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Cureus Dec 2023The increasing prevalence of type II diabetes mellitus (T2DM) is a worldwide healthcare concern. Over the years, our understanding of T2DM has grown considerably in... (Review)
Review
The increasing prevalence of type II diabetes mellitus (T2DM) is a worldwide healthcare concern. Over the years, our understanding of T2DM has grown considerably in uncovering the pathophysiology of the disease and, in turn, understanding how improved treatment methods can be used to slow disease progression. Some long-term complications that are responsible for most T2DM mortalities include cardiovascular disease, neurological decline, and renal failure. In treating T2DM, it is important that not only glycemic control be obtained but also control of associated complications. Bromocriptine and colesevelam hydrochloride have both been approved by the Food and Drug Administration (FDA) to treat T2DM but are not readily used in practice. These medications are known to treat glycemic dysregulation via unconventional mechanisms, which might contribute to their potential to provide protection against common diabetic complications such as cardiovascular disease. In order to ensure that these overlooked medications become more readily used, it is vital that more research be performed to further elucidate their efficacy in a clinical setting. Future studies should continue to provide clinicians a better understanding of the role these medications have on the treatment of T2DM such as their ability to be used in combination with other commonly used T2DM medications or as monotherapies.
PubMed: 38192911
DOI: 10.7759/cureus.50138 -
Hepatology International Apr 2022Obesity, non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality...
BACKGROUND
Obesity, non-alcoholic fatty liver disease (NAFLD) and its more advanced form non-alcoholic steatohepatitis (NASH) are important causes of morbidity and mortality worldwide. Bile acid dysregulation is a pivotal part in their pathogenesis. The aim of this study was to evaluate the bile acid sequestrant colesevelam in a microbiome-humanized mouse model of diet-induced obesity and steatohepatitis.
METHODS
Germ-free C57BL/6 mice were associated with stool from patients with NASH and subjected to 20 weeks of Western diet feeding with and without colesevelam.
RESULTS
Colesevelam reduced Western diet-induced body and liver weight gain in microbiome-humanized mice compared with controls. It ameliorated Western diet-induced hepatic inflammation, steatosis, fibrosis and insulin resistance. Colesevelam increased de novo bile acid synthesis and decreased hepatic cholesterol content in microbiome-humanized mice fed a Western diet. It further induced the gene expression of the antimicrobials Reg3g and Reg3b in the distal small intestine and decreased plasma levels of LPS.
CONCLUSIONS
Colesevelam ameliorates Western diet-induced steatohepatitis and obesity in microbiome-humanized mice.
Topics: Animals; Bile Acids and Salts; Colesevelam Hydrochloride; Disease Models, Animal; Humans; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity
PubMed: 35075592
DOI: 10.1007/s12072-022-10296-w -
Vascular Health and Risk Management 2007Colesevelam HCl is a bile acid sequestrant (BAS) which has been specifically designed with a unique structure for the purpose of improving tolerability and reducing... (Review)
Review
Colesevelam HCl is a bile acid sequestrant (BAS) which has been specifically designed with a unique structure for the purpose of improving tolerability and reducing potential drug interactions compared to older BAS, such as cholestyramine and colestipol. As a class, BAS are known to reduce cholesterol and glucose levels, and to reduce atherosclerotic coronary heart disease (CHD) risk as monotherapy, and in combination with other lipid-altering drug therapies. Colesevelam HCl has specifically been shown to reduce total and low-density lipoprotein (LDL) cholesterol levels, and has been approved as a cholesterol-lowering drug since year 2000. It has also been shown to reduce glucose levels. This discussion reviews mechanisms by which BAS lower cholesterol, and potential mechanisms by which BAS lower glucose levels in patients with type 2 diabetes mellitus. Finally this paper specifically reviews colesevelam HCl's pharmacology, lipid and glucose efficacy, safety/tolerability, and clinical use.
Topics: Allylamine; Animals; Atherosclerosis; Bile Acids and Salts; Colesevelam Hydrochloride; Coronary Disease; Humans; Lipid Metabolism; Risk Factors
PubMed: 18078024
DOI: No ID Found -
Adolescent Health, Medicine and... 2010Colesevelam hydrochloride is a synthetic, nonsystemically absorbed polymer that functions as a bile acid sequestrant for the treatment of hypercholesterolemia. Recently,... (Review)
Review
BACKGROUND
Colesevelam hydrochloride is a synthetic, nonsystemically absorbed polymer that functions as a bile acid sequestrant for the treatment of hypercholesterolemia. Recently, colesevelam was investigated for the treatment of heterozygous familial hypercholesterolemia (HeFH) in the pediatric/adolescent population aged 10-17 years.
OBJECTIVE
The purpose of this article is to review the disease state of HeFH in children and adolescents, review the pharmacologic mechanism of action, kinetics, and safety profile of colesevelam, analyze the results of a recent clinical trial of colesevelam in the pediatric/adolescent HeFH population, and discuss the role of colesevelam as a viable treatment option for HeFH.
METHODS
A literature search using Medline (1966-03 May 2010), PubMed (1950-03 May 2010), Science Direct (1994-03 May 2010), and International Pharmaceutical Abstracts (2004-2010) was performed using the search term colesevelam. English language, original research, and review articles were examined, and citations from these articles were also assessed. The manufacturer's prescribing information and the Food and Drug Administration review of the new drug application for the powder formulation were also examined.
RESULTS
A 32-week trial was performed investigating the efficacy of colesevelam as monotherapy or combination therapy with a stable statin regimen. Upon completion of the trial, significant benefits were found in regard to the treatment of HeFH and the lowering of low-density lipoprotein cholesterol, total cholesterol, and other secondary measures. Safety and tolerability were also examined throughout the duration of the clinical trial, with adverse drug reactions considered mild in severity.
CONCLUSION
Colesevelam has been shown to reduce low-density lipoprotein cholesterol levels significantly in pediatric/adolescent patients with HeFH, while maintaining a mild side effect profile. Although further research would be beneficial for long-term effects in this population, colesevelam should be considered when developing a treatment regimen for HeFH in the pediatric/adolescent population.
PubMed: 24600261
DOI: 10.2147/AHMT.S9272 -
American Journal of Cardiovascular... Oct 2013Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for... (Review)
Review
Hyperlipidemia is associated with an increased risk of cardiovascular events; reducing low-density lipoprotein cholesterol (LDL-C), the primary target for cholesterol-lowering therapy, lowers the risk for such events. Although bile acid sequestrants were the first class of drugs to show a mortality benefit related to LDL-C lowering, statins are now considered first-line pharmacological therapy for reducing LDL-C levels because of their potency and their remarkable record of successful outcomes studies. Nevertheless, a substantial proportion of patients do not achieve LDL-C goals with statin monotherapy. In addition, because of adverse effects (primarily myopathy), some patients may be unwilling to use or unable to tolerate statin therapy at all or may not tolerate a full therapeutic statin dose. Also, statins may increase risk of new-onset diabetes in patients at high risk for diabetes. Thus, there remains a need for other lipid-lowering drugs to be used in combination with or in place of statins. The purpose of this article is to review available data from the literature on the use of colesevelam, a second-generation bile acid sequestrant, in combination with other lipid-lowering agents. Colesevelam has been studied in combination with statins, niacin, fibrates, and ezetimibe (including some three-drug combinations). An additive reduction in LDL-C was seen with all combinations. Other observed effects of colesevelam in combination with other lipid-lowering drugs include reductions in apolipoprotein (apo) B (with statins, fibrates, ezetimibe, statin plus niacin, or statin plus ezetimibe) and high-sensitivity C-reactive protein (with statins), and increases in apo A-I (with statins, ezetimibe, or statins plus niacin). Triglyceride levels remained relatively unchanged when colesevelam was combined with statins, fibrates, ezetimibe, or statin plus ezetimibe, and decreased with the triple combination of colesevelam, statin, and niacin. Colesevelam offset the negative glycemic effects of statins and niacin in subjects with insulin resistance or impaired glucose tolerance. Colesevelam was generally well tolerated when added to other lipid-lowering therapies in clinical trials, with gastrointestinal effects such as constipation being the predominant adverse events. Since colesevelam is not absorbed and works primarily in the intestine, it has a low potential for systemic metabolic drug-drug interactions with other drugs. Colesevelam has been shown to not interact with the lipid-lowering drugs lovastatin and fenofibrate; where interaction may be anticipated, separating dosing times by 4 h reduces the impact of any interaction. Available data confirms that colesevelam has additive cholesterol-lowering effects when used in combination with other lipid-lowering therapies. Furthermore, in some patient populations, the additional glucose-lowering effect of colesevelam may be beneficial in offsetting hyperglycemic effects of other lipid-lowering drugs.
Topics: Allylamine; Anticholesteremic Agents; Cholesterol, LDL; Colesevelam Hydrochloride; Drug Interactions; Drug Therapy, Combination; Humans; Hyperlipidemias
PubMed: 23913404
DOI: 10.1007/s40256-013-0037-0 -
P & T : a Peer-reviewed Journal For... Jan 2015Diabetes mellitus (DM) is a chronic disease with a U.S. prevalence of 25.8 million, and 90-95% of all cases are type-2 diabetes mellitus (T2DM). Despite the known...
Diabetes mellitus (DM) is a chronic disease with a U.S. prevalence of 25.8 million, and 90-95% of all cases are type-2 diabetes mellitus (T2DM). Despite the known mortality and morbidity associated with T2DM, the majority of patients do not achieve their hemoglobin A1c (HbA1c) goals. Nonadherence is one of the contributing factors to the lackluster attainment of treatment goals. Drug tolerability may impact medication nonadherence; therefore, strategies to improve tolerability are important. Colesevelam, a second-generation bile acid resin, was designed with greater specificity and affinity for bile acids. Its physiochemical attributes contribute to an improved tolerability profile. Colesevelam has demonstrated efficacy in lowering HbA1c in addition to low-density lipoprotein-cholesterol, although clinical outcomes data are lacking. Several mechanisms of colesevelam's effect in T2DM have been proposed, including effects on insulin sensitivity and secretion, incretin effects, changes in bile acid composition, and splanchnic sequestration of mealtime glucose. Colesevelam is associated with reductions in HbA1c in T2DM patients ranging from 0.32 to 1.1 percentage points. Colesevelam is generally well tolerated, and indirect comparisons with cholestyramine suggest that it is associated with fewer gastrointestinal symptoms. Reported adherence and persistence to colesevelam treatment in observational studies are 33.3% and 49%, respectively.
PubMed: 25628509
DOI: No ID Found -
The American Journal of Gastroenterology Oct 2020Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue... (Review)
Review
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.
Topics: Benzothiazoles; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestenones; Cholestyramine Resin; Chronic Disease; Colesevelam Hydrochloride; Colestipol; Diarrhea; Diet, Fat-Restricted; Feces; Humans; Intestinal Mucosa; Irritable Bowel Syndrome; Isoxazoles; Liver; Malabsorption Syndromes; Receptors, Cytoplasmic and Nuclear; Sequestering Agents; Taurocholic Acid
PubMed: 32558690
DOI: 10.14309/ajg.0000000000000696 -
The Cochrane Database of Systematic... Dec 2012Colesevelam is a second-generation bile acid sequestrant that has effects on both blood glucose and lipid levels. It provides a promising approach to glycaemic and lipid... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Colesevelam is a second-generation bile acid sequestrant that has effects on both blood glucose and lipid levels. It provides a promising approach to glycaemic and lipid control simultaneously.
OBJECTIVES
To assess the effects of colesevelam for type 2 diabetes mellitus.
SEARCH METHODS
Several electronic databases were searched, among these The Cochrane Library (Issue 1, 2012), MEDLINE, EMBASE, CINAHL, LILACS, OpenGrey and Proquest Dissertations and Theses database (all up to January 2012), combined with handsearches. No language restriction was used.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared colesevelam with or without other oral hypoglycaemic agents with a placebo or a control intervention with or without oral hypoglycaemic agents.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected the trials and extracted the data. We evaluated risk of bias of trials using the parameters of randomisation, allocation concealment, blinding, completeness of outcome data, selective reporting and other potential sources of bias.
MAIN RESULTS
Six RCTs ranging from 8 to 26 weeks investigating 1450 participants met the inclusion criteria. Overall, the risk of bias of these trials was unclear or high. All RCTs compared the effects of colesevelam with or without other antidiabetic drug treatments with placebo only (one study) or combined with antidiabetic drug treatments. Colesevelam with add-on antidiabetic agents demonstrated a statistically significant reduction in fasting blood glucose with a mean difference (MD) of -15 mg/dL (95% confidence interval (CI) -22 to - 8), P < 0.0001; 1075 participants, 4 trials, no trial with low risk of bias in all domains. There was also a reduction in glycosylated haemoglobin A1c (HbA1c) in favour of colesevelam (MD -0.5% (95% CI -0.6 to -0.4), P < 0.00001; 1315 participants, 5 trials, no trial with low risk of bias in all domains. However, the single trial comparing colesevelam to placebo only (33 participants) did not reveal a statistically significant difference between the two arms - in fact, in both arms HbA1c increased. Colesevelam with add-on antidiabetic agents demonstrated a statistical significant reduction in low-density lipoprotein (LDL)-cholesterol with a MD of -13 mg/dL (95% CI -17 to - 9), P < 0.00001; 886 participants, 4 trials, no trial with low risk of bias in all domains. Non-severe hypoglycaemic episodes were infrequently observed. No other serious adverse effects were reported. There was no documentation of complications of the disease, morbidity, mortality, health-related quality of life and costs.
AUTHORS' CONCLUSIONS
Colesevelam added on to antidiabetic agents showed significant effects on glycaemic control. However, there is a limited number of studies with the different colesevelam/antidiabetic agent combinations. More information on the benefit-risk ratio of colesevelam treatment is necessary to assess the long-term effects, particularly in the management of cardiovascular risks as well as the reduction in micro- and macrovascular complications of type 2 diabetes mellitus. Furthermore, long-term data on health-related quality of life and all-cause mortality also need to be investigated.
Topics: Allylamine; Blood Glucose; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Fasting; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic
PubMed: 23235674
DOI: 10.1002/14651858.CD009361.pub2 -
Diabetes, Obesity & Metabolism May 2010Simultaneous control of blood glucose and other risk factors such as hypertension and dyslipidaemia is essential for reducing the risk of complications associated with... (Review)
Review
Simultaneous control of blood glucose and other risk factors such as hypertension and dyslipidaemia is essential for reducing the risk of complications associated with type 2 diabetes mellitus (T2DM). As relatively few patients with T2DM have their risk factors managed to within the limits recommended by the American Diabetes Association, American College of Endocrinology or National Cholesterol Education Program Adult Treatment Panel III guidelines, treatment that can simultaneously control more than one risk factor is of therapeutic benefit. Clinical studies have shown that bile acid sequestrants have glucose-lowering effects in addition to their low-density lipoprotein cholesterol-lowering effects in patients with T2DM. The bile acid sequestrant colesevelam hydrochloride is approved as an adjunct to antidiabetes therapy for improving glycaemic control in adults with T2DM. This review examines data from three phase III clinical trials that evaluated the glucose- and lipid-lowering effects of colesevelam when added to the existing antidiabetes treatment regimen of patients with T2DM.
Topics: Adult; Allylamine; Anticholesteremic Agents; Blood Glucose; Cardiovascular Diseases; Colesevelam Hydrochloride; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Female; Glycated Hemoglobin; Humans; Lipids; Male
PubMed: 20415686
DOI: 10.1111/j.1463-1326.2009.01181.x -
Diabetes & Vascular Disease Research May 2013A randomised, double-blind, placebo-controlled study evaluated lipid- and glucose-lowering effects of colesevelam in patients with prediabetes and primary... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A randomised, double-blind, placebo-controlled study evaluated lipid- and glucose-lowering effects of colesevelam in patients with prediabetes and primary hyperlipidaemia. We report the effect of colesevelam on lipoprotein particle concentration and particle size (determined by nuclear magnetic resonance spectroscopy) in these patients.
METHODS
Adults with prediabetes (World Health Organization criteria), low-density lipoprotein cholesterol (LDL-C) ≥ 100 mg/dL (≥2.6 mmol/L) and triglycerides < 500 mg/dL (<5.6 mmol/L) were randomised to colesevelam 3.75 g/day or placebo for 16 weeks. The intent-to-treat population comprised 103 colesevelam and 106 placebo recipients.
RESULTS
At the end of the study, mean reduction from baseline in total LDL particle concentration was significantly greater with colesevelam versus placebo (mean treatment difference: -113 nmol/L; p = 0.02). Increases in total very low-density lipoprotein particle concentration (VLDL-P) and high-density lipoprotein particle concentration (HDL-P) did not differ significantly between the groups; however, with colesevelam versus placebo, there were significantly (p < 0.05) greater increases in large and medium VLDL-P and large HDL-P and reductions in small VLDL-P. Mean size increases were significantly greater with colesevelam for VLDL (mean treatment difference: 5.3 nm; p < 0.0001) and HDL (0.1 nm; p = 0.002).
CONCLUSIONS
Colesevelam improved the overall atherogenic lipoprotein profile in adults with prediabetes and primary hyperlipidaemia, despite potentially less favourable changes in VLDL particles.
Topics: Adult; Allylamine; Cholesterol, LDL; Colesevelam Hydrochloride; Constipation; Diarrhea; Double-Blind Method; Dyspepsia; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Intention to Treat Analysis; Lipoproteins; Lipoproteins, HDL; Lipoproteins, VLDL; Male; Nuclear Magnetic Resonance, Biomolecular; Particle Size; Prediabetic State; Triglycerides
PubMed: 23152373
DOI: 10.1177/1479164112461657