Efficacy of Colesevelam on Lowering Glycemia and

Journal of Cardiovascular Pharmacology Publish Ahead of Print DOI: 10.1097/FJC.0b013e31823a109f

Efficacy of Colesevelam on Lowering Glycemia and Lipids Saurabh Aggarwal, M.D.1, Rohit S Loomba, M.D.* 2, Rohit R Arora, M.D. 3 *Corresponding Author

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Chicago Medical School Rosalind Franklin University Department of Medicine 3333 Green Bay Road, North Chicago, IL 60064

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Captain James A. Lovell Federal Health Care Center 3001 Green Bay Road, North Chicago, IL 60064

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*Children’s Hospital of Wisconsin/Medical College of Wisconsin Affiliated Hospitals Department of Pediatrics 9000 Wisconsin Avenue, Wauwatosa, WI 53202 [email protected] 630-881-8342

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We acknowledge that all authors have contributed to this manuscript and are aware of its submission. This manuscript is not under simultaneous review elsewhere and represents the work of the listed authors. The authors have no financial disclosures to make.

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Keywords: colesevelam, glycemic, lipid, meta-analysis, diabetes

Copyright Ó Lippincott Williams & Wilkins. All rights reserved.

Abstract

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A few trials have investigated the efficacy of colesevelam in the reduction of glycemic and lipid outcomes. This meta-analysis pooled data from 8 such trials and found that colesevelam is associated with significant reductions in plasma fasting glucose, hemoglobin A1c, and LDL. Insignificant reductions in HDL and total cholesterol were also noted along with significant increase in triglycerides. This analysis concludes that colesevelam may be of particular benefit in managing type 2 diabetic patients with hyperlipidemia in whom LDL levels are of particular concern. Caution should be taken in patients who have hypertriglyceridemia or low HDL levels before starting therapy.


Introduction Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Nearly 80 million people are estimated to be effected by CVD, making it the leading cause of death in both men and women [1, 2]. Though recent reports suggest that deaths from CVD have decreased, it still causes an average of 1 death every 39 seconds in America [3] .

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Diabetes mellitus and hypercholesterolemia are both associated with worse cardiovascular outcomes and the management of these risk factors consists of lifestyle modification with or without pharmacotherapy. Drugs such as sulfonylureas, metformin, thiazolidinediones and insulin are the mainstays for treatment of diabetes while statins, fibrates, niacin and bile acid sequestrants (BAS) are used to treat elevated cholesterol levels. Colesevelam hydrochloride is a BAS that is different from the conventional bile acid sequestrants, such as cholestyramine and colestipol, in a number of ways. Apart from its effects on lipid levels, it has also been found to improve glycemic control in type 2 diabetics. Colesevelam is the only drug that has been approved for reduction of LDL in the setting of hyperlipidemia and for glycemic control in the setting of type 2 diabetes mellitus.

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Many of the studies investigating colesevelam and its effect on lipids and glycemia have had demonstrated differing results in regards to high density lipoprotein, total cholesterol, and triglycerides. This article reviews the use of colesevelam in treatment of hypercholesterolemia and type 2 diabetes mellitus by assessing pooled results from these studies. Methods

Literature sources, search terms, and study selection

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Medical literature was systematically reviewed by all authors. Studies evaluating percutaneous balloon dilation and surgical valvuloplasty were identified and collected by searching MEDLINE and the Cochrane Library using web-based search engines such as OVID. All relevant studies were then assessed for inclusion using a standardized check list. Search terms used included colesevelam, lipids, diabetes, glycemic and various combinations of these terms. The references of identified and collected studies were then used to identify additional studies which were also assessed for inclusion. Figure 1 outlines study selection.

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Endpoints and Definitions

A total of 6 endpoints were extracted from 8 studies [4-11]. Endpoints studied were levels of fasting plasma glucose, hemoglobin A1c, LDL, HLD, triglycerides, and total cholesterol. Only studies with corresponding endpoint definitions were included in the analysis. Data extraction and Quality Assessment After studies were collected and screened for inclusion, full articles were retrieved for titles fulfilling inclusion criteria. Studies were then scored for quality and data was extracted for studied endpoints. Statistical Analysis


Summary statistics reported in each study were used for the meta-analysis as individual patient data was not accessible. Statistical analysis was performed using the MedCalc software package (Version 11.6.0.0, Mariakerke, Belgium). Cochrane’s Q statistics were calculated and used to determine the heterogeneity of included studies for each endpoint. The fixed-effects model was used for analysis of endpoints that were homogenous and the random-effects model was used for analysis of endpoints that were heterogeneous. Heterogeneity analysis is summarized in Table 1.

Results

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Baseline Characteristics

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The included studies did not show significant differences in baseline patient characteristics (Table 2). Results of the analysis are shown in figures 2 through 7 and there were no significant differences in baseline characteristics within endpoints once data was pooled. Hemoglobin A1c

Fasting Plasma Glucose

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There was a statistically significant reduction in hemoglobin A1c associated with colesevelam (odds ratio, -0.594, confidence interval, -0.747 to -0.442) (Figure 2).

There was a statistically significant reduction in fasting plasma glucose associated with colesevelam (odds ratio, -0.302, confidence interval, -0.448 to -0.156) (Figure 3). LDL

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There was a statistically significant reduction in LDL associated with colesevelam (odds ratio, -1.346, confidence interval, -2.411 to -0.279) (Figure 4). HDL There was a statistically insignificant reduction in HDL associated with colesevelam (odds ratio, -0.0806, confidence interval, -0.527 to 0.365) (Figure 5).

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Total Cholesterol

There was a statistically insignificant reduction in total cholesterol associated with colesevelam (odds ratio, -0.487, confidence interval, -1.641 to 0.667) (Figure 6). Triglycerides There was a statistically significant increase in triglycerides associated with colesevelam (odds ratio, 0.300, confidence interval, 0.0130 to 0.587) (Figure 7).


Discussion This meta-analysis pools data from 8 studies for a total of 1,038 patients, analyzing 6 separate outcomes [4-11]. When compared to placebo, colesevelam was associated with significant reductions in hemoglobin A1c, fasting plasma glucose, and LDL. Statistically significant increases in triglycerides were also noted. Colesevelam was also associated with statistically insignificant reductions in total cholesterol and HDL.

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Bile acids are manufactured in the liver and transported to the duodenum via bile. Bile acids enter the enterohepatic circulation with almost 90% of bile acids being reabsorbed in the terminal ileum. Bile acids are required for the digestion and absorption of cholesterol and fats and are formed by the breakdown of cholesterol, with the enzyme cholesterol 7-alpha-hydroxylase serving as the rate limiting enzyme in this process. Cholesterol is synthesized both in the liver and peripheral tissues and then transported in the blood as low density lipoprotein (LDL), very low density lipoprotein (VLDL), high density lipoprotein (HDL) and chylomicrons. Hepatic cholesterol levels are maintained by uptake of circulating LDL cholesterol via the LDL receptors.

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Colesevelam is a bile acid sequestrants, thus, its lipid modifying effects are analogous to those of cholestyramine and colestipol. The BAS bind to the bile acids in the intestine and form complexes that are excreted in feces, thus lowering the concentration of bile acids. This causes decreased enterohepatic circulation of bile acids, which prompts the liver to increase the synthesis of bile acids achieved by breakdown of cholesterol. This leads to a decrease in hepatic cholesterol which in-turn leads to upregulation of LDL receptors. This upregulation of LDL receptors finally leads to increased clearance of LDL cholesterol and hence lower blood LDL cholesterol levels (Figure 8) [12, 13].

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The mechanisms underlying the glycemic control achieved with colesevelam are unclear [13]. Multiple mechanisms have been proposed. One proposed mechanism is that it may be due to the effects of colesevelam on farnesyl X receptors (FXR) which are present in both the intestine and liver and on TGR5, a G protein coupled receptor present in the intestine [14, 15]. Colesevelam, by reducing bile acid cycling, reduces liver FXR activity. This can cause an increased liver X receptor (LXR) activity which leads to reduction in gluconeogenesis, increased insulin secretion and increased expression of glucokinase and glucose transporter 4 [16-19]. Another proposed mechanism is that colesevelam improves glycemic control by causing increased secretion of fasting, as well as postprandial glucagon-like peptide-1, levels and glucose-dependent insulinotropic peptides [20, 21]. The mechanism of action of colesevelam has been depicted in Figure 8. Colesevelam is a hydrophilic and insoluble polymer that undergoes minimal systemic distribution and absorption [22]. Volume of distribution and plasma protein binding are minimal due to insignificant systemic absorption. Both animal and human studies have found that colesevelam is mainly excreted in feces with minimal renal clearance [22, 23]. Since colesevelam is not absorbed systemically, the only factor that plays a role in administration of colesevelam is the transit time of the drug through the gut [13]. Once or twice daily dosing may be considered[13]. To increase the efficacy of colesevelam in lowering LDL and total cholesterol levels it can be taken along with food as this causes colesevelam to bind more avidly with bile acids [24]. For those patients who have difficulty in swallowing tablets, colesevelam powder for oral suspension is also available. It has been recently shown to be better tasting than cholestyramine powder though patients found the powder was better in appearance [25]. A majority of the people in this study rated taste as a very important measure for long-term compliance.


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Many studies have reported low adherence rates to conventional BAS therapies [26-30] . In contrast, trials studying colesevelam have found almost 90% adherence rates [5, 9, 31]. Colesevelam is not absorbed systemically, so the safety profile is presumably good. Most common side effects reported with colesevelam are gastrointestinal: constipation, dyspepsia and flatulence [4, 8, 13, 32, 33]. Colesevelam has been shown to be well tolerated by various populations [34, 35]. There are certain populations, however, that should avoid colesevelam. Patients with deficiency of fat soluble vitamins should use colesevelam with caution due to lack of clinical data [13]. Colesevelam may cause increase in triglycerides and is contraindicated in patients with triglyceride levels > 500 mg/dl and history of triglyceride-induced pancreatitis [13]. According to NCEP guidelines, colesevelam is absolutely contraindicated in patients with triglycerides more than 400 mg/dl and relatively contraindicated in those with triglycerides more than 200 mg/dl [36]. Since it has not been studied in women, and studies done in animals have not shown any increased risk to the fetus, it is a class B drug for pregnancy [13].

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Our analysis shows trends similar to the individual studies included, although it should be noted that specific discussion of triglycerides, HDL and total cholesterol is rare in the literature despite the inclusion of this data. The increase in triglycerides associated with colesevelam was minimal in this analysis but is worthy of mention. The actual implication of triglycerides when it comes to cardiovascular risk is still debated with some studies concluding that hypertriglyceridemia is an independent risk factor for cardiovascular morbidity while others conclude that it is merely a marker [37-40]. Additionally, there was a statistically insignificant reduction in HDL with colesevelam in our analysis. Low HDL bears a negative implication on cardiovascular morbidity and mortality [37, 39]. In regards to these trends in triglycerides and HDL, the effects noted were minimal and may not to bear negative outcomes. Caution should be exercised when thinking of prescribing colesevelam in patients with low HDL and hypertriglyceridemia at baseline before further studies can outline the impact of colesevelam on these parameters.

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In our analysis, colesevelam caused significant reductions in LDL and glycemic parameters. These benefits make the use of colesevelam of potentially greater utility in patients with both high LDL and type 2 diabetes mellitus. A reduction in total cholesterol was, surprisingly, not noted in this analysis, although it was expected. An increase in total cholesterol oxidation secondary to bile acid depletion should have led to a decrease of total plasma cholesterol but this wasn’t noted. It is likely that the increase in triglycerides offset the reduction afforded by the increase in cholesterol oxidation.

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Possible limitations of this study include potential publication bias, particularly with smaller studies showing no significant difference in endpoints after colesevelam. Heterogeneity in particular endpoints also limits the study, although heterogeneity rarely impacted significance of the result in noted endpoints. It should be noted that in some studies, patients were also on anti-glycemic medications such as metformin. The patients in these studies were on these other medications at baseline and after therapy so that the difference recorded is attributable to the intervention studied.

Conclusion In our analysis, colesevelam led to significant reductions in plasma fasting glucose, hemoglobin A1c, and LDL, making them of potentially particular utility in patients with both high LDL and type 2 diabetes mellitus. Caution should be taken when considering the use of colesevelam in patients with low HDL and hypertriglyceridemia at baseline.


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Captions

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Table 1. Results of heterogeneity analysis Table 2. Baseline characteristics of included studies Figure 1. Study selection methodology Figure 2. Forest plot demonstrating the effect of colesevelam on hemoglobin a1c Figure 3. Forest plot demonstrating the effect of colesevelam on fasting plasma glucose Figure 4. Forest plot demonstrating the effect of colesevelam on low density lipoprotein Figure 5. Forest plot demonstrating the effect of colesevelam on high density lipoprotein Figure 6. Forest plot demonstrating the effect of colesevelam on total cholesterol Figure 7. Forest plot demonstrating the effect of colesevelam on triglycerides Figure 8. Colesevelam mechanism of action


Table 1. Results of heterogeneity analysis Q

P- Value

Result

Model Used

3.9053

Degrees of Freedom 4

.4190

Homogeneous

Fixed effects

5.1825

3

0.1589

Homogeneous

Fixed effects

34.9014

7