348 Endocrine Care
The Glucose and Lipid Effects of Colesevelam as Monotherapy in Drug-Naïve Type 2 Diabetes
Affiliations
Key words
▶ bile acid sequestrants ● ▶ hemoglobin A1c ● ▶ LDL cholesterol ●
received 29.03.2013 accepted 31.10.2013 Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1358759 Published online: December 19, 2013 Horm Metab Res 2014; 46: 348–353 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence J. Rosenstock, MD Dallas Diabetes and Endocrine Center 7777 Forest Lane Suite C-685 Dallas TX 75230 USA Tel.: + 1/972/566 7799 Fax: + 1/972/566 7399 juliorosenstock@dallasdiabetes. com
J. Rosenstock1, S. P. Rigby2, 3, D. M. Ford4, B. Tao4, H. S. Chou4 1
Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA Summit Research Group, Stow, Ohio, USA 3 Primary Care Associates of Northeast Ohio, Kent, OH, USA 4 Daiichi Sankyo Pharma Development, Edison, NJ, USA 2
Abstract
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Colesevelam has shown efficacy in adults with type 2 diabetes mellitus (T2DM) in combination with metformin-, sulfonylurea-, or insulin-based therapy, lowering hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol levels. A study was conducted to evaluate colesevelam as monotherapy in drug-naïve patients with T2DM. In this randomized, double-blind, placebo-controlled, parallel-group study, adults with T2DM who had inadequate glycemic control (HbA1c ≥ 7.5 % and ≤ 9.5 %) with diet and exercise alone were randomized to receive colesevelam 3.75 g/day (n = 176) or placebo (n = 181) for 24 weeks. The primary efficacy variable was HbA1c at week 24. Colesevelam as compared to placebo showed significant reductions from baseline in HbA1c (–2.92 mmol/mol [0.3 %]; p = 0.01) and fasting plasma glucose (–10.3 mg/dl; p = 0.04) at
Introduction
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The management of type 2 diabetes mellitus (T2DM) involves improving glycemic control and reducing the risk of complications such as cardiovascular disease [1]. The bile acid sequestrant colesevelam HCl has demonstrated consistent efficacy in lowering low-density lipoprotein cholesterol (LDL-C) levels in adults with primary hypercholesterolemia [2] and in adults and children with familial hypercholesterolemia [3, 4], primarily as an add-on to HMG-CoA reductase inhibitor (statin) therapy. In addition, colesevelam has been evaluated in the setting of combination therapy for glycemic control in adults with T2DM, with demonstrated antihyperglycemic efficacy when used in combination with metformin-, sulfonylurea-, or insulin-based therapy [5–8]. The current study evaluated the effects of colesevelam monotherapy alone on glycemic control
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
week 24 with last observation carried forward. Colesevelam also significantly reduced low-density lipoprotein cholesterol (–11.2 %; p < 0.0001), total cholesterol (–5.1 %; p = 0.0005), non-highdensity lipoprotein cholesterol (–7.4 %; p = 0.0001), and apolipoprotein B (–6.5 %; p = 0.0001) and increased apolipoprotein A-I (+ 2.4 %; p = 0.04), and triglycerides (+ 9.7 %; p = 0.03). Colesevelam monotherapy resulted in statistically significant improvements in glycemic and most lipid parameters in subjects with type 2 diabetes, with no new or unexpected safety and tolerability issues. Modest reductions in HbA1c and low-density lipoprotein cholesterol levels with colesevelam further support its use in combination with other antidiabetes agents when treatment targets for these parameters are close but are not quite achieved. ClinicalTrials.gov identifier: NCT00789737
in a drug-naïve adult population with T2DM inadequately controlled by diet and exercise, in order to explore the specific glucose-lowering effects of colesevelam without being confounded by other oral antidiabetes drugs.
Subjects and Methods
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This was a 24-week, randomized, double-blind, placebo-controlled, parallel-group study conducted at 74 study centers in the United States. The study was conducted in compliance with independent ethics committee/institutional review board regulations, good clinical practice guidelines, and the principles of the Declaration of Helsinki. Institutional review board (IRB) approval was obtained before initiation of the study (Goodwyn IRB, Cincinnati, OH; Western IRB, Olympia, WA; Human Studies Subcommittee IRB, Salem, VA; University of Arizona, Human
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Authors
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Assessments Scheduled clinic visits were at Weeks 0, 4, 8, 16, and 24, after an overnight fast. In addition, telephone contacts occurred at Weeks 12 and 20 for assessment of safety and compliance. The primary efficacy variable was HbA1c level at Week 24. Secondary efficacy variables included FPG, high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglyceride (TG), apolipoprotein A-I (apoA-I), and apoB levels. The proportion of subjects achieving glycemic response, that is, a HbA1c reduction from baseline of ≥ 8 mmol/mol (0.7 %) or ≥ 30 mg/dl in FPG at Week 24, was also evaluated. A standard meal tolerance test (MTT) was conducted at baseline and at Week 24 to evaluate the glucose excursion, with evaluation samples taken for insulin, glucose, and C-peptide at 0, 0.5, 1 and 2 h after ingestion of 2 cans of Ensure® with Fiber (each can providing 250 total calories; 14 % of calories from protein (9 g), 22 % from lipid (6 g), and 64 % from carbohydrate [40 g (sugar
23 g)]). Insulin resistance was estimated by homeostatic model assessment (HOMA-IR). Of the 74 sites contributing to the laboratory data listing for meal tolerance testing, 22 selected sites also measured fasting and 2-h postprandial levels of active glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and proinsulin, based on the facility’s expertise and sample handling capability. Safety assessments throughout the study included adverse events (AEs), clinical laboratory measurements (hematology, blood chemistry, and urinalysis), vital signs, physical examinations, and prior and concomitant medications. Vitamin D (25-hydroxy-vitamin D) levels were assessed at baseline and end of treatment; supplementation was recommended if low. Important cardiovascular events were evaluated by an independent board for masked adjudication.
Statistical methods The primary analysis population was the intent-to-treat (ITT) population, which included all randomized subjects who took ≥ 1 dose of study medication and had a HbA1c or FPG measurement at baseline and at least once post-baseline prior to taking any rescue medication. Safety analyses were performed according to the actual treatment subjects received, and utilized the safety population, which included all randomized subjects who took ≥ 1 dose of study medication and had ≥ 1 post-baseline safety measurement. It was planned that a total of 320 subjects would be randomized to receive colesevelam or placebo in a 1:1 ratio to provide > 82 % power to detect a difference between colesevelam and placebo for the change in HbA1c from baseline of 4 mmol/mol (0.4 %), with a common standard deviation of 1.2 % and a 2-sided type I error of 0.05. A statistical power analysis was not planned or performed for the exploratory sub-study on active GLP-1 and GIP. To minimize short-term lipid variability, baseline lipid parameters were defined as the average of 2 values from screening and randomization. All other efficacy variables had baseline defined as the last measurement prior to the first dose of randomized study medication. Missing data at Week 24 was imputed using the last post-baseline observation carried forward (LOCF). For rescued subjects, data was censored up to the time of initiation of rescue therapy and the last pre-rescue value was carried forward. For continuous variables, the mean and SD, or median and range, were determined. For categorical variables, the frequency and percentage in each category were determined. Safety analyses were descriptive, with the appropriate summary statistics determined. Baseline homogeneity between treatment groups was tested by analysis of variance on continuous data and chi-square test on categorical data. For primary and secondary efficacy analyses, the treatment difference was tested using an analysis of covariance (ANCOVA) model, with treatment as a fixed effect and baseline as a covariate. Due to large numbers of investigational sites in this study, center was not included as a factor in the model. The treatment effect was tested at a 2-sided significance level of 0.05. The least squares (LS) mean and 95 % confidence intervals (CIs) for each treatment group and the difference between the treatment groups were calculated. The comparison between treatment groups for the change and percent change in TGs was performed using a nonparametric ANCOVA. The median difference was calculated using Hodges-Lehmann estimate and a 2-sided 95 % CI was calculated using the method of Moses.
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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Subjects Protection Program, Tucson, AZ), and all subjects provided written informed consent. The study enrolled subjects aged ≥ 18 years with a diagnosis of T2DM (based on American Diabetes Association [ADA] diagnostic criteria [9]) who were untreated at the time of screening (i. e., never received or not receiving antihyperglycemic medication within ≥ 3 months prior to screening) and had a hemoglobin A1c (HbA1c) value ≥ 58 mmol/mol [7.5 %] and ≤ 80 mmol/mol [9.5 %], a fasting C-peptide level > 0.5 ng/ml, and a fasting plasma glucose (FPG) level ≤ 240 mg/dl at randomization. Key study exclusion criteria were: a history of type 1 diabetes, ketoacidosis, bowel obstruction, hypertriglyceride-induced pancreatitis, dysphagia, difficulty swallowing, gastroparesis or major gastrointestinal surgery; a history of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within the previous 6 months; fasting serum triglyceride concentration > 500 mg/dl; use of a bile acid sequestrant (within the previous 3 months); body mass index > 40 kg/ m2; LDL-C level < 60 mg/dl; uncontrolled hypertension; and/or considerably abnormal hematologic or blood chemistry findings. In addition, the use of insulin ≥ 2 weeks was also an exclusion criterion to exclude patients with advanced T2DM or type 1 DM because the protocol was designed to evaluate colesevelam in drug-naïve T2DM. Subjects were not randomized if they had persistent FPG levels > 240 mg/dl during the placebo lead-in period. Following a 2-week single-blind placebo lead-in period, subjects were randomized to receive oral colesevelam 3.75 g/day (6 × 625 mg tablets) or matching placebo for 24 weeks. Study medication was administered either as 3 tablets twice daily (with the noon and evening meals) or as 6 tablets once daily (with the evening meal), per subject’s preference; the dosing schedule selected was to be maintained for the duration of the study. General instructions on diet, exercise, and diabetes self-care were provided. During the study, subjects with ≥ 2 self-monitored capillary blood glucose readings of > 240 mg/dl were brought into the clinic for further assessment. At or after Week 8, subjects who met protocol-specified hyperglycemia criteria ( > 240 mg/dl) received metformin as a rescue medication and continued in the study. Study discontinuation could be considered if hyperglycemia persisted with maximally tolerated metformin treatment or if the subject elected not to receive rescue medication.
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Screened (N= 1 368)
Not randomized (N= 70) • Withdrew consent (n= 18) • Hyperglycemia meeting discontinuation criteria (n= 18) • Lost to follow-up (n= 9) • Lack of efficacy* (n= 8) • Adverse event (n= 5) • Other (n= 12)
Did not enter lead-in period (N= 941)
Entered lead-in period (N= 427)
• Did not satisfy all inclusion/exclusion criteria (n=903) • Withdrew consent (n=15) • Lost to follow-up (n=7) • Investigator judgment (n=3) • Other (n=13)
Randomized (N= 357)
Colesevelam (N= 176)
Placebo (N= 181) Discontinued# (N= 55)
Withdrew consent (n= 13) Lost to follow-up (n= 10) Adverse event (n= 8) Lack of efficacy* (n= 3) Protocol violation (n= 3) Other (n= 11)
• • • •
Withdrawal of consent (n=22) Lost to follow-up (n=14) Adverse event (n=8) Hyperglycemia meeting discontinuation criteria (n=4) • Other (n=7)
Completed the study (N= 128)
Completed the study (N= 126)
Characteristic
Colesevelam (n = 176)
Placebo (n = 181)
Total (n = 357)
Age (years), mean (SD) Sex, n ( %) Male Race, n ( %) Caucasian Black Asian American Indian/Alaskan native Other Ethnicity, n ( %) Hispanic/Latino Not Hispanic/Latino Body mass index (kg/m2), mean (SD) HbA1c (mmol/mol ± SD [% ± SD]), mean Fasting plasma glucose (mg/dl), mean (SD) Fasting insulin (μIU/ml), mean (SD) Index of insulin resistance by homeostatic model assessment, mean (SD)* Low-density lipoprotein cholesterol (mg/dl), mean (SD) Duration of type 2 diabetes (years), mean (SD)
52.6 ± 10.3
51.8 ± 10.5
52.2 ± 10.4
94 (53)
89 (49)
183 (51)
122 (69) 27 (15) 12 (7) 12 (7) 3 (2)
131 (72) 29 (16) 8 (4) 11 (6) 2 (1)
253 (71) 56 (16) 20 (6) 23 (6) 5 (1)
86 (49) 90 (51) 32.0 (6.5) 66.7 ± 7.5 [8.3 ± 0.7] 173 (46) 17.7 (16.6) 7.2 (7.3)
80 (44) 101 (56) 31.8 (4.9) 65.9 ± 7.6 [8.2 ± 0.7] 168 (38) 17.9 (14.0) 7.2 (5.6)
166 (47) 191 (54) 31.9 (5.8) 66.3 ± 7.5 [8.2 ± 0.7] 170 (42) 17.8 (15.4) –
122.5 (33.8)
119.0 (33.2)
120.7 (33.5)
4.3 (4.7)
3.9 (4.4)
4.1 (4.5)
Table 1 Demographic and baseline characteristics (all randomized subjects).
SD: Standard deviation. * HOMA-IR data are based on the intent-to-treat population
Results
Efficacy Glycemic variables
▶ Fig. 1. Rescue medDetails of subject disposition are shown in ● ication was taken by 16 subjects in the colesevelam group and 19 in the placebo group; the majority of these (14 and 13 subjects, respectively) completed the study. The treatment groups were similar with regard to demographic and baseline charac▶ Table 1). Overall, the mean ( ± SD) age was 52.2 ± 10.4 teristics (● years, the mean duration of T2DM was 4.1 ± 4.5 years, 51 % were male, the majority of subjects were Caucasian (71 %), and a high proportion were Hispanic/Latino (47 %). At baseline, the mean HbA1c value was 66.3 mmol/mol ± 7.5 mmol/mol (8.2 ± 0.7 %), and the mean LDL-C level was 121 ± 33 mg/dl.
At Week 24, the LS mean ( ± SE) change from baseline in HbA1c was + 0.1 mmol/mol ± 0.8 mmol/mol (0.0 %) for the placebo group and − 2.9 mmol/mol ± 0.8 mmol/mol (0.3 %) for the colesevelam group (LS mean treatment difference − 2.9 mmol/ mol ± 1.2 mmol/mol [0.3 %]; p = 0.013), with treatment difference ▶ Fig. 2). The LS mean becoming evident as early as Week 4 (● change from baseline in FPG was + 5.7 mg/dl for the placebo group and − 4.6 mg/dl for the colesevelam group (LS mean treatment difference − 10.3 mg/dl; p = 0.037) at Week 24. Furthermore, glycemic response (as assessed by a reduction from baseline of ≥ 8 mmol/mol (0.7 %) in HbA1c or ≥ 30 mg/dl in FPG) was achieved in a significantly greater proportion of subjects receiving colesevelam than subjects receiving placebo at Week 24 (45 vs. 30 %; p = 0.005).
▼
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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Discontinued# (N= 48) • • • • • •
Fig. 1 Subject disposition. The safety population comprised 346 subjects (colesevelam, n = 175; placebo, n = 171), and the ITT population comprised 344 subjects (colesevelam, n = 175; placebo, n = 169). *The lack of efficacy category includes hyperglycemia that did not meet protocolspecified discontinuation criteria. #3 subjects in the colesevelam group and 4 in the placebo group withdrew due to persistent hyperglycemia before Week 8.
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Lipid variables At Week 24, subjects receiving colesevelam had significantly greater reductions from baseline in TC (LS mean treatment difference − 5.1 %; p < 0.001), LDL-C ( − 11.2 %; p < 0.0001), non-HDLC (− 7.4 %; p < 0.001), and apoB ( − 6.5 %; p < 0.001), and an increase in apoA-I (LS mean treatment difference + 2.4 %; p = 0.039) ▶ Fig. 3). In addition, a significantly greater increase in TGs (● (median treatment difference + 9.7 %; p = 0.029) was observed in the colesevelam group. There were no significant treatment changes in hsCRP (data not shown).
Safety A total of 91 (52.0 %) subjects in the colesevelam group and 77 (45.0 %) in the placebo group had an AE; 16 (9.4 %) subjects in the placebo group and 33 (18.9 %) in the colesevelam group had an AE that was considered to be related to study medication ▶ Table 3). Most AEs were mild or moderate in severity. (● Eight subjects in each treatment group discontinued from the study due to an AE. Seven (4.0 %) subjects in the colesevelam group and 3 (1.8 %) in the placebo group reported a serious AE (none considered related to study medication), and 4 subjects withdrew from the study. ▶ Table 3, the most frequently reported AEs in the As shown in ● colesevelam group were back pain (5.1 %), headache (4.6 %), diarrhea (4.0 %), urinary tract infection (4.0 %), and hypoglycemia (4.0 %), and in the placebo group were urinary tract infection (8.8 %), nasopharyngitis (5.3 %), and worsening glucose control (3.5 %). Subjects in the colesevelam group had a higher incidence of specific gastrointestinal adverse events, including constipation (3.4 vs. 1.8 %), diarrhea (4.0 vs. 1.8 %), and gastro▶ Table 3). The incidence esophageal reflux disease (2.3 vs. 0.6 %; ● of hypoglycemia was low overall, generally mild, and was higher in the colesevelam group (4.0 vs. 0.6 %). No clinically important differences were noted between the treatment groups in mean changes in chemistry, hematology, and urinalysis safety laboratory parameters. There was also no difference between treatment groups in mean changes in 25-hydroxy-vitamin D, a fat-soluble vitamin whose absorption may be interfered with by a bile acid sequestrant.
Discussion
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Fig. 2 Change from baseline in hemoglobin A1C at Weeks 4, 8, 16, and 24 (without last observation carried forward). * LS mean treatment difference: p = 0.042 vs. placebo; # LS mean treatment difference: p = 0.037 vs. placebo; NS: Not statistically significant.
Parameter
LS mean change from baseline ± SE
The development of colesevelam as a glucose-lowering agent focused on evaluating its use as an add-on to the commonly prescribed antidiabetes therapies. Consistent glycemic responses have been demonstrated when colesevelam is used in combination with metformin-, sulfonylurea-, or insulin-based therapies, in addition to the well-recognized LDL-C-lowering effects. Although statistically significant, the reductions in HbA1c with colesevelam as monotherapy in this trial are less than those observed in previous add-on combination trials (approximately − 0.5 % vs. placebo) [5–7]. On the other hand, 45 % of subjects on colesevelam monotherapy in the current study were
LS mean treatment
p-Value
difference (95 % CI) Colesevelam Glucose AUC0–2 (mg × h/dl) 2-h postprandial glucose (mg/dl) Fasting insulin (μIU/ml) 2-h postprandial insulin (μIU/ml) HOMA-IR index Fasting C-peptide (ng/ml) 2-h postprandial C-peptide (ng/ml)
n = 132 − 28.0 ± 10.66 n = 131 − 9.3 ± 5.72 n = 137 0.29 ± 1.007 n = 131 − 1.29 ± 3.715 n = 129 0.15 ± 0.521 n = 143 − 0.16 ± 0.103 n = 135 − 0.20 ± 0.217
Placebo n = 127 0.7 ± 10.87 n = 125 − 1.5 ± 5.86 n = 134 1.03 ± 1.019 n = 124 − 9.38 ± 3.819 n = 123 0.62 ± 0.533 n = 141 0.12 ± 0.104 n = 128 − 0.58 ± 0.223
− 28.7 ( − 58.7, 1.3) − 7.8 ( − 23.9, 8.4) − 0.75 ( − 3.6, 2.1) 8.09 ( − 2.4, 18.6) − 0.46 ( − 1.9, 1.0) − 0.28 ( − 0.6, 0.0) 0.38 ( − 0.2, 1.0)
Table 2 Changes from baseline in meal tolerance test variables at Week 24 (with last observation carried forward).
0.06 0.34 0.60 0.13 0.53 0.056 0.22
CI: Confidence interval; LS: Least squares; SE: Standard error
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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There were no significant differences between the colesevelam and placebo groups in the MTT fasting insulin and C-peptide, 2-h postprandial glucose, insulin, and C-peptide levels, the 2-h glucose area under the curve (AUC0–2), and the HOMA-IR index ▶ Table 2). At Week 24, the LS mean change from baseline in (● fasting active GLP-1 in the MTT was − 0.1 pM with colesevelam and − 1.1 pM with placebo (LS mean treatment difference + 1.0 pM; p = 0.029). There were no significant differences in 2-h postprandial active GLP-1, fasting or 2-h postprandial GIP, proinsulin, or glucagon levels.
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Table 3 Adverse events occurring in ≥ 2 % of subjects in either treatment group. AE, n ( %) All AEs Arthralgia Aspartate aminotransferase increased Back pain Blood creatine phosphokinase increased Bronchitis C-reactive protein increased Constipation Cough Diabetes mellitus (worsening/ exacerbated) Diarrhea Dizziness Gastroesophageal reflux disease Headache Hyperglycemia Hypertension Hypoglycemia Hypokalemia Nasopharyngitis Nausea Pain in extremity Tooth abscess Upper respiratory tract infection Urinary tract infection Any drug-related AE Any serious AE Any drug-related serious AE
Colesevelam
Placebo
(n = 175)
(n = 171)
91 (52.0) 4 (2.3) 4 (2.3) 9 (5.1) 4 (2.3) 2 (1.1) 6 (3.4) 6 (3.4) 4 (2.3) 5 (2.9)
77 (45.0) 3 (1.8) 2 (1.2) 1 (0.6) 1 (0.6) 4 (2.3) 4 (2.3) 3 (1.8) 4 (2.3) 6 (3.5)
7 (4.0) 4 (2.3) 4 (2.3) 8 (4.6) 5 (2.9) 4 (2.3) 7 (4.0) 0 (0.0) 2 (1.1) 1 (0.6) 3 (1.7) 4 (2.3) 6 (3.4) 7 (4.0) 33 (18.9) 7 (4.0) 0 (0.0)
3 (1.8) 4 (2.3) 1 (0.6) 5 (2.9) 3 (1.8) 2 (1.2) 1 (0.6) 4 (2.3) 9 (5.3) 5 (2.9) 4 (2.3) 1 (0.6) 2 (1.2) 15 (8.8) 16 (9.4) 3 (1.8) 0 (0.0)
AE: Adverse event
responders, with a reduction of ≥ 8 mmol/mol (0.7 %) in HbA1c or ≥ 30 mg/dl in FPG. The reason for the difference in glycemic effect between this study and the pivotal trials is not clear, but may be due to differences in study design, subject withdrawal or rescue, a larger than expected placebo effect, or other factors. A
component of the current study not included in previous studies was the option to initiate rescue therapy after 8 weeks. A greater proportion of subjects with LOCF because of withdrawal or rescue can reduce the likelihood of observing differences between treatment groups. This study also assessed colesevelam postprandial effects. The numeric reductions in glucose AUC0–2, 2-h postprandial glucose, and lower fasting insulin were not statistically significant. Thus, consistent with a previous report [10], colesevelam has no demonstrable effects on postprandial glucose disposal or estimates of insulin resistance. The mechanism of action of colesevelam in improving glycemic control is not fully understood; however, a recent preclinical study in diet-induced obese mice suggests that colesevelam activates TGR5 in the colon, resulting in induction of GLP-1 and leading to reduced hepatic glucose production via suppression of hepatic glycogenolysis [11]. The rational use of combination therapy involves the use of agents with complementary but different mechanisms of action (or from more than one class). As the proposed mechanism of action of colesevelam is different from other antidiabetes agents, colesevelam could potentially be used in combination with other agents. The effects of colesevelam as monotherapy have not been previously characterized, and although colesevelam is effective in glycemic improvement, it is considered unlikely based on the findings of this study that it will compete with the universally accepted and highly effective metformin for use as first-line monotherapy for the treatment of T2DM. However, it can be considered as a valid additional option for combination therapy. The 2012 ADA/European Association for the Study of Diabetes (EASD) recommendations for antihyperglycemic therapy in T2DM emphasize the importance of individualizing treatment to account for factors such as the degree of hyperglycemia and patient characteristics [12]. In many cases, this influences the decision to initiate combination therapy. The current study confirmed modest improvements in glycemic control and clinically relevant reductions of LDL-C that support the use of colesevelam in combination with other antidiabetes agents when treatment
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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Fig. 3 Changes from baseline in lipid parameters at Week 24 (with last observation carried forward). * Reported as median.
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Conclusions
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Colesevelam monotherapy resulted in statistically significant improvements in glycemic control, with consistent changes in lipid parameters, especially reductions in LDL-C, in subjects with T2DM. There were no new or unexpected safety and tolerability issues. Use of colesevelam monotherapy had smaller glycemic effects compared to prior studies. Thus, colesevelam may have its greatest use as an antidiabetes agent when used in combination with other antidiabetes therapies and not as monotherapy.
Acknowledgements
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Sushma Soni of inScience Communications, Springer Healthcare, provided medical writing support funded by Daiichi Sankyo, Inc.
Conflict of Interest
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Julio Rosenstock MD, has served on scientific advisory boards and received honorarium or consulting fees from Roche, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, Takeda, Daiichi Sankyo, Johnson & Johnson, Novartis, Boehringer Ingelheim, and Lexicon. He has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, Lexicon, and Boehringer
Ingelheim. Scott P. Rigby MD, has received remuneration from Daiichi Sankyo, Inc. for participation in clinical trials. Daniel M. Ford Ph.D., Ben Tao MS, and Hubert Chou MD, Ph.D., are employees of Daiichi Sankyo, Inc.
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Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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targets for these parameters are close but are not quite achieved. Indeed, the ADA/EASD guidelines additionally note that improvement of glycemic control should be just one component of a multifactorial risk reduction framework, given that patients with T2DM are at increased risk of cardiovascular morbidity and mortality and therefore are likely to gain particular benefit from aggressive management of cardiovascular risk factors [12]. This makes colesevelam potentially useful as an adjunctive therapy in T2DM, both as an add-on to statins to provide lipid-lowering benefits (a key component of the management of cardiovascular risk referenced by the ADA/EASD), and as an add-on to other antidiabetes therapies to provide glycemic benefits. However, the effect of colesevelam on cardiovascular morbidity and mortality has not been determined.
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The Glucose and Lipid Effects of Colesevelam as Monotherapy in Drug-Naïve Type 2 Diabetes
Affiliations
Key words
▶ bile acid sequestrants ● ▶ hemoglobin A1c ● ▶ LDL cholesterol ●
received 29.03.2013 accepted 31.10.2013 Bibliography DOI http://dx.doi.org/ 10.1055/s-0033-1358759 Published online: December 19, 2013 Horm Metab Res 2014; 46: 348–353 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence J. Rosenstock, MD Dallas Diabetes and Endocrine Center 7777 Forest Lane Suite C-685 Dallas TX 75230 USA Tel.: + 1/972/566 7799 Fax: + 1/972/566 7399 juliorosenstock@dallasdiabetes. com
J. Rosenstock1, S. P. Rigby2, 3, D. M. Ford4, B. Tao4, H. S. Chou4 1
Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA Summit Research Group, Stow, Ohio, USA 3 Primary Care Associates of Northeast Ohio, Kent, OH, USA 4 Daiichi Sankyo Pharma Development, Edison, NJ, USA 2
Abstract
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Colesevelam has shown efficacy in adults with type 2 diabetes mellitus (T2DM) in combination with metformin-, sulfonylurea-, or insulin-based therapy, lowering hemoglobin A1c (HbA1c) and low-density lipoprotein cholesterol levels. A study was conducted to evaluate colesevelam as monotherapy in drug-naïve patients with T2DM. In this randomized, double-blind, placebo-controlled, parallel-group study, adults with T2DM who had inadequate glycemic control (HbA1c ≥ 7.5 % and ≤ 9.5 %) with diet and exercise alone were randomized to receive colesevelam 3.75 g/day (n = 176) or placebo (n = 181) for 24 weeks. The primary efficacy variable was HbA1c at week 24. Colesevelam as compared to placebo showed significant reductions from baseline in HbA1c (–2.92 mmol/mol [0.3 %]; p = 0.01) and fasting plasma glucose (–10.3 mg/dl; p = 0.04) at
Introduction
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The management of type 2 diabetes mellitus (T2DM) involves improving glycemic control and reducing the risk of complications such as cardiovascular disease [1]. The bile acid sequestrant colesevelam HCl has demonstrated consistent efficacy in lowering low-density lipoprotein cholesterol (LDL-C) levels in adults with primary hypercholesterolemia [2] and in adults and children with familial hypercholesterolemia [3, 4], primarily as an add-on to HMG-CoA reductase inhibitor (statin) therapy. In addition, colesevelam has been evaluated in the setting of combination therapy for glycemic control in adults with T2DM, with demonstrated antihyperglycemic efficacy when used in combination with metformin-, sulfonylurea-, or insulin-based therapy [5–8]. The current study evaluated the effects of colesevelam monotherapy alone on glycemic control
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
week 24 with last observation carried forward. Colesevelam also significantly reduced low-density lipoprotein cholesterol (–11.2 %; p < 0.0001), total cholesterol (–5.1 %; p = 0.0005), non-highdensity lipoprotein cholesterol (–7.4 %; p = 0.0001), and apolipoprotein B (–6.5 %; p = 0.0001) and increased apolipoprotein A-I (+ 2.4 %; p = 0.04), and triglycerides (+ 9.7 %; p = 0.03). Colesevelam monotherapy resulted in statistically significant improvements in glycemic and most lipid parameters in subjects with type 2 diabetes, with no new or unexpected safety and tolerability issues. Modest reductions in HbA1c and low-density lipoprotein cholesterol levels with colesevelam further support its use in combination with other antidiabetes agents when treatment targets for these parameters are close but are not quite achieved. ClinicalTrials.gov identifier: NCT00789737
in a drug-naïve adult population with T2DM inadequately controlled by diet and exercise, in order to explore the specific glucose-lowering effects of colesevelam without being confounded by other oral antidiabetes drugs.
Subjects and Methods
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This was a 24-week, randomized, double-blind, placebo-controlled, parallel-group study conducted at 74 study centers in the United States. The study was conducted in compliance with independent ethics committee/institutional review board regulations, good clinical practice guidelines, and the principles of the Declaration of Helsinki. Institutional review board (IRB) approval was obtained before initiation of the study (Goodwyn IRB, Cincinnati, OH; Western IRB, Olympia, WA; Human Studies Subcommittee IRB, Salem, VA; University of Arizona, Human
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Authors
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Assessments Scheduled clinic visits were at Weeks 0, 4, 8, 16, and 24, after an overnight fast. In addition, telephone contacts occurred at Weeks 12 and 20 for assessment of safety and compliance. The primary efficacy variable was HbA1c level at Week 24. Secondary efficacy variables included FPG, high-sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), non-HDL-C, triglyceride (TG), apolipoprotein A-I (apoA-I), and apoB levels. The proportion of subjects achieving glycemic response, that is, a HbA1c reduction from baseline of ≥ 8 mmol/mol (0.7 %) or ≥ 30 mg/dl in FPG at Week 24, was also evaluated. A standard meal tolerance test (MTT) was conducted at baseline and at Week 24 to evaluate the glucose excursion, with evaluation samples taken for insulin, glucose, and C-peptide at 0, 0.5, 1 and 2 h after ingestion of 2 cans of Ensure® with Fiber (each can providing 250 total calories; 14 % of calories from protein (9 g), 22 % from lipid (6 g), and 64 % from carbohydrate [40 g (sugar
23 g)]). Insulin resistance was estimated by homeostatic model assessment (HOMA-IR). Of the 74 sites contributing to the laboratory data listing for meal tolerance testing, 22 selected sites also measured fasting and 2-h postprandial levels of active glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and proinsulin, based on the facility’s expertise and sample handling capability. Safety assessments throughout the study included adverse events (AEs), clinical laboratory measurements (hematology, blood chemistry, and urinalysis), vital signs, physical examinations, and prior and concomitant medications. Vitamin D (25-hydroxy-vitamin D) levels were assessed at baseline and end of treatment; supplementation was recommended if low. Important cardiovascular events were evaluated by an independent board for masked adjudication.
Statistical methods The primary analysis population was the intent-to-treat (ITT) population, which included all randomized subjects who took ≥ 1 dose of study medication and had a HbA1c or FPG measurement at baseline and at least once post-baseline prior to taking any rescue medication. Safety analyses were performed according to the actual treatment subjects received, and utilized the safety population, which included all randomized subjects who took ≥ 1 dose of study medication and had ≥ 1 post-baseline safety measurement. It was planned that a total of 320 subjects would be randomized to receive colesevelam or placebo in a 1:1 ratio to provide > 82 % power to detect a difference between colesevelam and placebo for the change in HbA1c from baseline of 4 mmol/mol (0.4 %), with a common standard deviation of 1.2 % and a 2-sided type I error of 0.05. A statistical power analysis was not planned or performed for the exploratory sub-study on active GLP-1 and GIP. To minimize short-term lipid variability, baseline lipid parameters were defined as the average of 2 values from screening and randomization. All other efficacy variables had baseline defined as the last measurement prior to the first dose of randomized study medication. Missing data at Week 24 was imputed using the last post-baseline observation carried forward (LOCF). For rescued subjects, data was censored up to the time of initiation of rescue therapy and the last pre-rescue value was carried forward. For continuous variables, the mean and SD, or median and range, were determined. For categorical variables, the frequency and percentage in each category were determined. Safety analyses were descriptive, with the appropriate summary statistics determined. Baseline homogeneity between treatment groups was tested by analysis of variance on continuous data and chi-square test on categorical data. For primary and secondary efficacy analyses, the treatment difference was tested using an analysis of covariance (ANCOVA) model, with treatment as a fixed effect and baseline as a covariate. Due to large numbers of investigational sites in this study, center was not included as a factor in the model. The treatment effect was tested at a 2-sided significance level of 0.05. The least squares (LS) mean and 95 % confidence intervals (CIs) for each treatment group and the difference between the treatment groups were calculated. The comparison between treatment groups for the change and percent change in TGs was performed using a nonparametric ANCOVA. The median difference was calculated using Hodges-Lehmann estimate and a 2-sided 95 % CI was calculated using the method of Moses.
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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Subjects Protection Program, Tucson, AZ), and all subjects provided written informed consent. The study enrolled subjects aged ≥ 18 years with a diagnosis of T2DM (based on American Diabetes Association [ADA] diagnostic criteria [9]) who were untreated at the time of screening (i. e., never received or not receiving antihyperglycemic medication within ≥ 3 months prior to screening) and had a hemoglobin A1c (HbA1c) value ≥ 58 mmol/mol [7.5 %] and ≤ 80 mmol/mol [9.5 %], a fasting C-peptide level > 0.5 ng/ml, and a fasting plasma glucose (FPG) level ≤ 240 mg/dl at randomization. Key study exclusion criteria were: a history of type 1 diabetes, ketoacidosis, bowel obstruction, hypertriglyceride-induced pancreatitis, dysphagia, difficulty swallowing, gastroparesis or major gastrointestinal surgery; a history of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within the previous 6 months; fasting serum triglyceride concentration > 500 mg/dl; use of a bile acid sequestrant (within the previous 3 months); body mass index > 40 kg/ m2; LDL-C level < 60 mg/dl; uncontrolled hypertension; and/or considerably abnormal hematologic or blood chemistry findings. In addition, the use of insulin ≥ 2 weeks was also an exclusion criterion to exclude patients with advanced T2DM or type 1 DM because the protocol was designed to evaluate colesevelam in drug-naïve T2DM. Subjects were not randomized if they had persistent FPG levels > 240 mg/dl during the placebo lead-in period. Following a 2-week single-blind placebo lead-in period, subjects were randomized to receive oral colesevelam 3.75 g/day (6 × 625 mg tablets) or matching placebo for 24 weeks. Study medication was administered either as 3 tablets twice daily (with the noon and evening meals) or as 6 tablets once daily (with the evening meal), per subject’s preference; the dosing schedule selected was to be maintained for the duration of the study. General instructions on diet, exercise, and diabetes self-care were provided. During the study, subjects with ≥ 2 self-monitored capillary blood glucose readings of > 240 mg/dl were brought into the clinic for further assessment. At or after Week 8, subjects who met protocol-specified hyperglycemia criteria ( > 240 mg/dl) received metformin as a rescue medication and continued in the study. Study discontinuation could be considered if hyperglycemia persisted with maximally tolerated metformin treatment or if the subject elected not to receive rescue medication.
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Screened (N= 1 368)
Not randomized (N= 70) • Withdrew consent (n= 18) • Hyperglycemia meeting discontinuation criteria (n= 18) • Lost to follow-up (n= 9) • Lack of efficacy* (n= 8) • Adverse event (n= 5) • Other (n= 12)
Did not enter lead-in period (N= 941)
Entered lead-in period (N= 427)
• Did not satisfy all inclusion/exclusion criteria (n=903) • Withdrew consent (n=15) • Lost to follow-up (n=7) • Investigator judgment (n=3) • Other (n=13)
Randomized (N= 357)
Colesevelam (N= 176)
Placebo (N= 181) Discontinued# (N= 55)
Withdrew consent (n= 13) Lost to follow-up (n= 10) Adverse event (n= 8) Lack of efficacy* (n= 3) Protocol violation (n= 3) Other (n= 11)
• • • •
Withdrawal of consent (n=22) Lost to follow-up (n=14) Adverse event (n=8) Hyperglycemia meeting discontinuation criteria (n=4) • Other (n=7)
Completed the study (N= 128)
Completed the study (N= 126)
Characteristic
Colesevelam (n = 176)
Placebo (n = 181)
Total (n = 357)
Age (years), mean (SD) Sex, n ( %) Male Race, n ( %) Caucasian Black Asian American Indian/Alaskan native Other Ethnicity, n ( %) Hispanic/Latino Not Hispanic/Latino Body mass index (kg/m2), mean (SD) HbA1c (mmol/mol ± SD [% ± SD]), mean Fasting plasma glucose (mg/dl), mean (SD) Fasting insulin (μIU/ml), mean (SD) Index of insulin resistance by homeostatic model assessment, mean (SD)* Low-density lipoprotein cholesterol (mg/dl), mean (SD) Duration of type 2 diabetes (years), mean (SD)
52.6 ± 10.3
51.8 ± 10.5
52.2 ± 10.4
94 (53)
89 (49)
183 (51)
122 (69) 27 (15) 12 (7) 12 (7) 3 (2)
131 (72) 29 (16) 8 (4) 11 (6) 2 (1)
253 (71) 56 (16) 20 (6) 23 (6) 5 (1)
86 (49) 90 (51) 32.0 (6.5) 66.7 ± 7.5 [8.3 ± 0.7] 173 (46) 17.7 (16.6) 7.2 (7.3)
80 (44) 101 (56) 31.8 (4.9) 65.9 ± 7.6 [8.2 ± 0.7] 168 (38) 17.9 (14.0) 7.2 (5.6)
166 (47) 191 (54) 31.9 (5.8) 66.3 ± 7.5 [8.2 ± 0.7] 170 (42) 17.8 (15.4) –
122.5 (33.8)
119.0 (33.2)
120.7 (33.5)
4.3 (4.7)
3.9 (4.4)
4.1 (4.5)
Table 1 Demographic and baseline characteristics (all randomized subjects).
SD: Standard deviation. * HOMA-IR data are based on the intent-to-treat population
Results
Efficacy Glycemic variables
▶ Fig. 1. Rescue medDetails of subject disposition are shown in ● ication was taken by 16 subjects in the colesevelam group and 19 in the placebo group; the majority of these (14 and 13 subjects, respectively) completed the study. The treatment groups were similar with regard to demographic and baseline charac▶ Table 1). Overall, the mean ( ± SD) age was 52.2 ± 10.4 teristics (● years, the mean duration of T2DM was 4.1 ± 4.5 years, 51 % were male, the majority of subjects were Caucasian (71 %), and a high proportion were Hispanic/Latino (47 %). At baseline, the mean HbA1c value was 66.3 mmol/mol ± 7.5 mmol/mol (8.2 ± 0.7 %), and the mean LDL-C level was 121 ± 33 mg/dl.
At Week 24, the LS mean ( ± SE) change from baseline in HbA1c was + 0.1 mmol/mol ± 0.8 mmol/mol (0.0 %) for the placebo group and − 2.9 mmol/mol ± 0.8 mmol/mol (0.3 %) for the colesevelam group (LS mean treatment difference − 2.9 mmol/ mol ± 1.2 mmol/mol [0.3 %]; p = 0.013), with treatment difference ▶ Fig. 2). The LS mean becoming evident as early as Week 4 (● change from baseline in FPG was + 5.7 mg/dl for the placebo group and − 4.6 mg/dl for the colesevelam group (LS mean treatment difference − 10.3 mg/dl; p = 0.037) at Week 24. Furthermore, glycemic response (as assessed by a reduction from baseline of ≥ 8 mmol/mol (0.7 %) in HbA1c or ≥ 30 mg/dl in FPG) was achieved in a significantly greater proportion of subjects receiving colesevelam than subjects receiving placebo at Week 24 (45 vs. 30 %; p = 0.005).
▼
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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Discontinued# (N= 48) • • • • • •
Fig. 1 Subject disposition. The safety population comprised 346 subjects (colesevelam, n = 175; placebo, n = 171), and the ITT population comprised 344 subjects (colesevelam, n = 175; placebo, n = 169). *The lack of efficacy category includes hyperglycemia that did not meet protocolspecified discontinuation criteria. #3 subjects in the colesevelam group and 4 in the placebo group withdrew due to persistent hyperglycemia before Week 8.
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Lipid variables At Week 24, subjects receiving colesevelam had significantly greater reductions from baseline in TC (LS mean treatment difference − 5.1 %; p < 0.001), LDL-C ( − 11.2 %; p < 0.0001), non-HDLC (− 7.4 %; p < 0.001), and apoB ( − 6.5 %; p < 0.001), and an increase in apoA-I (LS mean treatment difference + 2.4 %; p = 0.039) ▶ Fig. 3). In addition, a significantly greater increase in TGs (● (median treatment difference + 9.7 %; p = 0.029) was observed in the colesevelam group. There were no significant treatment changes in hsCRP (data not shown).
Safety A total of 91 (52.0 %) subjects in the colesevelam group and 77 (45.0 %) in the placebo group had an AE; 16 (9.4 %) subjects in the placebo group and 33 (18.9 %) in the colesevelam group had an AE that was considered to be related to study medication ▶ Table 3). Most AEs were mild or moderate in severity. (● Eight subjects in each treatment group discontinued from the study due to an AE. Seven (4.0 %) subjects in the colesevelam group and 3 (1.8 %) in the placebo group reported a serious AE (none considered related to study medication), and 4 subjects withdrew from the study. ▶ Table 3, the most frequently reported AEs in the As shown in ● colesevelam group were back pain (5.1 %), headache (4.6 %), diarrhea (4.0 %), urinary tract infection (4.0 %), and hypoglycemia (4.0 %), and in the placebo group were urinary tract infection (8.8 %), nasopharyngitis (5.3 %), and worsening glucose control (3.5 %). Subjects in the colesevelam group had a higher incidence of specific gastrointestinal adverse events, including constipation (3.4 vs. 1.8 %), diarrhea (4.0 vs. 1.8 %), and gastro▶ Table 3). The incidence esophageal reflux disease (2.3 vs. 0.6 %; ● of hypoglycemia was low overall, generally mild, and was higher in the colesevelam group (4.0 vs. 0.6 %). No clinically important differences were noted between the treatment groups in mean changes in chemistry, hematology, and urinalysis safety laboratory parameters. There was also no difference between treatment groups in mean changes in 25-hydroxy-vitamin D, a fat-soluble vitamin whose absorption may be interfered with by a bile acid sequestrant.
Discussion
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Fig. 2 Change from baseline in hemoglobin A1C at Weeks 4, 8, 16, and 24 (without last observation carried forward). * LS mean treatment difference: p = 0.042 vs. placebo; # LS mean treatment difference: p = 0.037 vs. placebo; NS: Not statistically significant.
Parameter
LS mean change from baseline ± SE
The development of colesevelam as a glucose-lowering agent focused on evaluating its use as an add-on to the commonly prescribed antidiabetes therapies. Consistent glycemic responses have been demonstrated when colesevelam is used in combination with metformin-, sulfonylurea-, or insulin-based therapies, in addition to the well-recognized LDL-C-lowering effects. Although statistically significant, the reductions in HbA1c with colesevelam as monotherapy in this trial are less than those observed in previous add-on combination trials (approximately − 0.5 % vs. placebo) [5–7]. On the other hand, 45 % of subjects on colesevelam monotherapy in the current study were
LS mean treatment
p-Value
difference (95 % CI) Colesevelam Glucose AUC0–2 (mg × h/dl) 2-h postprandial glucose (mg/dl) Fasting insulin (μIU/ml) 2-h postprandial insulin (μIU/ml) HOMA-IR index Fasting C-peptide (ng/ml) 2-h postprandial C-peptide (ng/ml)
n = 132 − 28.0 ± 10.66 n = 131 − 9.3 ± 5.72 n = 137 0.29 ± 1.007 n = 131 − 1.29 ± 3.715 n = 129 0.15 ± 0.521 n = 143 − 0.16 ± 0.103 n = 135 − 0.20 ± 0.217
Placebo n = 127 0.7 ± 10.87 n = 125 − 1.5 ± 5.86 n = 134 1.03 ± 1.019 n = 124 − 9.38 ± 3.819 n = 123 0.62 ± 0.533 n = 141 0.12 ± 0.104 n = 128 − 0.58 ± 0.223
− 28.7 ( − 58.7, 1.3) − 7.8 ( − 23.9, 8.4) − 0.75 ( − 3.6, 2.1) 8.09 ( − 2.4, 18.6) − 0.46 ( − 1.9, 1.0) − 0.28 ( − 0.6, 0.0) 0.38 ( − 0.2, 1.0)
Table 2 Changes from baseline in meal tolerance test variables at Week 24 (with last observation carried forward).
0.06 0.34 0.60 0.13 0.53 0.056 0.22
CI: Confidence interval; LS: Least squares; SE: Standard error
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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There were no significant differences between the colesevelam and placebo groups in the MTT fasting insulin and C-peptide, 2-h postprandial glucose, insulin, and C-peptide levels, the 2-h glucose area under the curve (AUC0–2), and the HOMA-IR index ▶ Table 2). At Week 24, the LS mean change from baseline in (● fasting active GLP-1 in the MTT was − 0.1 pM with colesevelam and − 1.1 pM with placebo (LS mean treatment difference + 1.0 pM; p = 0.029). There were no significant differences in 2-h postprandial active GLP-1, fasting or 2-h postprandial GIP, proinsulin, or glucagon levels.
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Table 3 Adverse events occurring in ≥ 2 % of subjects in either treatment group. AE, n ( %) All AEs Arthralgia Aspartate aminotransferase increased Back pain Blood creatine phosphokinase increased Bronchitis C-reactive protein increased Constipation Cough Diabetes mellitus (worsening/ exacerbated) Diarrhea Dizziness Gastroesophageal reflux disease Headache Hyperglycemia Hypertension Hypoglycemia Hypokalemia Nasopharyngitis Nausea Pain in extremity Tooth abscess Upper respiratory tract infection Urinary tract infection Any drug-related AE Any serious AE Any drug-related serious AE
Colesevelam
Placebo
(n = 175)
(n = 171)
91 (52.0) 4 (2.3) 4 (2.3) 9 (5.1) 4 (2.3) 2 (1.1) 6 (3.4) 6 (3.4) 4 (2.3) 5 (2.9)
77 (45.0) 3 (1.8) 2 (1.2) 1 (0.6) 1 (0.6) 4 (2.3) 4 (2.3) 3 (1.8) 4 (2.3) 6 (3.5)
7 (4.0) 4 (2.3) 4 (2.3) 8 (4.6) 5 (2.9) 4 (2.3) 7 (4.0) 0 (0.0) 2 (1.1) 1 (0.6) 3 (1.7) 4 (2.3) 6 (3.4) 7 (4.0) 33 (18.9) 7 (4.0) 0 (0.0)
3 (1.8) 4 (2.3) 1 (0.6) 5 (2.9) 3 (1.8) 2 (1.2) 1 (0.6) 4 (2.3) 9 (5.3) 5 (2.9) 4 (2.3) 1 (0.6) 2 (1.2) 15 (8.8) 16 (9.4) 3 (1.8) 0 (0.0)
AE: Adverse event
responders, with a reduction of ≥ 8 mmol/mol (0.7 %) in HbA1c or ≥ 30 mg/dl in FPG. The reason for the difference in glycemic effect between this study and the pivotal trials is not clear, but may be due to differences in study design, subject withdrawal or rescue, a larger than expected placebo effect, or other factors. A
component of the current study not included in previous studies was the option to initiate rescue therapy after 8 weeks. A greater proportion of subjects with LOCF because of withdrawal or rescue can reduce the likelihood of observing differences between treatment groups. This study also assessed colesevelam postprandial effects. The numeric reductions in glucose AUC0–2, 2-h postprandial glucose, and lower fasting insulin were not statistically significant. Thus, consistent with a previous report [10], colesevelam has no demonstrable effects on postprandial glucose disposal or estimates of insulin resistance. The mechanism of action of colesevelam in improving glycemic control is not fully understood; however, a recent preclinical study in diet-induced obese mice suggests that colesevelam activates TGR5 in the colon, resulting in induction of GLP-1 and leading to reduced hepatic glucose production via suppression of hepatic glycogenolysis [11]. The rational use of combination therapy involves the use of agents with complementary but different mechanisms of action (or from more than one class). As the proposed mechanism of action of colesevelam is different from other antidiabetes agents, colesevelam could potentially be used in combination with other agents. The effects of colesevelam as monotherapy have not been previously characterized, and although colesevelam is effective in glycemic improvement, it is considered unlikely based on the findings of this study that it will compete with the universally accepted and highly effective metformin for use as first-line monotherapy for the treatment of T2DM. However, it can be considered as a valid additional option for combination therapy. The 2012 ADA/European Association for the Study of Diabetes (EASD) recommendations for antihyperglycemic therapy in T2DM emphasize the importance of individualizing treatment to account for factors such as the degree of hyperglycemia and patient characteristics [12]. In many cases, this influences the decision to initiate combination therapy. The current study confirmed modest improvements in glycemic control and clinically relevant reductions of LDL-C that support the use of colesevelam in combination with other antidiabetes agents when treatment
Rosenstock J et al. Type 2 Diabetes: Colesevelam Monotherapy … Horm Metab Res 2014; 46: 348–353
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Fig. 3 Changes from baseline in lipid parameters at Week 24 (with last observation carried forward). * Reported as median.
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Conclusions
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Colesevelam monotherapy resulted in statistically significant improvements in glycemic control, with consistent changes in lipid parameters, especially reductions in LDL-C, in subjects with T2DM. There were no new or unexpected safety and tolerability issues. Use of colesevelam monotherapy had smaller glycemic effects compared to prior studies. Thus, colesevelam may have its greatest use as an antidiabetes agent when used in combination with other antidiabetes therapies and not as monotherapy.
Acknowledgements
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Sushma Soni of inScience Communications, Springer Healthcare, provided medical writing support funded by Daiichi Sankyo, Inc.
Conflict of Interest
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Julio Rosenstock MD, has served on scientific advisory boards and received honorarium or consulting fees from Roche, Sanofi, Novo Nordisk, Eli Lilly, GlaxoSmithKline, Takeda, Daiichi Sankyo, Johnson & Johnson, Novartis, Boehringer Ingelheim, and Lexicon. He has also received grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Roche, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Takeda, Novartis, AstraZeneca, Amylin, Johnson & Johnson, Daiichi Sankyo, MannKind, Lexicon, and Boehringer
Ingelheim. Scott P. Rigby MD, has received remuneration from Daiichi Sankyo, Inc. for participation in clinical trials. Daniel M. Ford Ph.D., Ben Tao MS, and Hubert Chou MD, Ph.D., are employees of Daiichi Sankyo, Inc.
References 1 American Diabetes Association. Standards of medical care in diabetes 2013. Diabetes Care 2013; 36 (Suppl. 1): S11–S66 2 Davidson MH, Dillon MA, Gordon B, Jones P, Samuels J, Weiss S, Isaacsohn J, Toth P, Burke SK. Colesevelam hydrochloride (Cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med 1999; 159: 1893–1900 3 Huijgen R, Abbink EJ, Bruckert E, Stalenhoef AFH, Imholz BPM, Durrington PN, Trip MD, Eriksson M, Visseren FLJ, Schaefer JR, Kastelein JJP; for the Triple Study Group. Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial. Clin Ther 2010; 32: 615–625 4 Stein EA, Marais AD, Szamosi T, Raal FJ, Schurr D, Urbina EM, Hopkins PN, Karki S, Xu J, Misir S, Melino M. Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia. J Pediatr 2010; 156: 231–236, e231−e233 5 Fonseca VA, Rosenstock J, Wang AC, Truitt KE, Jones MR. Colesevelam HCl improves glycemic control and reduces LDL cholesterol in patients with inadequately controlled type 2 diabetes on sulfonylurea-based therapy. Diabetes Care 2008; 31: 1479–1484 6 Bays HE, Goldberg RB, Truitt KE, Jones MR. Colesevelam hydrochloride therapy in patients with type 2 diabetes mellitus treated with metformin: glucose and lipid effects. Arch Intern Med 2008; 168: 1975–1983 7 Goldberg RB, Fonseca VA, Truitt KE, Jones MR. Efficacy and safety of colesevelam in patients with type 2 diabetes mellitus and inadequate glycemic control receiving insulin-based therapy. Arch Intern Med 2008; 168: 1531–1540 8 Rosenstock J, Fonseca VA, Garvey WT, Goldberg RB, Handelsman Y, Abby SL, Lai Y-L, Jin X, Misir S, Nagendran S, Jones MR. Initial combination therapy with metformin and colesevelam for achievement of glycemic and lipid goals in early type 2 diabetes. Endocr Pract 2010; 16: 629–640 9 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31 (Suppl. 1): S55–S60 10 Henry RR, Aroda VR, Mudaliar S, Garvey WT, Chou HS, Jones MR. Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2012; 14: 40–46 11 Potthoff MJ, Potts A, He T, Duarte JAG, Taussig R, Mangelsdorf DJ, Kliewer SA, Burgess SC. Colesevelam suppresses hepatic glycogenolysis by TGR5-mediated induction of GLP-1 action in DIO mice. Am J Physiol Gastrointest Liver Physiol 2013; 304: G371–G380 12 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35: 1364–1379
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targets for these parameters are close but are not quite achieved. Indeed, the ADA/EASD guidelines additionally note that improvement of glycemic control should be just one component of a multifactorial risk reduction framework, given that patients with T2DM are at increased risk of cardiovascular morbidity and mortality and therefore are likely to gain particular benefit from aggressive management of cardiovascular risk factors [12]. This makes colesevelam potentially useful as an adjunctive therapy in T2DM, both as an add-on to statins to provide lipid-lowering benefits (a key component of the management of cardiovascular risk referenced by the ADA/EASD), and as an add-on to other antidiabetes therapies to provide glycemic benefits. However, the effect of colesevelam on cardiovascular morbidity and mortality has not been determined.
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