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Secretin was recently shown to constitute a postprandial satiety signal in mice. This effect was proposed to be mediated by secretin-induced activation of brown adipose tissue (BAT) and subsequent hypothalamic registration of body temperature rise. We investigated the effect of a 5-hour infusion of secretin on appetite sensations, food intake, BAT activity and resting energy expenditure (REE) in man. In a randomized, double-blind, placebo-controlled, crossover study, 25 healthy males aged (mean ± SD) 25.7 ± 6.1 years with a BMI of 23.4 ± 1.8 kg/m2 underwent 5-hour infusions of secretin (1 pmol/kg/min) and placebo, respectively, on separate days with an interposed 8-week washout period. During the infusions, before and several times after a liquid mixed meal test, we assessed appetite sensations (by visual analogue scales), REE (by indirect calorimetry) and supraclavicular BAT activity (by thermal imaging). Before terminating the infusions, ad libitum food intake (primary outcome) was assessed. Compared to placebo, secretin did not affect appetite sensations, but it decreased ad libitum food intake by [mean±SEM] 173 ± 88 kcal (P = 0.039). Within the first 15 minutes of infusion, secretin decreased supraclavicular temperature by 0.10 ± 0.02°C (P In conclusion, a 5-hour infusion of secretin in healthy males decreased ad libitum food intake and exhibited a biphasic effect of supraclavicular BAT activity. Disclosure S. M. Nguyen heimbürger: Speaker’s Bureau; Self; AstraZeneca. M. J. Bentzen: None. B. Hartmann: None. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S.

In persons with type 2 diabetes (T2D), dipeptidyl peptidase 4 (DPP-4) inhibitor treatment improves glycemic control by raising the active levels of the insulinotropic gut hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide (GIP). Using the GIP receptor antagonist GIP(3-30)NH2, we investigated endogenous GIP’s contribution to the insulinotropic effect of DPP-4 inhibition (assessed by insulin secretion rate (ISR) relative to plasma glucose). In a double-blind, placebo-controlled, cross-over study, 12 persons (eight men and four women) with T2D (mean ± SD; BMI 27.4 ± 2.6 kg/m2, HbA1c 7.1 ± 1.4% (54 ± 15 mmol/mol)) underwent two randomized 12-13-day treatment courses with DPP-4 inhibitor (sitagliptin 100 mg once-daily) and placebo, respectively, with an interposed 1-3-week washout period. In the end of each treatment period, two randomized 5-hour liquid mixed-meal tests with infusion of GIP(3-30)NH2 (1,200 pmol/kg/min) or saline (placebo) were performed. During placebo treatment, GIP(3-30)NH2 lowered postprandial serum C-peptide (determined as difference in baseline-subtracted area under curve (ΔbsAUC%) ± SEM: −31 ± 9%, P = 0.005) and increased postprandial plasma glucose excursions (ΔAUC% ± SEM: 7.3 ± 2.8%, P = 0.017) compared to saline. Sitagliptin increased concentrations of active GIP(1-42) (ΔAUC% ± SEM: 153 ± 21%, P < 0.0001) and lowered fasting plasma glucose (mean: 8.7 vs. 7.6 mmol/L, P < 0.0004), whereas postprandial glucose excursions were unchanged compared to placebo treatment. GIP(3-30)NH2 caused a reduction in AUCISR/AUCglucose ratio equivalent to 37 ± 12% of the increments due to sitagliptin. In conclusion, we demonstrate an insulinotropic and glucose-lowering effect of endogenous GIP in persons with T2D and show that endogenous GIP is responsible for more than one third of the improved beta cell function observed during DPP-4 inhibitor treatment. Disclosure S. Stensen: None. L. S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M. M. Rosenkilde: Board Member; Self; Bainan Biotech, Synklino ApS, Board Member; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Consultant; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Self; Antag Therapeutics, Bainan Biotech, Synklino ApS, Stock/Shareholder; Spouse/Partner; Antag Therapeutics, Bainan Biotech. B. Hartmann: None. T. Vilsbøll: Consultant; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Gilead Sciences, Inc., Lilly Diabetes, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd. J. J. Holst: Consultant; Self; Novo Nordisk, Other Relationship; Self; Antag Therapeutics, Bainan Biotech, MSD Corporation, Novo Nordisk, Other Relationship; Spouse/Partner; Antag Therapeutics, Bainan Biotech, Synklino ApS. M. B. Christensen: None. F. K. Knop: Advisory Panel; Self; MSD Corporation, Novo Nordisk A/S, Sanofi, Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Novo Nordisk A/S, Pharmacosmos, Zealand Pharma A/S, Research Support; Self; Novo Nordisk A/S, Zealand Pharma A/S, Speaker’s Bureau; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, MSD Corporation, Novo Nordisk A/S. Funding European Foundation for the Study of Diabetes/Lilly European Diabetes Research Programme (2018); A.P. Møller Foundation

The insulinotropic gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are key factors in the regulation of normal postprandial glucose homeostasis, but in most reports, the glucose-lowering effect of GIP has been shown to be blunted or even absent in people with type 2 diabetes (T2D) (1). Despite previous reports that GIP does not potentiate the glucose-lowering effect of GLP-1 in type 2 diabetes (2), a dual GIP/GLP-1 receptor agonist (tirzepatide/LY3298176) has recently been reported to reduce HbA1c and body weight in overweight/obese individuals with type 2 diabetes beyond that of GLP-1 receptor monoagonism (dulaglutide) (3).

Type 1 diabetes is characterised by reduced glucagon response to hypoglycaemia, increasing the risk of insulin treatment-associated hypoglycaemia known to hamper glycaemic control. We previously reported a glucagonotropic effect of exogenous glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycaemia in individuals with type 1 diabetes. Here we investigate the effect of a 6-day s.c. GIP infusion on time in glycaemic range as assessed by continuous glucose monitoring (CGM) in individuals with type 1 diabetes.In a randomised, placebo-controlled, double-blind crossover study, time in glycaemic range (assessed by double-blinded CGM) was evaluated in 20 men with type 1 diabetes (18-75 years, stable insulin treatment ≥3 months, diabetes duration 2-15 years, fasting plasma C-peptide below 200 pmol/l, BMI 20-27 kg/mThere were no significant differences in time below range (3.9 mmol/l, p = 0.53) or above range (10 mmol/l, p = 0.32) during night-time or daytime, in mean glucose, or in hypoglycaemic events as assessed by CGM. GIP altered neither self-reported hypoglycaemia nor safety measures. Compared with placebo, GIP significantly increased time in tight range (3.9-7.8 mmol/l) during daytime (06:00-23:59 hours) by [mean ± SEM] 11.2 ± 5.1% [95% CI 0.41, 21.9] (p = 0.02).Six-day s.c. GIP infusion in men with type 1 diabetes did not procure convincing effect on overall time in range, but increased time in tight glycaemic range during daytime by ~2 h per day.ClinicalTrials.gov NCT03734718.The study was funded by grants from The Leona M. and Harry B. Helmsley Charitable Trust and Aase og Ejnar Danielsens Fond.

BackgroundWe aimed to synthesise qualitative studies exploring medication-related experiences of polypharmacy among patients with multimorbidity.MethodsWe systematically searched PubMed, Embase and Cumulative Index to Nursing and Allied Health Literature in February 2020 for primary, peer-reviewed qualitative studies about multimorbid patients’ medication-related experiences with polypharmacy, defined as the use of four or more medications. Identified studies were appraised for methodological quality by applying the Critical Appraisal Skills Programme checklist for qualitative research, and data were extracted and synthesised by the meta-aggregation approach.ResultsWe included 13 qualitative studies, representing 499 patients with polypharmacy and a wide range of chronic conditions. Overall, most Critical Appraisal Skills Programme items were reported in the studies. We extracted 140 findings, synthesised these into 17 categories, and developed five interrelated syntheses: (1) patients with polypharmacy are a heterogeneous group in terms of needing and appraising medication information; (2) patients are aware of the importance of medication adherence, but it is difficult to achieve; (3) decision-making about medications is complex; (4) multiple relational factors affect communication between patients and physicians, and these factors can prevent patients from disclosing important information; and (5) polypharmacy affects patients’ lives and self-perception, and challenges with polypharmacy are not limited to practical issues of medication-taking.DiscussionPolypharmacy poses many challenges to patients, which have a negative impact on quality of life and adherence. Thus, when dealing with polypharmacy patients, it is crucial that healthcare professionals actively solicit individual patients’ perspectives on challenges related to polypharmacy. Based on the reported experiences, we recommend that healthcare professionals upscale communicative efforts and involve patients’ social network on an individualised basis to facilitate shared decision-making and treatment adherence in multimorbidpatients with polypharmacy.

The number of people suffering from type 2 diabetes (T2D) and its complications is on the rise; and, thus continues to expand the market for pharmacologic agents targeting the disease. At present, only the glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter 2 inhibitors (SGLT-2i) have demonstrated macrovascular benefits and reduction in mortality in T2D.This review provides an overview of the more than 20 drug classes in clinical development for T2D, with an outline of their mode of action, efficacy, safety, and current status.New GLP-1 RA and SGLT-2i are dominating the clinical pipeline. A range of glucoregulatory hormone-based drugs are also under development (e.g. GLP-1/glucose-dependent insulinotropic polypeptide/glucagon receptor co-agonists) for the treatment of T2D and associated conditions such as obesity and nonalcoholic fatty liver disease. Glucokinase activators and imeglimin are in phase III of development. Other drugs in phase I-II (e.g. fructose-1,6-bisphosphatase inhibitors, activators of adenosine monophosphate-activated protein kinase and Lyn kinase; and agonists of the receptor for growth differentiation factor 15, fibroblast growth factor-21, and G protein-coupled receptor-119) show promising diverse mechanisms of action, but have yet to show net clinical benefits.

In healthy individuals, GIP enhances insulin secretion and reduces bone resorption As GIP has impaired insulinotropic effects in patients with type 2 diabetes (T2D), we investigated the effect of glucose and GIP on bone resorption in these patients. In a randomized, double-blinded, cross-over study, 12 male patients with T2D underwent six study days with 90-minute GIP or matching placebo (saline) infusions on paired days with plasma glucose (PG) clamped at three levels: Fasting hyperglycemia (mean PG ∼8 mmol/l), aggravated hyperglycemia (mean PG ∼12 mmol/l), or insulin-induced hypoglycemia (mean PG 3-8 mmol/l). Primary outcome measure was CTX (a marker of bone resorption expressed as %-change from baseline ± SD). On days with fasting hyperglycemia, CTX was suppressed by 36±15% during GIP compared to 0±9% during saline infusion (p In conclusion, Short-term GIP infusions during hyperglycemia reduce bone resorption by more than a third suggesting that GIP has preserved effects on bone in patients with T2D. Disclosure M.B. Christensen: None. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. N.R. Jørgensen: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

The glucagonotropic effect of glucose-dependent insulinotropic polypeptide (GIP) during insulin-induced hypoglycemia in patients with type 1 diabetes (T1D) prompted us to investigate the effect of a 6-day subcutaneous (sc) GIP infusion on glucose variability in patients with T1D. In a randomized, placebo-controlled, double-blinded, crossover study, 20 men with T1D (age [mean± SD] 26±8 years, BMI 23.8±1.8 kg/m2, HbA1c 51±10 mmol/mol), underwent 2 × 6 days of continuous sc GIP (6 pmol/kg/min) and placebo (saline) infusion, respectively, with an interposed 7-day washout period. Participants wore a continuous glucose monitoring system. GIP significantly increased daytime time in range (3.9-7.8 mmol/L) by [mean±SEM] 104±69 min/day (P=0.035) without statistically significant effects on time below range (10.1 mmol/L), mean glucose or hypoglycemic events. Compared to placebo, GIP increased hepatic fat content by 12.6±4.2 percentage points (assessed by FibroScan®) (P=0.006), decreased 24-hour systolic and diastolic blood pressure by 4.6±2.8 (P=0.001) and 2.6±1.3 mmHg (P=0.028), respectively, and increased heart rate by 4.4±2.0 beats per minute (P=0.002) (Figure). Compared to placebo, a 6-day sc GIP infusion in patients with T1D increased glycemic time in range and hepatic fat content and reduced systolic and diastolic blood pressure while increasing heart rate. Disclosure S.M. Nguyen Heimbürger: None. B. Hoe: None. C.N. Nielsen: None. N.C. Bergmann: Employee; Self; Zealand Pharma A/S. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. J. Størling: None. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

Gluco-regulatory effects of the insulinotropic and glucagonotropic gut hormone glucose-dependent insulinotropic polypeptide (GIP) in type 1 diabetes (T1D) are unclear. We evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of prandial insulin over-dose and physical activity after meal ingestion. In a randomized, placebo-controlled, double-blinded, crossover study, 12 men with T1D (age [mean±SD]: 26±6.6 years; BMI: 23±2.3 kg/m2; HbA1c: 6.5±2.7% (48.4±6.3 mmol/mol); diabetes duration: 11.3±5.5 years; plasma C-peptide The GIP infusion attenuated postprandial plasma glucose excursions (Cmax-Cmin) by [mean±SEM] 1.5±0.5 mmol/L and 0.92±0.56 mmol/L compared to GIP(3-30)NH2 and placebo, respectively (P=0.03). Infused glucose needed to avoid plasma glucose In conclusion, GIP infusion seems to attenuate postprandial plasma glucose excursions without significantly increasing the need of glucose to avoid hypoglycemia in patients with T1D. Disclosure B. Hoe: None. S.M. Nguyen Heimbürger: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.B. Lynggaard: None. B. Hartmann: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. A. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. S. Engberg: None. T.F. Dejgaard: Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. Funding The Leona M. and Harry B. Helmsley Charitable Trust (2018PG-T1D037)

We have previously shown that totally pancreatectomized (PX) patients secrete substantial amounts of glucagon (most likely from enteroendocrine cells) during an oral glucose tolerance test (OGTT) whereas these patients suppress circulating glucagon concentrations during intravenous glucose infusions. Here, we investigated the effect of insulin-induced hypoglycemia on extrapancreatic glucagon secretion and other counterregulatory factors in PX patients and in healthy controls (CTRLs). On two separate days, 12 PX patients (age 65.5±5.5 [mean±SD] years; BMI: 23.8±3.6 kg/m2) and 12 matched, healthy CTRLs (age 64.8±6.5 years; BMI: 24.5±2.9 kg/m2) underwent 1) a 50-g OGTT with 1.5 g acetaminophen (for assessment of gastric emptying) and 2) an insulin-induced hypoglycemic clamp followed by a 30-minute recovery period and a subsequent 50-g OGTT with acetaminophen. Blood was intermittently sampled throughout both experimental days. Plasma glucagon responses to OGTT (as assessed by baseline-subtracted area under curve) were greater in PX patients compared to CTRLs (386±150 vs. -340±50 min×pmol/l [mean±SEM], P=0.0001). During the hypoglycemic clamp, PX patients did not increase plasma glucagon concentrations and, thus, glucagon responses to hypoglycemia were higher in CTRLs (903±104 vs. -21±16 min×pmol/l, P Disclosure M. Baekdal: None. A.B. Lund: Speaker’s Bureau; Self; AstraZeneca, Novo Nordisk A/S, Sanofi. M. Baldassarre: None. J.I. Egholk: None. K. Rose: None. C. Hansen: None. J.H. Storkholm: None. M.B. Christensen: None. B. Hartmann: None. J. Faber: None. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S.

Patients with type 2 diabetes (T2D) have a markedly altered cardiac metabolism and twice the risk of developing heart failure compared to individuals without diabetes. The effect of acute changes in plasma glucose (PG) on cardiac function is unclear. We evaluated the effect of acute hyperglycemia and hypoglycemia on cardiac function. Insulin-treated patients with T2D (N=21, [mean±SD] age 62.8±6.5 years, BMI 29.0±4.2 kg/m2, HbA1c 51.0±5.4 mmol/mol) and matched controls (N=21, age 62.2±8.3 years, BMI 29.2±3.5, HbA1c 34.3±3.3 mmol/l) with normal glucose tolerance underwent a 3-step glucose clamp day with 30 min of steady-state PG during each step: 1) fasting PG (FPG), 2) hyperglycemia (FPG+10 mmol/l), and 3) hyperinsulinemic hypoglycemia (PG Acute hyperglycemia increased left ventricular ejection fraction (LVEF) from baseline in T2D patients ([mean±SEM, P-value] 4.5±1.7%, P=0.0108) whereas no change was observed in controls (2.0±1.7%, P=0.2525). Furthermore, left ventricular systolic function measured by s’ increased during hyperglycemia in both patients and controls (0.4±0.1 m/s (P=0.0007) and 0.6±0.1 m/s (P In conclusion, we demonstrate that LVEF increases during acute hyperglycemia in insulin-treated patients with T2D and that acute hypoglycemia markedly increases all measures of left ventricular systolic function. These results point to the importance of glycemia when evaluating left ventricular systolic function by echocardiography in patients with T2D. Disclosure A. Andersen: None. P.G. Jørgensen: None. J.I. Bagger: Speaker’s Bureau; Self; Novo Nordisk A/S. M. Baldassarre: None. M.B. Christensen: None. K.U. Abelin: None. U. Pedersen-Bjergaard: Advisory Panel; Self; Novo Nordisk A/S, Sanofi. Research Support; Self; Novo Nordisk A/S. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. T.B. Lindhardt: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S, Sanofi. Consultant; Self; Carmot Therapeutics, Inc., Eli Lilly and Company, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Gubra, Novo Nordisk A/S, Sanofi, Zealand Pharma A/S. Speaker’s Bureau; Self; AstraZeneca, Lupin Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Norgine B.V., Novo Nordisk A/S. T. Vilsbøll: Advisory Panel; Self; AstraZeneca, Mundipharma International, Novo Nordisk A/S, Sun Pharmaceutical Industries Ltd. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Medscape, Merck Sharp & Dohme Corp., Sanofi.

The glucose-dependent insulinotropic polypeptide (GIP) fragment GIP(3-30)NH

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are secreted postprandially and contribute importantly to postprandial glucose tolerance. In this study, we assessed the individual and combined contributions of endogenous GIP and GLP-1 to the postprandial changes in glucose and glucoregulatory hormones using the novel GIP receptor antagonist GIP(3-30)NH2 and the well-established GLP-1 receptor antagonist exendin(9-39)NH2. During 4-h oral glucose tolerance tests (75 g) combined with an ad libitum meal test, 18 healthy men received on four separate days in randomized, double-blinded order intravenous infusions of A) GIP(3-30)NH2 (800 pmol/kg/min) plus exendin(9-39)NH2 (0–20 min: 1,000 pmol/kg/min; 20–240 min: 450 pmol/kg/min), B) GIP(3-30)NH2, C) exendin(9-39)NH2, and D) saline, respectively. Glucose excursions were significantly higher during A than during B, C, and D, while glucose excursions during B were higher than during C and D. Insulin secretion (assessed by C-peptide/glucose ratio) was reduced by 37 ± 16% (A), 30 ± 17% (B), and 8.6 ± 16% (C) compared with D (mean ± SD). A and C resulted in higher glucagon levels and faster gastric emptying. In conclusion, endogenous GIP affects postprandial plasma glucose excursions and insulin secretion more than endogenous GLP-1, but the hormones contribute additively to postprandial glucose regulation in healthy individuals.

Bisacodyl and sodium picosulfate are classified both as stimulant laxatives, approved for short-term treatment of constipation and sold without prescription (OTC). Stimulant laxatives are associated with harmful long-term colonic effects and possible carcinogenic risk - and evidence support that these agents are used for longer periods. We aimed to compile and review the clinical trial evidence describing the effectiveness and safety of long-term treatment (14 continuous days) with stimulant laxatives.The PubMed database was searched for all randomised clinical trials (RCTs) examining the effect of bisacodyl or sodium picosulfate in adult patients diagnosed with constipation.Five RCTs (one open-label and four double-blinded) with intervention periods of four weeks duration were eligible. These included 1008 patients, whereof 26% dropped out. A positive global assessment of efficacy was obtained in 78-99% of the patients treated with bisacodyl or sodium picosulfate. Notably, the same global assessment was obtained in 46-54% of the placebo-treated patients. Compared to placebo, an improvement in stool consistency and a significant increase in number of bowel movements peer week were seen in favor of bisacodyl and sodium picosulfate. However, for pyridostigmine, a significant difference was seen compared to bisacodyl. AEs were generally mild, but frequent (up to 72%) mostly diarrhea and abdominal pain.The evidence base does not support use of stimulant laxatives for more than four weeks. Due to the substantial use of stimulant laxatives including sold OTC, longer term RCTs and epidemiological studies investigating effects and safety on the longer term are warranted.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are well known for their insulinotropic effects and they are thought to affect bone homeostasis as mediators in the so-called entero-osseous axis. We examined the contributions of endogenous GIP and GLP-1, respectively, to postprandial bone homeostasis, in healthy subjects in two randomized and double-blind crossover studies. We included healthy men who received either four oral glucose tolerance tests (OGTTs) (n = 18, median age 27 (range 20–70), BMI 27.2 (22.4–37.0) kg/m2) or liquid mixed meal tests (MMTs) (n = 12, age 23 (19–65), BMI 23.7 (20.3–25.5) kg/m2) with infusions of 1) the GIP receptor antagonist GIP(3-30)NH2, 2) the GLP-1 receptor antagonist exendin(9–39)NH2, 3) both GIP(3–30)NH2 and exendin(9–39)NH2, or 4) placebo infusions (saline) on four separate visits. Bone resorption was evaluated from levels of circulating carboxy-terminal collagen crosslinks (CTX) and bone formation from levels of procollagen type 1 amino-terminal propeptide (P1NP). During placebo infusions, baseline-subtracted area under the curve values for CTX were −39 ± 5.0 (OGTT) and −57 ± 4.3 ng/ml × min (MMT). When GIP(3–30)NH2 was administered, CTX suppression was significantly diminished compared to placebo (−30 ± 4.8 (OGTT) and −45 ± 4.6 ng/ml × min (MMT), P = 0.0104 and P = 0.0288, respectively, compared to placebo. During exendin(9–39)NH2 infusion, CTX suppression after OGTT/MMT was similar to placebo (P = 0.28 (OGTT) and P = 0.93 (MMT)). The relative contribution of endogenous GIP to postprandial suppression of bone resorption during both OGTT and MMT was similar and reached 22–25%. There were no differences in P1NP concentrations between interventions. In conclusion, endogenous GIP contributes by up to 25% to postprandial suppression of bone resorption in humans whereas an effect of endogenous GLP-1 could not be demonstrated.

The gastric hormone ghrelin stimulates food intake and increases plasma glucose through activation of the growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) has been proposed to inhibit actions of ghrelin through inverse effects on GHSR activity. Here, we investigate the effects of exogenous LEAP2 on postprandial glucose metabolism and ad libitum food intake in a randomized, double-blind, placebo-controlled, crossover trial of 20 healthy men. We report that LEAP2 infusion lowers postprandial plasma glucose and growth hormone concentrations and decreases food intake during an ad libitum meal test. In wild-type mice, plasma glucose and food intake are reduced by LEAP2 dosing, but not in GHSR-null mice, pointing to GHSR as a potential mediator of LEAP2's glucoregulatory and appetite-suppressing effects in mice.

In a double-blinded, randomized, crossover trial, we investigated the hemodynamic effects of high-dose intravenous lipid emulsion (ILE) with/without metoprolol. Ten healthy volunteers each completed 4 trial days (placebo + ILE; metoprolol + placebo; metoprolol + ILE; placebo + placebo) in random order. Metoprolol was administered as an initial bolus (10 mg), followed by an infusion (50 mg) from 5 to 30 minutes. ILE was administered as a bolus at 12.5 minutes (2.5 mL/kg), followed by a 15-minute infusion (0.25 mL/kg per minute). On metoprolol + ILE days (compared with metoprolol + placebo) after 120 minutes, mean heart rates were significantly higher (difference, 5.5 beats per minute (bpm); 95% confidence interval (CI), 3.0-8.1 bpm; P < 0.001), and average relative cardiac output was higher (difference, 10 percentage points; 95% CI, 5-15 percentage points; P < 0.001). The hemodynamic effect of ILE developed gradually. ILE had no effect on plasma metoprolol or major adverse events. In conclusion, high-dose ILE has relatively marginal and delayed hemodynamic effects that may have limited clinical relevance in the short-term clinical toxicological setting.

Fasting hyperglucagonemia can be detrimental to glucose metabolism in patients with type 2 diabetes (T2D) and may contribute to metabolic disturbances in obese and/or prediabetic subjects. However, the mechanisms underlying fasting hyperglucagonemia remain elusive.We evaluated the interrelationship between fasting hyperglucagonemia and demographic and biochemical parameters in 106 patients with T2D (31% female, age: 57 ± 9 years [mean ± standard deviation; body mass index (BMI): 30.1 ± 4.4 kg/mFasting plasma glucagon concentrations were significantly higher among patients with T2D (13.5 ± 6.3 vs. 8.5 ± 3.8 mM, P 0.001) together with HbA1c (P 0.001), FPG (P 0.001), and insulin (84.9 ± 56.4 vs. 57.7 ± 35.3 mM, P 0.001). When adjusted for T2D, HbA1c and insulin were significantly positive determinants for fasting plasma glucagon concentrations. Furthermore, WHR comprised a significant positive determinant.We confirm that fasting plasma glucagon concentrations are abnormally high in patients with T2D, and show that fasting plasma glucagon concentrations are influenced by WHR (in addition to glycemic control and fasting plasma insulin concentrations), which may point to visceral fat deposition as an important determinant of increased fasting plasma glucagon concentrations.

Introduction: Type 2 diabetes (T2D) is a major global health challenge associated with increased cardiovascular morbidity and mortality. Intervention strategies managing multiple risk facto...

A large overdose of insulin is a serious health matter. Information concerning administration and duration of intravenous (IV) glucose, other treatment options or complications besides hypoglycaemia following large insulin overdoses is not readily apparent from the literature. A systematic search, compilation and review of case reports on insulin overdoses, published 1986-2017, was performed in PubMed, EMBASE, Cochrane and PROSPERO databases. Of 1523 published articles, 45 cases of insulin overdoses were included with a total median insulin dose of 900 international units (IU) (range 26-4800 IU). Hospitalization occurred in 44 cases with a median hospitalization duration of 94 hr (range 12-721 hr), and one-third (n = 15) admitted to the intensive care unit. First-line treatment was IV glucose treatment in 95% of cases. Treatment options besides IV glucose that were reported beneficial included glucagon IV or intramuscular (IM), octreotide IV or IM, surgical excision, hydrocortisone IV and oral intake of complex carbohydrates. Prevalent complications were intermittent cerebral impairment (73%), hypokalaemia (49%), other electrolyte disturbances (42%), and hepatic disturbances (7%) and cardiac toxicity (e.g. cardiac arrhythmia) (9%). Long-term consequences were one case of lasting hypoglycaemic encephalopathy and one death. In conclusion, following large insulin overdoses, in-hospital admission and treatment with IV glucose may be needed for up to a week. Monitoring of electrolytes and hepatic and cardiac functions seems important. Several experimental treatment options may be considered in addition to glucose administration. With appropriate pre- and in-hospital treatment, cases with severe hypoglycaemia and neurologic complications may have a favourable outcome.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NH2 in in vivo and in in vitro receptor studies. In transiently transfected COS-7 cells, GIP(3-30)NH2 was evaluated with homologous receptor binding and receptor activation (cAMP accumulation) studies at the glucagon-like peptide 1 (GLP-1), glucagon-like peptide-2 (GLP-2), glucagon, secretin and growth hormone-releasing hormone (GHRH) receptors. Ten healthy men (eligibility criteria: age 20–30 years, HbA1c less than 6.5% [48 mmol/mol] and fasting plasma glucose [FPG] less than 7 mmol/l) were included in the clinical study. Data were collected as plasma and serum samples from a cubital vein cannula. As primary outcome, insulin secretion and glucose requirements were evaluated together with in a randomised, four-period, crossover design by infusing GIP(3-30)NH2 (800 pmol kg−1 min−1), GIP (1.5 pmol kg−1 min−1), a combination of these or placebo during hyperglycaemic clamp experiments. The content of the infusions were blinded to the study participants and experimental personnel. No study participants dropped out. GIP(3-30)NH2 neither bound, stimulated nor antagonised a series of related receptors in vitro. The elimination plasma half-life of GIP(3-30)NH2 in humans was 7.6 ± 1.4 min. Markedly larger amounts of glucose were required to maintain the clamp during GIP infusion compared with the other days. GIP-induced insulin secretion was reduced by 82% (p

Infusion of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) suppresses the bone resorption marker carboxy-terminal type 1 collagen crosslinks (CTX). Using separate and combined infusions of the selective GIP receptor (GIPR) antagonist, GIP(3-30)NH2, and GIP, we investigated how GIPR inhibition affects bone turnover markers. Ten healthy men (median age 22.5 years (range 21-25), BMI 21.3kg/m2 (19.9-24.7)) participated in a randomized, doubled blinded, placebo-controlled, crossover study with four 1h 12mmol/l-hyperglycemic clamps on four separate study days with concomitant infusions of GIP, GIP+GIP(3-30)NH2, GIP(3-30)NH2, and placebo, respectively, separated by a period of at least one week. GIP was infused at 1.5pmol/kg/min and GIP(3-30)NH2 at 800pmol/kg/min. Plasma glucose was clamped at 12.0±1.2mmol/l and plasma levels of GIP and GIP(3-30)NH2 amounted to ∼80pmol/l and ∼50nmol/l, respectively. GIP suppressed CTX more than placebo (baseline-subtracted AUC -6,811±1,260 vs. -3,012±3,018ng/l×min, P= 0.002) and resulted in CTX values of 53 ± 6.9% (GIP) versus 81 ± 10% of baseline (placebo), respectively (P = 0.0006), at the end of the hyperglycemic clamp. Co-infusion of GIP and GIP(3-30)NH2 attenuated the GIP-induced CTX suppression by 51±33% (P = 0.01). The peak value of the bone formation marker N-terminal propeptide of type 1 procollagen (P1NP) peaked at higher levels during GIP (109±6.7% of baseline) than during GIP(3-30)NH2 infusion (101±8.9%) (P = 0.049) and GIP suppressed PTH levels compared to GIP(3-30)NH2 alone (P = 0.0158). In conclusion, blockade of the GIPR with GIP(3-30)NH2 diminished GIP-induced CTX and P1NP responses, showing that these effects are GIPR-mediated and that GIPR antagonism might interfere with bone resorption.

Context In healthy individuals, glucose-dependent insulinotropic polypeptide (GIP) enhances insulin secretion and reduces bone resorption by up to 25% estimated by absolute placebo-corrected changes in carboxy-terminal type 1 collagen crosslinks (CTX) during GIP and glucose administration. In patients with type 2 diabetes (T2D), GIP’s insulinotropic effect is impaired and effects on bone may be reduced. Objective To investigate GIP’s effect on bone biomarkers in patients with T2D. Design Randomized, double-blinded, crossover study investigating 6 interventions. Patients Twelve male patients with T2D. Interventions A primed continuous 90-minute GIP infusion (2 pmol/kg/min) or matching placebo (saline) administered at 3 plasma glucose (PG) levels (i.e., paired days with “insulin-induced hypoglycemia” (PG lowered to 3 mmol/L), “fasting hyperglycemia” (mean PG ~8 mmol/L), or “aggravated hyperglycemia” (mean PG ~12 mmol/L). Main Outcome Measures Bone biomarkers: CTX, procollagen type 1 N-terminal propeptide (P1NP) and PTH. Results On days with insulin-induced hypoglycemia, CTX was suppressed by up to 40 ± 15% during GIP administration compared with 12 ± 11% during placebo infusion (P Conclusions Short-term GIP infusions reduce bone resorption by more than one-third (estimated by absolute placebo-corrected CTX reductions) in patients with T2DM, suggesting preserved bone effects of GIP in these patients. Précis Short-term GIP infusions reduce the bone resorption marker CTX by one-third in patients with type 2 diabetes independent of glycemic levels.

Context: N-acetylcysteine (NAC) is used worldwide to prevent liver injury after paracetamol overdoses. Anaphylactoid reactions to NAC occur frequently and often lead to treatment interruptions or d...

During the past four decades derangements in glucose-dependent insulinotropic polypeptide (GIP) biology has been viewed upon as contributing factors to various parts of the pathophysiology type 2 diabetes. This overview outlines and discusses the impaired insulin responses to GIP as well as the effect of GIP on glucagon secretion and the potential involvement of GIP in the obesity and bone disease associated with type 2 diabetes. As outlined in this review, it is unlikely that the impaired insulinotropic effect of GIP occurs as a primary event in the development of type 2 diabetes, but rather develops once the diabetic state is present and beta cells are unable to maintain normoglycemia. In various models, GIP has effects on glucagon secretion, bone and lipid homeostasis, but whether these effects contribute substantially to the pathophysiology of type 2 diabetes is at present controversial. The review also discusses the substantial uncertainty surrounding the translation of preclinical data relating to the GIP system and outline future research directions.

Background Tsetse flies (Glossina sp.) are the vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse flies are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood-specific diet by both sexes, and obligate bacterial symbiosis. This work describes the comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans, G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes), and Fusca (G. brevipalpis) which represent different habitats, host preferences, and vectorial capacity. Results Genomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex-linked scaffolds show increased rates of female-specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse-specific genes are enriched in protease, odorant-binding, and helicase activities. Lactation-associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other insects. Vision-associated Rhodopsin genes show conservation of motion detection/tracking functions and variance in the Rhodopsin detecting colors in the blue wavelength ranges. Conclusions Expanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.

Accumulating evidence suggests that glucose-dependent insulinotropic polypeptide (GIP) in addition to its involvement in type 2 diabetic pathophysiology may be involved in the development of obesity and the pathogenesis of cardiovascular disease. In this review, we outline recent preclinical and clinical cardiovascular-related discoveries about GIP. These include chronotropic and blood pressure-lowering effects of GIP. Furthermore, GIP has been suggested to control vasodilation via secretion of nitric oxide, and vascular leukocyte adhesion and inflammation via expression and secretion of endothelin 1. Also, GIP seems to regulate circulating lipids via effects on adipose tissue uptake and metabolism of lipids. Lastly, we discuss how dysmetabolic conditions such as obesity and type 2 diabetes may shift the actions of GIP in an atherogenic direction, and we provide a perspective on the therapeutic potential of GIP receptor agonism and antagonism in cardiovascular diseases. We conclude that GIP actions may have implications for the development of cardiovascular disease, but also that the potential of GIP-based drugs for the treatment of cardiovascular disease currently is uncertain.

Infusion of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) suppresses the bone resorption marker carboxy-terminal type 1 collagen crosslinks (CTX). Using separate and combined infusions of the selective GIP receptor (GIPR) antagonist, GIP(3-30)NH

Background Maternal exposure to methotrexate (MTX) during pregnancy is known to be teratogenic, but less is known about the risk due to paternal MTX exposure. Because of a theoretical teratogenic risk from paternal exposure, treatment recommendations advocate that men should discontinue MTX three months before conception and continue discontinuation during the partners pregnancy. This may lead to suboptimal adherence to treatment, fear among the future parents and pregnancy termination. Objectives The aim was to systematically review and meta-analyze the collective data on paternal MTX exposure and the risk of congenital malformations. Methods We performed a systematic search in the databases PubMed, Embase, Cochrane Central, and Cinahl on March 1, 2018. We included studies with an English abstract that assessed major or all (both major and minor) malformations following any paternal exposure to MTX. Studies that included a control group were included in the meta-analysis. No time restriction was applied. Review Manager Version 5.3 was used for the meta-analysis. Results We identified 36 studies assessing the risk of congenital malformations following paternal exposure to MTX of which 20 contained original data. Five studies met the inclusion criteria for the meta-analysis: Three studies from Denmark had a major overlap in study populations, one study from Norway, and one German study. All studies were cohort studies using national registries except the German that used structured interviews and phone interviews. Because of the overlapping Danish studies, only the largest Danish study for each of the outcomes were included. We included a total of 265 fathers exposed to MTX and 1,004,834 controls in the meta-analysis investigating risk of major congenital malformations. Among the offspring of the MTX-exposed 7 (2.64%) had a major malformation compared to 33,816 (3.37%) among the unexposed. Pooled odds ratios were 1.02 (95% confidence interval [CI] 0.48-2.20) for major malformations and 1.02 (CI 0.62-1.66) for all malformations. Conclusion(s) In this systematic review and meta-analysis, we found no association between preconceptional paternal MTX use and major or all congenital malformations. The current recommendations to avoid paternal MTX use before conception do not appear to be supported by evidence and paternal treatment with MTX could be continued when planning a pregnancy. Disclosure of Interests Thomas Bo Jensen: None declared, Mikkel Bring Christensen: None declared, Nicole Tsao: None declared, Seoyoung Kim Grant/research support from: Pfizer, Bristol-Myers Squibb, Roche/Genentech and AbbVie., Jon Trrup Andersen: None declared

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is released from the small intestine following meal ingestion and potentiates glucose-stimulated insulin secretion. Exogenous GIP has a poor insulinotropic effect in patients with type 2 diabetes (T2D). We investigated postprandial effects of endogenous GIP in patients with T2D using the GIP receptor antagonist, GIP(3-30)NH2. In a randomized, double-blinded, placebo-controlled, cross-over study, 10 patients with T2D (mean±SD; HbA1c 6.9±3.2%; BMI 32.5±4.8 kg/m2) received 250-minute infusions of GIP(3-30)NH2 (1,200 pmol/kg/min) or placebo (saline) during two separate standardized liquid meal tests. Compared with placebo, GIP(3-30)NH2 infusion caused lower postprandial insulin (Δ%±SD; -19±15%, P=0.010) and C-peptide (-14±21%, P=0.021) responses (area under the curve) but had no effect on plasma glucagon (P=0.580) or glucose excursions (P=0.692). Postprandial inhibition of bone resorption (assessed by carboxy-terminal collagen crosslinks) was ∼50% lower during GIP(3-30)NH2 infusion compared with placebo (P=0.005; Figure 1). In conclusion, endogenous GIP slightly reduced postprandial insulin secretion with no effect on postprandial glucagon or glucose concentrations in patients with T2D. In contrast, endogenous GIP was a major determinant of postprandial suppression of bone resorption in these patients. Disclosure S. Stensen: None. L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. L.S. Krogh: None. A.H. Sparre-Ulrich: Other Relationship; Self; Antag Therapeutics. K. Skov-Jeppesen: None. M. Jensen: Employee; Self; Antag Therapeutics. B. Hartmann: None. T. Vilsbøll: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. M.M. Rosenkilde: Consultant; Self; Antag Therapeutics. M.B. Christensen: None. F.K. Knop: Advisory Panel; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk A/S, Sanofi. Consultant; Self; Amgen Inc., Carmot Therapeutics, Novo Nordisk A/S. Research Support; Self; AstraZeneca, Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, MedImmune, Merck Sharp & Dohme Corp., Mundipharma, Norgine, Novo Nordisk A/S. Funding Novo Nordisk Foundation; European Foundation for the Study of Diabetes

Albiglutide is a long-acting, glucagon-like peptide-1 receptor agonist for subcutaneous administration with a recommended dose of 30-50 mg once weekly. The aim of this article is to outline the pharmacokinetic and pharmacodynamic properties of albiglutide including the clinical efficacy and safety data underlying the approval of albiglutide for the treatment of type 2 diabetes mellitus in both Europe and USA. Albiglutide is cleared from the circulation (by a mechanism partially dependent on renal function) with an elimination half-life of 5 days, allowing once-weekly administration. In the clinical trial program called HARMONY, albiglutide demonstrated placebo-corrected reductions in glycosylated hemoglobin of 0.8-1.0%. In addition, reductions in fasting plasma glucose in the range of 1.3-2.4 mmol/L compared with placebo were reported. Albiglutide caused weight reductions at a level comparable to placebo in the HARMONY trials, possibly related to limited central nervous system penetration of the large albiglutide molecule. Albiglutide demonstrated a generally favorable safety profile, although with a signal of an increased risk of pancreatitis. The well-known adverse events related to glucagon-like peptide-1 receptor activation such as nausea, diarrhea, and vomiting were less frequent with albiglutide compared with another glucagon-like peptide-1 receptor agonist, liraglutide, but slightly more frequent following treatment with albiglutide than with placebo or active comparators from other classes of anti-hyperglycemic drugs. The full risk-benefit profile for albiglutide used in treating type 2 diabetes will not be clear until reporting of the long-term cardiovascular outcome trial (HARMONY Outcome) with planned completion in 2019.

Introduction: Polypharmacy – i.e. the use of multiple medications – is correlated with increases in mortality, adverse drug events, falls, length of hospital stay, and rates of re-admission among the elderly. Polypharmacy has also been linked with non-adherence, and issues concerning the quality of care for this group of patients have been documented. To identify areas relevant to care provision from the perspective of the patients, our objective was to explore medication-related experiences in polypharmacy patients. Methods: We systematically searched PubMed, Embase, and CINAHL up to June 2018 for primary qualitative studies about patient experiences with polypharmacy. Studies were appraised for their methodological quality by applying the Critical Appraisal Skills Programme (CASP) checklist for qualitative research, and data were extracted and synthesized using the meta-aggregation approach. Results: We included 11 qualitative studies, representing 451 patients with polypharmacy and a wide range of chronic conditions. Overall, most items of the CASP checklist were reported in the studies. We extracted 113 findings, we synthesized these into 17 categories, and we developed five interrelated syntheses: 1) Polypharmacy patients are a heterogeneous group in terms of needing and appraising information, 2) The importance of adherence is self-evident but difficult to achieve, 3) Decision-making about medications is complex, 4) Multiple relational factors affect communication between patients and doctors and can prevent patients from disclosing important information, and 5) Polypharmacy affects patients’ lives and self-perception, and the challenges with polypharmacy are not only related to the practical issues of medication-taking. Discussions/Limitations: Through this systematic review, we identified a plethora of medication-related experiences of polypharmacy that demonstrates the complexity and different needs of polypharmacy but also the shared challenges experiences by this patient population. Even though two researchers carried out the screening and sifting of articles, the quality appraisal, and the development of the categories and syntheses, the data extraction was carried out by a single researcher, which could have biased the results. However, we have applied the approach of meta-aggregation, which dictates a transparent reporting of findings, categories, and syntheses, making our analytical process clear to the reader. Conclusion/Lessons learned: Polypharmacy has widespread consequences and poses many challenges for the patient. Challenges include difficulties in organizing medication-intake, navigating the healthcare system, and interacting with healthcare professionals. In addition, polypharmacy has a stigma attached to it and impacts the self-perception of patients. All these factors can potentially affect patients’ ability to follow medication regimens and influence their quality of life. It is central that healthcare professionals consider patient experiences to limit the negative effects on adherence, health, and well-being. Suggestions for future research: Given that most of the included studies were of older patients with polypharmacy (60 years or older), future research should cover the entire age spectrum, as younger people with multimorbidity constitute a high number of the multimorbidity population. Also, research is needed into the effect of stigmatization on medication-related behavior, and ways to reduce the societal stigma of medication- and disease-related factors.

Introduction A solid body of preclinical evidence shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the effects of substance use disorder related behaviors. The mechanisms underlying these effects remain elusive. In the present study, we hypothesized that GLP-1R activation modulates dopaminetransporter (DAT) and thus dopamine (DA) homeostasis in striatum. This was evaluated in three different experiments: two preclinical and one clinical. Methods Rat striatal DA uptake, DA clearance and DAT cell surface expression was assessed following GLP-1 (7-36)-amide exposure in vitro. DA uptake in mice was assesed ex vivo following systemic treatment with the GLP-1R agonist exenatide. In addition, DA uptake was measured in GLP-1R knockout mice and compared with DA-uptake in wild type mice. In healthy humans, changes in DAT availability was assessed during infusion of exenatide measured by single-photon emission computed tomography imaging. Results In rats, GLP-1 (7-36)-amide increased DA uptake, DA clearance and DAT cell surface expression in striatum. In mice, exenatide did not change striatal DA uptake. In GLP-1R knockout mice, DA uptake was similar to what was measured in wildtype mice. In humans, systemic infusion of exenatide did not result in acute changes in striatal DAT availability. Conclusions The GLP-1R agonist-induced modulation of striatal DAT activity in vitro in rats could not be replicated ex vivo in mice and in vivo in humans. Therefore, the underlying mechanisms of action for the GLP-1R agonists-induced efficacy in varios addiction-like behavioural models still remain.

CONTEXT: The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) have been suggested to play a role in bone metabolism. Exogenous administration of GIP inhibits bone resorption, but the effect of GLP-1 is less clear. Furthermore, the combined effect of exogenous GIP and GLP-1 on bone metabolism is unknown. OBJECTIVE: To investigate the effect of separate and combined infusions of the incretin hormones GIP and GLP-1 on bone resorption and formation. DESIGN: Randomized, double-blinded, placebo-controlled, crossover study including five study days. PARTICIPANTS: Seventeen overweight/obese men. INTERVENTIONS: On the first study day, a 50-g oral glucose tolerance test (OGTT) was performed. On the next four study days, isoglycemic IV glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, were performed with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively), or placebo, respectively. PRIMARY OUTCOMES: Changes in bone resorption assessed by measurements of carboxy-terminal type I collagen crosslinks (CTX) and in bone formation as assessed by procollagen type 1 N-terminal propeptide (P1NP) concentrations. RESULTS: During the OGTT, CTX was significantly lowered by 54 ± 13% from baseline (mean ± SD) compared with 28 ± 12% during IIGI + saline (P < 0.0001). During IIGI+GLP-1 and IIGI+GIP, CTX was lowered by 65 ± 16% and 74 ± 9%, respectively, from baseline, whereas IGII+GIP+GLP-1 lowered CTX by 84 ± 4% from baseline. P1NP levels were unaffected by the interventions. CONCLUSIONS: Our data suggest that GLP-1, like GIP, may be involved in regulation of bone resorption and that GIP and GLP-1 together have partially additive inhibitory effects.

Background: Tsetse flies (Glossina sp.) are the sole vectors of human and animal trypanosomiasis throughout sub-Saharan Africa. Tsetse are distinguished from other Diptera by unique adaptations, including lactation and the birthing of live young (obligate viviparity), a vertebrate blood specific diet by both sexes and obligate bacterial symbiosis. This work describes comparative analysis of six Glossina genomes representing three sub-genera: Morsitans (G. morsitans morsitans (G.m. morsitans), G. pallidipes, G. austeni), Palpalis (G. palpalis, G. fuscipes) and Fusca (G. brevipalpis) which represent different habitats, host preferences and vectorial capacity. Results: Genomic analyses validate established evolutionary relationships and sub-genera. Syntenic analysis of Glossina relative to Drosophila melanogaster shows reduced structural conservation across the sex-linked X chromosome. Sex linked scaffolds show increased rates of female specific gene expression and lower evolutionary rates relative to autosome associated genes. Tsetse specific genes are enriched in protease, odorant binding and helicase activities. Lactation associated genes are conserved across all Glossina species while male seminal proteins are rapidly evolving. Olfactory and gustatory genes are reduced across the genus relative to other characterized insects. Vision associated Rhodopsin genes show conservation of motion detection/tracking functions and significant variance in the Rhodopsin detecting colors in the blue wavelength ranges. Conclusions: Expanded genomic discoveries reveal the genetics underlying Glossina biology and provide a rich body of knowledge for basic science and disease control. They also provide insight into the evolutionary biology underlying novel adaptations and are relevant to applied aspects of vector control such as trap design and discovery of novel pest and disease control strategies.

The influence by gut-derived hormones on bone remodelling appears increasingly important as research on the enteroendocrine-osseous axis accelerates. Glucose-dependent insulinotropic polypeptide (GIP) is secreted from the gut and potentiates insulin secretion in a glucose-dependent manner. GIP has, like the two other gut-derived hormones, glucagon-like peptide 1 and glucagon-like peptide 2, been shown to affect bone remodelling as part of the enteroendocrine-osseous axis. Observational studies have shown that a mutation in the GIP receptor causing reduced receptor signalling leads to lower bone mineral density and increased fracture risk. Rodent as well as human studies have shown that GIP causes serum levels of the bone resorption marker carboxy-terminal type 1 collagen crosslinks to decline. GIP may also increase bone formation indicating a potential uncoupling of bone resorption and formation. Here, we review past and recent discoveries elucidating the enteroendocrine-osseous axis with a special focus on GIP.

The gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are known for insulinotropic and glucose-lowering effects. However, their individual roles in postprandial glucose homeostasis are unknown. We infused the GIP receptor antagonist GIP(3-30)NH2 and the GLP-1 receptor antagonist exendin(9-39) during a meal to determine the roles of endogenous GIP and GLP-1 on postprandial glucose metabolism. On four separate days, 12 healthy men (age 19-65 years, BMI 20-25 kg/m2) received a liquid mixed meal test with randomized and double-blinded infusions of GIP(3-30)NH2 (800 pmol/kg/min) + Ex(9-39) (450 pmol/kg/min) (A), GIP(3-30)NH2 (B), Ex(9-39) (C), and saline (D). On Day A, B and C, glucose excursions were significantly increased by 85%, 55% and 15%, respectively, compared to D. Day A and B excursions were significantly higher than C (Figure). Glucagon levels at 60 min differed between Day A and B (11.5±1.2 vs. 7.5±0.6 pmol/l, P=0.01), and Day B and C (11.5±1.2 vs. 12.9±1.5 pmol/l, P=0.008). GLP-1 was higher on Day A (P=0.01) and C (P=0.02) than D. No significant effects on insulin, C-peptide, gastric emptying, or GIP were observed. We conclude that endogenous GIP affects postprandial plasma glucose excursions more pronouncedly than GLP-1, and that both hormones additively contribute to control postprandial glycemia in healthy subjects. Disclosure L.S. Gasbjerg: Stock/Shareholder; Self; Antag Therapeutics. M.M. Helsted: None. A.H. Sparre-Ulrich: Employee; Self; Antag Therapeutics ApS. A.R. Lanng: None. S. Stensen: None. M. Jakobsen: None. B. Hartmann: None. M.B. Christensen: None. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. Board Member; Self; Zealand Pharma A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Self; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Self; Antag Therapeutics. Other Relationship; Spouse/Partner; Antag Therapeutics. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. M.M. Rosenkilde: Other Relationship; Self; Antag Therapeutics. Advisory Panel; Spouse/Partner; Novo Nordisk A/S. Board Member; Spouse/Partner; Zealand Pharma A/S. Speaker's Bureau; Spouse/Partner; Merck Sharp & Dohme Corp., AstraZeneca. Research Support; Spouse/Partner; Danish Diabetes Academy, Novo Nordisk Foundation. Other Relationship; Spouse/Partner; Antag Therapeutics. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

We investigated the effect of mono- and co-administration of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) on bone resorption and formation. Seventeen overweight/obese men without diabetes were included in a randomized, double-blinded, placebo-controlled, cross-over study and subjected to a 50g oral glucose tolerance test (OGTT) and four isoglycemic intravenous glucose infusions (IIGI), mimicking the glucose excursions from the OGTT, with concomitant infusions of GIP (4 pmol/kg/min), GLP-1 (1 pmol/kg/min), GIP+GLP-1 (4 and 1 pmol/kg/min, respectively) or placebo. Bone resorption and formation were assessed by measurements of carboxy-terminal type 1 collagen crosslinks (CTX), and procollagen type 1 N-terminal propeptide (P1NP), respectively. Suppression of CTX is shown in Fig. 1. During OGTT the baseline subtracted area under the curve (bsAUC) was significantly lower than during IIGI+saline infusion (-9,117±566 (mean±SEM) vs. -4,333±583 %×min, P Disclosure N.C. Bergmann: Employee; Self; Zealand Pharma A/S. A.B. Lund: Other Relationship; Self; Novo Nordisk A/S. S.M. Heimbürger: Research Support; Self; Novo Nordisk A/S. L. Jessen: Employee; Self; Zealand Pharma A/S. Stock/Shareholder; Self; Zealand Pharma A/S, Novo Nordisk A/S. M.B. Christensen: None. T. Vilsbøll: Advisory Panel; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Consultant; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Speaker's Bureau; Self; Amgen Inc., Boehringer Ingelheim GmbH, Eli Lilly and Company, AstraZeneca, MSD K.K., Sanofi, Novo Nordisk A/S. Research Support; Self; Eli Lilly and Company, Novo Nordisk A/S. F.K. Knop: Advisory Panel; Self; AstraZeneca. Consultant; Self; AstraZeneca. Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Merck Sharp & Dohme Corp.. Advisory Panel; Self; Novo Nordisk A/S. Consultant; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S. Consultant; Self; Amgen Inc.. Advisory Panel; Self; MedImmune, Sanofi. Consultant; Self; Sanofi. Research Support; Self; Sanofi. Speaker's Bureau; Self; Sanofi.

BackgroundIntravenous lipid emulsion (ILE) is used to treat drug poisonings. The resultant hyperlipemia may affect laboratory tests but the consequences are poorly characterized. In a clinical trial we therefore investigated the effects of ILE on laboratory tests analyzed on common analytical platforms (Roche®cobas 8000 and SYSMEX®flow-cytometry).MethodsTen healthy participants each completed 4 trial days (two with ILE and two with placebo). ILE (5.25 mL/kg) was administered from 12.5 to 30 min from baseline. At 0, 30 and 60 min, blood samples were drawn for measurement of 20 analytes. We investigated the effects of ILE on analyte levels and frequencies of exceedance of predefined analyzer hemolysis (H) or lipemia (L)-index cut-offs and test-specific reference change values (RCVs) on ILE-days. If the results were blocked due to exceedance of index values, we manually extracted the results.ResultsSixteen out of 20 tests were blocked because H- or L-index cut-offs were exceeded on ILE-days. Differences in analyte levels between ILE- and placebo-days above the RCV were observed for aspartate aminotransferase, total calcium, lactate dehydrogenase (LDH), sodium and neutrophils. Mean values outside the normal range after ILE were observed for LDH (219 U/L), sodium (135.3 mmol/L) and total calcium (2.1 mmol/L).ConclusionsILE-infusion caused report failure of nearly all laboratory tests performed on a cobas 8000-platform, but it was possible to manually retrieve the results. For most test results – particularly alkaline phosphatase, bilirubin, phosphate and carbamide – the consequences of ILE were marginal, and the effects of ILE were reduced at the 60-min timepoint.

Glucagon is believed to be a pancreas-specific hormone, and hyperglucagonemia has been shown to contribute significantly to the hyperglycemic state of patients with diabetes. This hyperglucagonemia has been thought to arise from α-cell insensitivity to suppressive effects of glucose and insulin combined with reduced insulin secretion. We hypothesized that postabsorptive hyperglucagonemia represents a gut-dependent phenomenon and subjected 10 totally pancreatectomized patients and 10 healthy control subjects to a 75-g oral glucose tolerance test and a corresponding isoglycemic intravenous glucose infusion. We applied novel analytical methods of plasma glucagon (sandwich ELISA and mass spectrometry–based proteomics) and show that 29–amino acid glucagon circulates in patients without a pancreas and that glucose stimulation of the gastrointestinal tract elicits significant hyperglucagonemia in these patients. These findings emphasize the existence of extrapancreatic glucagon (perhaps originating from the gut) in man and suggest that it may play a role in diabetes secondary to total pancreatectomy.

Introduction: Albiglutide is a once-weekly, glucagon-like peptide-1 receptor agonist approved during 2014 in both the US and Europe for the treatment of adults with type 2 diabetes. The recommended dose is 30 mg with the possibility of uptitration to 50 mg based on individual glycemic response.Areas covered: Here, we outline the pharmacokinetics, pharmacodynamics and clinical efficacy data originating from the Phase I – III studies carried out to obtain market authorization for albiglutide.Expert opinion: The eight Phase III clinical trials have provided evidence that albiglutide in monotherapy and as an add-on to different background therapies confers placebo-corrected reductions in glycemia with changes in glycated hemoglobin of −0.8 to −1.0%. Albiglutide did not cause significant weight loss compared to placebo, but the adverse events profile was favorable with gastrointestinal adverse events occurring only slightly more with albiglutide than placebo. There is no clinical evidence of an effect of albig...

RATIONALE, AIMS, AND OBJECTIVES: Medication-related problems are frequent and can lead to serious adverse events resulting in increased morbidity, mortality, and costs. Medication use in frail older patients is even more complex. The aim of this study was to investigate the effect of a pharmacist-led medicines management model among older patients at admission, during inpatient stay and at discharge on medication-related readmissions.METHOD: A randomized controlled trial conducted at the acute admission unit in a Danish hospital with acutely admitted medical patients, randomized to either a control group or one of two intervention groups. The intervention consisted of pharmacist-led medication review and patient interview upon admission (intervention ED) or pharmacist-led medication review and patient interview upon admission, medication review during inpatient stay, and medication report and patient counselling at discharge (intervention STAY).RESULTS: In total, 600 patients were included. The pharmacist identified 920 medication-related problems with 57% of the recommendations accepted by the physician. After 30 days, 25 patients had a medication-related readmission, with no statistical significant difference between the groups on either primary or secondary outcomes.CONCLUSIONS: This study showed that a clinical pharmacist can be used to identify and solve medication-related problems, but this study did not find any effect on the selected outcomes. The frequency of medication-related readmissions was low, leaving little room for improvement. Future research should consider other study designs or outcome measures.

Context Glucagon's effects on hemodynamic parameters, most notably heart rate and cardiac contractility, are often overlooked. The glucagon receptor is a central target in novel and anticipated type 2 diabetes therapies, and hemodynamic consequences of glucagon signaling have therefore become increasingly important. In this review, we summarize and evaluate published studies on glucagon pharmacology with a focus on clinical hemodynamic effects in humans. Evidence Acquisition PubMed, Embase, and the Cochrane Library were searched for clinical studies concerning hemodynamic effects of glucagon (no year restriction). Papers reporting effects of a defined glucagon dose on any hemodynamic parameter were included. Reference searches were conducted in retrieved articles. Evidence Synthesis Hemodynamic effects of glucagon have been investigated mainly in cohort studies of patients suffering from heart failure receiving large glucagon bolus injections. The identified studies had shortcomings related to restricted patient groups, lack of a control group, randomization, or blinding. We identified no properly conducted randomized clinical trials. The majority of human studies report stimulating effects of pharmacological glucagon doses on heart rate, cardiac contractility, and blood pressure. The effects were characterized by short duration, interindividual variation, and rapid desensitization. Some studies reported no measurable effects of glucagon. Conclusions The level of evidence regarding hemodynamic effects of glucagon is low, and observations in published studies are inconsistent. Actual effects, interindividual variation, dose-response relationships, and possible long-term effects of supraphysiological glucagon levels warrant further investigation.

Glucose-dependent insulinotropic polypeptide (GIP) is an intestinal hormone with a broad range of physiological actions. In the postprandial state, the hormone stimulates insulin secretion and during eu- and hypoglycemia, it stimulates glucagon secretion. In addition, GIP increases triacylglycerol (TAG) uptake in adipose tissue and decreases bone resorption. However, the importance of these actions in humans are not clearly understood as a specific GIP receptor (GIPR) antagonist - an essential tool to study GIP physiology - has been missing. Several different GIPR antagonists have been identified comprising both peptides, vaccines against GIP, GIP antibodies or antibodies against the GIPR. However, most of these have only been tested in rodents. In vitro, N- and C-terminally truncated GIP variants are potent and efficacious GIPR antagonists. Recently, GIP(3-30)NH2, a naturally occurring peptide, was shown to block the GIPR in humans and decrease GIP-induced insulin secretion as well as adipose tissue blood flow and TAG uptake. So far, there are no studies with a GIPR antagonist in patients with type 2 diabetes (T2D), but because the elevations in fasting plasma glucagon and paradoxical postprandial glucagon excursions, seen in patients with T2D, are aggravated by GIP, a GIPR antagonist could partly alleviate this and possibly improve the fasting and postprandial glycemia. Since the majority of patients with T2D are overweight, inhibition of GIP-induced fat deposition may be beneficial as well. Here we summarize the studies of GIPR antagonists and discuss the therapeutic potential of the GIP system in humans.

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone secreted postprandially from enteroendocrine K cells, but despite therapeutically interesting effects, GIP physiology in humans remains incompletely understood. Progress in this field could be facilitated by a suitable GIP receptor antagonist. For the first time in humans, we investigated the antagonistic properties of the naturally occurring GIP(3-30)NHIn transiently transfected COS-7 cells, GIP(3-30)NHGIP(3-30)NHWe conclude that GIP(3-30)NHClinicalTrials.gov registration no. NCT02747472.The study was funded by Gangstedfonden, the European Foundation for the Study of Diabetes, and Aase og Ejnar Danielsens fond.

The aim of this study was to characterize the clinical signs and symptoms of exposures to aripiprazole overdoses. We retrospectively identified all aripiprazole exposures reported to the Danish Poison Information Centre (DPIC) from June 2007 to May 2015. Information concerning demographics, ingested dose and symptoms was extracted from the DPIC database and medical records. Information on death and admission to hospital was obtained from Danish national registers. We analysed 239 cases, 86 concerning single-drug exposures to aripiprazole, and 153 cases where aripiprazole had been taken with at least one other substance (mixed-drug). The median ingested aripiprazole dose was 105 mg (IQR: 50-1680 mg) in the single-drug exposure group and 120 mg (IQR: 60-225 mg) in the mixed-drug exposure group. The most commonly reported symptom was light sedation, reported in 63% of the single-drug group and 50% of the mixed-drug exposure group. There were no malignant arrhythmias or ECG abnormalities after single-drug exposures. No deaths were recorded in relation to the intake. We found a long-term mortality rate of 13 deaths per 1000 person-years (95% CI: 7; 23 per 1000 person-years), which is significantly higher than in an age- and gender-matched background population. In conclusion, we found that aripiprazole overdoses had few and mild symptoms predominantly related to the sedative properties. We detected a benign cardiovascular safety profile and no new safety concerns. Our findings may support an increased threshold of 300 mg for hospital admission after a single-drug exposure with aripiprazole and symptoms not worse than light sedation.