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Colesevelam HCl effects on atherogenic lipoprotein subclasses in subjects with type 2 diabetes
Atherosclerosis 204 (2009) 342–344
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Letter to the Editor a r t i c l e
i n f o
Keywords: Colesevelam HCl Type 2 diabetes LDL-cholesterol Lipoprotein subclasses Total cholesterol Apolipoprotein B Small LDL particles LDL particles
a b s t r a c t Research design and methods: Glucose-Lowering Effect of Welchol Study (GLOWS) was a randomized, double-blind, placebo-controlled trial to examine the effects of colesevelam HCl on glycemic and lipid control in type 2 diabetes patients with HbA1c (A1C) between 7.0% and 10.0%. After a 4-week placebo leadin period, 65 subjects (31 colesevelam, 34 placebo) were randomized to receive colesevelam 3.75 g/day or matching placebo for 12 weeks in addition to maintaining their previous oral antihyperglycemic regimen (metformin, sulfonylurea, or both). Lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy were secondary efficacy variables evaluated in 56 subjects (26 colesevelam, 30 placebo) at baseline and week 12. Results: Previously published data demonstrated that colesevelam resulted in significant reductions in LDL-C, and Apo B. This analysis demonstrates that relative to placebo, colesevelam treatment reduced mean total LDL particle concentration (LDL-P) by 15.5% (−242 nmol/L [−412, −72], p = 0.006) primarily due to lowering in small LDL-P (−207 nmol/L [−418, 4], p = 0.054) and a lesser reduction in large LDL-P [−30 nmol/L [−118, 58], p = 0.496) and IDL-P (−5 nmol/L [−21, 11], p = 0.557). Conclusions: In type 2 diabetes patients, colesevelam improves glycemic status and reduces the concentration of LDL-C and LDL-P with little change in concentrations of other lipoprotein particles. © 2008 Elsevier Ireland Ltd. All rights reserved.
Colesevelam HCl effects on atherogenic lipoprotein subclasses in subjects with type 2 diabetes 1. Background Lipoprotein abnormalities that characterize insulin resistance include high concentrations of plasma triglycerides that are carried in large very low density lipoprotein (VLDL) particles and low concentrations of high density lipoprotein cholesterol (HDLC) that are carried in small HDL particles [1]. Through facilitated lipid exchange, the low density lipoprotein particles (LDL-P) that accompany insulin resistance are small and cholesterol-depleted, yet abundant in concentration. LDL-C remains the principal target of lipid lowering therapies to prevent cardiovascular events in patients with type 2 diabetes, based on results from large randomized clinical trials, but residual cardiovascular risk remains high despite treatment with LDL-C lowering therapies [2]. Prospective population studies demonstrate that LDL-P by NMR spectroscopy provides a better assessment of the atherogenic lipoprotein load than LDL-C [2]. This randomized, double-blind, placebo-controlled trial examined the effects of colesevelam HCl on atherogenic lipoprotein subclasses (LDL-P, VLDL-P, intermediate density lipoprotein [IDLP] in type 2 diabetes subjects with HbA1c (A1C) between 7.0% and 10.0%. 2. Methods After a 4-week placebo lead-in period, 65 type 2 diabetes subjects (31 colesevelam HCl, 34 placebo) were randomized to receive colesevelam 3.75 g/day or matching placebo for 12 weeks in addi0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.09.026
tion to maintaining their previous oral antihyperglycemic regimen (metformin, sulfonylurea, or both). Baseline characteristics of the study population and primary endpoints of the Glucose-Lowering Effect of Welchol Study (GLOWS) were previously published [3]. Lipoprotein subclasses measured by NMR spectroscopy were secondary efficacy variables evaluated in 56 subjects (26 colesevelam, 30 placebo) at baseline and week 12. The lipid and lipoprotein data were normally distributed, and are reported as means ± standard errors. Treatment differences are reported as least square mean differences with 95% confidence intervals.
3. Results The baseline characteristics of the two treatment groups are shown in Table 1. The patient population was typical of patients with type 2 diabetes in the United States. Colesevelam treatment was associated with a change in A1C of −0.3% (7.9 ± 0.8% to 7.7 ± 0.6%) compared with a change of +0.2% (8.1 ± 0.9% to 8.3 ± 1.2% in the placebo group (treatment difference, −0.5%, p = 0.007). The mean percentage change in LDL-C was −9.6% (122.6 ± 32.7 to 107.8 ± 27.5 mg/dL) in the colesevelam group compared with +2.1% (119.6 ± 26.2 to 121.8 ± 28.5 mg/dL) in the placebo group (treatment difference, −11.7%, p = 0.007). The mean percentage change in Apo B was −6.3% (128.5 ± 30.3 to 118.3 ± 25.4 mg/dL) in the colesevelam group compared with +5.5% (122.6 ± 22.2 to 128.6 ± 24.6 mg/dL) in the placebo group (treatment difference, −11.8%, p = 0.003). There was a non-significant 7.8% increase in plasma triglycerides in colesevelam vs. placebo-treated subjects (182.1 ± 96.7 to 228.6 ± 110.2 mg/dL vs. 213.7 ± 306.2 to 206.9 ± 139.9 mg/dL, respectively; p = 0.570) and a non-significant reduction in HDL-C in subjects assigned to colesevelam vs. placebo
Letter to the Editor / Atherosclerosis 204 (2009) 342–344
343
Table 1 Baseline characteristics. Characteristics Age, years
Colesevelam (n = 31) 56.7 (9.1)
Placebo (n = 34) 55.7 (9.7)
Sex, no. (%) Men Women
16 (51.6) 15 (48.4)
20 (58.8) 14 (41.2)
Race, no. (%)a White Black Hispanic Other
14 (45.2) 7 (22.6) 8 (25.8) 2 (6.5)
21 (61.8) 4 (11.8) 9 (26.5) 0
BMI (kg/m2 )
32.5 (5.2)
32.2 (5.5)
Weight (kg)
91.6 (20.3)
92.9 (22.1)
Concomitant antihyperglycemic medication, no. (%)a Sulfonylurea alone 10 (32.3) Metformin alone 4 (12.9) Sulfonylurea and metformin 17 (54.8) a
Fig. 1. LDL particle subclasses.
17 (50.0) 5 (14.7) 12 (35.3)
Percentages may not total 100 due to rounding.
(48.1 ± 11.7 to 46.1 ± 10.6 mg/dL vs. 44.3 ±10.3 to 42.9 ± 8.6 mg/dL, p = 0.585). The overall changes in the concentrations of lipoprotein particles are shown in Table 2. The most significant effect on particle concentrations was a mean percent reduction in LDL-P of 15.5% (−113 ± 62 nmol/L vs. 129 ± 57 nmol/L; p = 0.006) primarily due to lowering in small LDL-P of 82.2% (−41 ± 77 nmol/L vs. 167 ± 71 nmol/L; p = 0.054) in colesevelam-treated subjects vs. placebo-treated subjects, respectively (Fig. 1). The mean percent change of total atherogenic lipoproteins (LDL-P, IDL-P and VLDL-P) was reduced by 14.2% (1792 ± 92 to 1690 ± 91 nmol/L in colesevelam-treated subjects vs. 1746 ± 57 to 1883 ± 71 nmol/L in placebo-treated subjects; p = 0.011 (Fig. 2). Reduction in LDL-P correlated with improvement in A1C (r = 0.30, p = 0.025); however no other changes in lipid or lipoproteins were correlated with change in A1C (Fig. 3). 4. Discussion Colesevelam added on to metformin, sulfonylurea, or both in subjects with type 2 diabetes resulted in improvement in glycemic
Fig. 2. Effects of treatment with colesevelam and placebo on total atherogenic lipoprotein concentrations.
status and reductions in total cholesterol, LDL-C, Apo B and LDLP concentration. A recent consensus document by the American Diabetes Association/American College of Cardiology emphasized reduction in LDL-C < 100 mg/dL as the primary target of therapy, but recognized limitations in LDL-C as a biomarker to guide therapeutic decisions among patients at high cardiometabolic risk. Secondary targets of therapy were established for apolipoprotein B, a surrogate marker for LDL-P [2].
Table 2 Effects of treatment with colesevelam and placebo on lipoprotein concentrations. Mean ± S.E.
LS mean ± S.E. (95% CI)
Baseline
Week 12
LDL-P (nmol/L) Colesevelam Placebo
Treatment effect
p value
1669 ± 82 1626 ± 51
1556 ± 83 1755 ± 64
−242 ± 84 (−412, −72)
0.006
Small LDL-P (nmol/L) Colesevelam Placebo
1186 ± 91 1183 ± 68
1145 ± 98 1349 ± 76
−207 ± 105 (−418, 4)
0.054
Large LDL-P (nmol/L) Colesevelam Placebo
450 ± 40 408 ± 49
377 ± 39 366 ± 42
−30 ± 44 (−118, 58)
0.496
IDL-P (nmol/L) Colesevelam Placebo
33 ± 6 35 ± 5
33 ± 5 40 ± 5
VLDL-P (nmol/L) Colesevelam Placebo
89 ± 10 84 ± 8
101 ± 11 89 ± 7
HDL-P (mol/L) Colesevelam Placebo
33.9 ± 1.1 33.4 ± 1.4
34.1 ± 1.3 34.2 ± 1.4
−5 ± 8 (−21, 11)
0.557
+7 ± 11 (−15, 30)
0.525
−0.6 ± 1.1 (−3, 2)
0.576
344
Letter to the Editor / Atherosclerosis 204 (2009) 342–344
Fig. 3. Scatter plot of change in A1C (%) and change in LDL-P (nmol/L).
In type 2 diabetes subjects, colesevelam primarily reduced small LDL-P such that the mean percent reduction in LDL-P exceeded that in LDL-C (−15.5% vs. −11.7%, respectively). This data is supportive of colesevelam improving the overall atherogenic lipoprotein profile in patients at high cardiometabolic risk. The utilization of bile acid sequestrants in patients with type 2 diabetes may have been limited due to concerns that these agents increase fasting triglyceride levels and potentially diminish favorable changes on LDL-C on reducing the risk of atherosclerosis and cardiovascular events. In this study of subjects with type 2 diabetes, the non-significant increase in triglyceride-containing VLDL particles was small (10 nmol/L) in comparison to the significant reduction in LDL-P (−113 nmol/L) such that the total concentration of atherogenic lipoproteins was reduced by −101 nmol/L. It is worth noting that the greatest LDL-P lowering was seen in subjects who had the greatest improvement in glycemic status. While the exact mechanism(s) by which colesevelam HCl improves glycemic status in patients with type 2 diabetes are not fully understood. Bile acids are ligands for intestinal and hepatic farnesoid X receptors (FXR) which are bile acid activated nuclear receptors involved in the metabolism of bile acids, cholesterol and glucose. FXR appears to act as the metabolic modulator having multiple downstream effects that impact glucose and lipid metabolism, specifically actions on Cyp7A1 and liver X receptor (LXR) which modulate lipid metabolism and FGF-19 and GLP-1 which appear to modulate glucose control. It has been proposed that by blocking bile acid reabsorption, bile acid sequestrants modulate FXR. This may subsequently lead to increased LXR activity that could have various favorable effects on glucose and lipid metabolism [4,5].
References [1] Garvey WT, Kwon S, Zheng D, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453–62. [2] Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the ADA and the ACC Foundation. Diabetes Care 2008;31:811–22. [3] Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL. Results of the Glucose-Lowering Effect of Welchol Study (GLOWS): a randomized, doubleblind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther 2007;29:74–83. [4] Goldfine AB. Modulating LDL cholesterol and glucose in patients with type 2 diabetes mellitus: targeting the bile acid pathway. Curr Opin Cardiol 2008;23:502–11. [5] Bays H, Goldberg R. The “forgotten” bile acid sequestrants: is now a good time to remember? Am J Ther 2007;14:567–80.
Robert S. Rosenson a,∗ Stacey L. Abby b Michael R. Jones b a University of Michigan Medical Center, Division of Cardiovascular Medicine, 2722D Cardiovascular Center, 1500 E. Medical Center Dr. SPC 5853, Ann Arbor, MI 48106-5853, United States b Daiichi Sankyo, Inc., Parsippany, NJ, United States ∗ Corresponding author. Fax: +1 734 232-4129. E-mail address: [email protected] (R.S. Rosenson)
16 July 2008 Available online 5 October 2008
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Letter to the Editor a r t i c l e
i n f o
Keywords: Colesevelam HCl Type 2 diabetes LDL-cholesterol Lipoprotein subclasses Total cholesterol Apolipoprotein B Small LDL particles LDL particles
a b s t r a c t Research design and methods: Glucose-Lowering Effect of Welchol Study (GLOWS) was a randomized, double-blind, placebo-controlled trial to examine the effects of colesevelam HCl on glycemic and lipid control in type 2 diabetes patients with HbA1c (A1C) between 7.0% and 10.0%. After a 4-week placebo leadin period, 65 subjects (31 colesevelam, 34 placebo) were randomized to receive colesevelam 3.75 g/day or matching placebo for 12 weeks in addition to maintaining their previous oral antihyperglycemic regimen (metformin, sulfonylurea, or both). Lipoprotein subclasses measured by nuclear magnetic resonance spectroscopy were secondary efficacy variables evaluated in 56 subjects (26 colesevelam, 30 placebo) at baseline and week 12. Results: Previously published data demonstrated that colesevelam resulted in significant reductions in LDL-C, and Apo B. This analysis demonstrates that relative to placebo, colesevelam treatment reduced mean total LDL particle concentration (LDL-P) by 15.5% (−242 nmol/L [−412, −72], p = 0.006) primarily due to lowering in small LDL-P (−207 nmol/L [−418, 4], p = 0.054) and a lesser reduction in large LDL-P [−30 nmol/L [−118, 58], p = 0.496) and IDL-P (−5 nmol/L [−21, 11], p = 0.557). Conclusions: In type 2 diabetes patients, colesevelam improves glycemic status and reduces the concentration of LDL-C and LDL-P with little change in concentrations of other lipoprotein particles. © 2008 Elsevier Ireland Ltd. All rights reserved.
Colesevelam HCl effects on atherogenic lipoprotein subclasses in subjects with type 2 diabetes 1. Background Lipoprotein abnormalities that characterize insulin resistance include high concentrations of plasma triglycerides that are carried in large very low density lipoprotein (VLDL) particles and low concentrations of high density lipoprotein cholesterol (HDLC) that are carried in small HDL particles [1]. Through facilitated lipid exchange, the low density lipoprotein particles (LDL-P) that accompany insulin resistance are small and cholesterol-depleted, yet abundant in concentration. LDL-C remains the principal target of lipid lowering therapies to prevent cardiovascular events in patients with type 2 diabetes, based on results from large randomized clinical trials, but residual cardiovascular risk remains high despite treatment with LDL-C lowering therapies [2]. Prospective population studies demonstrate that LDL-P by NMR spectroscopy provides a better assessment of the atherogenic lipoprotein load than LDL-C [2]. This randomized, double-blind, placebo-controlled trial examined the effects of colesevelam HCl on atherogenic lipoprotein subclasses (LDL-P, VLDL-P, intermediate density lipoprotein [IDLP] in type 2 diabetes subjects with HbA1c (A1C) between 7.0% and 10.0%. 2. Methods After a 4-week placebo lead-in period, 65 type 2 diabetes subjects (31 colesevelam HCl, 34 placebo) were randomized to receive colesevelam 3.75 g/day or matching placebo for 12 weeks in addi0021-9150/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2008.09.026
tion to maintaining their previous oral antihyperglycemic regimen (metformin, sulfonylurea, or both). Baseline characteristics of the study population and primary endpoints of the Glucose-Lowering Effect of Welchol Study (GLOWS) were previously published [3]. Lipoprotein subclasses measured by NMR spectroscopy were secondary efficacy variables evaluated in 56 subjects (26 colesevelam, 30 placebo) at baseline and week 12. The lipid and lipoprotein data were normally distributed, and are reported as means ± standard errors. Treatment differences are reported as least square mean differences with 95% confidence intervals.
3. Results The baseline characteristics of the two treatment groups are shown in Table 1. The patient population was typical of patients with type 2 diabetes in the United States. Colesevelam treatment was associated with a change in A1C of −0.3% (7.9 ± 0.8% to 7.7 ± 0.6%) compared with a change of +0.2% (8.1 ± 0.9% to 8.3 ± 1.2% in the placebo group (treatment difference, −0.5%, p = 0.007). The mean percentage change in LDL-C was −9.6% (122.6 ± 32.7 to 107.8 ± 27.5 mg/dL) in the colesevelam group compared with +2.1% (119.6 ± 26.2 to 121.8 ± 28.5 mg/dL) in the placebo group (treatment difference, −11.7%, p = 0.007). The mean percentage change in Apo B was −6.3% (128.5 ± 30.3 to 118.3 ± 25.4 mg/dL) in the colesevelam group compared with +5.5% (122.6 ± 22.2 to 128.6 ± 24.6 mg/dL) in the placebo group (treatment difference, −11.8%, p = 0.003). There was a non-significant 7.8% increase in plasma triglycerides in colesevelam vs. placebo-treated subjects (182.1 ± 96.7 to 228.6 ± 110.2 mg/dL vs. 213.7 ± 306.2 to 206.9 ± 139.9 mg/dL, respectively; p = 0.570) and a non-significant reduction in HDL-C in subjects assigned to colesevelam vs. placebo
Letter to the Editor / Atherosclerosis 204 (2009) 342–344
343
Table 1 Baseline characteristics. Characteristics Age, years
Colesevelam (n = 31) 56.7 (9.1)
Placebo (n = 34) 55.7 (9.7)
Sex, no. (%) Men Women
16 (51.6) 15 (48.4)
20 (58.8) 14 (41.2)
Race, no. (%)a White Black Hispanic Other
14 (45.2) 7 (22.6) 8 (25.8) 2 (6.5)
21 (61.8) 4 (11.8) 9 (26.5) 0
BMI (kg/m2 )
32.5 (5.2)
32.2 (5.5)
Weight (kg)
91.6 (20.3)
92.9 (22.1)
Concomitant antihyperglycemic medication, no. (%)a Sulfonylurea alone 10 (32.3) Metformin alone 4 (12.9) Sulfonylurea and metformin 17 (54.8) a
Fig. 1. LDL particle subclasses.
17 (50.0) 5 (14.7) 12 (35.3)
Percentages may not total 100 due to rounding.
(48.1 ± 11.7 to 46.1 ± 10.6 mg/dL vs. 44.3 ±10.3 to 42.9 ± 8.6 mg/dL, p = 0.585). The overall changes in the concentrations of lipoprotein particles are shown in Table 2. The most significant effect on particle concentrations was a mean percent reduction in LDL-P of 15.5% (−113 ± 62 nmol/L vs. 129 ± 57 nmol/L; p = 0.006) primarily due to lowering in small LDL-P of 82.2% (−41 ± 77 nmol/L vs. 167 ± 71 nmol/L; p = 0.054) in colesevelam-treated subjects vs. placebo-treated subjects, respectively (Fig. 1). The mean percent change of total atherogenic lipoproteins (LDL-P, IDL-P and VLDL-P) was reduced by 14.2% (1792 ± 92 to 1690 ± 91 nmol/L in colesevelam-treated subjects vs. 1746 ± 57 to 1883 ± 71 nmol/L in placebo-treated subjects; p = 0.011 (Fig. 2). Reduction in LDL-P correlated with improvement in A1C (r = 0.30, p = 0.025); however no other changes in lipid or lipoproteins were correlated with change in A1C (Fig. 3). 4. Discussion Colesevelam added on to metformin, sulfonylurea, or both in subjects with type 2 diabetes resulted in improvement in glycemic
Fig. 2. Effects of treatment with colesevelam and placebo on total atherogenic lipoprotein concentrations.
status and reductions in total cholesterol, LDL-C, Apo B and LDLP concentration. A recent consensus document by the American Diabetes Association/American College of Cardiology emphasized reduction in LDL-C < 100 mg/dL as the primary target of therapy, but recognized limitations in LDL-C as a biomarker to guide therapeutic decisions among patients at high cardiometabolic risk. Secondary targets of therapy were established for apolipoprotein B, a surrogate marker for LDL-P [2].
Table 2 Effects of treatment with colesevelam and placebo on lipoprotein concentrations. Mean ± S.E.
LS mean ± S.E. (95% CI)
Baseline
Week 12
LDL-P (nmol/L) Colesevelam Placebo
Treatment effect
p value
1669 ± 82 1626 ± 51
1556 ± 83 1755 ± 64
−242 ± 84 (−412, −72)
0.006
Small LDL-P (nmol/L) Colesevelam Placebo
1186 ± 91 1183 ± 68
1145 ± 98 1349 ± 76
−207 ± 105 (−418, 4)
0.054
Large LDL-P (nmol/L) Colesevelam Placebo
450 ± 40 408 ± 49
377 ± 39 366 ± 42
−30 ± 44 (−118, 58)
0.496
IDL-P (nmol/L) Colesevelam Placebo
33 ± 6 35 ± 5
33 ± 5 40 ± 5
VLDL-P (nmol/L) Colesevelam Placebo
89 ± 10 84 ± 8
101 ± 11 89 ± 7
HDL-P (mol/L) Colesevelam Placebo
33.9 ± 1.1 33.4 ± 1.4
34.1 ± 1.3 34.2 ± 1.4
−5 ± 8 (−21, 11)
0.557
+7 ± 11 (−15, 30)
0.525
−0.6 ± 1.1 (−3, 2)
0.576
344
Letter to the Editor / Atherosclerosis 204 (2009) 342–344
Fig. 3. Scatter plot of change in A1C (%) and change in LDL-P (nmol/L).
In type 2 diabetes subjects, colesevelam primarily reduced small LDL-P such that the mean percent reduction in LDL-P exceeded that in LDL-C (−15.5% vs. −11.7%, respectively). This data is supportive of colesevelam improving the overall atherogenic lipoprotein profile in patients at high cardiometabolic risk. The utilization of bile acid sequestrants in patients with type 2 diabetes may have been limited due to concerns that these agents increase fasting triglyceride levels and potentially diminish favorable changes on LDL-C on reducing the risk of atherosclerosis and cardiovascular events. In this study of subjects with type 2 diabetes, the non-significant increase in triglyceride-containing VLDL particles was small (10 nmol/L) in comparison to the significant reduction in LDL-P (−113 nmol/L) such that the total concentration of atherogenic lipoproteins was reduced by −101 nmol/L. It is worth noting that the greatest LDL-P lowering was seen in subjects who had the greatest improvement in glycemic status. While the exact mechanism(s) by which colesevelam HCl improves glycemic status in patients with type 2 diabetes are not fully understood. Bile acids are ligands for intestinal and hepatic farnesoid X receptors (FXR) which are bile acid activated nuclear receptors involved in the metabolism of bile acids, cholesterol and glucose. FXR appears to act as the metabolic modulator having multiple downstream effects that impact glucose and lipid metabolism, specifically actions on Cyp7A1 and liver X receptor (LXR) which modulate lipid metabolism and FGF-19 and GLP-1 which appear to modulate glucose control. It has been proposed that by blocking bile acid reabsorption, bile acid sequestrants modulate FXR. This may subsequently lead to increased LXR activity that could have various favorable effects on glucose and lipid metabolism [4,5].
References [1] Garvey WT, Kwon S, Zheng D, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003;52:453–62. [2] Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the ADA and the ACC Foundation. Diabetes Care 2008;31:811–22. [3] Zieve FJ, Kalin MF, Schwartz SL, Jones MR, Bailey WL. Results of the Glucose-Lowering Effect of Welchol Study (GLOWS): a randomized, doubleblind, placebo-controlled pilot study evaluating the effect of colesevelam hydrochloride on glycemic control in subjects with type 2 diabetes. Clin Ther 2007;29:74–83. [4] Goldfine AB. Modulating LDL cholesterol and glucose in patients with type 2 diabetes mellitus: targeting the bile acid pathway. Curr Opin Cardiol 2008;23:502–11. [5] Bays H, Goldberg R. The “forgotten” bile acid sequestrants: is now a good time to remember? Am J Ther 2007;14:567–80.
Robert S. Rosenson a,∗ Stacey L. Abby b Michael R. Jones b a University of Michigan Medical Center, Division of Cardiovascular Medicine, 2722D Cardiovascular Center, 1500 E. Medical Center Dr. SPC 5853, Ann Arbor, MI 48106-5853, United States b Daiichi Sankyo, Inc., Parsippany, NJ, United States ∗ Corresponding author. Fax: +1 734 232-4129. E-mail address: [email protected] (R.S. Rosenson)
16 July 2008 Available online 5 October 2008