Colesevelam has no acute effect on postprandial GLP-1 levels but abolishes gallbladder refilling.

OBJECTIVE: Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility. METHODS: In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline. RESULTS: Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043). CONCLUSION: Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.

A randomized double-blind trial of clonidine and colesevelam for women with fecal incontinence.

BACKGROUND: Diarrhea and rectal urgency are risk factors for fecal incontinence (FI). The effectiveness of bowel modifiers for improving FI is unclear. METHODS: In this double-blind, parallel-group, randomized trial, women with urge FI were randomly assigned in a 1:1 ratio to a combination of oral clonidine (0.1 mg twice daily) with colesevelam (1875 mg twice daily) or two inert tablets for 4 weeks. The primary outcome was a ≥50% decrease in number of weekly FI episodes. KEY RESULTS: Fifty-six participants were randomly assigned to clonidine-colesevelam (n = 24) or placebo (n = 32); 51 (91%) completed 4 weeks of treatment. At baseline, participants had a mean (SD) of 7.5 (8.2) FI episodes weekly. The primary outcome was met for 13 of 24 participants (54%) treated with clonidine-colesevelam versus 17 of 32 (53%) treated with placebo (p = 0.85). The Bristol stool form score decreased significantly, reflecting more formed stools with clonidine-colesevelam treatment (mean [SD], 4.5 [1.5] to 3.2 [1.5]; p = 0.02) but not with placebo (4.2 [1.9] to 4.1 [1.9]; p = 0.47). The proportion of FI episodes for semiformed stools decreased significantly from a mean (SD) of 76% (8%) to 61% (10%) in the clonidine-colesevelam group (p = 0.007) but not the placebo group (61% [8%] to 67% [8%]; p = 0.76). However, these treatment effects did not differ significantly between groups. Overall, clonidine-colesevelam was well tolerated. CONCLUSIONS AND INFERENCES: Compared with placebo, clonidine-colesevelam did not significantly improve FI despite being associated with more formed stools and fewer FI episodes for semiformed stools.

Efficacy and safety of colesevelam for the treatment of bile acid diarrhoea: a double-blind, randomised, placebo-controlled, phase 4 clinical trial.

BACKGROUND: Bile acid diarrhoea is a common but overlooked cause of chronic watery diarrhoea. Plasma 7α-hydroxy-4-cholesten-3-one (C4) is an alternative to the gold standard tauroselcholic [75Se] acid (SeHCAT) test. Low-certainty evidence supports sequestrant treatment, including colesevelam. We aimed to determine the efficacy and safety of colesevelam in bile acid diarrhoea. METHODS: In this randomised, double-blind, placebo-controlled, investigator-initiated phase 4 trial of the sequestrant colesevelam in bile acid diarrhoea (SINBAD), we enrolled consecutive patients aged 18-79 years without inflammatory bowel disease attending SeHCAT testing for suspected bile acid diarrhoea at four Danish secondary care centres. Participants were randomly allocated 1:1 to receive 12 days of treatment with colesevelam (overencapsulated tablets of 625 mg) or placebo, with the starting dose of two capsules twice daily and titrated to effect during the first 5 days of treatment. A pharmacist independent of the clinical investigators generated a randomisation list on the web page randomization.com using block randomisation (randomisation was not stratified). C4 and SeHCAT diagnostic results were blinded during treatment. We treated all patients with diarrhoea, with a daily mean of 3·0 or more bowel movements or 1·0 or more watery bowel movements (Bristol stool scale type 6 and 7). Remission was defined as the absence of both these criteria during treatment days 6-12. The primary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by C4 concentration greater than 46 ng/mL. A secondary outcome was the intention-to-treat remission rate in bile acid diarrhoea diagnosed by SeHCAT retention of 10% or less. This trial is registered with ClinicalTrials.gov, NCT03876717. FINDINGS: Between Oct 25, 2018, and July 1, 2021, 168 patients were randomly assigned to receive colesevelam (n=84) or placebo (n=84). 41 patients had C4 concentration greater than 46 ng/mL (22 assigned to the colesevelam group and 19 to the placebo group). For the C4-defined primary outcome, 14 (64%) of 22 participants receiving colesevelam versus three (16%) of 19 participants receiving placebo achieved remission (adjusted odds ratio 9·1, 95% CI 1·9-62·8; p=0·011). For the SeHCAT-defined secondary outcome, 75 of the 168 participants had retention of less than 10% (37 assigned to the colesevelam group and 38 assigned to the placebo group); 22 (59%) of 37 participants receiving colesevelam achieved remission versus five (13%) of 38 participants receiving placebo (adjusted odds ratio 11·1, 95% CI 3·4-45·6; p=0·00020). There were no serious adverse events. Common adverse events were transient. For patients receiving colesevelam within the primary outcome population, five had abdominal pain, nine had bloating, and four had nausea. For patients receiving placebo, four had abdominal pain, four had bloating, and one had nausea. No participants with bile acid diarrhoea withdrew due to adverse events. INTERPRETATION: Colesevelam was superior to placebo at inducing remission of bile acid diarrhoea diagnosed with C4 concentration greater than 46 ng/mL. Secondary outcome data suggest similar efficacy treating SeHCAT-defined bile acid diarrhoea. Colesevelam was safe during the treatment. FUNDING: Fabrikant Vilhelm Pedersen og hustrus mindelegat; recommended by the Novo Nordisk Foundation.

Effects of Manipulating Circulating Bile Acid Concentrations on Postprandial GLP-1 Secretion and Glucose Metabolism After Roux-en-Y Gastric Bypass.

Background: Altered bile acid (BA) turnover has been suggested to be involved in the improved glucose regulation after Roux-en-Y gastric bypass (RYGB), possibly via stimulation of GLP-1 secretion. We investigated the role of exogenous as well as endogenous BAs for GLP-1 secretion after RYGB by administering chenodeoxycholic acid (CDCA) and the BA sequestrant colesevelam (COL) both in the presence and the absence of a meal stimulus. Methods: Two single-blinded randomized cross-over studies were performed. In study 1, eight RYGB operated participants ingested 200 ml water with 1) CDCA 1.25 g or 2) CDCA 1.25 g + colesevelam 3.75 g on separate days. In study 2, twelve RYGB participants ingested on separate days a mixed meal with addition of 1) CDCA 1.25 g, 2) COL 3.75 g or 3) COL 3.75 g × 2, or 4) no additions. Results: In study 1, oral intake of CDCA increased circulating BAs, GLP-1, C-peptide, glucagon, and neurotensin. Addition of colesevelam reduced all responses. In study 2, addition of CDCA enhanced meal-induced increases in plasma GLP-1, glucagon and FGF-19 and lowered plasma glucose and C-peptide concentrations, while adding colesevelam lowered circulating BAs but did not affect meal-induced changes in plasma glucose or measured gastrointestinal hormones. Conclusion: In RYGB-operated persons, exogenous CDCA enhanced meal-stimulated GLP-1 and glucagon secretion but not insulin secretion, while the BA sequestrant colesevelam decreased CDCA-stimulated GLP-1 secretion but did not affect meal-stimulated GLP-1, C-peptide or glucagon secretion, or glucose tolerance. These findings suggest a limited role for endogenous bile acids in the acute regulation of postprandial gut hormone secretion or glucose metabolism after RYGB.

Real-world effectiveness of treatments for type 2 diabetes, hypercholesterolemia, and hypertension in Canadian routine care - Results from the CardioVascular and metabolic treatment in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry, 12-months results.

AIMS: The CV-CARE registry provides RWE in Canadian routine clinical practice. METHODS: CV-CARE is a multi-site, observational, prospective Canadian registry enrolling patients initiating treatment with metformin hydrochloride extended-release (MetER) for T2D; colesevelam (C) for HCh; and azilsartan (AZI), azilsartan/chlorthalidone (AZI/CHL) or diltiazem extended-release (TXC) for HTN. Patient characteristics/assessment were performed at baseline and 12 ± 6 months. Primary outcome was absolute change in HbA1c and FPG (MetER); % change in LDL-C (C); and absolute change in BP (AZI-AZI/CHL-TXC). RESULTS: Of the 4194 patients in the primary analysis population, 24% were taking MetER, 39% were taking C, 33% were taking AZI, 12% were taking AZI/CHL, and 3% were taking TXC. At 12 months, MetER-treated patients had an absolute mean (95% CI) change in HbA1c of -0.3% [-0.4; -0.2] and in FPG of 0.7 mmol/L [-1.0; -0.4]. C-treated patients had a mean (95% CI) % change in LDL-C of -13.0% [-14.6; -11.4]. Absolute mean (95% CI) changes in SBP were -18.7 mmHg [-19.7; -17.7](AZI), -21.3 mmHg [-23.1; -19.5](AZI/CHL), and -12.3 mmHg [-15.1; -9.6](TXC). CONCLUSION: In a real-world Canadian setting, MetER, C, AZI, AZI/CHL, and TXC show improvement of the cardiometabolic profile of T2D, HCh, and HTN patients.

Regional variability in Canadian routine care of type 2 diabetes, hypercholesterolemia, and hypertension: Results from the The Cardio-Vascular and metabolic treatments in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry.

BACKGROUND: Regional differences in the profile and treatment strategies of patients with cardiometabolic diseases have been studied in several different countries. The Cardio-Vascular and metabolic treatments in Canada: Assessment of REal-life therapeutic value (CV-CARE) registry was designed to evaluate patient profiles and medical management of cardiometabolic diseases in routine clinical care settings across Canada. Primary objectives were to (1) evaluate regional variability of patient profiles with cardiometabolic disease(s) and (2) assess treatment differences of patients treated for type 2 diabetes (T2D), hypercholesterolemia (HCh), and hypertension (HTN) across Canada. METHODS: CV-CARE is a multi-center, observational, prospective registry that enrolled Canadian patients treated with metformin-extended release (MetER) for T2D, colesevelam (C) for HCh, azilsartan (AZI) for mild-to-moderate essential HTN and azilsartan/chlorthalidone (AZI/CHL) for severe, essential HTN. Patient characteristics and treatments were assessed at baseline. RESULTS: The registry enrolled 6960 patients, with a total of 4194 patients making up the primary analysis population [MetER (n=995); C (n=1639); AZI (n=1364); AZI/CHL (n=498)]. First-line use of MetER was more common in British Columbia (BC; 45.5%) compared to Ontario (ON; 29.8%), and Quebec (QC; 12.9%). C treatment for HCh was used as monotherapy most readily in BC (68.7%) compared with QC (59.7%) and ON (35.8%). Dual action of low-density lipoprotein cholesterol and hemoglobin A1c reduction was the predominant reason for C add-on therapy (46.8%), with highest usage seen in ON (62.9%). AZI treatment for HTN was most frequently used in BC (43.8%), and AZI/CHL was most commonly used in ON (12.0%). First-line use of AZI was more common in QC (50%) vs. ON (34.9%) and BC (24.1%). The primary reason for switching to AZI and AZI/CHL from prior treatment was lack of efficacy across provinces. CONCLUSION: This is the first regional description of the CV-CARE cohort. Significant variations in both baseline profile and treatments were observed which could have an impact on long-term outcomes.

The Role of Bile Acids in Chronic Diarrhea.

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease. Diagnosis of BA diarrhea is based on Se-homocholic acid taurine retention, 48-hour fecal BA excretion, or serum 7αC4; the latter being a marker of hepatic BA synthesis. BA diarrhea tends to be associated with higher body mass index, increased stool weight and stool fat, and acceleration of colonic transit. Biochemical markers of increased BA synthesis or excretion are available through reference laboratories. Current treatment of BA diarrhea is based on BA sequestrants, and, in the future, it is anticipated that farsenoid X receptor agonists may also be effective. The optimal conditions for an empiric trial with BA sequestrants as a diagnostic test are still unclear. However, such therapeutic trials are widely used in clinical practice. Some national guidelines recommend definitive diagnosis of BA diarrhea over empirical trial.

A Meta-Analysis Assessing Additional LDL-C Reduction from Addition of a Bile Acid Sequestrant to Statin Therapy.

BACKGROUND: Statins are the first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C). However, there are secondary prevention patients who are either intolerant to maximal statin therapy or do not get adequate effects from a high-intensity statin. While data exist for the additional LDL-C-lowering effects of ezetimibe, there are no data on additional LDL-C lowering of bile acid sequestrants when combined with statin therapy. The purpose of this study was to quantify the LDL-C-lowering effects of bile acid sequestrants when added to statin therapy. METHODS: Databases (Medline via PubMed, Embase, and the Cochrane Library) were searched for randomized controlled trials comparing statin therapy to statin therapy with the addition of bile acid sequestrants. Nine studies were included in the meta-analysis. A meta-regression was performed to estimate the mean difference in LDL-C between the 2 groups. RESULTS: Without controlling for other variables, data suggest that combining statin with bile acid sequestrant increases the percentage change in LDL-C by 16.2 points, on average, compared with statin use alone. CONCLUSION: In patients unable to tolerate an adequate statin dosage, bile acid sequestrants offer a viable alternative with additional LDL-C-lowering benefit.

Targeting neratinib-induced diarrhea with budesonide and colesevelam in a rat model.

PURPOSE: Neratinib is an irreversible pan-ErbB tyrosine kinase inhibitor used for the extended adjuvant treatment of early-stage HER2-positive breast cancer. Its use is associated with the development of severe diarrhea in up to 40% of patients in the absence of proactive management. We previously developed a rat model of neratinib-induced diarrhea and found inflammation and anatomical disruption in the ileum and colon. Here we tested whether anti-diarrheal interventions, budesonide and colesevelam, can reduce neratinib-induced diarrhea and intestinal pathology. METHODS: Rats were treated with 50 mg/kg neratinib via oral gavage for 14 or 28 days (total n = 64). Body weight and diarrhea severity were recorded daily. Apoptosis was measured using immunohistochemistry for caspase-3. Inflammation was measured via a multiplex cytokine/chemokine assay. ErbB levels were measured using PCR and Western Blot. RESULTS: Budesonide co-treatment caused rats to gain significantly less weight than neratinib alone from day 4 of treatment (P = 0.0418). Budesonide (P = 0.027) and colesevelam (P = 0.033) each reduced the amount of days with moderate diarrhea compared to neratinib alone. In the proximal colon, rats treated with neratinib had higher levels of apoptosis compared to controls (P = 0.0035). Budesonide reduced histopathological injury in the proximal (P = 0.0401) and distal colon (P = 0.027) and increased anti-inflammatory IL-4 tissue concentration (ileum; P = 0.0026, colon; P = 0.031) compared to rats treated with neratinib alone. In the distal ileum, while budesonide decreased ErbB1 mRNA expression compared to controls (P = 0.018) (PCR), an increase in total ErbB1 protein was detected (P = 0.0021) (Western Blot). CONCLUSION: Both budesonide and colesevelam show potential as effective interventions against neratinib-induced diarrhea.

Intestinal bile acid sequestration improves glucose control by stimulating hepatic miR-182-5p in type 2 diabetes.

Colesevelam is a bile acid sequestrant approved to treat both hyperlipidemia and type 2 diabetes, but the mechanism for its glucose-lowering effects is not fully understood. The aim of this study was to investigate the role of hepatic microRNAs (miRNAs) as regulators of metabolic disease and to investigate the link between the cholesterol and glucose-lowering effects of colesevelam. To quantify the impact of colesevelam treatment in rodent models of diabetes, metabolic studies were performed in Zucker diabetic fatty (ZDF) rats and db/db mice. Colesevelam treatments significantly decreased plasma glucose levels and increased glycolysis in the absence of changes to insulin levels in ZDF rats and db/db mice. High-throughput sequencing and real-time PCR were used to quantify hepatic miRNA and mRNA changes, and the cholesterol-sensitive miR-96/182/183 cluster was found to be significantly increased in livers from ZDF rats treated with colesevelam compared with vehicle controls. Inhibition of miR-182 in vivo attenuated colesevelam-mediated improvements to glycemic control in db/db mice. Hepatic expression of mediator complex subunit 1 (MED1), a nuclear receptor coactivator, was significantly decreased with colesevelam treatments in db/db mice, and MED1 was experimentally validated to be a direct target of miR-96/182/183 in humans and mice. In summary, these results support that colesevelam likely improves glycemic control through hepatic miR-182-5p, a mechanism that directly links cholesterol and glucose metabolism. NEW & NOTEWORTHY Colesevelam lowers systemic glucose levels in Zucker diabetic fatty rats and db/db mice and increases hepatic levels of the sterol response element binding protein 2-responsive microRNA cluster miR-96/182/183. Inhibition of miR-182 in vivo reverses the glucose-lowering effects of colesevelam in db/db mice. Mediator complex subunit 1 (MED1) is a novel, direct target of the miR-96/182/183 cluster in mice and humans.

Select medications that unexpectedly lower HbA1c levels.

WHAT IS KNOWN AND OBJECTIVE: A variety of medication classes are available for diabetes; however, treatment options become limited due to adverse effect profiles and cost. Current diabetes guidelines include agents not originally developed for diabetes treatment, bromocriptine and colesevelam. COMMENT: Other non-diabetes medications demonstrating haemoglobin A1c lowering, including agents for weight loss, depression, anaemia and coronary artery disease, are described in this review article. WHAT IS NEW AND CONCLUSION: More research looking into the impact of non-diabetes medications on blood glucose may offer additional diabetes treatment strategies.

Colesevelam attenuates cholestatic liver and bile duct injury in Mdr2-/- mice by modulating composition, signalling and excretion of faecal bile acids.

BACKGROUND AND AIMS: Interruption of the enterohepatic circulation of bile acids (BAs) may protect against BA-mediated cholestatic liver and bile duct injury. BA sequestrants are established to treat cholestatic pruritus, but their impact on the underlying cholestasis is still unclear. We aimed to explore the therapeutic effects and mechanisms of the BA sequestrant colesevelam in a mouse model of sclerosing cholangitis. METHODS: Mdr2-/- mice received colesevelam for 8 weeks. Gene expression profiles of BA homeostasis, inflammation and fibrosis were explored in liver, intestine and colon. Hepatic and faecal BA profiles and gut microbiome were analysed. Glucagon-like peptide 1 (GLP-1) levels in portal blood were measured by ELISA. Furthermore, Mdr2-/- mice as well as wild-type 3,5-diethoxy-carbonyl-1,4-dihydrocollidine-fed mice were treated with GLP-1-receptor agonist exendin-4 for 2 weeks prior to analysis. RESULTS: Colesevelam reduced serum liver enzymes, BAs and expression of proinflammatory and profibrogenic markers. Faecal BA profiling revealed increased levels of secondary BAs after resin treatment, while hepatic and biliary BA composition showed a shift towards more hydrophilic BAs. Colonic GLP-1 secretion, portal venous GLP-1 levels and intestinal messenger RNA expression of gut hormone Proglucagon were increased, while ileal Fgf15 expression was abolished by colesevelam. Exendin-4 treatment increased bile duct mass without promoting a reactive cholangiocyte phenotype in mouse models of sclerosing cholangitis. Microbiota analysis showed an increase of the phylum δ-Proteobacteria after colesevelam treatment and a shift within the phyla Firmicutes from Clostridiales to Lactobacillus. CONCLUSION: Colesevelam increases faecal BA excretion and enhances BA conversion towards secondary BAs, thereby stimulating secretion of GLP-1 from enteroendocrine L-cells and attenuates liver and bile duct injury in Mdr2-/- mice.

Bile acid sequestrants for glycemic control in patients with type 2 diabetes: A systematic review with meta-analysis of randomized controlled trials.

AIM: To evaluate the effects of bile acid sequestrants (BASs) versus placebo, no intervention or active comparators on glycemic control in type 2 diabetes. METHODS: Data were retrieved and a systematic review with meta-analyses was performed. We evaluated bias control and subgroup and sensitivity analyses were performed to evaluate heterogeneity and bias. RESULTS: We included 17 trials with a total of 2950 patients randomized to BASs (colesevelam or colestimide) versus placebo, no intervention, statins or sitagliptin. Random-effects meta-analysis showed that patients randomized to BASs had a lower hemoglobin A1c at the end of treatment compared with the control group (mean difference-0.55%; 95% confidence interval-0.64 to -0.46). Analysis of trials with low risk of bias in all domains confirmed the findings. Data on adverse events were limited. There were no differences between trials stratified by the control group and no evidence of publication bias or small study effects. CONCLUSIONS: Our analyses found that BAS treatment improves glycemic control. The size of the effect was clinically relevant and despite limited safety data, our findings support the inclusion of BASs in current diabetes management algorithms for type 2 diabetes.

75SeHCAT scan in bile acid malabsorption in chronic diarrhoea. / Gammagrafía con 75SeHCAT en la diarrea crónica por malabsorción de ácidos biliares.

Chronic diarrhoea is a common entity in daily clinical practice and it leads to a loss in these patients quality of life. It may be the main symptom of multiple ethiologies including bile acid malabsorption (BAM) which has a comparable prevalence to celiac disease. The BAM results from imbalances in the homeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease or ileal dysfunction (BAM type i), it can be considered idiopathic or primary (BAM type ii) or associated with other gastrointestinal entities (BAM type iii). Among the different diagnostic methods available, 75SeHCAT study is the primary current method due to its sensitivity, specificity, safety and low cost. The main disadvantage is that it's not available in all countries, so other diagnostic methods have appeared, such as serum measurement of FGF19 and C4, however they are significantly more complex and costly. The first-line treatment of bile acid diarrhoea is bile acid sequestrant, such as cholestyramine, which can be difficult to administer due to its poor tolerability and gastrointestinal side effects. These are less prominent with newer agents such as colesevelam. In summary, the BAM is a common entity underdiagnosed and undertreated, so it is essential to establish a diagnosis algorithm of chronic diarrhoea in which the 75SeHCAT study would be first or second line in the differential diagnosis of these patients.

Type 2 Diabetes Medication Review.

BACKGROUND: Patients with type 2 diabetes and their healthcare providers have a variety of medication options available for treating elevated blood glucose values. These medication choices have expanded drastically over the last 10 years with a large number of glucose lowering medications gaining FDA approval. METHODS: Here, we have included an extensive search of the type 2 diabetes literature focusing on articles which impact patient-oriented evidence that maters (POEMs). RESULTS: Choosing the best agent(s) can be challenging and requires weighing the risks and benefits of each particular medication. Tailoring medications to individual patients should be prioritized based on trials with cardiovascular outcome data, potential hemoglobin A1c reduction/goal, serious medication precautions and side-effects, co-morbid medical conditions, and cost. CONCLUSIONS: This paper will provide the reader with an overview of the pros and cons for each antiglycemic medication class and specific drugs where appropriate. Data relevant to most patient centered encounters will be provided, including safety, tolerability, efficacy, cost, and simplicity of use.

Review article: bile acid diarrhoea - pathogenesis, diagnosis and management.

BACKGROUND: Bile acid diarrhoea results from imbalances in the homoeostasis of bile acids in the enterohepatic circulation. It can be a consequence of ileal disease/dysfunction, associated with other GI pathology or can be idiopathic. AIMS: To summarise the different types of bile acid diarrhoea and discuss the currently available diagnostic methods and treatments. RESULTS: Bile acid diarrhoea is found in up to 40% of patients diagnosed as having functional diarrhoea/IBS-D, and in up to 80% of patients who have undergone ileal resection. It is likely under-diagnosed and under-treated. In idiopathic disease, errors in regulation feedback of fibroblast growth factor 19 contribute to the development of the condition. Clinical therapeutic trials for bile acid diarrhoea have been used to diagnose it, but the 75 SeHCAT test is the primary current method. It is sensitive, specific and widely available, though not in the USA. Other diagnostic methods (such as serum measurement of the bile acid intermediate 7α-hydroxy-4-cholesten-3-one, or C4) have less widespread availability and documentation, and some (such as faecal measurement of bile acids) are significantly more complex and costly. First-line treatment of bile acid diarrhoea is with the bile acid sequestrant cholestyramine, which can be difficult to administer and dose due to gastrointestinal side effects. These side effects are less prominent in newer agents such as colesevelam, which may provide higher efficacy, tolerability and compliance. CONCLUSION: Bile acid diarrhoea is common, and likely under-diagnosed. Bile acid diarrhoea should be considered relatively early in the differential diagnosis of chronic diarrhoea.