Effect of imipramine on urethral opening pressure: A randomized, double-blind, placebo-controlled crossover study in healthy women.

AIMS: In two open-label trials, imipramine alleviated symptoms in patients with stress urinary incontinence and is therefore used off-label for this indication. However, it has never been confirmed that imipramine increases urethral pressure in a placebo-controlled setting. The purpose of this study was to investigate whether imipramine increases the opening urethral pressure compared to placebo in healthy women using urethral pressure reflectometry. METHODS: A randomized, double-blind, placebo-controlled, crossover study in 16 healthy women. Opening urethral pressure was measured predose and 1 hour after a single dose of 50 mg imipramine or placebo. The washout period was minimum of 1 week. The study was approved by the local ethics committee, conducted according to the Good Clinical Practice guidelines, and registered on ClinicalTrials.gov and EudraCT before recruitment of subjects. Funding was provided by the clinical department. RESULTS: There were no dropouts and no serious adverse events. There were 13 adverse drug reactions related to imipramine in seven subjects, one adverse event related to placebo, and two adverse events related to the measurements with urethral pressure reflectometry. Imipramine compared to placebo increased opening urethral pressure in the resting condition with 6.5 cmH2 O (95% confidence interval [CI]: -0.5, 13.5), P = 0.07, and in the squeeze condition with 7.9 cmH 2 O (95% CI: -0.3, 16.1), P = 0.06. CONCLUSIONS: In conclusion, the increase in opening urethral pressure after imipramine treatment compared to placebo was neither statistically significant nor clinically relevant, and we do therefore not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

Insulin secretagogues for prevention or delay of type 2 diabetes mellitus and its associated complications in persons at increased risk for the development of type 2 diabetes mellitus.

BACKGROUND: The projected rise in the incidence of type 2 diabetes mellitus (T2DM) could develop into a substantial health problem worldwide. Whether insulin secretagogues (sulphonylureas and meglitinide analogues) are able to prevent or delay T2DM and its associated complications in people at risk for the development of T2DM is unknown. OBJECTIVES: To assess the effects of insulin secretagogues on the prevention or delay of T2DM and its associated complications in people with impaired glucose tolerance, impaired fasting blood glucose, moderately elevated glycosylated haemoglobin A1c (HbA1c) or any combination of these. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of systematic reviews, articles and health technology assessment reports. We asked investigators of the included trials for information about additional trials. The date of the last search of all databases was April 2016. SELECTION CRITERIA: We included randomised controlled trials (RCTs) with a duration of 12 weeks or more comparing insulin secretagogues with any pharmacological glucose-lowering intervention, behaviour-changing intervention, placebo or no intervention in people with impaired fasting glucose, impaired glucose tolerance, moderately elevated HbA1c or combinations of these. DATA COLLECTION AND ANALYSIS: Two review authors read all abstracts and full-text articles/records, assessed quality and extracted outcome data independently. One review author extracted data which were checked by a second review author. We resolved discrepancies by consensus or the involvement of a third review author. For meta-analyses we used a random-effects model with investigation of risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes, using 95% confidence intervals (CIs) for effect estimates. We carried out trial sequential analyses (TSAs) for all outcomes that could be meta-analysed. We assessed the overall quality of the evidence by using the GRADE instrument. MAIN RESULTS: We included six RCTs with 10,018 participants; 4791 participants with data on allocation to intervention groups were randomised to a second- or third-generation sulphonylurea or a meglitinide analogue as monotherapy and 29 participants were randomised to a second-generation sulphonylurea plus metformin. Three trials investigated a second-generation sulphonylurea, two trials investigated a third-generation sulphonylurea and one trial a meglitinide analogue. A total of 4873 participants with data on allocation to control groups were randomised to a comparator group; 4820 participants were randomised to placebo, 23 to diet and exercise, and 30 participants to metformin monotherapy. One RCT of nateglinide contributed 95% of all participants. The duration of the intervention varied from six months to five years. We judged none of the included trials as at low risk of bias for all 'Risk of bias' domains.All-cause and cardiovascular mortality following sulphonylurea (glimepiride) treatment were rarely observed (very low-quality evidence). The RR for incidence of T2DM comparing glimepiride monotherapy with placebo was 0.75; 95% CI 0.54 to 1.04; P = 0.08; 2 trials; 307 participants; very low-quality evidence. One of the trials reporting on the incidence of T2DM did not define the diagnostic criteria used. The other trial diagnosed T2DM as two consecutive fasting blood glucose values ≥ 6.1 mmol/L. TSA showed that only 4.5% of the diversity-adjusted required information size was accrued so far. No trial reported data on serious adverse events, non-fatal myocardial infarction (MI), non-fatal stroke, congestive heart failure (HF), health-related quality of life or socioeconomic effects.One trial with a follow-up of five years compared a meglitinide analogue (nateglinide) with placebo. A total of 310/4645 (6.7%) participants allocated to nateglinide died compared with 312/4661 (6.7%) participants allocated to placebo (hazard ratio (HR) 1.00; 95% CI 0.85 to 1.17; P = 0.98; moderate-quality evidence). The two main criteria for diagnosing T2DM were a fasting plasma glucose level ≥ 7.0 mmol/L or a 2-hour post challenge glucose ≥ 11.1 mmol/L. T2DM developed in 1674/4645 (36.0%) participants in the nateglinide group and in 1580/4661 (33.9%) in the placebo group (HR 1.07; 95% CI 1.00 to 1.15; P = 0.05; moderate-quality evidence). One or more serious adverse event was reported in 2066/4602 (44.9%) participants allocated to nateglinide compared with 2089/4599 (45.6%) participants allocated to placebo. A total of 126/4645 (2.7%) participants allocated to nateglinide died because of cardiovascular disease compared with 118/4661 (2.5%) participants allocated to placebo (HR 1.07; 95% CI 0.83 to 1.38; P = 0.60; moderate-quality evidence). Comparing participants receiving nateglinide with those receiving placebo for the outcomes MI, non-fatal stroke and HF gave the following event rates: MI 116/4645 (2.5%) versus 122/4661 (2.6%), stroke 100/4645 (2.2%) versus 110/4661 (2.4%) and numbers hospitalised for HF 85/4645 (1.8%) versus 100/4661 (2.1%) - (HR 0.85; 95% CI 0.64 to 1.14; P = 0.27). The quality of the evidence was moderate for all these outcomes. Health-related quality of life or socioeconomic effects were not reported. AUTHORS' CONCLUSIONS: There is insufficient evidence to demonstrate whether insulin secretagogues compared mainly with placebo reduce the risk of developing T2DM and its associated complications in people at increased risk for the development of T2DM. Most trials did not investigate patient-important outcomes.

A First-in-Human Randomized Clinical Study Investigating the Safety and Tolerability of Stabilized Hypochlorous Acid in Patients with Chronic Leg Ulcers.

Objective: Biofilm infections in chronic wounds are common and pose a significant clinical challenge. This challenge was addressed by developing the SoftOx Biofilm Eradicator (SBE) composed of hypochlorous acid (HOCl) and acetic acid with strong broad-spectrum antimicrobial activity. Approach: First-in-human study investigating the safety and tolerability as primary endpoints and wound size effect and antimicrobial efficacy as secondary endpoints of SBE treatment in chronic leg wound patients. The study was divided into two as follows: a randomized, double-blinded, Single Ascending Dose (SAD) phase (n = 16 SBE; n = 4 placebo), where patients were treated with SBE or saline (placebo) only once, followed by an open-label, Multiple Ascending Dose (MAD) phase (n = 8), where patients were treated with SBE once daily or twice daily over five days. Reporting is according to CONSORT guidelines. Results: SBE was safe and well-tolerated in chronic leg wound patients. There were no significant differences in pain during and after treatment with SBE or the placebo. The SBE treatment reduced bioburden in wounds compared to baseline, with 98% and 49% median reduction after SBE or placebo treatment, respectively. A dose-dependent trend in absolute wound size reduction was observed in the MAD groups with a median (min, max) change of -2.99 (-14.25, -1.5) cm2 in the once-daily and -10.48 (-17.95, -0.38) cm2 in the twice-daily group, respectively. Innovation and Conclusion: This study demonstrated the safe use of HOCl-based SBE in chronic leg wounds with promising trends of immediate antimicrobial action and beneficial effect on wound healing.

The Body weight Reducing Effects of Tirzepatide in People with and without Type 2 Diabetes: A Review on Efficacy and Adverse Effects.

Obesity is becoming more frequent and has several negative health impacts. Recent advances in weight management strategies have primarily resided in pharmaceutical treatments, and the glucagon-like peptide-1 (GLP-1) receptor agonists have shown great potential in terms of body weight reduction in addition to improving glycemic control in patients with type 2 diabetes (T2D). Recently, the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has been developed. Tirzepatide has shown strong effects on glycated hemoglobin (HbA1C) levels in several clinical trials including participants with T2D (SURPASS program). In addition to its lowering effect on HbA1C, tirzepatide leads to substantial reductions in body weight, and a series of clinical trials (SURMOUNT program) have investigated the effects on body weight as the primary outcome. In these two trial programs, tirzepatide in doses of 5 mg to 15 mg administered subcutaneously once weekly resulted in body weight reduction of up to 15% in participants with T2D and up to 21% in participants without T2D, despite comparable baseline bodyweight. Across the two trial programs, adverse effects were mainly gastrointestinal (nausea, diarrhea, and vomiting) occurring with similar incidences of vomiting and lower incidences of diarrhea and nausea in trial participants with T2D compared to trials participants without T2D. Overall, discontinuation due to adverse events occurred in 3-7% of participants with no major differences between individuals with and without T2D. The higher weight-reducing efficacy of tirzepatide in trial participants without T2D is currently unexplained and may be partly reflected in dissimilarities in frequencies of gastrointestinal adverse events. The weight reducing effects of tirzepatide hold great promise for weight management in obese patients regardless of the presence of T2D.

Octreotide improves human lymphatic fluid transport a translational trial.

OBJECTIVES: Chylothorax is a complex condition and many different pharmacological agents have been tried as treatment. Octreotide is used off-label to treat chylothorax, but the efficacy of octreotide remains unclear. A decrease in lymph production is suggested as the mechanism. In this cross-over study, we explore the direct effect of octreotide on human lymphatic drainage. METHODS: Pre-clinical: the effect of octreotide on force generation was assessed during acute and prolonged drug incubation on human lymphatic vessels mounted in a myograph. Clinical: in a double-blinded, randomized, cross-over trial including 16 healthy adults, we administered either octreotide or saline as an intravenous infusion for 2.5 h. Near-infrared fluorescence imaging was used to examine spontaneous lymphatic contractions and lymph pressure in peripheral lymphatic vessels and plethysmography was performed to assess the capillary filtration rate, capillary filtration coefficient and isovolumetric pressures of the lower leg. RESULTS: Pre-clinical: human thoracic duct (n = 12) contraction rate was concentration-dependently stimulated by octreotide with a maximum effect at 10 and 100 nmol/l in the myograph chamber. Clinical: spontaneous lymphatic contractions and lymph pressure evaluated by near-infrared fluorescence did not differ between octreotide or placebo (P = 0.36). Plethysmography revealed similar capillary filtration coefficients (P = 0.057), but almost a doubling of the isovolumetric pressures (P = 0.005) during octreotide infusion. CONCLUSIONS: Octreotide stimulated lymphatic contractility in the pre-clinical setup but did not affect the spontaneous lymphatic contractions or lymph pressure in healthy individuals. Plethysmography revealed a doubling in the isovolumetric pressure. These results suggest that octreotide increases lymphatic drainage capacity in situations with high lymphatic afterload.

Sulphonylurea monotherapy for patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. Whether sulphonylureas show better, equal or worse therapeutic effects in comparison with other antidiabetic interventions for patients with T2DM remains controversial. OBJECTIVES: To assess the effects of sulphonylurea monotherapy versus placebo, no intervention or other antidiabetic interventions for patients with T2DM. SEARCH METHODS: We searched publications in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS and CINAHL (all until August 2011) to obtain trials fulfilling the inclusion criteria for our review. SELECTION CRITERIA: We included clinical trials that randomised patients 18 years old or more with T2DM to sulphonylurea monotherapy with a duration of 24 weeks or more. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias. The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes were other patient-important outcomes and metabolic variables. Where possible, we used risk ratios (RR) with 95% confidence intervals (95% CI) to analyse the treatment effect of dichotomous outcomes. We used mean differences with 95% CI to analyse the treatment effect of continuous outcomes. We evaluated the risk of bias. We conducted trial sequential analyses to assess whether firm evidence could be established for a 10% relative risk reduction (RRR) between intervention groups. MAIN RESULTS: We included 72 randomised controlled trials (RCTs) with 22,589 participants; 9707 participants randomised to sulphonylureas versus 12,805 participants randomised to control interventions. The duration of the interventions varied from 24 weeks to 10.7 years. We judged none of the included trials as low risk of bias for all bias domains. Patient-important outcomes were seldom reported.First-generation sulphonylureas (FGS) versus placebo or insulin did not show statistical significance for all-cause mortality (versus placebo: RR 1.46, 95% CI 0.87 to 2.45; P = 0.15; 2 trials; 553 participants; high risk of bias (HRB); versus insulin: RR 1.18, 95% CI 0.88 to 1.59; P = 0.26; 2 trials; 1944 participants; HRB). FGS versus placebo showed statistical significance for cardiovascular mortality in favour of placebo (RR 2.63, 95% CI 1.32 to 5.22; P = 0.006; 2 trials; 553 participants; HRB). FGS versus insulin did not show statistical significance for cardiovascular mortality (RR 1.36, 95% CI 0.68 to 2.71; P = 0.39; 2 trials; 1944 participants; HRB). FGS versus alpha-glucosidase inhibitors showed statistical significance in favour of FGS for adverse events (RR 0.63, 95% CI 0.52 to 0.76; P = 0.01; 2 trials; 246 participants; HRB) and for drop-outs due to adverse events (RR 0.28, 95% CI 0.12 to 0.67; P = 0.004; 2 trials; 246 participants; HRB).Second-generation sulphonylureas (SGS) versus metformin (RR 0.98, 95% CI 0.61 to 1.58; P = 0.68; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 0.92, 95% CI 0.60 to 1.41; P = 0.70; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.79 to 1.18; P = 0.72; 4 trials; 1642 participants; HRB), meglitinides (RR 1.44, 95% CI 0.47 to 4.42; P = 0.52; 7 trials; 2038 participants; HRB), or incretin-based interventions (RR 1.39, 95% CI 0.52 to 3.68; P = 0.51; 2 trials; 1503 participants; HRB) showed no statistically significant effects regarding all-cause mortality in a random-effects model. SGS versus metformin (RR 1.47; 95% CI 0.54 to 4.01; P = 0.45; 6 trials; 3528 participants; HRB), thiazolidinediones (RR 1.30, 95% CI 0.55 to 3.07; P = 0.55; 7 trials; 4955 participants; HRB), insulin (RR 0.96, 95% CI 0.73 to 1.28; P = 0.80; 4 trials; 1642 participants; HRB) or meglitinide (RR 0.97, 95% CI 0.27 to 3.53; P = 0.97; 7 trials, 2038 participants, HRB) showed no statistically significant effects regarding cardiovascular mortality. Mortality data for the SGS versus placebo were sparse. SGS versus thiazolidinediones and meglitinides did not show statistically significant differences for a composite of non-fatal macrovascular outcomes. SGS versus metformin showed statistical significance in favour of SGS for a composite of non-fatal macrovascular outcomes (RR 0.67, 95% CI 0.48 to 0.93; P = 0.02; 3018 participants; 3 trials; HRB). The definition of non-fatal macrovascular outcomes varied among the trials. SGS versus metformin, thiazolidinediones and meglitinides showed no statistical significance for non-fatal myocardial infarction. No meta-analyses could be performed for microvascular outcomes. SGS versus placebo, metformin, thiazolidinediones, alpha-glucosidase inhibitors or meglitinides showed no statistical significance for adverse events. SGS versus alpha-glucosidase inhibitors showed statistical significance in favour of SGS for drop-outs due to adverse events (RR 0.48, 95% CI 0.24 to 0.96; P = 0.04; 9 trials; 870 participants; HRB). SGS versus meglitinides showed no statistical significance for the risk of severe hypoglycaemia. SGS versus metformin and thiazolidinediones showed statistical significance in favour of metformin (RR 5.64, 95% CI 1.22 to 26.00; P = 0.03; 4 trials; 3637 participants; HRB) and thiazolidinediones (RR 6.11, 95% CI 1.57 to 23.79; P = 0.009; 6 trials; 5660 participants; HRB) for severe hypoglycaemia.Third-generation sulphonylureas (TGS) could not be included in any meta-analysis of all-cause mortality, cardiovascular mortality or non-fatal macro- or microvascular outcomes. TGS versus thiazolidinediones showed statistical significance regarding adverse events in favour of TGS (RR 0.88, 95% CI 0.78 to 0.99; P = 0.03; 3 trials; 510 participants; HRB). TGS versus thiazolidinediones did not show any statistical significance for drop-outs due to adverse events. TGS versus other comparators could not be performed due to lack of data.For the comparison of SGS versus FGS no meta-analyses of all-cause mortality, cardiovascular mortality, non-fatal macro- or microvascular outcomes, or adverse events could be performed.Health-related quality of life and costs of intervention could not be meta-analysed due to lack of data.In trial sequential analysis, none of the analyses of mortality outcomes, vascular outcomes or severe hypoglycaemia met the criteria for firm evidence of a RRR of 10% between interventions. AUTHORS' CONCLUSIONS: There is insufficient evidence from RCTs to support the decision as to whether to initiate sulphonylurea monotherapy. Data on patient-important outcomes are lacking. Therefore, large-scale and long-term randomised clinical trials with low risk of bias, focusing on patient-important outcomes are required.

Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial.

BACKGROUND: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS). METHOD: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry. RESULTS: Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (-169, -28; p = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. CONCLUSION: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

Protocol for a randomised, double-blinded, placebo-controlled, double-dummy 6-week clinical trial comparing the treatment effects of the glucagon-like peptide 1 receptor agonist liraglutide versus the bile acid sequestrant colesevelam on bile acid malabsorption.

INTRODUCTION: Bile acid malabsorption (BAM) is a socially debilitating disease characterised by high stool frequency and urgency caused by a spillover of bile acids into the colon. Bile acid sequestrants (BASs) have limited therapeutic effect but represent the only available treatment option. Cases reporting total remission of BAM-related symptoms after treatment with liraglutide, a glucagon-like peptide 1 analogue, prompted us to design a clinical trial investigating the therapeutic effect of this compound in patients with BAM. METHODS AND ANALYSIS: Fifty adult individuals with moderate or severe BAM as assessed by the 75selenium-homotaurocholic acid test (SeHCAT) will, after a run-in period of 10 days with no BAM treatment, be randomised to either treatment with the BAS colesevelam or liraglutide (double blinded) for 6 weeks. Daily symptom diaries and questionnaires will be filled in. Blood and faecal samples will be collected and SeHCAT will be performed at baseline, after week 3 and at end of trial. The primary endpoint is change in daily stool frequency. Secondary endpoints include changes from baseline in questionnaires, biochemistry, SeHCAT and faecal bile acid content and microbial composition. ETHICS AND DISSEMINATION: The study complies with Danish and European Union legislation and is approved by the Danish Medicines Agency, the Regional Scientific Ethics Committee of the Capital Region of Denmark and the Danish Data Protection Agency. The study is monitored by the Capital Region of Denmark's good clinical practice unit. All results, positive, negative and inconclusive, will be disseminated at national and/or international scientific meetings and in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: EudraCA: 2018-003575-34; Pre-results.

What is on the horizon for type 2 diabetes pharmacotherapy? - An overview of the antidiabetic drug development pipeline.

INTRODUCTION: 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. AREAS COVERED: 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. EXPERT OPINION: 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.

Cholecystokinin-Induced Gallbladder Emptying and Metformin Elicit Additive Glucagon-Like Peptide-1 Responses.

CONTEXT: Bile acids have been suggested to mediate glucagon-like peptide-1 (GLP-1) secretion. Metformin, too, has been shown to increase GLP-1 levels. The effect of gallbladder emptying, metformin, or a combination has, however, never been studied. OBJECTIVE: We hypothesized that cholecystokinin (CCK)-8-induced gallbladder emptying stimulates human GLP-1 secretion and that metformin would potentiate this effect. DESIGN: A double-blinded, randomized study. SETTING: The study was conducted at a specialized research unit. PARTICIPANTS: Ten healthy male subjects with no family history of diabetes (age, 22 [range, 20-32] years; body mass index, 21.7 [19.3-24.2] kg/m(2); fasting plasma glucose, 4.9 [4.7-5.3] mm; and glycosylated hemoglobin A1c, 5.1 [4.4-5.8] %). INTERVENTION: On 4 separate days, the subjects received metformin or placebo and a concomitant 60-minute intravenous infusion of saline or CCK. Blood was sampled for 4 hours, and gallbladder volume was measured by ultrasound. MAIN OUTCOME MEASURES: Plasma levels of GLP-1. RESULTS: CCK-induced gallbladder emptying and metformin alone (no observed effect on gallbladder emptying) both elicited significant and additive GLP-1 responses. Metformin alone or combined with gallbladder emptying elicited a significant peptide YY response. CCK-induced gallbladder emptying resulted in a short-lasting glucose-dependent insulinotropic polypeptide response independent of metformin. No effects were seen on plasma glucose, insulin, C-peptide, or gastrin. CONCLUSIONS: CCK-induced gallbladder emptying in healthy subjects elicits significant GLP-1 secretion, which can be potentiated by metformin.

Effect of bile acid sequestrants on glycaemic control: protocol for a systematic review with meta-analysis of randomised controlled trials.

INTRODUCTION: In addition to the lipid-lowering effect of bile acid sequestrants (BASs), they also lower blood glucose and, therefore, could be beneficial in the treatment of patients with type 2 diabetes mellitus (T2DM). Three oral BASs are approved by the US Food and Drug Administration (FDA) for the treatment of hypercholesterolaemia: colestipol, cholestyramine and colesevelam. The BAS colestimide/colestilan is used in Japan. Colesevelam was recently approved by the FDA for the treatment of T2DM. We plan to provide a systematic review with meta-analysis of the glucose-lowering effect of BASs with the aim to evaluate their potential as glucose-lowering agents in patients with T2DM. METHODS AND ANALYSIS: In accordance with the preferred reporting items for systematic reviews and meta-analyses statement, a systematic review with meta-analysis of randomised clinical trials of BASs (vs placebo, oral antidiabetes drugs or insulin), reporting measures of glycaemic control in adult patients with T2DM, will be performed. Change in glycated haemoglobin constitutes the primary endpoint, and secondary endpoints include changes in fasting plasma glucose, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglycerides, body weight and body mass index and adverse events. Electronic searches will be performed in The Cochrane Library, MEDLINE and EMBASE, along with manual searches in the reference lists of relevant papers. The analyses will be performed based on individual patient data and summarised data. The primary meta-analysis will be performed using random effects models owing to expected intertrial heterogeneity. Dichotomous data will be analysed using risk difference and continuous data using weighted mean differences, both with 95% CIs. ETHICS AND DISSEMINATION: The study will evaluate the potential of BASs as glucose-lowering agents and possibly contribute to the clinical management of patients with T2DM. RESULTS: The study will be disseminated by peer-review publication and conference presentation. PROTOCOL REGISTRATION: PROSPERO CRD42012002552.