Endocrine Care 943

Efficacy and Safety of Colesevelam in Combination with Pioglitazone in Patients with Type 2 Diabetes Mellitus

Affiliations

Key words ▶ bile acid sequestrants ● ▶ cholesterol ● ▶ glycemic control ● ▶ glucose ● ▶ thiazolidinediones ● ▶ type 2 diabetes mellitus ●

received 28.02.2014 accepted 05.06.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1383648 Published online: July 23, 2014 Horm Metab Res 2014; 46: 943–949 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0018-5043 Correspondence J. Rosenstock Dallas Diabetes and Endocrine Center at Medical City 7777 Forest Lane, Suite C-685 Dallas TX 75230 USA Tel.: + 1/972/566 7799 Fax: + 1/972/566 7399 [email protected] com

J. Rosenstock1, K. E. Truitt2, M. Baz-Hecht2, D. M. Ford2, B. Tao2, H. S. Chou2 1 2

Dallas Diabetes and Endocrine Center at Medical City, Dallas, TX, USA Daiichi Sankyo Pharma Development, Edison, NJ, USA

Abstract



Colesevelam improves glycemic control in patients with type 2 diabetes when added to existing metformin-, sulfonylurea-, or insulinbased regimens. We evaluated colesevelam’s effects in subjects on stable pioglitazone-based therapy. This 24-week multicenter, doubleblind, randomized, placebo-controlled study enrolled adults with type 2 diabetes who had suboptimal glycemic control [HbA1c ≥ 58 mmol/ mol (7.5 %) and ≤ 80 mmol/mol (9.5 %)] on pioglitazone (30 or 45 mg) with or without 1–2 other oral antidiabetes medications. Subjects were randomized to colesevelam 3.8 g/day (n = 280) or placebo (n = 282) added to existing pioglitazone-based therapy. Primary efficacy variable was mean change in HbA1c from baseline to Week 24. Secondary variables included safety and tolerability, fasting plasma glucose changes, glycemic responses, and lipid profile. Tertiary variables included lipid particle profile changes by nuclear magnetic resonance. Colesevelam decreased HbA1c [least-squares mean treatment difference, − 3.5 mmol/mol (− 0.32 %); p < 0.001] and fasting plasma glucose (− 14.7 mg/

Introduction



Effective treatment of type 2 diabetes mellitus (T2DM) requires management of hyperglycemia as well as cardiovascular risk factors such as dyslipidemia [1]. In adults with T2DM, the bile acid sequestrant colesevelam has been shown to improve glycemic control in addition to reducing low-density lipoprotein cholesterol (LDL-C) levels when added to metformin-, sulfonylurea-, or insulin-based therapy, significantly reducing hemoglobin A1c (HbA1c) levels by approximately 5.5 mmol/mol (0.5 %) [2–4]. Although the mechanism of action by which colesevelam improves glycemic control in patients

dl; p < 0.001) vs. placebo at Week 24. More subjects receiving colesevelam vs. placebo achieved HbA1c reduction ≥ 7.7 mmol/mol (0.7 %) (40 % vs. 25 %; p < 0.001) or HbA1c < 53 mmol/mol (7.0 %) (21 % vs. 13 %; p = 0.012). Colesevelam also decreased total cholesterol (mean treatment difference, − 6.5 %), LDL-cholesterol (− 16.4 %), non-HDL-cholesterol (− 9.8 %), apolipoprotein B (− 8.8 %), and total LDL particle concentration, and increased apolipoprotein A1 ( + 3.4 %) and triglycerides (median treatment difference, + 11.3 %) vs. placebo (all p < 0.001). There were no serious drug-related adverse events, and the majority of adverse events were mild or moderate. In subjects with type 2 diabetes inadequately controlled with pioglitazone-based therapy, add-on colesevelam therapy improved glycemic control and lipid parameters and was well tolerated. ClinicalTrials.gov identifier: NCT00789750.

with T2DM is not fully understood, available evidence as summarized in a recent review suggests that this mechanism is distinct from that of other classes of antidiabetes drugs [5]. Based on both nonclinical and clinical studies, colesevelam is postulated to increase portal glucagon-like peptide-1 (GLP-1) secretion via activation of TGR5, a G protein-coupled receptor for bile acids in the colon [6]. This increase in GLP-1 primarily affects the liver, leading to inhibition of hepatic glycogenolysis [6, 7]. In addition, colesevelam inhibition of farnesoid X receptor (FXR) activity, resulting in increased glucose clearance, may also contribute to its glycemic effects [6, 7].

Rosenstock J et al. Colesevelam + Pioglitazone in T2DM … Horm Metab Res 2014; 46: 943–949

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Authors

Colesevelam has not previously been extensively studied in T2DM patients treated with thiazolidinediones. Although the use of thiazolidinediones has become more restricted over time because of their adverse event (AE) profile, pioglitazone is still used mainly in combination with other oral antidiabetes agents, due to its glucose-lowering effectiveness as an insulin sensitizer with low risk of hypoglycemia. Since the addition of colesevelam to a pioglitazone-based treatment regimen is a reasonable pharmacologic combination for patients not achieving HbA1c goals, further data were necessary to elucidate the safety and efficacy of this combination. Both of these agents decrease HbA1c and tend to increase high-density lipoprotein cholesterol (HDL-C). Colesevelam also lowers LDL-C and increases triglycerides (TG), whereas pioglitazone decreases TG. The present study evaluated the safety and efficacy of colesevelam on glycemic control and the lipid profile, as well as assessing its effect on various lipoprotein particle subclasses, in subjects with uncontrolled T2DM on a stable pioglitazone-based antidiabetes regimen (NCT00789750).

Subjects and Methods



This 24-week, randomized, multicenter, double-blind, placebocontrolled, parallel-group study was conducted at 145 sites in the United States. The study protocol was approved by each site’s institutional review board, and the study was conducted in compliance with good clinical practice guidelines and the principles set forth in the Declaration of Helsinki. All subjects provided written informed consent prior to study entry. This study enrolled subjects aged 18 years or older with a diagnosis of T2DM as defined by the American Diabetes Association (ADA) [8] and inadequate glycemic control [HbA1c ≥ 58 mmol/mol (7.5 %) and ≤ 80 mmol/mol (9.5 %)] on a stable dose ( ≥ 2 months prior to screening) of pioglitazone (30 or 45 mg/day) with or without 1 or 2 other oral antidiabetes agents (metformin, sulfonylurea, or a dipeptidyl peptidase-4 inhibitor). Additional inclusion criteria were a fasting plasma glucose (FPG) level < 240 mg/dl at randomization and a fasting C-peptide level > 0.5 ng/ml at screening. Subjects were excluded for the following reasons: type 1 diabetes and/or history of ketoacidosis; fasting serum TG level > 500 mg/dl or history of hypertriglyceride-induced pancreatitis; history of bowel obstruction; dysphagia, difficulty swallowing, gastroparesis, or major gastrointestinal surgery; history of unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack, or any revascularization within 6 months of screening; use of insulin ( ≥ 2 weeks) or any bile acid sequestrant within 3 months of screening; body mass index > 40 kg/m2; LDL-C level < 60 mg/dl; and/or systolic blood pressure ≥ 180 mm Hg or diastolic blood pressure ≥ 100 mm Hg. Additionally, subjects with repeated fasting blood glucose level > 240 mg/dl during the placebo lead-in period were not randomized. After an initial screening visit, subjects entered a 2-week singleblind placebo lead-in period and were administered colesevelam-matching placebo tablets in addition to their prestudy antidiabetes therapy. Following the placebo lead-in period, subjects were randomized in a 1:1 ratio to receive oral colesevelam 3.75 g/day (6 × 625 mg tablets) or matching placebo double-blind treatment for 24 weeks. Subjects chose to follow a study medication dosing schedule of either 3 tablets administered twice daily (noon and evening meals) or 6 tablets once daily (evening meal), and maintained this schedule throughout the

double-blind treatment period. Subjects continued taking their prestudy oral antidiabetes medication(s) at the same dose and time as before their enrollment in the study. Subjects were also instructed to continue taking any concomitant statins at the same dosage. General instructions on diet, exercise, and diabetes self-care were provided. During the study, subjects with 2 or more selfmonitored fasting blood glucose readings of > 240 mg/dl were instructed to go into the clinic for laboratory repeat and, if confirmed, for study discontinuation. Clinic visits were scheduled for all subjects at Weeks 0 (baseline), 4, 8, 16, and 24, and blood samples were collected after fasting overnight for ≥ 8 h. In addition, subjects were contacted by telephone to assess compliance and safety at Weeks 12 and 20. Vital signs and weight were measured at every visit. Physical examination was performed at screening and Week 24. Chemistry and hematology samples were collected at screening and Weeks 0, 4, 8, 16, and 24. Urinalysis samples were collected at screening, Week 0, and Week 24. Laboratory evaluations of HbA1c levels, standard blood tests, and urine tests were performed by a centralized clinical pathology laboratory. Fasting blood samples were collected to assess lipid particle parameters at Weeks 0 and 24. Particle parameters were determined by nuclear magnetic resonance spectroscopy [9]. The primary efficacy variable was the mean change in HbA1c from baseline to Week 24. Key secondary efficacy variables included change in HbA1c from baseline to Weeks 4, 8, and 16; change in FPG from baseline to Weeks 4, 8, 16, and 24; the proportions of subjects achieving HbA1c < 53 mmol/mol (7.0 %) at Week 24 and those achieving a reduction in HbA1c of ≥ 7.7 mmol/mol (0.7 %) or ≥ 5.5 mmol/mol (0.5 %) from baseline at Week 24; changes and percentage changes in plasma lipids, including total cholesterol, LDL-C, HDL-C, non-HDL-C, TG, apolipoprotein (apo) A-I, and apoB, from baseline to Weeks 8 and 24; change in highsensitivity C-reactive protein (hsCRP) from baseline to Week 24; and changes in insulin levels, homeostatic model assessment (HOMA) indices, and C-peptide from baseline to Week 24. The tertiary endpoints included change and percent change in mean lipoprotein sizes and particle concentrations from baseline to Week 24. Safety assessments included treatment-emergent AEs, clinical laboratory tests, changes in vital signs and levels of 25-hydroxy vitamin D, and physical examination findings. Compliance to the study medication regimen was evaluated by counting unused tablets. A Clinical Event Committee (CEC) consisting of 3 external academic/clinical cardiology experts independently adjudicated clinically relevant cardiovascular events occurring from the time of first dose of study medication through 30 calendar days after the last dose. Cardiovascular events that required adjudication included standard Medical Dictionary for Regulatory Activities terms referable to death, angina, acute coronary syndrome, cerebrovascular events, revascularization procedures, and hospitalization for/with heart failure (or prolongation of an existing hospitalization).

Statistical methods The intent-to-treat (ITT) population was the primary analysis population for all efficacy parameters and included all randomized subjects who took at least 1 dose of double-blind study medication and had an HbA1c or FPG measurement at baseline and at least once post-baseline. Treatment differences were tested with an analysis of covariance (ANCOVA) model with

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944 Endocrine Care

Endocrine Care 945

treatment group using previous oral antidiabetes medication stratum (pioglitazone monotherapy and pioglitazone combination therapy as categories) as fixed effects and baseline HbA1c as a covariate. A treatment-by-previous-oral-antidiabetes medication-stratum interaction term was added to the model and tested at the 0.10 significance level. If the p-value for the null hypothesis was ≤ 0.05 or the interaction term was significant at the 0.10 level, then the placebo-corrected effects of colesevelam on glycemic control in the pioglitazone monotherapy cohort and in the pioglitazone combination therapy cohort were further evaluated for positive study conclusions at the nominal 0.05 significance level. The assumption of parallelism was evaluated by adding a treatmentby-baseline interaction term to the model and assessing the interaction at the 0.10 significance level. If a significant treatmentby-baseline interaction was suggested by the data, then the qualitative or quantitative nature of the interaction was evaluated. The normality of the residuals from the ANCOVA model were assessed using the Shapiro-Wilk statistic and graphical examination. If the residuals were not normally distributed, then the primary efficacy analysis was carried out using the Wilcoxon rank sum test instead. Summary statistics are presented by treatment arm. For continuous variables, the least-squares (LS) mean and standard deviation (SD), or median and range (for variables not normally distributed, such as TG), were determined. For categorical variables, the frequency and percentage in each category were determined. Summary statistics were calculated for HbA1c at baseline, post-baseline, and the change from baseline for each treatment group. Measurements from scheduled visits were summarized. Missing data at Week 24 was imputed using the last post-baseline observation carried forward (LOCF); Week 24 data are presented as LOCF unless specified otherwise. The safety population included all randomized subjects who took at least 1 dose of double-blind study medication and had at least 1 post-baseline safety measurement. All safety analyses were performed on the safety population. Safety analyses were

descriptive, with the appropriate summary statistics determined.

Results



Subject disposition and baseline characteristics ▶ Fig. 1. In total, 562 subSubject disposition data are shown in ● jects were randomized (colesevelam, n = 280; placebo, n = 282). The ITT population comprised 547 subjects (97.3 %) and the safety population comprised 551 subjects (98.0 %). Four randomized subjects (1.4 %) in the placebo group and 3 (1.1 %) in the colesevelam group discontinued from the study due to meeting protocol-specified discontinuation criteria for hyperglycemia. Baseline demographics and characteristics were generally simi▶ Table 1). The mean age was lar for both treatment groups (● 56.0 years, 56.9 % were male, 62.5 % were Caucasian, and 34.3 % were Hispanic/Latino. The placebo group had a slightly higher proportion of males than the colesevelam group (62.4 % vs. 51.4 %, respectively). The mean duration of T2DM was 8.4 years and most subjects (91 %) had previously taken pioglitazone in combination with other oral antidiabetes medications. At baseline, mean ± SD HbA1c was 66 ± 7.7 mmol/mol (8.2 % ± 0.7 %), and mean LDL-C level was 107.0 ± 32 mg/dl. Concomitant statins were used by 41.1 % of colesevelam recipients and 49.6 % of placebo recipients.

Efficacy Glycemic parameters At Week 24, the LS mean change from baseline in HbA1c was − 3.7 mmol/mol (− 0.34 %) for the colesevelam group and − 0.2 mmol/mol (− 0.02 %) for the placebo group [LS mean treatment difference, 3.5 mmol/mol (− 0.32 %); p < 0.001]. As shown ▶ Fig. 2a, significant between-group separation in HbA1c in ● levels was seen as early as Week 4. Greater reductions from baseline in HbA1c were seen with colesevelam compared with placebo at Week 4 [LS mean treatment difference, − 1.9 mmol/mol

Rosenstock J et al. Colesevelam + Pioglitazone in T2DM … Horm Metab Res 2014; 46: 943–949

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Fig. 1 Subject disposition. During the lead-in period all subjects received single-blind placebo. *Lack of efficacy category includes hyperglycemia that did not meet protocol-specified discontinuation criteria.

946 Endocrine Care

Characteristics

Placebo (n = 282)

Colesevelam (n = 280)

Total (N = 562)

Age (years), mean ± SD Sex, n ( %) Male Race, n ( %) Caucasian Black Asian American Indian or Alaskan native Native Hawaiian or Pacific Islander Other Ethnicity Hispanic/Latino Not Hispanic/Latino BMI (kg/m2), mean ± SD Hemoglobin A1c (mmol/mol) ( %), mean ± SD FPG (mg/dl), mean ± SD LDL-C (mg/dl), mean ± SD Concomitant statin usage, n ( %) Previous antidiabetes medication status, n ( %) Pioglitazone monotherapy Pioglitazone in combination with other oral antidiabetes therapies Metformin only SU only DPP-4 inhibitor only Metformin + SU Metformin + DPP-4 inhibitor Metformin + SU + DPP-4 inhibitor Duration of T2DM (years), mean ± SD

55.6 ± 10.6

56.3 ± 10.2

56.0 ± 10.4

176 (62.4)

144 (51.4)

320 (56.9)

172 (61) 56 (20) 30 (11) 21 (7) 1 (0.4) 2 (0.7)

179 (64) 59 (21) 23 (8) 16 (6) 0 (0.0) 3 (1.1)

351 (62) 115 (20) 53 (9) 37 (7) 1 (0.2) 5 (0.9)

99 (35) 183 (65) 31.7 ± 4.7 65 ± 7.7 (8.1 ± 0.7) 157 ± 38 105 ± 30 140 (50)

94 (34) 186 (66) 31.9 ± 4.8 66 ± 7.7 (8.2 ± 0.7) 156 ± 38 109 ± 33 115 (41)

193 (34) 369 (66) 31.8 ± 4.7 66 ± 7.7 (8.2 ± 0.7) 156 ± 38 107 ± 32 255 (45)

26 (9) 256 (91) 155 (55) 20 (7) 1 (0.4) 72 (26) 8 (3) 0 (0.0) n = 281 8.3 ± 7.0

25 (9) 255 (91) 143 (51) 32 (11) 3 (1.1) 67 (24) 9 (3) 1 (0.4) n = 275 8.5 ± 6.4

51 (9) 511 (91) 298 (53) 52 (9) 4 (0.7) 139 (25) 17 (3) 1 (0.2) N = 556 8.4 ± 6.7

BMI: Body mass index; DPP-4: Dipeptidyl peptidase-4; FPG: Fasting plasma glucose; LDL-C: Low-density lipoprotein cholesterol; SD: Standard deviation; SU: Sulfonylurea; T2DM: Type 2 diabetes mellitus

Fig. 2 Mean a HbA1c and b FPG over time (without last observation carried forward). *Change from baseline was significant (p < 0.001) vs. placebo; † Change from baseline was significant (p < 0.05) vs. placebo. HbA1c: Hemoglobin A1c; FPG: Fasting plasma glucose.

(− 0.17 %)], Week 8 [− 2.3 mmol/mol (− 0.21 %)], Week 16 [− 3.9 mmol/mol (− 0.36 %)], and Week 24 [− 3.7 mmol/mol (− 0.34 %)] without LOCF (all p < 0.001). Additionally, the LS mean change from baseline in FPG was − 4.8 mg/dl for the colesevelam group and + 9.9 mg/dl for the placebo group (LS mean treatment difference, − 14.7 mg/dl; p < 0.001) at Week 24; treatment differences were significant at Weeks 4, 16, and 24 (without ▶ Fig. 2b). LOCF; ● A significantly greater proportion of subjects receiving colesevelam, compared with placebo, achieved HbA1c < 53 mmol/mol (7.0 %) (21 % vs. 13 %; p = 0.012) or reductions from baseline in

HbA1c of ≥ 7.7 mmol/mol (0.7 %) (40 % vs. 25 %; p < 0.001) or ≥ 5.5 mmol/mol (0.5 %) (54 % vs. 38 %; p < 0.001) at Week 24. There were no significant treatment differences in fasting C-peptide (p = 0.065), HOMA index (p = 0.886), or fasting insulin (p = 0.729) at Week 24.

Lipid parameters The colesevelam group had significantly (p < 0.001) greater LS mean percent reductions in total cholesterol (LS mean treatment difference, − 6.5 %), LDL-C (− 16 %), non-HDL-C (− 10 %), and apoB (− 9 %), and a significantly greater LS mean increase in

Rosenstock J et al. Colesevelam + Pioglitazone in T2DM … Horm Metab Res 2014; 46: 943–949

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Table 1 Demographics and baseline characteristics (all randomized subjects).

Endocrine Care 947

Lipid particle parameters – Nuclear magnetic resonance data Subjects receiving colesevelam, compared with placebo, had significantly greater reductions from baseline to Week 24 in total low-density lipoprotein particle concentration (LDL-P; ▶ Fig. 4a), and LDL subclass particle concentrations p < 0.001; ● ▶ Fig. 4b). In addition, colesevelam increased concen(p < 0.05; ●

Fig. 3 Mean percent change from baseline in lipid parameters at Week 24 (with last observation carried forward). *Reported as median. Apo, apolipoprotein; HDL-C: High-density lipoprotein cholesterol; LDL-C: Lowdensity lipoprotein cholesterol; TG: Triglycerides.

trations of large HDL particles (LS mean treatment difference, 0.6 μmol/l; p = 0.004), large very low-density lipoprotein (VLDL) particles plus chylomicrons (1 nmol/l; p < 0.001), and medium VLDL particles (7 nmol/l; p < 0.001), and reduced small VLDL particle concentration (− 4 nmol/l; p = 0.004). Significantly greater increases in LS mean size of HDL (LS mean treatment difference, 0.1 nm; p = 0.002) and VLDL (2.0 nm; p < 0.001) particles from baseline to Week 24 were seen with colesevelam, compared with placebo.

Safety Overall, 137 placebo recipients (49.5 %) and 148 colesevelam ▶ Table 2). Drug-related AEs recipients (54.0 %) reported an AE (● (as assessed by the investigator) were reported by 44 placebo recipients (15.9 %) and 41 colesevelam recipients (15.0 %). The majority of AEs were mild or moderate in severity and there were no drug-related serious AEs in either treatment group. Five subjects (1.8 %) in the placebo group and 3 (1.1 %) in the colesevelam group withdrew from the study because of a drugrelated AE [placebo: increase in hepatic enzymes (n = 2), increase in HbA1c (n = 1), nausea (n = 1), and vomiting (n = 1); colesevelam: increase in HbA1c (n = 1), flatulence (n = 1), and fungal skin infection (n = 1)]. No deaths were reported during the study. The most frequent spontaneous investigator-reported AEs are ▶ Table 2. The colesevelam group had a higher incishown in ● dence than the placebo group for the following AEs: constipation (4.0 % vs. 2.9 %), increase in blood creatine phosphokinase (3.6 % vs. 1.1 %), and nausea (2.9 % vs. 1.1 %). There was no imbalance in laboratory-reported creatine phosphokinase elevation between colesevelam and placebo (data not shown). Four potential cardiovascular events were referred to the CEC for adjudication: 1 event was adjudicated as stroke and was considered unrelated to study treatment (colesevelam group), while 3 events were adjudicated as noncardiovascular events, that is, noncardiac chest pain (placebo, n = 1; colesevelam, n = 2). Mean changes in weight from baseline to Week 24/early termination were similar between the colesevelam and placebo

Fig. 4 Least-squares mean change from baseline in a total concentrations of LDL, VLDL/chylomicrons, IDL, and HDL particles, and b LDL subgroup particle concentrations, at Week 24 (with last observation carried forward). HDL: High-density lipoprotein; IDL: Intermediate-density lipoprotein; LDL: Low-density lipoprotein; VLDL: Very low-density lipoprotein.

Rosenstock J et al. Colesevelam + Pioglitazone in T2DM … Horm Metab Res 2014; 46: 943–949

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apoA-I ( + 3 %; p < 0.001), compared with the placebo group ▶ Fig. 3). A numerically greater increase in HDL-C was seen (● with colesevelam compared with placebo (p = 0.165). In addition, there was a median increase in TG with a median treatment difference of + 11.3 % compared to placebo (p < 0.001). There were no significant treatment changes in hsCRP (data not shown).

Table 2 Adverse events occurring in ≥ 2 % of subjects in either the colesevelam or the placebo group. AE, n ( %) Subjects with any AE Anemia Constipation Nausea Edema (peripheral) Bronchitis Nasopharyngitis Upper respiratory tract infection Urinary tract infection Blood creatine phosphokinase increased Blood glucose increased C-reactive protein increased Hypoglycemia Dizziness Headache Hypertension Subjects with any drug-related AE Subjects with any serious AE Subjects with any drug-related serious AE Discontinuations due to any AE Discontinuations due to any drug-related AE Discontinuations due to any serious AE

Placebo

Colesevelam

(n = 277)

(n = 274)

137 (49.5) 4 (1.4) 8 (2.9) 3 (1.1) 8 (2.9) 7 (2.5) 10 (3.6) 9 (3.2) 12 (4.3) 3 (1.1) 8 (2.9) 5 (1.8) 17 (6.1) 7 (2.5) 6 (2.2) 7 (2.5) 44 (15.9) 4 (1.4) 0 (0.0) 9 (3.2) 5 (1.8) 1 (0.4)

148 (54.0) 6 (2.2) 11 (4.0) 8 (2.9) 8 (2.9) 7 (2.6) 4 (1.5) 8 (2.9) 9 (3.3) 10 (3.6) 5 (1.8) 6 (2.2) 11 (4.0) 1 (0.4) 5 (1.8) 6 (2.2) 41 (15.0) 11 (4.0) 0 (0.0) 8 (2.9) 3 (1.1) 2 (0.7)

AE: Adverse event

groups (0.82 and 0.36 kg, respectively). There were no clinically meaningful differences between the treatment groups in mean changes from baseline to Week 24 in safety laboratory parameters, that is, chemistry, hematology, and urinalysis, including the fat-soluble 25-hydroxyvitamin D.

Discussion



This study demonstrated the efficacy of colesevelam in improving glycemic control and lipid levels when used as an add-on to pioglitazone-based therapy in subjects with T2DM. Previous studies similarly showed improvements in glycemic control and LDL-C levels with the addition of colesevelam to metformin-, sulfonylurea-, or insulin-based regimens [2–4]; however, the efficacy of colesevelam in combination with thiazolidinediones had not previously been studied. Colesevelam add-on therapy resulted in a significantly greater reduction in HbA1c than placebo at the end of the 24-week treatment period; a significant treatment difference was apparent from Week 4 onwards. The endpoint reduction in HbA1c in this study is slightly smaller than that reported in the 3 previously-reported colesevelam add-on studies [− 5.5 mmol/mol (− 0.5 %)] [2–4]. The reason for this smaller difference in HbA1c reduction is not clear. The smaller between-group HbA1c reduction may be at least partially explained by a larger HbA1c reduction in the placebo group observed in the present study than in the previous studies. The treatment difference in HbA1c reduction in the present study was similar to the placebo-subtracted HbA1c reduction in a recent colesevelam monotherapy study [− 3.3 mmol/mol (− 0.3 %)], in which a larger than expected placebo effect was also observed [10]. However, the patient population in the current study differed from the monotherapy study. In the current study, similar to the previous add-on studies,

subjects had a longer mean T2DM duration and were inadequately controlled on existing antidiabetes treatment, while in the monotherapy study, subjects had a shorter mean T2DM duration and were either newly diagnosed or not receiving antidiabetes drugs at screening. In addition to reducing HbA1c, colesevelam provided significant reduction in FPG. Importantly, a significantly greater proportion of subjects receiving colesevelam, compared with placebo, achieved the ADA-defined HbA1c target of < 53 mmol/mol (7.0 %) at Week 24, as well as greater proportions of responders with HbA1c reductions of ≥ 7.7 mmol/ mol (0.7 %) or ≥ 5.5 mmol/mol (0.5 %). Patients with T2DM are at an increased risk of cardiovascular morbidity and mortality, and treatment guidelines highlight the importance of managing dyslipidemia as well as hyperglycemia in this patient population [1, 11–13]. As improvements in glycemic control can have a positive effect on plasma lipid levels [1], adding on an agent such as colesevelam that improves both glycemic control and the lipid profile may be particularly beneficial in treating patients with T2DM. Although the subjects in this study were on stable long-standing pioglitazone-based therapy and a large proportion were on statins, colesevelam add-on therapy significantly improved the lipid profile (i. e., reduced total cholesterol, LDL-C, non-HDL-C, and apoB; increased HDL-C and apoA-I), in addition to improving glycemic control compared with placebo. The observed increase in TG is a known side effect of the bile acid sequestrant class, and is consistent with previous studies. Cardiovascular outcomes have not been assessed with colesevelam; however, in a study with the bile acid sequestrant cholestyramine, reductions in total and LDL cholesterol were associated with a 19 % reduced risk of coronary heart disease, despite increased TG levels [14]. Individuals with T2DM or insulin resistance often have abnormalities in the lipid profile and lipoprotein particle distribution [15] that may be associated with increased risk of cardiovascular disease [16]. Similar to previous colesevelam monotherapy [17] and add-on studies with sulfonylurea- and/or metformin-based therapy [18, 19], the current study showed that adding colesevelam to a pioglitazone-based regimen resulted in generally favorable changes to the lipoprotein particle profile. In the current study, colesevelam did not show any significant treatment effects on insulin sensitivity or inflammatory biomarkers. The lack of effect on insulin sensitivity is consistent with results of a study by Henry et al., wherein adding colesevelam onto a regimen of sulfonylurea or stable diet/exercise in subjects with T2DM and HbA1c ≥ 58 mmol/mol (7.5 %) did not affect hepatic or peripheral insulin sensitivity [20]. Although the mechanism of action of colesevelam for improving glycemic control is not yet fully understood, it is thought to be mediated through pathways independent of direct insulin actions [5]. Plausible mechanisms based on results from animal and human studies include a bile-acid induced increase in portal GLP-1 secretion leading to inhibition of hepatic glycogenolysis [6, 7] and possibly an inhibition of FXR activity leading to increased glucose clearance [7] (for more detail on the potential glucoselowering mechanism of action, refer to the review by Nwose and Jones [5]). Colesevelam was well tolerated with an AE profile similar to that observed in previous studies [2–4]. There were no reported cases of severe hypoglycemia. Consistent with earlier studies, constipation was the most common drug-related AE in the colesevelam group.

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948 Endocrine Care

Conclusion



The addition of colesevelam to pioglitazone-based therapy was well tolerated and improved glycemic parameters in patients with T2DM. In addition, colesevelam had a generally beneficial effect on the lipid and lipoprotein particle profile.

Acknowledgements



Alan Klopp Ph.D. and Sushma Soni of inScience Communications, Springer Healthcare, provided medical writing support funded by Daiichi Sankyo, Inc.

Conflict of Interest



Julio Rosenstock has served on scientific advisory boards and received honorarium or consulting fees from Merck, Roche, Sanofi , Novo Nordisk, Eli Lilly, GlaxoSmithKline, Takeda, Daiichi Sankyo, Janssen, Novartis, MannKind, Boehringer Ingelheim, Intarcia, 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, Janssen, Daiichi Sankyo, MannKind, Intarcia, Lexicon, and Boehringer Ingelheim. Kenneth E. Truitt, Merav Baz-Hecht, Daniel M. Ford, Ben Tao, and Hubert S. Chou are employees of Daiichi Sankyo Pharma Development.

References 1 American Diabetes Association. Standards of medical care in diabetes – 2014. Diabetes Care 2014; 37 (Suppl 1): S14–S80 2 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 3 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 4 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 5 Nwose OM, Jones MR. Atypical mechanism of glucose modulation by colesevelam in patients with type 2 diabetes. Clin Med Insights Endocrinol Diabetes 2013; 6: 75–79 6 Potthoff MJ, Potts A, He T, Duarte JA, 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

7 Beysen C, Murphy EJ, Deines K, Chan M, Tsang E, Glass A, Turner SM, Protasio J, Riiff T, Hellerstein MK. Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study. Diabetologia 2012; 55: 432–442 8 American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008; 31 (Suppl 1): S55–S60 9 Otvos JD, Jeyarajah EJ, Bennett DW, Krauss RM. Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement. Clin Chem 1992; 38: 1632–1638 10 Rosenstock J, Rigby SP, Ford DM, Tao B, Chou HS. The glucose and lipid effects of colesevelam as monotherapy in drug-naïve type 2 diabetes. Horm Metab Res 2014; 46: 348–353 11 Handelsman Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda O, Garber AJ, Hirsch IB, Horton ES, Ismail-Beigi F, Jellinger PS, Jones KL, Jovanovic L, Lebovitz H, Levy P, Moghissi ES, Orzeck EA, Vinik AI, Wyne KL. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 2011; 17 (Suppl 2): 1–53 12 National Cholesterol Education Program (NCEP) Expert Panel on Detection Evaluation and Treatment of High Blood Cholesterol In Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–2497 13 Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014; 129 (25 Suppl 2): S1–S45 14 Lipid Research Clinics Program. The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1984; 251: 365–374 15 Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A, Pugh K, Jenkins AJ, Klein RL, Liao Y. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes 2003; 52: 453–462 16 Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 2008; 31: 811–822 17 Rosenson RS, Rigby SP, Jones MR, Chou HS. Effect of colesevelam HCl monotherapy on lipid particles in type 2 diabetes mellitus. Cardiovasc Drugs Ther 2014; 28: 229–236 18 Goldberg RB, Rosenson RS, Hernandez-Triana E, Misir S, Jones MR. Initial combination therapy with metformin plus colesevelam improves lipoprotein particles in patients with early type 2 diabetes mellitus. J Clin Lipidol 2012; 6: 318–324 19 Rosenson RS, Abby SL, Jones MR. Colesevelam HCl effects on atherogenic lipoprotein subclasses in subjects with type 2 diabetes. Atherosclerosis 2009; 204: 342–344 20 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

Rosenstock J et al. Colesevelam + Pioglitazone in T2DM … Horm Metab Res 2014; 46: 943–949

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Efficacy and safety of colesevelam in combination with pioglitazone in patients with type 2 diabetes mellitus.

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