Colesevelam Plus Rosuvastatin 5 mg/Day Versus Rosuvastatin 10 mg/Day Alone on Markers of Insulin Resistance in Patients with Hypercholesterolemia and Impaired Fasting Glucose

Abstract

Background:

Statin use has been associated with adverse effects on insulin sensitivity and the development of new-onset diabetes. Colesevelam exhibits favorable effects on glucose metabolism. It is not known whether the combination of colesevelam plus low-dose statin has different effects on insulin resistance versus higher-dose statin in patients with impaired fasting glucose (IFG) and hypercholesterolemia.

Methods:

This was a prospective randomized open-label blinded end point (PROBE) study. Forty patients with hypercholesterolemia and IFG were randomized to receive rosuvastatin 5 mg/day plus colesevelam 3.75 g/day (RC, n=20) or rosuvastatin 10 mg (R, n=20) for 3 months. The primary end point was the difference in the change of homeostasis model assessment of insulin resistance (HOMA-IR) index between the groups.

Results:

HOMA-IR index significantly decreased in the RC group (−32%, P=0.04 vs. baseline) but nonsignificantly increased (+15%, P=NS) in the R group. Insulin levels decreased in the RC group (−26%, P=NS) but increased in the R group (+15%, P=NS). Both changes in HOMA-IR and insulin differed significantly between groups (both p<0.05). Glucose levels decreased in the RC group (−5%, P=NS), whereas they remained unaltered in the R group. Similar reductions in low-density lipoprotein cholesterol were observed in both groups (−45%; P<0.001 vs. baseline). Triglycerides remained unchanged in the RC group but decreased in the R group (−24%, P<0.001 vs. baseline and P=0.02 vs. RC group).

Conclusions:

The combination of colesevelam with rosuvastatin 5 mg/day may be associated with favorable effects on markers of insulin resistance compared with rosuvastatin 10 mg/day in patients with hypercholesterolemia and IFG. Whether this is associated with less new-onset diabetes remains unknown.

Introduction

D iabetes mellitus (DM) is a worldwide health problem with epidemic proportions today. The associated complications [e.g., coronary heart disease (CHD), chronic kidney disease, blindness, peripheral arterial disease] may lead to functional disability, vascular complications, and premature death.¹ Therefore, the prevention or delay of DM development is of major clinical importance.² Lipid-lowering drugs may affect glucose metabolism in different ways. A potentially diabetogenic role for statins has been suggested both from large studies³ and meta-analyses.^4,5 Previously, we showed that rosuvastatin may increase insulin resistance and homeostasis model assessment of insulin resistance (HOMA-IR) levels in patients with impaired fasting glucose (IFG) in a dose-dependent manner.⁶ Colesevelam is a novel bile acid sequestrant (BAS).⁷ Apart from low-density lipoprotein cholesterol (LDL-C) lowering,⁷ colesevelam has consistently been shown to improve glycemic control in patients with DM.^8,9 The combination of a low-dose statin plus colesevelam leads to similar LDL-C reductions compared with a higher-dose statin.^7,10 However, it is not known whether the combination of a low-dose statin plus colesevelam would have a different effect on insulin resistance compared with the same statin at a higher dose in patients with IFG and hypercholesterolemia.

Materials and Methods

Study population

Consecutive patients with IFG and hypercholesterolemia who attended the Outpatient Lipid and Obesity Clinic of the University Hospital of Ioannina, Ioannina, Greece, participated in the present study. The study took place between September, 2010, and March, 2012. The first patient was randomized in September, 2010, and the last patient was out in March, 2012.

Inclusion criteria were fasting serum glucose levels between 5.6 and 6.9 mmol/L (100 and 125 mg/dL) and LDL-C levels >3.36 mmol/L (130 mg/dL). Patients with known cardiovascular disease, DM, triglycerides >3.39 mmol/L (300 mg/dL), renal disease (serum creatinine levels >122 μmol/L; 1.6 mg/dL), hypothyroidism (thyroid-stimulating hormone >5 IU/mL), and liver disease [alanine aminotransferase (ALT) and/or aspartate aminotransferase levels (AST) levels more than three times the upper limit of normal in two consecutive measurements] were excluded. Patients with hypertension were included in the study if they were on stable medication for at least 3 months and their blood pressure was adequately controlled (no change in their treatment was made during the study period). Patients currently taking lipid-lowering drugs or having stopped them less than 4 weeks before study entry as well as patients taking other medications that could affect glucose homeostasis (e.g., steroids) were excluded.

Study design

This was a prospective randomized open-label blinded end point (PROBE) study. Patients were randomly allocated to treatment with rosuvastatin 5 mg/day plus colesevelam 3.75 grams/day or rosuvastatin 10 mg/day. At randomization, all subjects received dietary instructions according to National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines¹¹ by a clinical nutritionist. The primary efficacy end point was the difference in changes of HOMA-IR index between the two groups 3 months after treatment initiation. Secondary end points included differences in changes of glucose and insulin levels as well as lipid profile between the two groups. Adherence with medication was assessed at 3 months by tablet count; patients were considered adherent if they took 80%–100% of the prescribed number of tablets. All study participants gave their written informed consent and the Ethics Committee of the University Hospital of Ioannina approved the study protocol.

Laboratory measurements

All laboratory measurements were carried out after an overnight fast (water consumption was allowed) and performed blindly regarding treatment allocation. Serum levels of fasting glucose, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and triglycerides were determined enzymatically in the laboratory of the University Hospital of Ioannina using an Olympus AU 600 analyzer (Olympus Diagnostica GmbH, Hamburg, Germany). Intra-assay and total coefficient variations for glucose assay were 0.7% and 1.6%, respectively. LDL-C was calculated using the Friedewald equation. Non-HDL-C was calculated as follows: Total cholesterol minus HDL-C. Fasting serum insulin was measured by an AxSYM insulin assay microparticle enzyme immunoassay on an AzSYM analyzer (Abbott Diagnostics, Illinois, USA). Intra-assay and total coefficient variations for insulin assay were 4.1% and 5.3%, respectively. The HOMA-IR index was calculated as follows: HOMA-IR index=fasting insulin (mU/L)×fasting glucose (mg/dL)/405.

Statistics

We used G*Power 3.0.10 (UCLA Academic Technology Services) to calculate sample size. On the basis of previous studies, we estimated that rosuvastatin monotherapy 10 mg/day would increase HOMA-IR by 25% whereas the effect of colesevelam plus rosuvastatin 5 mg/day was thought to be neutral. Power analysis revealed that a sample size of 20 patients per group would give 85% power to detect differences between groups at an α-level of <0.05. Values are given as mean±standard deviation (SD) and median (range) for parametric and nonparametric data, respectively. The Fisher exact test was used to compare categorical variables. Continuous variables were tested for lack of normality by the Kolmogorov–Smirnov test and logarithmic transformations were accordingly performed for nonparametric variables. Analysis of covariance (ANCOVA) adjusted for baseline values was applied for comparisons between treatment groups. Two-tailed significance was defined as P<0.05. Analyses were performed using the Statistical Package for the Social Sciences (SPSS) 15.0 (SPSS Inc, Chicago, IL).

Results

Forty individuals (19 men, mean age 63 years old) were included in the present study; half were randomized to colesevelam plus rosuvastatin (RC) 5 mg/day and half to rosuvastatin (R) 10 mg/day. Characteristics of study participants are shown in Table 1. No difference in baseline parameters was found between the two groups. None of the participants dropped out. Adherence rate was >80% in all subjects.

Table 1.

Baseline Characteristics of Study Participants (n=40)

	Colesevelam/ rosuvastatin 5 mg/day (n=20)	Rosuvastatin 10 mg/day (n=20)	P
Age (years)	62.8±10.0	62.1±11.2	NS
Sex (men/women)	9/11	10/10	0.60
Smoking (yes/no)	5/15	6/14	0.45
Weight (kg)	77±18	79±20	NS
BMI (kg/m²)	28±5	29±5	NS
Waist circumference (cm)	99±13	101±14	NS
SBP (mmHg)	131±13	134±11	NS
DBP (mmHg)	81±7	83±8	NS
Hypertension (yes/no)	4/16	6/14	0.60
Metabolic syndrome (yes/no)	7/13	9/11	0.71
Beta-blockers (yes/no)	1/19	2/18	0.63
ACEIs/ARBs (yes/no)	3/17	4/16	0.74
CCBs (yes/no)	1/19	1/19	1.00
Aspirin (yes/no)	2/18	1/19	0.63

NS, not significant; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACEIs, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers; CCBs, calcium channel blockers.

HOMA-IR index decreased by 32% in the RC group [from 1.60 (0.4–9.2) to 1.06 (0.3–3.4), P=0.04 vs. baseline] but increased by 15% [from 1.42 (0.4–7.9) to 1.64 (0.4–8.2), P=NS] in R group with the difference being significant between groups (P<0.05 for the comparison between groups). Glucose and insulin levels were nonsignificantly reduced (−5% and −26%, respectively) in the RC group. In contrast, insulin increased (+15%, P=NS) and glucose remained unaltered in the R group (Table 2). The change in insulin levels differed significantly between groups (P<0.05 for the comparison between groups). Similar significant reductions in total cholesterol (−31% and −35%, P<0.001 vs. baseline in RC and R group, respectively), LDL-C (−45%; p<0.001 vs. baseline in both groups), and non-HDL-C (−40% and −42%, P<0.001 vs. baseline in the RC and R groups, respectively) were observed. Triglycerides remain unchanged in the RC group but decreased in the R group (−24%, P<0.001 vs. baseline and P=0.02 vs. the RC group). No significant changes were seen in HDL-C in either group (Table 2). No significant elevations in creatine kinase, ALT, and/or AST were observed (data not shown). Both treatments were well tolerated.

Table 2.

Laboratory Parameters at Baseline and 3 Months Posttreatment ^a

	Baseline	3 Months	Percentage change (%)
Total cholesterol, mmol/L (mg/dL)
Colesevelam/rosuvastatin 5 mg/day	6.59±0.54 (255±21)	4.55±0.93 (176±36)	−31^††
Rosuvastatin 10 mg/day	6.88±0.85 (266±33)	4.55±1.14 (172±44)	−35^††
Triglycerides, mmol/L; mg/dL
Colesevelam/rosuvastatin 5 mg/day	1.42 (0.73–1.84); 126 (65–163)	1.40 (0.79–2.22); 124 (70–197)	−1
Rosuvastatin 10 mg/day	1.76 (0.88–3.25); 156 (78–288)	1.33 (0.85–1.96); 118 (75–174)	−24^††,§§
HDL-C, mmol/L (mg/dL)
Colesevelam/rosuvastatin 5 mg/day	1.50±0.36 (58±14)	1.45±0.21 (56±8)	−3
Rosuvastatin 10 mg/day	1.45±0.31 (56±12)	1.37±0.36 (53±14)	−5
LDL-C, mmol/L (mg/dL)
Colesevelam/rosuvastatin 5 mg/day	4.47±0.52 (173±20)	2.46±0.83 (95±32)	−45^††
Rosuvastatin 10 mg/day	4.60±0.75 (178±29)	2.53±0.75 (98±29)	−45^††
Non-HDL-C, mmol/L (mg/dL)
Colesevelam/rosuvastatin 5 mg/day	5.1±0.63 (197±25)	3.1±0.95 (120±37)	−40^††
Rosuvastatin 10 mg/day	5.35±0.80 (207±31)	3.08±0.93 (119±36)	−42^††
Glucose, mmol/L (mg/dL)
Colesevelam/rosuvastatin 5 mg/day	5.8±0.8 (105±15)	5.6±0.7 (100±12)	−5
Rosuvastatin 10 mg/day	5.5±0.7 (99±13)	5.5±1.1 (98±19)	−1
Insulin, pmol/L [mU/L]
Colesevelam/rosuvastatin 5 mg/day	40 (14–263) [5.6 (2.0–36.7)]	30 (8–115) [4.2 (1.1–16.0)]	−26^§
Rosuvastatin 10 mg/day	45 (14–212) [6.3 (2.0–29.6)]	53 (14–181) [7.4 (2.0–25.2)]	+15
HOMA-IR index
Colesevelam/rosuvastatin 5 mg/day	1.60 (0.4–9.2)	1.06 (0.3–3.4)	−32^†,§
Rosuvastatin 10 mg/day	1.42 (0.4–7.9)	1.64 (0.4–8.2)	+15

Analysis of covariance (ANCOVA) adjusted for baseline values was applied for comparisons between treatment groups.

Values are expressed as mean±standard deviation (SD) [except for triglycerides, insulin and HOMA-IR which are expressed as median (range)].

†

P<0.05 vs baseline.

††

P<0.001 vs baseline.

P<0.05 vs rosuvastatin 10 mg/day group.

§§

P=0.02 vs colesevelam/rosuvastatin 5 mg/day group.

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; non-HDL-C, non-high-density lipoprotein cholesterol; HOMA-IR, homeostasis model of assessment-insulin resistance.

Discussion

We demonstrated for the first time that the combination of colesevelam with a low-dose of a potent statin (rosuvastatin 5 mg/day) may favorably affect HOMA-IR, a marker of insulin resistance, compared with higher dose of the same statin (rosuvastatin 10 mg/day) in patients with hypercholesterolemia and IFG. In other words, the addition of colesevelam may more than offset the possible insulin resistance-induced effect of statins. Taking into account the increasing interest regarding an excess risk of DM development with statins, these findings are of importance.

Concerns regarding the effects of statins on glucose metabolism rose by the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) study. An increase in the incidence of physician-reported diabetes with rosuvastatin 20 mg/day in apparently healthy subjects with LDL-C<3.36 mmol/L (130 mg/dL) and high-sensitivity C-reactive protein (hsCRP) >2 mg/L was reported in this study.³ A meta-analysis conducted in 2009 demonstrated a small increase in diabetes risk with statins [relative risk 1.13 (95% confidence interval (CI) 1.03–1.23)] with no evidence of heterogeneity across trials.⁴ However, this estimate was attenuated and became no longer significant when the West of Scotland Coronary Prevention Study (WOSCOPS) was included.⁴ A subsequent meta-analysis demonstrated that statin therapy was associated with a 9% increased risk for incident diabetes [odds ratio (OR)=1.09; 95% CI 1.02–1.17] with little heterogeneity between trials.⁵ This effect of statins seems to be dose-dependent.¹² Although it remains unknown what effect, if any, statin-induced diabetes might have on the development of long-term micro- and macrovascular complications, it would be prudent to diminish or delay this unfavorable action of statins.

To our knowledge, this is the first study to assess the effects of colesevelam plus a statin on a marker of insulin resistance in patients with IFG and hypercholesterolemia. Several studies with colesevelam have been conducted in patients with DM. The Glucose Lowering Effect of Welchol Study (GLOWS) was an initial pilot study which evaluated the glycated hemoglobin (HbA1c)-lowering effect of colesevelam in subjects with inadequately controlled type 2 diabetes (HbA1c=7%–10%).⁸ Colesevelam or placebo was added to standard antidiabetic treatment with sulfonylurea and/or metformin for 12 weeks. The difference in HbA1c between colesevelam and placebo was −0.5% (P=0.007). Several subsequent studies have confirmed the hypoglycemic capacity of colesevelam in patients with diabetes currently treated with metformin monotherapy¹³ or with added sulfonylurea¹⁴ or insulin¹⁵ and in comparison with thiazolidinedione and dipeptidyl peptidase-4 inhibitors (on top of metformin).¹⁶ The magnitude of HbA1c reduction is of approximately 0.5% depending on the initial baseline level. Of note, in 2009 in a statement released by the American Association of Clinical Endocrinologists/American College of Endocrinology Consensus Panel, it was suggested that colesevelam may be added to metformin monotherapy in patients with HbA1c values between 6.5% and 7.5% who do not achieve hypoglycemic goals with current treatment.¹⁷

We only found two studies that assessed the effects of colesevelam on glucose metabolism in patients without overt diabetes. In one study (n=216) colesevelam monotherapy reduced fasting plasma glucose (FPG) (−0.1 mmol/L; 2 mg/dL, P=0.02) and HbA1c levels (−0.10%, P=0.02), but not 2-hour post-oral glucose tolerance test glucose levels in patients with hypercholesterolemia and IFG or impaired glucose tolerance.¹⁸ In a recent study in 20 men with metabolic syndrome (out of which 17 were taking a statin), colesevelam reduced FPG (−0.3 mmo/L; 5 mg/dL, P<0.03) and postprandial glucose levels, but not HbA1c.¹⁹ The effect on fasting glucose levels was unrelated to the changes in insulin resistance (which was not altered) or fatty acid oxidation.¹⁹ Although the exact mechanisms for the hypoglycemic effects of colesevelam are not clear, it is likely that liver farnesoid X receptor (FXR) and oxysterol liver X receptor (LXR) are implicated,⁷ of which colesevelam is an endogenous ligand.^20,21 FXR is a bile acid–activated nuclear receptor expressed in the liver and intestine and plays an important role in bile acid, cholesterol and glucose metabolism.^20,22 The nuclear hormone receptor LXR may also play a role in glucose metabolism.²³ Specifically, upregulation of LXR has been shown to improve glycemic control.²⁴ Of note, triglycerides remained unchanged with the combination of colesevelam with rosuvastatin 5 mg/day. Probably the colesevelam-induced increase in triglycerides is compensated by the reduction induced by rosuvastatin.

Study limitations

Small sample size and the open-label design are the major limitations of our study. However, proper power calculations were made, and a PROBE design is an acceptable alternative to double-blind studies. Also, it would have probably been meaningful to measure HbA1c and perform hyperinsulinemic–euglycemic clamp test. HbA1c is now taken into account for patients with prediabetes,²⁵ while it identifies a more long-term effect on glucose metabolism. The hyperinsulinemic–euglycemic clamp is considered the most scientifically sound technique for measuring insulin sensitivity.²⁶ However, it is not very practical at an office setting as it is expensive, time consuming, and labor intensive.

Conclusion

Overall, this study demonstrated that the use of colesevelam with rosuvastatin 5 mg/day beneficially affects insulin resistance in patients with hypercholesterolemia and IFG compared with rosuvastatin 10 mg/day. This combination may be a treatment option in patients with this profile, because it achieves both adequate LDL-C reduction and may delay progression to overt diabetes. Of note, LDL-C lowering with a BAS, cholestyramine, has been associated with reductions in cardiovascular events in men.²⁷ Large studies with longer duration are warranted to investigate whether colesevelam plus statin is associated with less new-onset diabetes compared with statin monotherapy at higher dose in people with prediabetes.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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