Colesevelam hydrochloride (colesevelam) lowers low-density lipoprotein (LDL) cholesterol and glycated hemoglobin in patients with type 2 diabetes mellitus. The present study examined the effects of colesevelam treatment in nondiabetic men with metabolic syndrome. Twenty men completed the study, which consisted of two 8-week phases of treatment with colesevelam (3.75 g/day) or placebo and a 6-week washout between study phases. Of the 20 men, 17 took statins throughout. The fasting plasma LDL cholesterol, triglyceride, glucose, and glycated hemoglobin levels were measured in the last 2 weeks of each study phase. Nonesterified fatty acids and 3-hydroxybutyrate, insulin, and glucose were measured hourly for 5 hours during fasting and during an extended glucose tolerance test. The colesevelam treatment reduced LDL cholesterol from 96 ± 28 mg/dl to 78 ± 32 mg/dl (p <0.006) and non–high-density lipoprotein cholesterol by 8.2% (p = 0.07). Triglycerides increased by 17% (p <0.02). The fasting plasma glucose was reduced by 5 mg/dl (p <0.03), and glycated hemoglobin remained unchanged by colesevelam. No significant treatment changes were noted for the 2-hour glucose test or insulin sensitivity. The fasting nonesterified fatty acid level was significantly reduced with treatment but the 3-hydroxybutyrate level was unchanged. Insulin-mediated suppression of nonesterified fatty acids during extended glucose tolerance test was significantly less effective during treatment than during placebo. In conclusion, colesevelam significantly reduced the LDL cholesterol levels, even though the baseline LDL cholesterol level was low owing to statin treatment. The fasting and postprandial blood glucose level but not the glycated hemoglobin level was lowered by colesevelam therapy. The effect on fasting glucose was unrelated to the changes in insulin resistance or fatty acid oxidation. Finally, an increase in triglycerides with colesevelam therapy might have been related to a lesser suppression of nonesterified fatty acids levels in the postprandial state.
Bile acid sequestrants are therapeutic adjuncts to statins for lowering low-density lipoprotein (LDL) cholesterol. In patients with type 2 diabetes mellitus, they also reduce the fasting blood glucose and glycated hemoglobin. Similar studies have been performed in patients with prediabetes and showed reductions in the fasting plasma glucose and glycated hemoglobin levels. One study examined the effect of bile acid sequestrants on dyslipidemia in patients with type 2 diabetes mellitus or the metabolic syndrome. The study included 16 statin-intolerant subjects who were treated with coleselevam and ezitimibe. The drug combination reduced LDL cholesterol more than baseline monotherapy of either a bile acid sequestrant or ezitimibe alone. The metabolic syndrome is present in >24% of the United States adult population. It is possible that this patient population would benefit from LDL cholesterol lowering by bile acid sequestrants to prevent cardiovascular disease and from glucose lowering to reduce the risk of diabetes. No studies have examined the effect of coleselevam on the blood glucose levels in nondiabetic patients with the metabolic syndrome. The present study was designed to examine the effect of colesevelam hydrochloride (colesevelam) on fasting and postprandial glycemia in men with the metabolic syndrome. The question addressed was whether colesevelam reduces the fasting and/or postprandial glucose level and improves insulin sensitivity in patients with the metabolic syndrome.
Methods
A total of 31 men were recruited at the Metabolic Unit or Clinical Research Unit of the Dallas Veterans Affairs North Health Care System to participate in the present trial. The subjects were included in the present study if they were 18 to 75 years old and had the metabolic syndrome, as defined by the Adult Treatment Panel III. The subjects treated with statins were also included, and the doses taken at recruitment into the study were not changed during the trial.
The subjects were excluded if they had diabetes mellitus or a known contraindication for participating in research procedures or taking another study medication. They were also excluded if they had a history of coronary artery disease, unstable angina, congestive heart failure, transient ischemic attacks, myocardial infarction, or angioplasty. Subjects taking hypolipidemic agents other than statins were excluded. Subjects with unstable angina were not recruited.
Of the 31 men recruited into the study, 20 completed the trial and 11 withdrew. Of those who withdrew, 5 did so because of the events expected or possibly related to the study medication. Some of the expected events included constipation, nausea, and vomiting; 6 discontinued for reasons unrelated to the study medication.
The study was a placebo-controlled, double-blind study, with a crossover design with a 6-week washout period between phases. Each study phase lasted 8 weeks; each study subject participated for a total of 22 weeks. The randomization code and study medication were dispensed through the research pharmacy of the North Texas Veterans Affairs Health Care System. The study medication and placebo were provided by Daiichi Sankyo (Parsippany, New Jersey). Coleselevam was used at a daily dose of 3.75 g taken as tablets of 625 mg, 3 tablets in the morning and 3 tablets in the evening with meals. The study was designed by the investigators and was conducted at 1 center only.
The patients were seen at the Clinical Research Unit during weeks 1, 4, 8, 14, 18, and 22. They had blood drawn for safety and efficacy chemistry tests and anthropometry. They underwent a clinical history and physical examination on weeks 1, 8, 14, and 22. During weeks 8 and 22, the subjects underwent 5 1-hour measurements of fasted glucose, insulin, nonesterified fatty acids, and 3-hydroxybutyrate. They also underwent an extended oral glucose tolerance test with a 5-hour duration that included measurements of the same analytes. For all these visits, the subjects had taken their study medication with their evening meal before the morning visit to the Clinical Research Unit. None of the men took the study medication on the morning of the study.
The subjects received instructions regarding their diet at every study visit, and they were counseled regarding their caloric intake to maintain a constant weight.
The institutional review board for Investigation in Humans at the Dallas Veterans Affairs North Health Care System approved the study.
The fasting levels of plasma lipids and lipoprotein cholesterol, glucose, glycated hemoglobin were measured at weeks 1, 4, 8, 14, 18, and 22. The mean levels measured at weeks 4 and 8 were calculated for the first phase and measurements made at weeks 18 and 22 were averaged for the second phase to calculate the efficacy and safety parameters.
At 6 p.m. on the day before admission to the Clinical Research Unit, the subjects had a light meal (400 calories), and they took their evening dose of study medication. At 12:00 a.m. (midnight), they were instructed to consume an 800-calorie meal containing 28% fat, 57% carbohydrate, and 15% protein. They then fasted until 12:00 p.m. (noon) the next day. At 6:00 a.m. , subjects reported to the Clinical Research Unit for metabolic tests. They had a catheter placed in a hand vein; the arterialized blood samples were obtained after placing the hand in an isothermic box. The blood samples were drawn hourly through 12:00 p.m. (noon). The measurements included glucose, nonesterified fatty acids, insulin, and 3-hydroxybutyrate.
After completion of the fast at 12:00 p.m. (noon), an extended glucose tolerance test was performed to estimate the insulin sensitivity index. The study medication was not taken during this test. At 12:00 p.m. (noon), 3 fasting blood samples were drawn within 30 minutes. Next, each subject was given 75 g of glucose orally. Eleven blood samples were drawn during the ensuing 5 hours until 5:00 p.m. Nonesterified fatty acids, 3-hydroxybutyrate, triglyceride, and glucose were measured enzymatically (Wako Diagnostics, Wako Chemicals United States, Richmond, Virginia). Insulin was measured by radioimmunoassay (Millipore, Bellerica, Massachusetts). The insulin sensitivity was calculated by the extended oral glucose tolerance test model developed by Mari et al. The insulin sensitivity determined using this method correlates highly with the insulin sensitivity indexes derived using the clamp method.
The primary end point for the present study was the insulin sensitivity to glucose regulation. The secondary end points of the study were the fasting levels and changes in nonesterified fatty acid levels during the oral glucose tolerance test. The main objective was to compare the insulin sensitivity between baseline and treatment. For the sample size calculation, we assumed a 20% difference between treatment medications (placebo vs clolesevelam treatment) and a 20% standard deviation, an α of 0.05, and a power of >0.85. Therefore, we estimated about 20 subjects plus 5 more for attrition. All measurements are summarized as the mean ± SD or SEM. Repeated measures analysis of variance was used to compare the changes in insulin sensitivity and other parameters between the 2 study phases. Bonferroni adjustments were made as needed. An α <0.05 was considered significant. All other metabolic parameters were analyzed accordingly. Box and whisker plots were used to summarize the metabolic parameter levels. These plots included the 10th, 25th, 50th, 75th, and 90th percentiles. The StatView and Statistical Package for Social Sciences, version 12.01, SAS programs (SAS Institute, Cary, North Carolina) were used in the analysis of the data and the generation of the figures.
Results
The study participants had a diagnosis of the metabolic syndrome. Most were taking simvastatin at doses of 20 to 40 mg/day. Their age ranged from 41 to 69 years, and most were of European descent ( Table 1 ). Most had ≥3 risk factors for the metabolic syndrome, including impaired fasting glucose (100 to 125 mg/dl) and, therefore, also qualified for the classification of prediabetes ( Table 1 ). The compliance with treatment was >85%.
| Subject Number | Age (y) | Body Mass Index (kg/m 2 ) | Waist/Hip Ratio | Fasting Plasma Glucose (mg/dl) | Glycated Hemoglobin (%) | Metabolic Syndrome Risks (n) |
|---|---|---|---|---|---|---|
| 1 ⁎ † | 41 | 32 | 1.02 | 105 | 6.1 | 3 |
| 2 ⁎ | 46 | 36 | 1.10 | 117 | 5.9 | 4 |
| 3 ⁎ | 48 | 24 | 0.85 | 107 | 5.8 | 3 |
| 4 | 51 | 32 | 0.93 | 104 | 5.9 | 3 |
| 5 ⁎ | 56 | 31 | 0.97 | 99 | 5.5 | 3 |
| 6 | 58 | 33 | 1.09 | 106 | 5.9 | 4 |
| 7 | 60 | 30 | 0.88 | 113 | 6.0 | 3 |
| 8 ‡ | 61 | 26 | 1.04 | 110 | 6.0 | 5 |
| 9 † | 61 | 27 | 0.89 | 116 | 5.9 | 3 |
| 10 | 61 | 41 | 1.06 | 103 | 6.4 | 4 |
| 11 | 62 | 42 | 1.09 | 118 | 6.2 | 5 |
| 12 | 62 | 32 | 0.93 | 117 | 5.1 | 2 |
| 13 | 63 | 31 | 1.01 | 110 | 5.6 | 5 |
| 14 † ‡ | 64 | 32 | 1.05 | 101 | 5.1 | 4 |
| 15 ‡ | 65 | 31 | 1.04 | 100 | 6.0 | 4 |
| 16 | 65 | 34 | 1.03 | 102 | 6.2 | 4 |
| 17 | 67 | 32 | 1.05 | 104 | 5.8 | 5 |
| 18 | 69 | 32 | 1.02 | 102 | 5.7 | 5 |
| 19 § | 72 | 35 | 0.94 | 125 | 6.5 | 4 |
| 20 | 73 | 34 | 1.05 | 100 | 5.6 | 4 |
| Mean | 60 | 32 | 1.00 | 108 | 5.9 | 4 |
| SD | 8 | 4 | 0.07 | 7 | 0.4 | 1 |
§ Nondiabetic patient; highest fasting blood glucose level during screening.
The mean LDL cholesterol levels measured in the last 2 weeks of each study phase were significantly reduced by 18.8%, from 96 ± 29 to 78 ± 33 mg/dl during treatment ( Figure 1 ). During the placebo phase, 60% of the subjects had an LDL cholesterol level of <100 mg/dl; 80% had an LDL cholesterol level of <100 mg/dl during treatment with colesevelam. The non–high-density lipoprotein cholesterol level ( Figure 1 ) decreased by 8% from 134 ± 29 to 123 ± 31 mg/dl. The plasma triglycerides increased significantly by 17% during treatment from a mean placebo level of 193 ± 84 mg/dl to a treatment level of 226 ± 88 mg/dl ( Figure 1 ). No changes were seen in high-density lipoprotein cholesterol ( Figure 1 ) during treatment (placebo mean of 37 ± 12 mg/dl vs treatment mean of 37 ± 11 mg/dl).
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