Bile Acid Sequestrants

Bile acid sequestrants have been used in the treatment of hypercholesterolemia for decades. More recently, they have been shown to improve glycaemic control in patients with type 2 diabetes. The dual-effect on cholesterol and blood glucose lowering is an appealing property of an drug for diabetes, but bile acid sequestrants are less efficacious than first-line therapies such as statins and metformin. Although the mode of action underlying the cholesterol-lowering effect of bile acid sequestrants is well described, the mechanism behind the glucose-lowering effect remains is not well understood. Tolerance is good with primarily gastrointestinal adverse events. Bile acid sequestrants include the first-generation cholestyramine and colestipol, and second-generation colestimide and colesevelam. They can be combined with other drugs for diabetes including metformin and insulin, as well as statins.

Bile acids

Bile acids are synthesized in the liver from cholesterol and have traditionally been regarded as simple detergent molecules involved in absorption of dietary lipids and in cholesterol homeostasis. In the last decade, bile acids have also emerged as endocrine signaling molecules modulating lipid and glucose metabolism. Bile acids are natural ligands of the nuclear receptor farnesoid X receptor (FXR) and the membrane G protein-coupled receptor TGR5. Bile acid synthesis and the composition of the bile acid pool is regulated by feedback signalling through FXR in the liver and intestine, and it has been speculated that FXR activation is involved in lipid and glucose metabolism. TGR5 is widely expressed in the intestine and associated glands, including enteroendocrine L cells. Activation of TGR5 on the L cells has been shown to promote GLP-1 secretion. It was recently shown that TGR5 is expressed in beta cells, and that activation of TGR5 increases insulin secretion.

Mechanism of action

Bile acid sequestrants are orally administered nonabsorbed large molecules that bind bile acids in the intestine, thus preventing reabsorption and promoting increased faecal excretion of bile acids. This increases bile acid synthesis, resulting in increased expression of LDL receptors in the liver and reducing the concentration of circulating LDL cholesterol.

The glucose-lowering mode of action of the bile acid sequestrants is incompletely understood, and data from in vitro, animal and human studies have suggested several mechanisms [1]. The observation that they alter the bile acid pool composition has led to the hypothesis that this might explain the improved glucose control. However, clinical studies do not support altered bile acid pool composition as an important pathway in their glucose-lowering mode of action.

Animal studies suggest that bile acid sequestrants improve glycaemic control by improving hepatic glucose metabolism, but they do appear to improve hepatic glucose metabolism in humans with type 2 diabetes. Both animal and human studies have shown that bile acids administered in the L cell-rich colon and rectum lead to GLP-1 secretion, and a number of animal studies have shown that bile acid sequestrants also increase GLP-1 secretion through TGR5 activation. An in vitro study has offered an explanation to this apparent paradox, by showing that bile acids bound to a sequestrant are able to activate TGR5 and promote GLP-1 secretion [2]. This has led to the hypothesis that bile acid sequestrants carry bile acids to distal parts of the intestine which are rich in L cells and hence function as GLP-1 secretagogues.

In humans, colesevelam improve oral glucose tolerance, but not iv glucose tolerance [3]. This may point to a mode of action involving enteroendocrine hormone secretion, but clinical studies have failed to provide consistent evidence that sequestrants increase GLP-1 secretion in humans.

Clinical efficacy

In a clinical trial from 1984, cholestyramine treatment in male patients with hypercholesterolemia reduced LDL cholesterol by 20%, which was associated with a 19% relative risk reduction in myocardial infarction and death by coronary heart disease [4]. Ten years later, Garg and Grundy reported that cholestyramine reduced fasting plasma glucose in patients with type 2 diabetes, with a tendency towards reduction in HbA1c [5].

Since then several studies have shown that second generation BASs reduce HbA1c by ≈0.5% vs. placebo, while reductions in LDL cholesterol between 6.7% and 15.9% and increases in serum triglyceride levels between 4.7% and 21.5% have been reported [6][7][8]. Bile acid sequestrants therapy is generally considered to be weight neutral. In 2008, the US Food and Drug Administration approved colesevelam for treatment of hyperglycaemia in type 2 diabetes. Recently, colesevelam was included in the diabetes treatment algorithm of the American Association of Clinical Endocrinologist, as add on to metformin or other first-line therapies [9]. In contrast, bile acid sequestrants are not included in the latest joint position statement on the management of hyperglycaemia in type 2 diabetes from American Diabetes association (ADA) and European association for the Study of Diabetes (EASD), and in Europe they are not approved for treatment of type 2 diabetes. Of note, bile acid sequestrants have not been tested in cardiovascular outcome trials in patients with type 2 diabetes.

Safety and tolerability

As mentioned, bile acid sequestrants remain unabsorbed in their passage through the gastrointestinal tract. Thus, have no systemic toxicity and are not dependent on liver and kidney function. bile acid sequestrants have not been associated with serious adverse events in clinical trials, but are associated with gastrointestinal adverse events, primarily constipation. Because of a higher affinity for bile acids, second-generation bile acid sequestrants are 4 to 6 times more potent than first-generation agents, which allows for lower dosing and better tolerability [10]. While bile acid sequestrants may increase serum triglycerides, the clinical implication of this is unknown. A prospective study including more than 300,000 people did not find a correlation between serum triglycerides and risk of coronary heart disease after controlling for standard risk factors [11]. However, bile acid sequestrants should not be used in patients with serum triglycerides >5.6 mmol/L, and should be used with caution in patients with serum triglycerides of 3.4–5.6 mmol/L. Drug interactions have been reported with first-generation agents, due to reduced absorption caused by non-specific binding in the intestine. Second-generation colesevelam, however, appears to have no clinically significant interaction with concurrently administered drugs [12].


  1. ^ Hansen M et al. Bile acid sequestrants: glucose-lowering mechanisms and efficacy in type 2 diabetes. Curr Diab Rep. 2014 May;14(5):482.

  2. ^ Harach T et al. TGR5 potentiates GLP-1 secretion in response to anionic exchange resins. Sci Rep. 2012;2:430.

  3. ^ Marina AL et al. Colesevelam improves oral but not intravenous glucose tolerance by a mechanism independent of insulin sensitivity and β-cell function. Diabetes Care. 2012 May;35(5):1119–25.

  4. ^ The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA J Am Med Assoc. 1984 Jan 20;251(3):365–74.

  5. ^ Garg A, Grundy SM. Cholestyramine therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. A short-term, double-blind, crossover trial. Ann Intern Med. 1994 Sep 15;121(6):416–22.

  6. ^ Bays HE et al. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med. 2008 Oct 13;168(18):1975–83.

  7. ^ Fonseca VA et al. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care. 2008 Aug;31(8):1479–84.

  8. ^ Neda T et al. Hypoglycemic effects of colestimide on type 2 diabetic patients with obesity. Endocr J. 2012;59(3):239–46.

  9. ^ Garber AJ et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol. 2013 Apr;19(2):327–36.

  10. ^ Braunlin W et al. In vitro comparison of bile acid binding to colesevelam HCl and other bile acid sequestrants. Polym Prepr. 2000;41:708– 709.

  11. ^ Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA J Am Med Assoc. 2009 Nov 11;302(18):1993–2000.

  12. ^ Donovan JM et al. Drug interactions with colesevelam hydrochloride, a novel, potent lipid-lowering agent. Cardiovasc Drugs Ther Spons Int Soc Cardiovasc Pharmacother. 2000 Dec;14(6):681–90.


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