Bile acid sequestrants (BASs) are efficacious drugs for lowering serum levels of LDL:-C. Three of these agents are in widespread use: colestipol, cholestyramine, and colesevelam. They act as anion exchange resins and are not absorbed systemically. All are orally administered and serve to bind bile acids in transit through the gut. They reduce LDL-C levels by increasing the diversion of hepatic cholesterol for BA biosynthesis and by stimulating increased expression of the LDL receptor and thereby increasing LDL-C clearance [17]. All of these drugs increase fecal elimination of BA significantly [18, 19] and can provide dose-dependent reductions in LDL-C of 12–30 %. The impact of these drugs on high-density lipoprotein cholesterol (HDL-C) tends to be modest (1–3 %). They should be taken with meals when intraluminal BA levels would be highest. They provide additive reductions in LDL-C when patients are concomitantly treated with statins. These drugs are contraindicated with patients with hypertriglyceridemia as the BAS can exacerbate the elevation in triglycerides.

In one study evaluating the addition of colesevelam to statin therapy, there was a 21 mg/dL incremental reduction in LDL-C compared to placebo and increased the number of patients able to reach an LDL-C < 100 mg/dL fourfold [20]. In addition, colesevelam therapy induced an incremental 23 % reduction in high-sensitivity C-reactive protein. Combination therapy with colesevelam and statins is safe and efficacious and can allow for the use of a lower dose of a statin and still attain a significant LDL-C reduction [12, 21–23]. The BAS can also be safely combined with ezetimibe [24] and fenofibrate [25] with additive reductions in LDL-C. Of interest is the observation that colesevelam significantly reduces LDL particle number and increases LDL particle size [26, 27].

Gastrointestinal side effects dominate the adverse event profile with all of the BASs. These include constipation, flatulence, and, occasionally, diarrhea. Rarely, bowel obstruction can occur [28]. There is no clinically significant risk for adverse events related to renal, hepatic, or hematologic function or drug-drug interactions since the drugs do not act systemically. It is generally advisable to take other medications 1 h before or 2 h after ingesting a BAS since these resins can also bind and prevent their absorption.

The Lipid Research Clinics Coronary Primary Prevention Trial evaluated the efficacy of cholestyramine for reducing first-time cardiovascular events in 3806 men with hypercholesterolemia. The trial was performed in the 1980s prior to the introduction of statins. Cholestyramine dosed at 24 g/day over a mean duration of 7.4 years. was associated with a significant 19 % reduction in risk for the primary composite end point of nonfatal myocardial infarction (MI) and mortality. Evaluated individually, nonfatal MI was reduced by 19 % and CV mortality decreased by 25 %. All-cause mortality was not decreased significantly. In addition, the incidence rates for new positive treadmill stress tests, angina pectoris, and need of coronary artery bypass grafting (CABG) surgery were decreased by 25, 20, and 21 %, respectively, in the cholestyramine group compared to the placebo treatment arm. [29] This trial demonstrated that a 20 % reduction in LDL-C correlates with a significant reduction in risk for CV events [30].

A variety of small coronary angiographic studies evaluated the capacity of BAS used in combination with other lipid-lowering medications to impact rates of CAD progression. In the National Heart, Lung and Blood Institute Type II Coronary Intervention Study, patients with dyslipidemia and CAD were treated with a low-fat, low-cholesterol diet and randomly assigned to treatment with either 6 g cholestyramine four times daily or placebo. This double-blind study evaluated the effects of cholestyramine on the progression of CAD as assessed by quantitative coronary angiography (QCA) in 116 patients treated for 5 years [31]. After adjustment for risk factor covariates between groups, 33 % of placebo-treated and 12 % of cholestyramine-treated patients manifested lesion progression among target lesions > 50 % occlusive (p < .05). The Cholesterol-Lowering Atherosclerosis Study (CLAS) was another randomized, placebo-controlled QCA trial that evaluated the impact of combined colestipol (30 g daily) and nicotinic acid (4.2 g daily) treatment in 162 men aged 40–59 years with a history of CABG revascularization [32]. During 2 years of treatment, there was a 43 % reduction in LDL-C and a 37 % increase in high-density lipoprotein cholesterol (HDL-C). Treated patients experienced a reduction in the mean number of lesions with progression as well as development of new coronary atheromatous plaque or occlusive disease in saphenous vein bypass grafts (all P < .03). This trial also demonstrated perceptible improvement in overall coronary status, which occurred in 16.2 % of colestipol-niacin-treated vs 2.4 % placebo-treated (P = .002) patients. In a subgroup analysis of the CLAS trial, 103 patients who remained on therapy demonstrated even more impressive results with 4 years of therapy [33]. Drug treatment was associated with continued improvement in nonprogression (52 % drug- vs 15 % placebo-treated) as well as regression (18 % drug- vs 6 % placebo-treated) of atherosclerotic plaque in coronary artery lesions. Significantly fewer drug-treated subjects developed new atherosclerotic plaques in coronary arteries (14 % drug- vs 40 % placebo-treated) and saphenous vein bypass grafts (16 % drug- vs 38 % placebo-treated).

Other studies also explored the impact of combination therapy on atherosclerotic disease burden using combinations of lipid-lowering therapies that included BAS. In the Familial Atherosclerosis Treatment Study, patients underwent dietary counseling and were randomly assigned to one of three treatments: lovastatin (20 mg twice daily) and colestipol (10 g three times daily); niacin (1 g four times daily) and colestipol (10 g three times daily); or conventional therapy (diet, exercise) with placebo [34]. Mean changes in LDL-C and HDL-C were relatively small in the conventional treatment group (−7 and +5 %, respectively). In the treatment arms, these changes were much more significant with lovastatin/colestipol (−46 and +15 %) or niacin/colestipol (−32 and +43 %). In the placebo group, 46 % of patients experienced plaque lesion progression, and 11 % experienced regression. In the active treatment arms, plaque progression occurred in 21 % of those treated with lovastatin and colestipol and 25 % of those treated with niacin and colestipol. Significantly more patients experienced plaque regression in the lovastatin/colestipol (32 %) and niacin/colestipol (39 %) treatment groups compared to placebo (both P < 0.005). Multivariate regression LDL-C reduction and HDL-C elevation both correlated with regression of established coronary plaques. The University of California, San Francisco, Specialized Center of Research Study (UCSF-SCOR) evaluated the impact of therapy with a combination of colestipol, niacin, and lovastatin on CAD progression in 72 patients with heterozygous familial hypercholesterolemia over 2 years of follow-up [35]. The primary outcome measure was within-patient mean change in percent area stenosis. The mean change in percent area stenosis for the control and treatment arms was +0.80 (net progression) and −1.53 (net regression), respectively (P = .039). The change in percent area stenosis correlated with attained levels of LDL-C. In the St. Thomas Arteriosclerosis Regression Study (STARS), the use of 16 g of cholestyramine plus dietary measures was more efficacious than placebo or diet alone for promoting coronary plaque regression in men with established CAD [36]. Clearly, BAS used either alone or in combination with other lipid-lowering medications impacts CAD in a beneficial manner in terms of both disease progression and risk for CV events.

In addition to their lipid-lowering effects, the BASs also have the capacity to beneficially impact glucose metabolism [37–39]. In general, the use of a BAS can reduce hemoglobin A1C levels by approximately 0.5 % and also beneficially impact fasting and postprandial serum glucose levels in a dose-dependent manner. The BASs have been shown to provide incremental reductions in hemoglobin A1C levels when used in combination with metformin [40], insulin [41], or sulfonylurea drugs [42]. In patients with both dyslipidemia and type 2 DM, BAS therapy can provide efficacy for reducing atherogenic lipoprotein burden in serum and improving glycemic control.

There appear to be multiple mechanisms by which the BAS may help to improve glycemic control. The first is mediated by FXR and results in less hepatic gluconeogenesis (via inhibition of phosphoenolpyruvate carboxykinase) [43] and increased glycogen synthesis [44, 45]. The second involves TGR-5, a G-protein-coupled bile acid receptor [46, 47]. As bile acids increase in the luminal compartment of the ileum, they can bind TGR-5, which in turn activates the production of glucagon-like peptide-1 (GLP-1) by enteric L cells [48]. As GLP-1 levels rise, insulin production is stimulated by pancreatic islet cells, and serum glucose levels improve. There is also evidence that activation of FGF19 suppresses hepatic gluconeogenesis [49]. Yet other mechanisms may also play a role.