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OBJECTIVE:--Hyperglycemia is a risk factor for microvascular complications and may increase the risk of cardiovascular disease in patients with type 2 diabetes. This study tested the LDL cholesterol-lowering agent colesevelam HCl (colesevelam) as a potential novel treatment for improving glycemic control in patients with type 2 diabetes on sulfonylurea-based therapy. RESEARCH DESIGN AND METHODS--A 26-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study was carried out between August 2004 and August 2006 to evaluate the efficacy and safety of colesevelam for reducing A1C in adults with type 2 diabetes whose glycemic control was inadequate (A1C 7.5-9.5%) with existing sulfonylurea monotherapy or sulfonylurea in combination with additional oral antidiabetes agents. In total, 461 patients were randomized (230 given colesevelam 3.75 g/day and 231 given placebo). The primary efficacy measurement was mean placebo-corrected change in A1C from baseline to week 26 in the intent-to-treat population (last observation carried forward). RESULTS:--The least squares (LS) mean change in A1C from baseline to week 26 was -0.32% in the colesevelam group and +0.23% in the placebo group, resulting in a treatment difference of -0.54% (P < 0.001). The LS mean percent change in LDL cholesterol from baseline to week 26 was -16.1% in the colesevelam group and +0.6% in the placebo group, resulting in a treatment difference of -16.7% (P < 0.001). Furthermore, significant reductions in fasting plasma glucose, fructosamine, total cholesterol, non-HDL cholesterol, and apolipoprotein B were demonstrated in the colesevelam relative to placebo group at week 26. CONCLUSIONS:--Colesevelam improved glycemic control and reduced LDL cholesterol levels in patients with type 2 diabetes receiving sulfonylurea-based therapy.

We designed an experiment to examine the effect of bile acid sequestration with Colesevelam on fasting and postprandial glucose metabolism in type 2 diabetes. To do so, we tested the hypothesis that Colesevelam increases the disposition index (DI), and this increase is associated with increased glucagon-like peptide-1 (GLP-1) concentrations. Thirty-eight subjects on metformin monotherapy were studied using a double-blind, placebo-controlled, parallel-group design. Subjects were studied before and after 12 weeks of Colesevelam or placebo using a labeled triple-tracer mixed meal to measure the rate of meal appearance (Meal Ra), endogenous glucose production (EGP), and glucose disappearance (Rd). Insulin sensitivity and β-cell responsivity indices were estimated using the oral minimal model and then used to calculate DI. Therapy with Colesevelam was associated with a decrease in fasting (7.0 ± 0.2 vs. 6.6 ± 0.2 mmol/L; P = 0.004) and postprandial glucose concentrations (3,145 ± 138 vs. 2,896 ± 127 mmol/6 h; P = 0.01) in the absence of a change in insulin concentrations. Minimal model–derived indices of insulin secretion and action were unchanged. Postprandial GLP-1 concentrations were not altered by Colesevelam. Although EGP and Rd were unchanged, integrated Meal Ra was decreased by Colesevelam (5,191 ± 204 vs. 5,817 ± 204 μmol/kg/6 h; P = 0.04), suggesting increased splanchnic sequestration of meal-derived glucose.

This study evaluated the glycosylated hemoglobin (HbA 1c-lowering effect of colesevelam hydrochloride, a bile acid sequestrant, in subjects with type 2 diabetes that was inadequately controlled by existing antihyperglycemic therapy. After a 4-week placebo run-in period, subjects with type 2 diabetes and an HbA 1c value of 7.0% to 10.0% were randomized to receive colesevelam 3.75 g/d or matching placebo for 12 weeks. Subjects' previous oral anti hyperglycemic medication (sulfonylurea and/or metformin) was continued throughout the study. Fasting blood samples were obtained at weeks −5, −1, 0, 1, 4, 8, and 12. The primary efficacy end point was the change in HbA 1c from baseline to week 12. Secondary end points included changes in fructosamine levels, fasting plasma glucose levels, postprandial glucose level, and meal glucose response (ie, difference between preprandial and postprandial levels), and percent changes in lipid parameters from baseline to week 12. The 65 randomized subjects (31 colesevelam, 34 placebo) had a mean age of 56.2 years and a mean body mass index of 32.4 kg/m 2; 55.4% were male and 53.8% were white. The difference in least squares (LS) mean (SE) change in HbA 1c between the colesevelam group and the placebo group was −0.5% (0.18) ( P = 0.007). In subjects with a baseline HbAIc ≥ 8.0%, the difference in LS mean change in HbA 1c was −1.0% (0.27) ( P = 0.002). Relative to placebo, colesevelam treatment was associated with reductions in levels of fructosamine (−29.0 [10.9] pmol/L; P = 0.011) and postprandial glucose (−31.5 [13.6] mg/dL; P = 0.026). The mean percent change in low-density lipoprotein cholesterol was -9.6% in the colesevelam group, compared with 2.1% in the placebo group (treatment difference, −11.7% [4.2]; P = 0.007); the respective mean percent changes in total cholesterol were −4.0% and 3.4% (treatment difference, −7.3% [3.0]; P = 0.019). Colesevelam also was associated with significant decreases in the percent change in apolipoprotein B (P = 0.003) and low-density lipoprotein particle concentration ( P = 0.037). The incidence of treatment-emergent adverse events (TEAEs) was similar in both groups, although treatment-related adverse events were more frequent in the colesevelam group than in the placebo group (29.0% vs 8.8%, respectively). The most frequent TEAEs in the colesevelam group were gastrointestinal disorders (22.6%), primarily constipation (19.4%), compared with an 8.8% incidence of gastrointestinal disorders (0% constipation) in the placebo group. There were no significant changes in body weight or the occurrence of hypoglycemia between treatment groups. In these subjects with type 2 diabetes, 12 weeks of colesevelam treatment were associated with significant reductions in HbA 1c and in fructosamine and postprandial glucose levels compared with placebo. The 2 groups had a similar adverse-event profile, with the exception of an increased incidence of constipation in the colesevelam group. These results suggest that colesevelam may improve both lipid control and glycemic control in patients with type 2 diabetes receiving oral antihyperglycemic medications.

Background: Familial hypercholesterolemia (FH) has been associated with increased cardiovascular risk when untreated or when normal LDL-C concentrations are not reached. Some patients with FH do not reach LDL-C goals despite intensive combination therapy. Objective: This study assessed the efficacy and tolerability of colesevelam added to maximally tolerated, stable-dose combination treatment with a statin + ezetimibe. Methods: This Phase IV, multicenter, randomized, double-blind, placebo-controlled trial enrolled patients aged 18 to 75 years with FH and an LDL-C concentration >2.5 mmol/L who were receiving a maximally tolerated and stable regimen of a statin + ezetimibe. Patients were randomly assigned to receive colesevelam 3.75 g/d or placebo added to the statin + ezetimibe for 12 weeks. The primary efficacy outcome was the difference in LDL-C between the colesevelam and placebo groups after 6 weeks. Secondary efficacy outcomes were between-group differences in LDL-C, total cholesterol (TC), HDL-C, triglyceride (Tg), apolipoprotein (apo) B, and apoA-I concentrations, as well as apoB/apoA-I ratio after 12 weeks. Tolerability was assessed based on the prevalences of adverse events by organ system class in each treatment group. Results: Eighty-six patients were randomized (45 colesevelam, 41 placebo), of whom 84 (44 colesevelam, 40 placebo) were included in the primary analysis. The mean (SD) age of the participants was 52.8 (10.8) years, and 51 (59%) were men. The difference (95% CI) in LDL-C between colesevelam and placebo after 6 weeks was −18.5% (−25.3 to −11.8). Between-group differences in LDL-C, TC, HDL-C, Tg, and apoB/apoA-I ratio after 12 weeks were −12.0% (−17.8 to −6.3), −7.3% (−12.0 to −2.6), +3.3% (−2.4 to +9.0), +2.8% (−10.4 to +15.9), and −12.2% (−20.2 to −4.2), respectively. Colesevelam was generally well tolerated, with gastrointestinal adverse events in 12 of 45 patients (27%) versus 7 of 40 (18%) in the placebo group ( P = NS). Conclusion: In these patients with FH, colesevelam added to a combination of a statin + ezetimibe was associated with significantly improved LDL-C concentrations compared with placebo during the 12-week study period and was generally well tolerated.

OBJECTIVE: To determine the mechanism by which the bile acid sequestrant colesevelam improves glycemic control. RESEARCH DESIGN AND METHODS: We performed a frequently sampled intravenous glucose tolerance test (FSIGT) with minimal model analysis and a meal tolerance test (MTT) in 20 subjects with impaired fasting glucose (11 men, 9 women; mean age 60.7 ± 1.9 years, BMI 29.4 ± 0.9 kg/m2) in a single-blind study after 2 weeks of placebo treatment and 8 weeks of colesevelam 3.75 g daily. From these tests, insulin sensitivity, β-cell function, and glucose tolerance were determined, along with gastrointestinal peptide levels during the MTT. RESULTS: Fasting plasma glucose and HbA1c decreased with colesevelam (from 5.9 ± 0.1 to 5.7 ± 0.1 mmol/L, P < 0.05, and from 5.86 ± 0.06 to 5.76 ± 0.06%, P = 0.01, respectively), but fasting insulin did not change. Colesevelam had no effect on any FSIGT measures. In contrast, the MTT incremental area under the curve (iAUC) for both glucose (from 249.3 ± 28.5 to 198.8 ± 23.6 mmol/L ⋅ min, P < 0.01) and insulin (from 20,130 [13,542–35,292] to 13,086 [9,804–21,138] pmol/L ⋅ min, P < 0.05) decreased with colesevelam. However, the ratio of iAUC insulin to iAUC glucose was not changed. iAUC for cholecystokinin (CCK) increased (from 43.2 [0–130.1] to 127.1 [47.2–295.2] pmol/L ⋅ min, P < 0.01), while iAUC for fibroblast growth factor 19 decreased (from 11,185 [1,346–17,661] to 2,093 [673–6,707] pg/mL ⋅ min, P < 0.01) with colesevelam. However, iAUC for glucagon, glucose-dependent insulinotropic peptide, and glucagon-like peptide 1 did not change. CONCLUSIONS: Colesevelam improves oral but not intravenous glucose tolerance without changing insulin sensitivity, β-cell function, or incretins. This effect may be at least partially explained by the colesevelam-induced increase in CCK.

Familial hypercholesterolemia (FH) is a common autosomal co-dominant genetic disorder that results in severely increased levels of LDL-C. Patients with FH are at an increased risk for premature coronary artery disease. Expert panels therefore recommend initiation of lipid-lowering therapy in childhood to reduce the very high lifetime risk of coronary artery disease. The bile acid sequestrant colesevelam is indicated to reduce elevated LDL-C levels in adults with primary hyperlipidemia and in boys and postmenarchal girls (aged 10–17 years) with heterozygous FH. The purpose of this article was to review currently available data on the use of colesevelam in the treatment of heterozygous FH. PubMed and Google Scholar were searched to identify clinical trials evaluating colesevelam in patients with heterozygous FH. The search returned 2 results (both multicenter, multinational studies): 1 study conducted in adults and the other in pediatric patients. In the study in adults with refractory FH, the addition of colesevelam to a maximally tolerated regimen of a statin plus ezetimibe provided a significantly greater reduction from baseline in LDL-C levels compared with placebo. Significantly greater reductions from baseline in LDL-C were also seen in pediatric patients with heterozygous FH receiving colesevelam (alone or in combination with statins) compared with placebo. Colesevelam was generally well tolerated in studies in patients with FH; consistent with other colesevelam studies, gastrointestinal disorders were the most common drug-related adverse events, but these events rarely led to study withdrawal. Currently available data demonstrate that colesevelam, alone or in combination therapy, is efficacious and well tolerated in the treatment of heterozygous FH in adults and pediatric patients, supporting its use as a treatment option in both of these patient populations.

Background and objectives Colesevelam significantly lowers cholesterol in patients with hypercholesterolemia, and both cholesterol and hemoglobin A1C (A1C) in patients with type 2 diabetes mellitus (T2DM). The purpose of this post hoc analysis was to evaluate the efficacy and safety/tolerability of colesevelam in older (≥65 years) and younger (<65 years) adults. Methods We conducted post hoc analyses of pooled clinical trial data from seven phase II and III randomized, double-blind, placebo-controlled, primary hyperlipidemia and T2DM clinical trials. The hyperlipidemia safety/tolerability analysis included seven studies (≥65 years, n  = 154; <65 years, n  = 381); the efficacy analysis utilized one study with sufficient patients in both age groups for meaningful comparison. The T2DM analyses included four studies (safety/tolerability: ≥65 years, n  = 249; <65 years, n  = 880) or three studies (efficacy). In the hyperlipidemia studies, patients received colesevelam 1.5–4.5 g/day or placebo, alone or with a statin, for 4 weeks to 6 months. In the T2DM studies, colesevelam 3.75 g/day or placebo was added to existing antidiabetes therapies for 16 or 26 weeks. Low-density lipoprotein cholesterol (LDL-C), A1C, and adverse events were assessed. Results In the hyperlipidemia analysis, colesevelam versus placebo produced similar mean reductions from baseline in LDL-C in older (−16.6 vs. +0.5 %) and younger (−13.7 vs. +0.4 %) patients. In the T2DM analysis, older and younger patients had similar reductions from baseline in A1C (treatment difference −0.59 and −0.54 %, respectively; both p  < 0.001) and LDL-C (−14.7 and −15.5 %, respectively; both p  < 0.001) with colesevelam. In both analyses, adverse event incidence was generally similar between subgroups. In the T2DM analysis, hypoglycemia was slightly more frequent with colesevelam versus placebo in older patients (5.8 vs. 2.3 %); no reports of hypoglycemia were considered serious adverse events. Conclusions In primary hyperlipidemia and in T2DM, colesevelam appeared to be generally as safe, well tolerated, and efficacious in patients aged ≥65 years as in those aged <65 years.

To evaluate the glucose- and lipid-altering efficacy of colesevelam hydrochloride (HCl) when added to background metformin therapy in patients with inadequately controlled type 2 diabetes mellitus (T2DM). This post hoc analysis included patients with T2DM from 3 randomized, double-blind, placebo-controlled pivotal studies who received metformin as part of their background antidiabetes therapy. In the pivotal studies, patients with T2DM were randomly assigned to receive colesevelam HCl (3.75 g/d) or placebo added to existing metformin (26 weeks), sulfonylurea (26 weeks), or insulin (16 weeks) monotherapy or combination therapy, wherein the combination therapies may have included metformin. In this pooled analysis of 696 patients with T2DM who were receiving metformin monotherapy or metformin combined with other antidiabetes therapies, 355 were randomly assigned to receive colesevelam HCl and 341 to receive placebo. In comparison with placebo, colesevelam HCl significantly reduced hemoglobin A1c (A1C) and fasting plasma glucose (mean treatment difference: -0.50% and -15.7 mg/dL, respectively; P<.001 for both), as well as significantly reduced levels of low-density lipoprotein cholesterol (LDL-C; mean treatment difference: -16.5%), total cholesterol (TC; -5.8%), non-high-density lipoprotein cholesterol (non-HDL-C; -8.2%), and apolipoprotein (apo) B (-7.6%) (P<.0001 for all). Median triglyceride levels were increased with colesevelam HCl (median treatment difference: +12.8%; P<.0001). In comparison with placebo, colesevelam HCl significantly increased apo A-I (mean treatment difference: +3.3%; P<.0001), whereas the mean increase in HDL-C with colesevelam HCl was not significant. Colesevelam HCl therapy was generally well tolerated. When added to metformin-including therapy, colesevelam HCl significantly reduced A1C and fasting glucose, as well as levels of LDL-C, TC, non-HDL-C, and apo B in patients with inadequately controlled T2DM.

ABSTRACT Objective: The primary aim of this study was to compare the effect of colesevelam HCl in combination with ezetimibe to ezetimibe monotherapy on low-density lipoprotein cholesterol (LDL.C) levels in subjects with primary hypercholesterolemia. Methods: Subjects with primary hypercholesterolemia (N = 86) were enrolled in a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4- to 8‐week washout period, subjects received colesevelam HCl 3.8 g/day plus ezetimibe 10 mg/day or colesevelam HCl placebo plus ezetimibe 10 mg/day for 6 weeks. The primary efficacy endpoint was the mean percent change in LDL‐C during randomized treatment. Secondary endpoints included mean absolute change in LDL‐C, mean absolute and mean percent change in levels of high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, total cholesterol (TC), apolipoprotein (apo) A-I and apo B, and median absolute and percent changes in triglycerides (TG) and high-sensitivity C‐reactive protein from baseline to end of treatment. Of the 86 subjects randomized to treatment, 85 were included in the intent-to-treat analysis. Results: After 6 weeks of treatment, colesevelam HCl plus ezetimibe produced a mean percent change in LDL‐C of –32.3% versus–21.4% with ezetimibe monotherapy ( p < 0.0001). Colesevelam HCl plus ezetimibe was significantly more effective than ezetimibe alone at producing mean percent reductions in TC, non‐HDL‐C, and apo B and increases in apo A-I ( p < 0.005 for all). Neither treatment regimen resulted in significant changes in median TG levels compared with baseline ( p = NS). Both treatments were safe and generally well tolerated. Conclusions: Colesevelam HCl plus ezetimibe combination therapy significantly reduced mean LDL‐C, TC, non-HDL‐C, and apo B levels and increased apo A-I levels ( p < 0.005 for all) without significantly increasing median TG levels in hypercholesterolemic subjects compared with ezetimibe alone. Although limited in that atherosclerotic coronary heart disease outcomes were not evaluated, this study demonstrated that combining colesevelam HCl with ezetimibe is a therapeutic option in hypercholesterolemic patients, such as those in whom statins are contraindicated and/or who may have intolerances to statin therapy.

To evaluate the glycemic effect of colesevelam, rosiglitazone, or sitagliptin when added to metformin monotherapy in patients with type 2 diabetes mellitus (DM) and to examine the effects of these antidiabetes agents on lipid and lipoprotein levels. This 16-week, open-label pilot study conducted between May 2007 and April 2008 at 20 sites in the United States, 7 sites in Mexico, and 6 sites in Colombia, enrolled adults with inadequately controlled type 2 DM (glycated hemoglobin [HbA1c], 7.0%-10.0%) on a stable metformin regimen (1500-2550 mg daily for > or = 3 months). At Week 0, participants were randomly assigned 1:1:1 to open-label colesevelam hydrochloride, 3.75 g daily; open-label rosiglitazone maleate, 4 mg daily; or open-label sitagliptin phosphate, 100 mg daily, in addition to existing metformin therapy. The primary efficacy variable was the change in HbA1c from baseline to Week 16 with last (post-baseline) observation carried forward. In total, 169 participants were randomly assigned to treatment groups (colesevelam, n = 57; rosiglitazone, n = 56; and sitagliptin, n = 56), and 141 participants (83.4%) completed the study. Least-squares mean reductions in HbA1c from baseline were observed in all groups at Week 16 last observation carried forward (colesevelam, -0.3% [P<.031]; rosiglitazone: -0.6% [P<.001]; sitagliptin: -0.4% [P<.009]) At study end, 10 of 56 participants (17.9%) in the colesevelam group, 19 of 54 (35.2%) in the rosiglitazone group, and 15 of 55 (27.3%) in the sitagliptin group achieved HbA1c <7.0%. Colesevelam significantly reduced mean low-density lipoprotein (LDL)-cholesterol levels relative to baseline (11.6%), whereas levels were significantly increased with rosiglitazone and sitagliptin at Week 16 last observation carried forward (7.8% and 7.7%, respectively). Twenty-two of 52 participants (42.3%) in the colesevelam group, 12 of 51 (23.5%) in the rosiglitazone group, and 13 of 53 (24.5%) in the sitagliptin group achieved LDL cholesterol <100 mg/dL at Week 16 last observation carried forward. All 3 antidiabetes agents significantly improved glycemic control, but only colesevelam also significantly reduced LDL-cholesterol levels in patients with type 2 DM.