Bile Acid Salt Binding with Colesevelam HCl is Not Affected by Suspension in Common Beverages

Hanuš, Martin; Zhorov, Eugene

doi:10.1002/jps.20734

Cited by 16 publications

(5 citation statements)

References 28 publications

(30 reference statements)

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“…In addition to lowering LDL cholesterol levels, colesevelam is also used as an adjunct therapy for glycaemic control in adults with Type 2 diabetes . Compared with the earlier generations of bile acid sequestrants, colesevelam has greater tolerability, fewer adverse effects and fewer potential drug interactions . The reported adverse effects are predominantly gastrointestinal and metabolic, and patients with gastrointestinal motility disorders may experience worsening dysphagia, oesophageal obstruction and constipation .…”

Section: Introductionmentioning

confidence: 99%

Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review*

Ooi

Loke

2013

Diabet. Med.

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Aim Colesevelam, a second-generation bile acid sequestrant, may be beneficial in controlling both glycaemia and lipids simultaneously. Our goal was to evaluate the systemic effects of colesevelam on Type 2 diabetes mellitus.Method The original Cochrane review was conducted using the methodology for the systematic review of interventions of the Cochrane Collaboration in RevMan 5.2. We comprehensively searched the literature in several databases up to January 2012. Two reviewing authors independently selected and extracted the data, and then evaluated the quality of the randomized controlled trials that met the inclusion criteria.Results Six randomized controlled trials were selected, which ranged from 8 to 26 weeks in duration. A total of 1450 participants were divided into two groups: those treated with colesevelam and no other anti-diabetic drug treatments/ placebo, or with colesevelam added on to anti-diabetic drug treatments. The colesevelam added on to anti-diabetic agents demonstrated a statistically significant reduction in the fasting blood glucose (mean difference of -0.82 mmol/l, 95% CI -1.2 to -0.44), HbA 1c (mean difference -0.5%, 95% CI -0.6 to -0.4) and LDL cholesterol (mean difference -0.34 mmol/l, 95% CI -0.44 to -0.23). There were no reported data on weight. Non-severe hypoglycaemic episodes were infrequently observed. ConclusionThe limited number of studies concerning the treatment with colesevelam added to anti-diabetic agents showed significant effects on glycaemic control; however, more research on the reduction of cardiovascular risks is required. Furthermore, long-term data on the health-related quality of life and all-cause mortality also need to be investigated.

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Section: Introductionmentioning

confidence: 99%

Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review*

Ooi

Loke

2013

Diabet. Med.

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“…To generate a Col/BA complex, Colesevelam was hydrated in simulated intestinal fluid as previously described (18). A sample (400 l) of 5 mg/ml Colesevelam (the maximum concentration determined not to disrupt the BRET signal) was incubated with 400 l of 100 mM TCA and 10 M oleic acid for 45 min.…”

Section: Methodsmentioning

confidence: 99%

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Potthoff

Potts

et al. 2013

American Journal of Physiology-Gastrointestinal and Liver Physi

140

130

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Potthoff MJ, Potts A, He T, Duarte JA, Taussig R, Mangelsdorf DJ, Kliewer SA, Burgess SC. Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol 304: G371-G380, 2013. First published December 20, 2012; doi:10.1152/ajpgi.00400.2012.-Bile acid sequestrants are nonabsorbable resins designed to treat hypercholesterolemia by preventing ileal uptake of bile acids, thus increasing catabolism of cholesterol into bile acids. However, sequestrants also improve hyperglycemia and hyperinsulinemia through less characterized metabolic and molecular mechanisms. Here, we demonstrate that the bile acid sequestrant, colesevelam, significantly reduced hepatic glucose production by suppressing hepatic glycogenolysis in diet-induced obese mice and that this was partially mediated by activation of the G protein-coupled bile acid receptor TGR5 and glucagon-like peptide-1 (GLP-1) release. A GLP-1 receptor antagonist blocked suppression of hepatic glycogenolysis and blunted but did not eliminate the effect of colesevelam on glycemia. The ability of colesevelam to induce GLP-1, lower glycemia, and spare hepatic glycogen content was compromised in mice lacking TGR5. In vitro assays revealed that bile acid activation of TGR5 initiates a prolonged cAMP signaling cascade and that this signaling was maintained even when the bile acid was complexed to colesevelam. Intestinal TGR5 was most abundantly expressed in the colon, and rectal administration of a colesevelam/bile acid complex was sufficient to induce portal GLP-1 concentration but did not activate the nuclear bile acid receptor farnesoid X receptor (FXR). The beneficial effects of colesevelam on cholesterol metabolism were mediated by FXR and were independent of TGR5/GLP-1. We conclude that colesevelam administration functions through a dual mechanism, which includes TGR5/GLP-1-dependent suppression of hepatic glycogenolysis and FXR-dependent cholesterol reduction. bile acids; glucagon-like peptide-1; TGR5; diabetes-induced obesity; FGF-15; FXR BILE ACID SEQUESTRANTS ARE orally administered nonabsorbable resins designed to treat hypercholesterolemia (23) but that have unexpected beneficial effects on glycemia in subjects with type 2 diabetes mellitus (T2DM) (17). This observation has been confirmed in multiple human studies, animal models, and with a variety of different bile acid binding resins (reviewed in Ref. 41). Colesevelam is a bile acid sequestrant used to treat T2DM, but the mechanisms by which it and other sequestrants act on glucose metabolism are incompletely understood. Inasmuch as colesevelam passes through the digestive track unaltered, its efficacy on both cholesterol and glucose metabolism are thought to originate from its high bile acid-binding affinity.Bile acids are amphipathic molecules synthesized in liver, stored in the gallbladder, and secreted into the small intestine to facilitate dietary lipid absorption (48). Ileal bile acid reabsorption and uptake by the liver is nearly q...

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“…For those individuals who may have difficulty swallowing tablets, colesevelam (WelChol ® ) is also available alternatively as a powder which can be mixed with a number of liquids to form a suspension that can be ingested. The affinity, capacity, and kinetics of the molecule’s binding of the sodium salts of glycocholic, glycochenodeoxycholic, and taurodeoxycholic acids are not significantly altered after suspension in water, carbonated water, Coca-Cola ® , Sprite ® , grape juice, orange juice, tomato juice, or Gatorade ® 29. Based upon the above, Food and Drug Administration (FDA) approval was eventually granted for a citrus-like flavored powder preparation of colesevelam which can be mixed with water (approval October 2009) or a variety of other beverages (approval July 2011).…”

Section: The Colesevelam Moleculementioning

confidence: 99%

Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action

Zema¹

2012

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Colesevelam hydrochloride is a molecularly engineered, second-generation bile acid sequestrant demonstrating enhanced specificity for bile acids which has been approved for use as adjunctive therapy to diet and exercise as monotherapy or in combination with a β-hydroxymethylglutaryl-coenzyme A reductase inhibitor for the reduction of elevated low-density lipoprotein cholesterol in patients with primary hypercholesterolemia. It is also the only lipid-lowering agent currently available in the United States which has been approved for use as adjunctive therapy in patients with type 2 diabetes mellitus whose glycemia remains inadequately controlled on therapy with metformin, sulfonylurea, or insulin. With the recent emphasis upon drug safety by the Food and Drug Administration and various consumer agencies, it is fitting that the role of nonsystemic lipid-lowering therapies such as bile acid sequestrants – with nearly 90 years of in-class, clinically safe experience – should be reexamined. This paper presents information on the major pharmacologic effects of colesevelam, including a discussion of recent data derived from both in vitro and in vivo rodent and human studies, which shed light on the putative mechanisms involved.

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Bile Acid Salt Binding with Colesevelam HCl is Not Affected by Suspension in Common Beverages

Cited by 16 publications

References 28 publications

Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review*

Colesevelam for Type 2 diabetes mellitus: an abridged Cochrane review*

Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice

Colesevelam hydrochloride: evidence for its use in the treatment of hypercholesterolemia and type 2 diabetes mellitus with insights into mechanism of action

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