pmol/l (1.5-2.28), P=0.79). By contrast, cortisol values were similar in patients and volunteers. CONCLUSIONS: In healthy volunteers, copeptin levels significantly increased after psychological stress testing; this response was blunted in patients with DI.