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Diabetes mellitus (DM), a multifactorial metabolic disease, affects more than 180 million people worldwide, and is expected to affect approximately 360 million people by 2030.1 In the United States, an estimated 24 million adults and children have been diagnosed with either type 1 or 2 DM.2 Type 1 DM, accounting for roughly 10% of the affected population, is characterized by the destruction of pancreatic insulin-producing beta-cells through an autoimmune mechanism. Type 2 DM (T2DM) accounts for the remaining 90% of DM cases in the United States, and is characterized by reduced sensitivity to insulin and decreased insulin production by pancreatic beta-cells, resulting in decreased peripheral glucose uptake and increased hepatic glucose production.3
Compared with patients without diabetes, those diagnosed with T2DM are at greater risk for developing primary and secondary complications, such as macrovascular and microvascular disease.4 Reducing a patient’s blood glucose levels and
glycosylated hemoglobin (A1C) reduces risks of such complications. Guidelines suggest that patients achieve an A1C level <7.0% or <6.5%, or as close to normal (ie, 6.0%) that does not produce significant hypoglycemia.5,6
Colesevelam hydrochloride (Welchol) is FDA-approved for the treatment of T2DM in combination with a sulfonylurea, metformin, and/or insulin therapy. 7 Colesevelam HCl is the only bile acid sequestrant that is FDA-approved as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. It is also approved for the treatment of primary hyperlipidemia (as monotherapy or in combination with a statin). In adults with T2DM, colesevelam HCl reduces both low-density lipoprotein cholesterol (LDL-C) and A1C.8
Mechanism of Action for Glycemic Effect
The exact mechanism by which colesevelam HCl lowers glucose is unknown and is currently under investigation. It may involve bile acid modulation, farnesoid X receptor/liver X receptor expression and its downstream effects on glucose production, and/or TGR5 receptor and its downstream effects with the release of glucagon-like peptide-1.8
Three randomized, placebo-controlled, phase 3 studies in T2DM investigated the effects of colesevelam HCl 3.75 g/day as add-on therapy to sulfonylurea, metformin, and insulin-based antidiabetic regimens. All 3 studies enrolled patients between 18 and 75 years of age with an A1C between 7.5% and 9.5% (inclusive) who were on stable diabetes medications (>90 days). They were conducted in a “real world” setting, with no washout of existing medications. Cholesterol-based inclusion criteria were serum LDL-C levels ≥60 mg/dL and serum triglyceride (TG) levels <500 mg/dL. Colesevelam HCl and placebo were both dosed as 3 tablets with lunch and dinner, or as 6 tablets once daily with dinner.7,9 The addition of colesevelam HCl produced positive results regarding both glucose and cholesterol management, by significantly lowering both A1C and LDL-C.10-12
The first study (Bays et al) evaluated the addition of colesevelam HCl or placebo to metformin monotherapy or metformin combination therapy over a 26-week period in 316 patients.10 Mean A1C values were 8.2% with colesevelam HCl and 8.1% with placebo, whereas baseline LDL-C values were 105.6 mg/dL and 99 mg/dL, respectively. Approximately half of the patients were receiving metformin monotherapy—52.2% in the colesevelam HCl group and 48.4% in the placebo group. A total of 39.0% and 47.8% of patients in the colesevelam HCl and placebo groups, respectively, were taking statins.
At week 26, the mean treatment difference in A1C from baseline was —0.54% (P <.001), while a reduction in A1C ≥0.7% was achieved in 38.3% of patients given colesevelam HCl, compared with 20.4% given placebo (P <.001).10 A reduction in A1C ≥0.7% or a reduction in fasting plasma glucose (FPG) ≥30 mg/dL from baseline was achieved in 47.7% of patients in the colesevelam HCl group, compared with 35.5% in the placebo group (P = .05). In the subpopulation receiving metfor-min monotherapy, the mean treatment difference in A1C at week 26 was —0.47% (P <.01). When compared with placebo, colesevelam HCl was also associated with greater overall reductions in LDL-C (treatment difference –15.9%, P <.001) and total cholesterol levels (treatment difference –7.2%, P <.001), with no significant increases in TG levels at study conclusion.
The second study (Goldberg et al), a 16-week study of 287 patients, investigated colesevelam HCl as add-on therapy to insulin therapy or insulin therapy with oral antidiabetic agents.11 Mean A1C was 8.3% in both the colesevelam HCl and placebo groups, while baseline LDL-C levels for both groups was 101.5 mg/dL. At study enrollment, 38.8% of patients given colesevelam HCl and 42.1% given placebo were on insulin-only therapy, while the remaining patients were receiving insulin in combination with oral antidiabetic agents. A total of 55.1% and 59.3% of patients in the colesevelam HCl and placebo groups, respectively, were on statin therapy.
At week 16, the mean treatment difference in A1C from baseline for the overall treatment group was —0.5%, and –0.57% among patients with an A1C level >8.0% at baseline (P <.001 for both).11 A reduction in FPG ≥30 mg/dL or a reduction in A1C ≥0.7% from baseline to week 16 was reported for 48.65% of patients given colesevelam HCl, compared with 31.6% taking placebo (P <.01). There were also significant reductions in LDL-C levels (treatment difference —12.8%, P <.001) and an increase in TG levels (treatment difference +21.45%, P <.001) with colesevelam HCl.
The third study (Fonseca et al) evaluated colesevelam HCl as add-on therapy to sulfonylurea monotherapy or sulfonylurea with other oral antidiabetic agents in 461 patients over a 26-week study period.12 Mean baseline A1C was 8.2% in patients given colesevelam HCl and 8.3% in those given placebo, whereas mean baseline FPG was 176.6 mg/dL and 181 mg/dL, respectively. Approximately one third of patients were receiving sulfonylurea monotherapy at enrollment (32.6% and 35.1% in the colesevelam HCl and placebo groups, respectively); the remainder received a sulfonylurea in combination with other antidiabetic agents. A total of 37.6% and 43.7% of patients in the colesevelam HCl and placebo groups, respectively, were on statin therapy.13
At week 26, the mean treatment difference from baseline in A1C at week 26 was —0.54% in the overall treatment group and –0.79% in the sulfonylurea monotherapy subgroup (P <.001 for both).12 A treatment difference in FPG in the overall colesevelam HCl population was observed as early as week 6 (13.7 mg/dL, P <.001), whereas a reduction in A1C ≥0.7% by week 26 was achieved in 35.2% of patients given colesevelam HCl, compared with 16.5% given placebo (P <.001). Compared with placebo, colesevelam HCl was also associated with greater reductions in LDL-C (treatment difference —16.7%, P <.001) and total cholesterol levels (treatment difference –5%, P <.001), as well as increases in TG levels (treatment difference +17.7%, P <.001).
The standard colesevelam HCl dosing schedule in these studies was 3.75 g daily (six 625-mg tablets), given as 3 tablets twice daily or 6 tablets once daily.7 A 3.75-g daily dose in the form of an oral suspension (sugar-free, citrus- flavored powder for reconstitution with water) was recently approved by the FDA.7,12 In clinical trials of adult patients with T2DM, colesevelam HCl administration was divided between the noon and evening meals, whereas a single daily-dose schedule was administered with the evening meal.10-12 Afternoon or evening dosing schedules are considered beneficial to patients with multiple medications, because this may avoid interactions with morning medications.
Whereas colesevelam HCl may block the absorption of many common medications, including other oral antidiabetic medications (eg, glyburide), it is recommended that all medications with potential interaction with colesevelam HCl be taken at least 4 hours before taking colesevelam HCl. Therefore, judicious review of drug interactions and risks must occur prior to colesevelam HCl administration.
Common side effects of colesevelam HCl observed in the studies mentioned above were dyspepsia (~3.9%) and constipation (8.7%).15 Colesevelam HCl may raise TG levels; therefore, levels need to be monitored. In addition, colesevelam HCl is contraindicated in patients with TG levels >500 mg/dL. Because colesevelam HCl can cause decreased blood glucose levels in patients with T2DM, it is important to advise these patients to monitor their blood glucose more frequently when starting colesevelam HCl (or any new therapy) to avoid hypoglycemia. In clinical trials, the reported incidence of hypoglycemia was similar among colesevelam HCl (3%) and placebo (2.3%).7 Summary The addition of colesevelam HCl to metformin, sulfonylurea, or insulin therapy results in significant reductions in both A1C and LDL-C and offers a unique treatment option for patients with T2DM. The reader is encouraged to refer to treatment guidelines that have evaluated the use of colesevelam HCl for T2DM.14,15
Please see Important Safety Information on back cover and accompanying full Prescribing Information on Welchol.
IMPORTANT INFORMATION ABOUT WELCHOL (colesevelam HCl)
Welchol is indicated as an adjunct to diet and exercise to:
â€reduce elevated lowâ€density lipoprotein cholesterol (LDLâ€C) in patients with primary hyperlipidemia (Fredrickson Type IIa) as monotherapy or in combination with an hydroxymethylglutarylâ€coenzyme (HMG CoA) reductase inhibitor (statin)
â€improve glycemic control in adults with type 2 diabetes mellitus
Important Limitations of Use
-Welchol should not be used for glycemic control in type 1 diabetes or for the treatment of diabetic ketoacidosis
-Welchol has not been studied in type 2 diabetes as monotherapy or in combination with a dipeptidyl peptidase 4 inhibitor and has not been extensively studied in combination with thiazolidinediones
-Welchol has not been studied in Fredrickson Type I, III, IV, and V dyslipidemias
Welchol is contraindicated in individuals with a history of bowel obstruction, those with serum triglyceride (TG) concentrations of >500 mg/dL, or with a history of hypertriglyceridemiaâ€induced pancreatitis.
Warnings and Precautions
The effect of Welchol on cardiovascular morbidity and mortality has not been determined.
Welchol can increase serum TG concentrations particularly when used in combination with sulfonylureas or insulin. Caution should be exercised when treating patients with TG levels >300 mg/dL.
Welchol may decrease the absorption of fatâ€soluble vitamins A, D, E, and K. Patients on vitamin supplements should take their vitamins at least 4 hours prior to Welchol. Caution should be exercised when treating patients with a susceptibility to vitamin K or fatâ€soluble vitamin deficiencies.
Caution should also be exercised when treating patients with gastroparesis, gastrointestinal motility disorders, a history of major gastrointestinal tract surgery, and when treating patients with dysphagia and swallowing disorders.
Welchol reduces gastrointestinal absorption of some drugs. Drugs with a known interaction with colesevelam (cyclosporine, glyburide, levothyroxine, and oral contraceptives [ethinyl estradiol, norethindrone]) should be administered at least 4 hours prior to Welchol. Drugs that have not been tested for interaction with colesevelam, especially those with a narrow therapeutic index, should also be administered at least 4 hours prior to Welchol. Alternatively, the physician should monitor drug levels of the coâ€administered drug.
To avoid esophageal distress, Welchol for Oral Suspension should not be taken in its dry form.
Due to tablet size, Welchol for Oral Suspension is recommended for, but not limited to, any patient who has difficulty swallowing tablets.
Phenylketonurics: Welchol for Oral Suspension contains 48 mg phenylalanine per 3.75 gram dose.
In clinical trials, the adverse reactions observed in ≥2% of patients, and more commonly with Welchol than placebo, regardless of investigator assessment of causality seen in:
-Adults with Primary Hyperlipidemia were: constipation (11.0% vs 7.0%), dyspepsia (8.3% vs 3.5%), nausea (4.2% vs 3.9%), accidental injury (3.7% vs 2.7%), asthenia (3.6% vs 1.9%), pharyngitis (3.2% vs 1.9%), flu syndrome (3.2% vs 3.1%), rhinitis (3.2% vs 3.1%), and myalgia (2.1% vs 0.4%)
-Adult patients with Type 2 Diabetes were: constipation (8.7% vs 2.0%), nasopharyngitis (4.1% vs 3.6%), dyspepsia (3.9% vs 1.4%), hypoglycemia (3.0% vs 2.3%), nausea (3.0% vs 1.4%), and hypertension (2.8% vs 1.6%)
Postâ€marketing experience: Due to the voluntary nature of these reports it is not possible to reliably estimate frequency or establish a causal relationship:
-Increased seizure activity or decreased phenytoin levels have been reported in patients receiving phenytoin concomitantly with Welchol
-Reduced International Normalized Ratio (INR) has been reported in patients receiving warfarin concomitantly with Welchol
-Elevated thyroid-stimulating hormone (TSH) has been reported in patients receiving thyroid hormone replacement therapy
Welchol is Pregnancy Category B.
Travis E. Sonnett, PharmD, is clinical assistant professor, Washington State University, College of Pharmacy, Department of Pharmacotherapy, and clinical consultant pharmacist, Family Home Care and Hospice, Pullman, Washington. R. Keith Campbell, RPh, FASHP, CDE, is distinguished professor in diabetes care, Washington State University, College of Pharmacy, Department of Pharmacotherapy, Pullman, Washington. Teresa Martin, RD, CDE, LD, is a clinical educator based in Bend, Oregon.