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Bile Acid Sequestrants in Type 2 Diabetes

Published Online: June 6th 2011 US Endocrinology, 2008;4(1):34-7 DOI: http://doi.org/10.17925/USE.2008.04.01.34
Authors: Philip Levy
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Type 2 diabetes bears significant risks of morbidity and mortality. Coronary artery disease (CAD) is the leading cause of death among patients with type 2 diabetes,1 and these patients face CAD risks as high as those of patients without diabetes who have a history of myocardial infarction.1–3 Microvascular complications such as retinopathy, nephropathy, and neuropathy also stem from type 2 diabetes, rendering the condition the leading cause of blindness, kidney failure, and non-traumatic limb amputations among adults.

Type 2 diabetes bears significant risks of morbidity and mortality. Coronary artery disease (CAD) is the leading cause of death among patients with type 2 diabetes,1 and these patients face CAD risks as high as those of patients without diabetes who have a history of myocardial infarction.1–3 Microvascular complications such as retinopathy, nephropathy, and neuropathy also stem from type 2 diabetes, rendering the condition the leading cause of blindness, kidney failure, and non-traumatic limb amputations among adults.

The pathogenesis of type 2 diabetes is multifactorial: impaired glucose tolerance, insulin resistance, and hyperglucagonemia are early hallmarks of diabetes. Early in the disease, patients with type 2 diabetes have altered insulin secretory capacity. As the disease progresses, the function of β cells declines until the capacity for insulin secretion becomes inadequate to maintain normal levels of glucose in the blood (normoglycemia; reviewed by Wajchenberg4). The mechanisms underlying this decline in β-cell function have not been fully elucidated. It has been suggested that hyperglycemia can negatively affect the function and mass of β cells (‘glucotoxicity’) by leading to their apoptosis without a compensatory increase in β-cell proliferation and neogenesis.5 The loss of β cells and the subsequent relative insulin deficiency leads to glucose intolerance and absolute insulin deficiency.6 The metabolism of glucose in the liver is also impaired in type 2 diabetes, and more recently it has been recognized that gastrointestinal peptides such as incretin hormones and amylin are key players in the regulation of serum glucose levels, particularly after meals.7 Preventive measures and lifestyle interventions such as proper diet and exercise are the basis of management. Still, as glucose balance deteriorates as diabetes advances, initiation of drug treatment is inevitable. The different pathogenic factors in type 2 diabetes have led to the development of therapeutics with distinct mechanisms of action, each targeted at one or more of the multiple defects that contribute to deregulation of glucose metabolism.

Interplay of Hormones Keeps Glucose Balanced
For many years insulin was the only pancreatic β-cell hormone known to reduce blood glucose concentrations and therefore was the main treatment for type 2 diabetes. However, insulin’s effectiveness is frequently counterbalanced by hypoglycemia and weight gain.8,9 Glucagon, the catabolic hormone secreted by the pancreatic α cells, counteracts insulin by stimulating production of glucose by the liver during fasting conditions. Glucagon secretion is normally suppressed post-prandially, but in patients with type 2 diabetes it is inadequately suppressed, resulting in elevated hepatic glucose production. Amylin, a pancreatic β-cell hormone, works with insulin to regulate blood glucose levels and complements insulin by suppressing post-prandial glucagon secretion,10 thus decreasing glucagonstimulated glucose production. In animal studies, amylin has been shown to delay gastric emptying and reduce food intake and bodyweight.8

Incretins, a group of hormones produced by intestinal cells, are also important regulators of glucose metabolism. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the prevailing incretins. GIP promotes insulin secretion and regulates fat metabolism, but has no effect on glucagon secretion or gastric emptying.8 GLP-1 enhances glucose-dependent insulin secretion, becoming inactive when glucose levels reach or fall below the normal range. Like amylin, GLP-1 suppresses post-prandial glucagon secretion, slows gastric emptying, and reduces food intake and bodyweight. In addition, GLP-1 has been reported to promote β-cell growth in rodents.11,12
Current Management of Type 2 Diabetes
A range of pharmacological agents are aimed at the different causes of diabetes. For example, sulfonylureas stimulate pancreatic release of endogenous insulin, while thiazolidinediones potentiate the action of insulin in the liver, adipose tissue, and skeletal muscle. Meglitinides also induce the secretion of insulin. Biguanides sensitize insulin in the liver and skeletal muscle. The α-glucosidase inhibitors are able to delay digestion and thus reduce post-prandial glucose. Incretin mimetics and dipeptidyl peptidase-4 (DPP-4) inhibitors enhance glucose-dependent insulin secretion. Finally, the newest agent for type 2 diabetes is the bile acid sequestrant colesevelam HCl, recently approved to improve glycemic control. Unlike most antidiabetic agents, which have only modest effects on dyslipidemia, bile acid sequestrants are established agents for lowering low-density lipoprotein (LDL) cholesterol.13 Statins, fibrates, niacin, and bile acid sequestrants have all been shown to significantly reduce LDL cholesterol, which is a major risk factor for CAD in patients with type 2 diabetes.

With lipid deregulation posing such a significant threat to type 2 diabetes patients, diabetes research has turned its focus toward bile acid sequestrants. Bile acid sequestrants have an established role in the management of LDL cholesterol.14,15 They are able to effectively decrease LDL cholesterol levels and modestly increase high-density lipoprotein (HDL) cholesterol.13 They were first shown to reduce cardiac events in the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT).16 This review discusses both the role of bile acid sequestrants in glucose homeostasis and the recent clinical evidence showing that these agents can be employed to alleviate the burden of type 2 diabetes.

Bile Acids
Bile acids are produced in the liver by the oxidation of cholesterol. They are secreted into the small intestine, where they facilitate the absorption of dietary fat and fat-soluble vitamins. Most bile acids excreted into the small intestine are reabsorbed in the terminal ileum and returned to the liver (enterohepatic circulation). The most abundant bile acids in humans include the primary bile acids—cholic acid (CA) and chenodeoxycholic acid (CDCA)—and their respective secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA).17 In addition to regulating the absorption of lipids, bile acids are versatile signalling molecules. They are ligands for both G-protein-coupled receptors (GPCRs) such as TGR5 and nuclear hormone receptors such as farnesoid X receptor-α (FXR-α).17–20 FXR-α is a bile acid receptor and the best characterized target of bile-acid-modulated effects to date.

Proposed Mechanisms of Bile Acid Sequestrants in Type 2 Diabetes
In the context of diabetes, the exact molecular mechanism by which bile acid sequestrants reduce blood glucose levels has not yet been fully elucidated, but several potential mechanisms have been proposed. Bile acids reduce their own biosynthesis from cholesterol through an elaborate negative feedback loop that involves both the liver and the intestine.21 The first pathway that governs this inhibitory mechanism is initiated by the bile-acid-mediated activation of FXR-α.22 FXR-α activation protects against accumulation of bile acids, which can prove toxic.

Binding of bile acids to FXR-α results in downregulation of bile acid synthesis from cholesterol both through direct action on hepatic FXR-α or indirectly via FXR-α-mediated induction of the fibroblast growth factor (FGF) 15 (in mice)/FGF19 (in humans) in the intestine (see Figure 1). Activation of FXR-α induces the hepatic expression of small heterodimer partner (SHP). In turn, SHP blocks the transcriptional activation of CYP7A1, the gene that encodes for the cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in the biosynthesis of bile acids from cholesterol. SHP inhibits transcription of CYP7A1 by repressing the nuclear receptor, the liver receptor homolog-1 (LRH-1).17,23,24

Hepatocyte nuclear factor 4α (HNF4α) regulates bile-acid biosynthesis,25 and also contributes to the feedback inhibition of CYP7A1 expression by bile acids. In the liver, SHP competes for binding to HNF-4α, which regulates the expression of genes involved in both bile acid synthesis (CYP7A1) and gluconeogenesis (including glucose-6-phosphatase, fructose-1,6-phosphatase, and phosphoenolpyruvate carboxykinase [PEPCK]) (see Figure 1).

Another receptor involved in bile acid signaling is TGR5, a guanine nucleotide-binding protein-coupled receptor (GPCR) activated by several bile acids (reviewed by Thomas et al.17).24 Initially associated with the immunomodulatory properties of bile acids, in vitro and in vivo studies have shown TGR5 signaling to modulate metabolism thanks to its effect on incretin production26 and mitochondrial energy homeostasis.27 TGR5 regulates expression of GLP-1, the incretin that modulates secretion of insulin. Effects on TGR5 signaling are another way by which bile acid sequestrants can induce glucose-lowering effects.

The enterohepatic circulation itself may function as an endocrine organ with autocrine, paracrine, and endocrine effects. FXR appears to be the primary modulator exerting multiple downstream effects that have an impact on glucose and lipid metabolism. Specifically, FXR’s downstream effects may play a role in modulating lipid metabolism (LXR and CYP7A1) and glucose control (FGF19 and GLP-1). Therefore, glucose modulation may occur via the gut, by meal-induced release of GLP-1, and/or via hepatic gluconeogenesis/glycogenolysis.
Bile Acid Sequestrants Take the Stage in Type 2 Diabetes
The American Diabetes Association (ADA) recommends that LDL cholesterol should be reduced by 30–40% in all patients with diabetes and overt CAD, as well as in patients with diabetes without overt CAD who are more than 40 years old, regardless of baseline LDL cholesterol levels.28 Despite these recommendations, many individuals have cholesterol levels that remain uncontrolled. More than 70% of adults with diabetes surveyed in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2000 failed to achieve the recommended LDL cholesterol goal. Only 3% simultaneously achieved their recommended goals for LDL cholesterol, HDL cholesterol (>40mg/dl/>1.0mmol/l), and triglycerides (<150mg/dl/<1.7mmol/l).29

The ADA recommends various classes of cholesterol-modifying drugs for treatment of dyslipidemia in patients with type 2 diabetes, with each class exerting different effects on the lipid profile. Statins, cholesterol absorption inhibitors (ezetimibe), fibrates, nicotinic acid (niacin), and bile acid sequestrants can each be used as monotherapy. Many of the recommended agents can be combined: for example, bile acid sequestrants have been shown to be safe and effective when combined with both statin and ezetimibe therapy. Indeed, the bile acid sequestrant colesevelam HCl (Choelestagel, Welchol) can reduce LDL cholesterol by 15–18% when used as monotherapy,30,31 while the combination of colesevelam HCl and a statin can reduce LDL cholesterol by as much as 48%.32 Recently, the ADA and the American College of Cardiology (ACC) published their consensus on lipoprotein management in patients with cardiometabolic risk, such as patients with inadequately controlled type 2 diabetes. The recommended levels for LDL cholesterol, non-HDL cholesterol, and apolipoprotein B (ApoB) for patients with known cardiovascular disease (CVD) or diabetes with one or more major CVD risk factors (smoking, hypertension, family history of premature CAD) are <70mg/dl, <100mg/dl, and <80mg/dl, respectively. For patients with diabetes but no other CVD factors, LDL-C, non-HDL, and ApoB should be <100mg/dl, <130mg/dl, and <90mg/dl, respectively.33

Cholestyramine, colestimide, and the newer agent colesevelam are bile acid sequestrants and their efficacy is being evaluated in type 2 diabetes patients. While the first two agents are under clinical investigation, colesevelam recently received approval from the US Food and Drug Administration (FDA) as an adjunct to existing antidiabetes therapy for improving glycemic control in patients with type 2 diabetes. Kawabata et al. have reported promising preliminary results from a clinical trial investigating the effects of colestimide on glycemic control. Individuals with type 2 diabetes and dyslipidemia (n=27) receiving colestimide 3g/day over three months showed a significant reduction in glycated hemoglobin (HbA1c) (0.91%; p<0.0001) and a non-significant reduction in fasting plasma glucose levels (12mg/dl/0.7mmol/l; p=0.08). In addition, insulin resistance was significantly reduced, while insulin secretory capacity was unaffected.34 Findings with cholysteramine were the trigger for investigating the role of bile acid sequestrants on glucose metabolism. Over 20 years ago, cholestyramine had yielded substantial reduction in LDL cholesterol (20%) as well as non-fatal myocardial infarction and CAD death (19%).16 A decade later, evidence from a lipidlowering trial in patients with type 2 diabetes suggested that, in addition to lowering LDL cholesterol, cholestyramine also improved glucose metabolism.35 This observation led investigators to assess the glucoselowering effects of the newer bile acid sequestrant colesevelam HCl.

Colesevelam Mechanism of Action
As with all bile acid sequestrants, colesevelam binds bile acids in the intestine and impedes their reabsorption. As the bile acid pool becomes depleted, cholesterol 7-α-hydroxylase is upregulated, increasing the conversion of cholesterol to bile acids. As more and more cholesterol is broken down and converted, liver cells have an increased demand for cholesterol. As a result, the transcription and activity of the cholesterol biosynthetic enzyme hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase are upregulated, increasing the number of LDL receptors in the liver. These compensatory effects lead to increased clearance of LDL cholesterol from the blood, resulting in decreased serum LDL cholesterol levels.36 For glycemic control, the bile acid receptor FXR-α appears to be the primary modulator exerting multiple downstream effects that have an impact on glucose metabolism.
Recent Clinical Evidence
The Glucose-Lowering effect Of WelChol Study (GLOWS), a 12-week randomized, double-blind pilot study, evaluated the effects of colesevelam HCl 3.75g/day on glycemic control in patients (n=65) with inadequately controlled type 2 diabetes (HbA1c 7.0–10.0%).37 The addition of colesevelam HCl to existing metformin and/or sulfonylurea therapy significantly reduced HbA1c compared with placebo (0.5%; p=0.007). In patients with a baseline HbA1c of at least 8.0%, the addition of colesevelam HCl reduced HbA1c by 1% relative to placebo (p=0.002). Colesevelam HCl also achieved significant reductions in LDL cholesterol (11.7%; p=0.007), total cholesterol (7.3%; p=0.019), and LDL particle concentration (p=0.037).37

Findings of phase III double-blind, placebo-controlled trials in more than 1,000 individuals with type 2 diabetes evaluating the efficacy and tolerability of adding colesevelam HCl to existing antidiabetes monotherapy or combination therapy have recently been published.38,39 This clinical trial program included a 16-week trial investigating the effects of colesevelam HCl added to insulin-based therapy and two independent 26-week trials investigating the effects of colesevelam HCl added to either metformin or sulfonylurea-based therapy.40 All three studies reported significant reductions in HbA1c and LDL cholesterol with colesevelam HCl versus placebo.

Colesevelam HCl Added to Metformin
Bays et al. evaluated the glucose-lowering effect of colesevelam in a double-bind, randomized, placebo-controlled trial that included patients with inadequately controlled type 2 diabetes (HbA1c 7.5–9.5% inclusive) receiving metformin monotherapy or metformin in combination with other oral antidiabetic agents. Intent-to-treat analysis revealed that colesevelam achieved reductions in HbA1c of 0.54% (p<0.001) compared with placebo; the effect was pronounced from as early as week six and remained significant up to week 26 (p=0.002). Significantly more colesevelamtreated (41%) than placebo-treated patients (22%) had a 0.7% reduction of HbA1c by week 26 (p=0.02). Among the metformin monotherapy cohort, colesevelam-treated patients showed a mean 0.47% reduction in HbA1c and a mean 17.8μmol/l reduction in fructosamine compared with placebo by week 26. Fasting plasma glucose was decreased at week 26, with significant reductions observed at weeks six and 12 (p<0.05 versus placebo).38 The colesevelam-treated group had a 15.9% reduction in LDL cholesterol concentration relative to placebo (p<0.001). Triglycerides, HDL cholesterol, and apolipoprotein A-I levels did not increase significantly. Colesevelam HCl Added to Insulin Therapy
The study by Goldberg et al. enrolled subjects 18–75 years of age with inadequately controlled type 2 diabetes (baseline HbA1c level 7.5–9.5% inclusive) receiving insulin therapy alone or insulin combined with one or more oral antidiabetes agents (biguanide, or biguanide–sulfonylurea combination, or sulfonylurea, or thiazolidinedione, or meglitinide). Overall, the mean (standard error [SE]) change in HbA1c level from baseline to week 16 was -0.41% (0.07%) for the colesevelam-treated group and 0.09% (0.07%) for the placebo group (treatment difference -0.50% [0.09%], 95% confidence interval [CI] -0.68 to -0.32%; p<0.001). Specifically, in the insulin monotherapy cohort the mean change in HbA1c level from baseline to week 16 was -0.59% compared with placebo (p<0.001). This profound effect of colesevelam was consistent in the insulin + oral antidiabetic cohort, where colesevelam reduced HbA1c levels by -0.41% compared with the 0.03% increase observed in the placebo group (p<0.001). Colesevelam also reduced fasting plasma glucose and fructosamine levels and lipid control measures. The median percent change in triglyceride with colesevelam and placebo was 22.7 versus 0.3% (p<0.001). As expected, the colesevelamtreated group had a 12.8% reduction in LDL cholesterol concentration relative to placebo (p<0.001), addressing the treatment goals suggested by ADA and the ACC.41

Colesevelam HCl Added to Sulfonylurea Therapy
Fonseca et al. analyzed the efficacy and safety of colesevelam in type 2 diabetes patients receiving sulfonylurea-based therapy. The least squares (LS) mean change in HbA1c from baseline to week 26 was -0.32% in the colesevelam group and +0.23% in the placebo group, producing a treatment difference of -0.54% (p<0.001).39 Specifically, in the patients receiving sulfonylurea monotherapy, the addition of colesevelam resulted in a reduction in HbA1c of 0.79% (p<0.001), a significant treatment difference compared with placebo. The LS mean percent change in LDL cholesterol from baseline to week 26 was -16.1% in the colesevelam group— significantly lower than the +0.6% observed in the placebo group (p<0.001). Triglycerides increased significantly in patients receiving colesevelam (median percent change 17.7%; p<0.001 versus placebo). Colesevelam yielded significant reductions in LDL-C, total cholesterol, non- HDL-C, and ApoB by week 26, offering a treatment alternative that improves glucose balance while controlling dyslipidemia.39

Safety
Overall, colesevelam displays a reasonable tolerability profile and mild adverse effects. The most frequent treatment-emergent adverse events occurring in type 2 diabetes patients treated with colesevelam were gastrointestinal disorders, mainly constipation.37,41 Other, less common, gastrointestinal adverse effects were dyspepsia, flatulence, and nausea.37,41 Colesevelam caused no serious adverse events and no difference compared with placebo in episodes of hypoglycemia or weight gain compared with placebo.37 As it is a non-systemically absorbed agent and therefore has a low propensity for drug–drug interactions, it provides an additional advantage to type 2 diabetes patients, who often require complicated therapeutic regimens.37

Of note, triglyceride levels were significantly higher with colesevelam HCl compared with placebo.37–39,41 The long-term consequences of this elevation in triglyceride levels are as yet unknown and the summary of product characteristics (SPC) for colesevelam HCl state that the agent should be used with caution when treating patients with triglyceride levels ≥3.4mmol/l.36 In a consensus statement by the ACC/ADA on lipid management in highcardiometabolic- risk patients, triglyceride was associated as a univariate predictor of cardiovascular disease in some studies; however, triglycerides are often not an independent predictor in multivariate analyses. This may be because triglycerides are highly linked to abnormalities in HDL and LDL.42 In addition, there are no clinical trial data establishing that lowering triglycerides in individuals with or without diabetes independently leads to lower cardiovascular disease events when adjusted for changes in HDL.42 Caution is also recommended when the agent is used to treat patients with a susceptibility to vitamin K or fat-soluble vitamin deficiencies. For this group of patients, monitoring vitamin A, D, and E levels and assessing vitamin K status through the measurement of coagulation parameters is recommended, and the vitamins should be supplemented if necessary. Furthermore, anticoagulant therapy should be monitored closely in patients receiving warfarin or similar agents, since bile acid sequestrants have been shown to interfere with warfarin’s anticoagulant effect.36
Summary and Conclusion
Glucose regulation is orchestrated by several hormones exerting their effects on multiple target tissues. Despite the current advances in pharmacological therapies for diabetes, achieving and maintaining optimal glycemic control remains elusive. Innovative interventions to complement the current therapeutic armamentarium avoiding any clinical limitations, such as the risk of hypoglycemia and weight gain, are needed. New clinical evidence has emerged confirming the therapeutic potential of bile acid sequestrants in glycemic control. The exact mechanism by which colesevelam lowers glucose has not been determined; however, the bile acid receptor FXR-α may be the primary modulator exerting multiple downstream effects that influence glucose metabolism. Colesevelam contributes to the management of both glucose and lipid abnormalities in diabetes, helping patients aim for two risk factors in diabetes that contribute towards both macro- and microvascular disease. Its good efficacy in terms of lowering glucose levels and excellent safety profile provide patients with type 2 diabetes with a promising drug that can be used in conjunction with a range of established antidiabetes agents.■

Editorial assistance for the preparation of this manuscript was supported by an educational grant from Daiichi Sankyo, Inc.

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