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Original Article

Reducing Cardiovascular Complications of Type 2 Diabetes by Targeting Multiple Risk Factors

Reasner, Charles A MD

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Journal of Cardiovascular Pharmacology: August 2008 - Volume 52 - Issue 2 - p 136-144
doi: 10.1097/FJC.0b013e31817ffe5a
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Diabetes affects more than 194 million people worldwide and more than 16 million in the United States.1,2 The prevalence of diabetes is increasing, with the lifetime risk for Americans born in 2000 estimated at 38.5% for women and 32.8% for men.3 Diabetes is diagnosed based on the level of hyperglycemia, which has been shown to increase the risk of microvascular complications, including retinopathy, neuropathy, and nephropathy.4-6 Hyperglycemia is caused by a combination of insulin resistance and a relative or absolute deficiency in insulin secretion. Because insulin affects the metabolism of various lipids and lipoproteins, it is not surprising that insulin resistance leads to a characteristic pattern of dyslipidemia, referred to as “atherogenic dyslipidemia” in patients with type 2 diabetes; this pattern includes elevated triglyceride levels, low high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense low-density lipoprotein (LDL) particles.7,8 While hyperglycemia increases the risk of microvascular complications, atherogenic dyslipidemia is the major risk factor for macrovascular complications in the patient with diabetes.

Diabetes is the sixth leading cause of death in the United States.9 Cardiovascular disease risk is 2 to 4 times greater in individuals with type 2 diabetes relative to individuals without diabetes.10,11 In fact, the risk of dying from coronary heart disease for patients with type 2 diabetes is comparable to that for individuals without diabetes who have had a myocardial infarction.12 As a result, approximately two-thirds of individuals with diabetes die from heart disease or stroke.9

Intensive multifactorial treatment of hyperglycemia, dyslipidemia, and hypertension in patients with type 2 diabetes can halve the incidence of cardiovascular and microvascular events.13 For example, in a 5.7-year observational study in patients with type 2 diabetes, the incidence of coronary heart disease or stroke was inversely correlated with the number of treatment targets achieved (glycosylated hemoglobin (A1C) <7.0%, LDL cholesterol (LDL-C) <100 mg/dL (2.6 mmol/L), and blood pressure <130/80 mm Hg).14 Therefore, consensus guidelines, including those of the American Diabetes Association,15 the American Association of Clinical Endocrinologists,16 and the International Diabetes Federation,17 advocate aggressive management of blood glucose, lipid profile (LDL-C, HDL-C and triglycerides), and blood pressure to minimize complications in patients with type 2 diabetes (Table 1). This often requires multiple medications, including antidiabetic and lipid-lowering agents (and antihypertensive agents, if necessary), to sufficiently manage all aspects of the pathology of this disease. Unfortunately, only approximately 7% of patients with diabetes achieve control of their hyperglycemia (A1C <7.0%), dyslipidemia (total cholesterol <200 mg/dL [5.18 mmol/L]), and hypertension (blood pressure <130/80 mm Hg).18

Treatment Goals for Patients With Type 2 Diabetes


Hyperglycemia, quantified by an elevated A1C level, is directly correlated with the development of microvascular complications in patients with type 2 diabetes.19-22 In the United Kingdom Prospective Diabetes Study (UKPDS), intensive glycemic control with insulin or a sulfonylurea significantly reduced the risk of microvascular complications in 3,867 newly diagnosed patients with type 2 diabetes.5 In fact, a follow-up UKPDS study revealed that each 1% reduction in A1C was associated with a 37% reduction in risk of microvascular complications.22 Therefore, the goal of antidiabetic therapy is to achieve an A1C level as close to normal as possible without inducing clinically significant hypoglycemia.


The American Diabetes Association and the International Diabetes Federation recommend initiating treatment of type 2 diabetes with lifestyle changes (modified diet and increased exercise) and metformin.2,15 If A1C remains elevated after 3 months of treatment, additional oral antidiabetic agents, including α-glucosidase inhibitors, dipeptidyl peptidase IV inhibitors, meglitinides, sulfonylureas, and thiazolidinediones, may be added. Generally, these agents reduce A1C levels by 0.5% to 2.0% as monotherapy (Table 2). In addition, the injectable glucagon-like peptide-1 (GLP-1) analogue exenatide is now approved for use with metformin, sulfonylurea, or thiazolidinedione therapy. Exenatide improves glycemic control and results in clinically significant weight loss in the majority of patients.

Oral Antidiabetic Agents: Classes and Mechanism of Action

Metformin is the recommended first-line therapy because it has been shown to reduce mortality in patients with type 2 diabetes.23 In the UKPDS, metformin was found to reduce cardiovascular events.23 In addition, metformin is well tolerated by most individuals and has a wide dosage range for titration. Metformin improves glycemic control by increasing insulin sensitivity (via increased peripheral uptake of glucose) and reducing hepatic gluconeogenesis.16 Sulfonylureas and thiazolidinediones are alternative therapeutic options that can be dosed alone or in combination with metformin if monotherapy is not sufficient to achieve glycemic control.17,24 Sulfonylureas improve glycemic control by stimulating the release of insulin from pancreatic β-cells and possibly increasing sensitivity of peripheral tissues to insulin.16 Alternatively, thiazolidinediones improve glycemic control by decreasing insulin resistance in the periphery and liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output.16

Glycemic control tends to deteriorate over time even when an individual is compliant with their treatment regimen as a result of the progressive decline in pancreatic β-cell function. As a result, more intensive treatment, including monotherapy dosage increases, combination therapy with multiple oral antidiabetic agents,17 the addition of the injectable agent exenatide, and eventually the initiation of insulin therapy,24 is required to maintain glycemic control.25


Insulin resistance is associated with the overproduction of very-low-density lipoproteins (VLDLs), which contain triglycerides. It is hypothesized that this ultimately leads to triglyceride enrichment of LDL and HDL and increased lipolysis, resulting in small, dense LDL and HDL (the latter of which is catabolized quickly, resulting in low HDL-C levels).11,26

Studies have shown that improving the lipid profile in patients with type 2 diabetes reduces overall mortality and the risk of cardiovascular events. Elevated total cholesterol and LDL-C levels have a clear association with coronary heart disease risk.27 In both the Cholesterol and Recurrent Events study and the Scandinavian Simvastatin Survival Study, reducing LDL-C levels decreased the risk of coronary heart disease in patients with diabetes.28,29 In the UKPDS, HDL-C was second only to LDL-C as a predictor of cardiovascular disease. Observational data demonstrated that a 38.7 mg/dL (1.00 mmol/L) increase in LDL-C was associated with a 57% increase in cardiovascular disease endpoints, while a 4 mg/dL (0.10 mmol/L) increase in HDL-C was associated with a 15% decrease in cardiovascular disease endpoints.30 Additionally, triglyceride concentrations are generally inversely correlated with HDL-C concentrations. However, the independent relationship of elevated plasma triglycerides to vascular risk remains controversial.31

HMG-CoA Reductase Inhibitors (Statins)

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert their LDL-C-lowering effect by inhibition of HMG-CoA reductase, the enzyme required for the rate-limiting step in cholesterol biosynthesis (Table 3).

Lipid-Lowering Drugs: Main Classes and Mechanisms of Action

Numerous clinical trials have shown improved cardiovascular outcomes with statin therapy in individuals with type 2 diabetes.13,28,32,33 In the Heart Protection Study,34 the effects of statin were evaluated in a cohort of 5,963 adults with type 2 diabetes and total cholesterol >135 mg/dL [3.50 mmol/L].33 In this study, treatment with simvastatin 40 mg/d significantly reduced (by approximately 25%) the risk of major coronary events, stroke, and revascularization compared with placebo.33 Results also demonstrated that the benefits of lipid-lowering therapy are irrespective of baseline LDL-C levels in individuals with coronary disease, other occlusive arterial disease or diabetes.34 In individuals presenting with LDL-C <100 mg/dL (2.59 mmol/L), further reducing LDL-C levels with simvastatin significantly reduced the incidence of major vascular events compared with placebo (16.4% vs. 21.0%; P = 0.0006).34 Furthermore, these benefits were in addition to those achieved with pre-existing drug regimens such as aspirin, β-blockers, and angiotensin converting enzyme (ACE) inhibitors.

The benefits of reducing LDL-C levels were confirmed in the Collaborative Atorvastatin Diabetes Study, which assessed the efficacy of atorvastatin 10 mg/d for the prevention of cardiovascular disease in 2,838 patients with type 2 diabetes and LDL-C ≤160 mg/dL (4.14 mmol/L).35 This trial was stopped 2 years early because significant benefits were observed at the second interim analysis. After a median follow-up of 3.9 years, atorvastatin significantly improved the primary endpoint, risk of an acute coronary heart disease event, coronary revascularization procedure, or stroke (hazard ratio [HR] 0.63; 95% CI 0.48-0.83; P = 0.001 vs. placebo). Assessed separately, atorvastatin reduced the risk of an acute coronary event by 36% (95% CI, −55 to −9), coronary revascularization by 31% (−59 to 16), stroke by 48% (−69 to −11), and death from any cause by 27% (−48 to 1; P = 0.059).35


Fibrates activate the peroxisome proliferator-activated receptor, which ultimately results in modest reductions in LDL-C and elevations in HDL-C. Fibrates increase lipolysis and elimination of triglyceride-rich particles from plasma. The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles to large, buoyant particles, the latter of which have a greater affinity for cholesterol receptors and are catabolized rapidly; these agents may also increase HDL-C (Table 3).

Beneficial lipid effects with fibrates were demonstrated in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial. This double-blind study in 2,531 individuals, many of which had diabetes, found that gemfibrozil 1200 mg/d significantly reduced mortality and major coronary events in men with coronary heart disease, whose primary lipid abnormality was low HDL-C.36 Results indicated that increasing HDL-C with gemfibrozil in individuals with low HDL-C (≤40 mg/dL [1.0 mmol/L]) and normal LDL-C (≤140 mg/dL [3.6 mmol/L]) significantly reduced the risk of death from coronary heart disease or nonfatal myocardial infarction compared with placebo (by 22%).36 In addition, treatment was especially effective in individuals with diabetes, significantly reducing coronary heart disease events.36 Overall, the study demonstrated a clinical benefit of lipid-lowering therapy to raise HDL-C and lower triglycerides and LDL-C in patients with coronary heart disease.

Bile Acid Sequestrants

Bile acid sequestrants reduce LDL-C by binding bile acids in the intestine, which depletes the bile acid pool, stimulating conversion of cholesterol into bile acids. This increases the demand for cholesterol in the liver, increasing hepatic LDL receptors, resulting in increased clearance of LDL-C and decreased serum LDL-C levels (Table 3).37

Bile acid sequestrants have long been used to reduce LDL-C in individuals with primary hypercholesterolemia. The Lipids Research Clinics Coronary Primary Prevention Trial was a randomized, double-blind study in 3,806 individuals with total cholesterol >265 mg/dL (6.88 mmol/L) and LDL-C >190 mg/dL (4.9 mmol/L) to evaluate the effects of cholestyramine on cholesterol levels and the risk of coronary heart disease.38 Those receiving cholestyramine reported reductions of 13.4% and 20.3% for total cholesterol and LDL-C, respectively. In addition, the cholestyramine group experienced a significant reduction in risk of coronary heart disease, death, and/or nonfatal myocardial infarction (19%; P < 0.05).38 These results were the first to suggest that reducing LDL-C levels can reduce the incidence of coronary heart disease morbidity and mortality in those at high risk for coronary heart disease.


Niacin can improve LDL-C and triglyceride levels, presumably by blocking fatty acid transport from adipose tissues. By inhibiting lipolysis in adipose tissue, hepatic triglyceride esterification is decreased and lipoprotein lipase activity is increased (Table 3).

The HDL-Atherosclerosis Treatment Study was a 3-year, double-blind trial to evaluate the efficacy of various lipid-lowering treatments. Individuals with low HDL-C (≤35 mg/dL for men, ≤40 mg/dL for women) and LDL-C ≤145 mg/dL (3.76 mmol/L) were randomized to one of four treatments: placebo, simvastatin (10-20 mg/d) plus niacin (2-4 g/d), antioxidant vitamins [consisting of vitamin E (800 IU/d), vitamin C (1000 mg/d), beta carotene (25 mg/d), and selenium (100 μg/d)], or simvastatin plus niacin plus antioxidant vitamins.39 Treatment with simvastatin plus niacin significantly reduced LDL-C and triglycerides by an average of 42% and 36%, respectively, and increased HDL-C by 26%. The group receiving antioxidant vitamin supplementation in addition to simvastatin plus niacin reported similar LDL-C and triglyceride reductions relative to the simvastatin plus niacin group; however, the HDL-C increase (+18%) was not as high as with simvastatin plus niacin alone (+26%).39 Furthermore, stenosis progressed with placebo (+3.9%), antioxidant vitamin (+1.8%), and simvastatin plus niacin plus antioxidant vitamin treatment (+0.7%), while stenosis regressed in the simvastatin plus niacin group (−0.4%). The frequency of the clinical endpoint (a composite of death from cardiovascular causes, nonfatal infarction, or revascularization procedure) was 24% with placebo, 21% with antioxidant vitamins, 14% with simvastatin plus niacin plus antioxidant vitamins, and 3% with simvastatin plus niacin alone.39 Importantly, the composite clinical endpoint of death from coronary causes, confirmed myocardial infarction or stroke, or revascularization was reduced by 90% in the simvastatin plus niacin group compared with placebo (P = 0.03).39


The American Diabetes Association recommends lipid goals of LDL-C <100 mg/dL [2.6 mmol/L; <70 mg/dL (1.8 mmol/L) in those with overt cardiovascular disease], triglycerides <150 mg/dL (1.7 mmol/L), and HDL-C of >40 mg/dL for men or >50 mg/dL for women.15,27 In addition, the American Diabetes Association recommends that LDL-C be reduced by 30% to 40% in all patients with diabetes and overt cardiovascular disease, as well as in patients with diabetes over 40 years of age without overt cardiovascular disease, regardless of baseline LDL-C levels.15 Although dyslipidemia can be moderately reduced with lifestyle modifications and adequate glycemic control, lipid-lowering therapy is generally needed to reach these recommended targets.11 Treatment of dyslipidemia may involve a statin, fibrate, bile acid sequestrant, niacin, or cholesterol absorption inhibitor (Table 3). Initial treatment to reduce LDL-C generally involves a statin, which as a class have been shown to reduce the risk of cardiovascular events.15 Fibrates or niacin may be added if HDL-C and triglyceride levels are not at goal with lifestyle changes and statin therapy. Fibrates produce modest reductions in LDL-C while increasing HDL-C. Niacin can improve LDL-C, HDL-C, and triglyceride levels. Bile acid sequestrants can significantly reduce LDL-C (by 15% to 25% in monotherapy),37 and can be combined with statins, fibrates, and cholesterol absorption inhibitors to further reduce LDL-C levels.


Tight glycemic control results in regulation of LDL and HDL particles and may be associated with moderate reductions in LDL-C levels and alterations in LDL composition.40 In addition, a reduction in atherogenic triglycerides may occur, resulting in a subsequent rise in large HDL particles. In contrast, glycemic control has minimal or no effect on HDL-C levels,41 although it may be associated with compositional changes to HDL lipoproteins, such as increasing HDL-2, which is antiatherogenic.42

Several oral antidiabetic agents affect both hyperglycemia and dyslipidemia, although they generally do not provide sufficient control of both parameters on their own.43 Metformin has been shown in several clinical studies to reduce total cholesterol, LDL-C, and triglyceride levels, while increasing HDL-C levels.44-48 Clinical studies with pioglitazone have shown that this agent may reduce triglyceride levels, elevate HDL-C levels, and improve LDL particle size and susceptibility to oxidation.49,50 In one clinical study, sitagliptin reduced total cholesterol, triglycerides, and non-HDL-C while increasing HDL-C.51 Tight glycemic control with insulin may reduce triglyceride levels.42 In one study, intensive insulin therapy for 4 weeks significantly reduced triglyceride levels (from 260 ± 28 mg/dL to 133 ± 14 mg/dL; P < 0.001) in individuals with uncontrolled type 2 diabetes on metformin or sulfonylurea monotherapy.42 Finally, there is accumulating evidence that bile acid sequestrants significantly reduce glucose levels in addition to their established LDL-C-lowering properties.52

Targeting Both Lipid and Glucose Metabolism via Bile Acid Modulation

Emerging evidence indicates that lipid and glucose homeostasis are interrelated through various metabolic pathways.53-55 Both are affected by bile acid-activated nuclear hormone receptor signaling pathways in the liver and other tissues.53 Bile acids play a role in the absorption of fat and in cholesterol metabolism.53 They are synthesized in the liver from cholesterol, forming the main route of cholesterol catabolism.53

Evidence suggests that bile acids provide negative feedback regulation by binding to the farnesoid X receptor alpha (FXRα), preventing activation of the bile acid synthesis pathway and thus preventing accumulation of toxic levels of bile acids in the liver. Bile acid synthesis is inhibited by small heterodimer partner (SHP) and fibroblast growth factor 15/19 (FGF15/19), which interact with hepatocyte nuclear factor 4 (HNF-4) and prevent transcription of cholesterol 7-alpha hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis. Furthermore, bile acid synthesis is also regulated by another FXR-dependent pathway involving peroxisome proliferator-activated receptor.

Bile acids also act as signaling molecules in pathways involved in glucose homeostasis, by activating FXRα, which regulates gluconeogenesis and glucagon synthesis.53 Bile acids can also activate the G-protein-coupled receptor TGR5,56 which is thought to have a role in insulin sensitization in diabetes-associated obesity.53 In vitro, TGR5 induces GLP-1, the incretin hormone associated with insulin production.57 In addition, bile acids may alter the expression of genes involved in hepatic gluconeogenesis including phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphate, and fructose-1,6-bisphosphatase via effects on HNF-4.58-60 Therefore, agents that modulate bile acids could potentially affect both cholesterol and glucose metabolism (Fig. 1).

Bile acid synthesis and glucose metabolism are regulated in the liver and intestine via related pathways involving nuclear hormone receptors. Bile acids activate FXRα in the liver, resulting in upregulation of SHP, an inhibitor of gluconeogenesis and bile acid synthesis. Bile acids also activate FXRα in the intestine, resulting in upregulation of FGF15/19, which ultimately inhibits bile acid synthesis. CYP7A1, cholesterol 7-alpha hydroxylase; GLP-1, glucagon-like peptide-1; GR, glucocorticoid receptor; FXRα, farnesoid X receptor alpha; FGF15/19, fibroblast growth factor 15/19; Foxo1, forkhead transcription factor 1; HNF-4, hepatocyte nuclear factor 4; JNK, Jun N-terminal kinase; LRH-1, liver receptor homologue 1; PPARα, peroxisome proliferator-activated receptor alpha; PEPCK, phosphoenolpyruvate carboxykinase; SHP, small heterodimer partner.

Clinical Evidence of Bile Acid Sequestrants Improving Glycemic Control

Bile acid sequestrants bind bile acids and prevent their reabsorption in the intestine, thereby depleting the bile acid pool. By altering the bile acid pool, these agents may alter the effects of various nuclear receptors, including FXRα, resulting in improved glycemic control.

Evidence supporting the beneficial glycemic effects of bile acid sequestrants was reported over a decade ago from a lipid-lowering study.61 A double-blind study investigated the efficacy and tolerability of cholestyramine in 21 patients with dyslipidemia (LDL-C >3.6 mmol/L and triglycerides >3.4 mmol/L) and type 2 diabetes receiving glyburide or insulin therapy.61 Treatment with cholestyramine 16 g/d for 6 weeks significantly reduced total cholesterol and LDL-C relative to placebo (by 18% and 28%, respectively; P < 0.001 for both). Furthermore, plasma glucose levels were reduced by 13% (P = 0.003) and mean glycosylated hemoglobin concentrations was reduced by 0.5%.61

However, conflicting reports of the effects of bile acid sequestrants on glycemic control have been reported. Although cholestyramine significantly reduced mean plasma glucose levels in patients with type 2 diabetes and dyslipidemia in one study,61 three other studies found no effect of either cholestyramine or colestipol on glycemic control.62-64

To definitively investigate the glucose-lowering efficacy of bile acid sequestrants, various clinical studies were carried out. A case control study included 33 patients with type 2 diabetes and hypercholesterolemia whose postprandial glucose levels were not well controlled with oral antidiabetic agents.65 Treatment with colestimide 3 g/d reduced fasting plasma glucose (from 124.9 ± 21.1 mg/dL to 116.2 ± 19.9 mg/dL), postprandial glucose (from 216.9 ± 37.2 mg/dL to 191.1 ± 40.9 mg/dL; P = 0.008), total cholesterol (from 223 ± 32 mg/dL to 184 ± 29 mg/dL; P < 0.001), and triglyceride levels (from 203 ± 123 mg/dL to 175 ± 92 mg/dL).65

A similar study was carried out to investigate the glycemic and lipid effects of colestimide in 70 patients with type 2 diabetes receiving treatment with oral antidiabetic agents or insulin who had baseline LDL-C >3.6 mmol/L.66 Following 12 weeks of treatment with 3 g/d colestimide, significant reductions in A1C (from 7.7 ± 0.7% to 6.8 ± 0.5%; P < 0.01), total cholesterol (from 5.5 ± 0.9 mmol/L to 4.8 ± 0.6 mmol/L; P < 0.01), and LDL-C (from 3.5 ± 0.8 mmol/L to 2.7 ± 0.5 mmol/L; P < 0.01) were reported, suggesting that colestimide may be clinically useful, providing dual effects on glycemic control and the lipid profile in patients with type 2 diabetes.66

Similar results were reported with another bile acid sequestrant colesevelam hydrochloride (HCl). Colesevelam HCl was specifically engineered to have a higher affinity for bile acids than older drugs of this class, including cholestyramine and colestipol.52 The Glucose-Lowering effect Of WelChol Study investigated the glucose-lowering efficacy of colesevelam HCl in 65 patients with type 2 diabetes who were inadequately controlled with metformin and/or sulfonylurea therapy. After 12 weeks of treatment with colesevelam HCl 3.75 g/d, significant reductions in A1C (0.5%; P < 0.007 vs. placebo; Fig. 2A), total cholesterol (7.3%; P = 0.019 vs. placebo; Fig. 2B), LDL-C (11.7%; P = 0.007 vs. placebo; Fig. 2B), and LDL particle concentration (209.6 mmol/L; P = 0.037 vs. placebo) were observed. In addition, a nonsignificant reduction in HDL-C was observed with colesevelam HCl (1.5%; P = 0.585 vs. placebo; Fig. 2B).52

Effect of adjunctive colesevelam HCl on glycemic control and lipid levels in patients with type 2 diabetes not adequately controlled on a stable regimen of metformin and/or sulfonylurea.52 A, Mean change from baseline in A1C after 4, 8, and 12 weeks. B, Mean percent change from baseline in LDL-C, total cholesterol, and HDL-C after 12 weeks. *P < 0.05 versus placebo; †P < 0.01 versus placebo.

As a result of the promising results from the pilot study with colesevelam HCl, phase III clinical trials were carried out to further investigate the potential for colesevelam HCl to improve both glycemic control and the lipid profile in patients with type 2 diabetes.67 These studies evaluated the effect of colesevelam HCl when added to existing insulin-, metformin- or sulfonylurea-based therapy, respectively. All three studies reported a significant reduction in A1C with the addition of colesevelam HCl relative to placebo by study end.68-70


Treatment of type 2 diabetes is evolving from focusing solely on glycemic control to metabolic control of hyperglycemia, dyslipidemia, and hypertension, in order to address the multiple risk factors that contribute to the morbidity and mortality of this disease. Therefore, the appropriate choice of antidiabetic agent may hinge upon effects on factors beyond glycemic control. Among currently available antidiabetic drugs, those agents (including metformin and thiazolidinediones) that act by reducing insulin resistance have demonstrated beneficial effects on the lipid profile. In addition, lipid-lowering agents, such as bile acid sequestrants, can improve glycemic control.

Lipid and glucose homeostasis are interrelated; this is an area where a single agent could have an effect on both glucose and lipid levels. A single agent that has significant lipid- and glucose-lowering efficacy would provide the benefit of potentially reducing the total number of medications a patient requires, simplifying their treatment regimen, and increasing compliance. Evidence is emerging that bile acid sequestrants-such as cholestyramine, colestimide, and colesevelam HCl, indicated for lipid lowering-can also significantly improve glycemic control in patients with type 2 diabetes. As a class, bile acid sequestrants may cause adverse gastrointestinal effects, including constipation and flatulence, and should not be used in patients with intestinal mobility disorders. Additionally, bile acid sequestrants may affect the absorption of fat-soluble vitamins as well as certain drugs, although this is less likely with the specially engineered bile acid sequestrant colesevelam HCl relative to previous generation bile acid sequestrants, such as cholestyramine or colestipol. Currently, colesevelam HCl is the only bile acid sequestrant approved by the U.S. Food and Drug Administration as an adjunct to diet and exercise for improving glycemic control in patients with type 2 diabetes. As such, colesevelam HCl represents a novel therapy, helping patients with type 2 diabetes to better manage their disease.


Editorial assistance was provided by Karen Stauffer, PhD.


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cardiovascular; cholesterol; colesevelam HCl; diabetes mellitus; glycemic control; hyperglycemia

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