Preclinical discovery and development of colesevelam for the treatment of type 2 diabetes

ABSTRACT

Introduction: Type 2 diabetes (T2D) is a major global health challenge associated with increased cardiovascular morbidity and mortality. Intervention strategies managing multiple risk factors (hyperglycemia, hypertension and dyslipidemia) in patients with T2D can reduce the risk of cardiovascular disease by ~50%.

Areas covered: Herein, the authors provide an update on the development and clinical potential of colesevelam as a glucose-lowering drug in T2D. Furthermore, they outline the pharmacokinetics, pharmacodynamics, and the clinical efficacy and safety data from the studies carried out to obtain market authorization for colesevelam.

Expert opinion: Four phase III clinical trials provide evidence that colesevelam, as a monotherapy and add-on to various background glucose-lowering treatments, confers placebo-corrected reductions in HbA1c of ~5 mmol/mol. In addition, colesevelam reduces low-density lipoprotein (LDL) cholesterol and total cholesterol. Some antidiabetic agents seem superior to colesevelam in terms of clinical efficiency (HbA1c lowering), tolerability/convenience, and price. Nonetheless, colesevelam offers a clinically relevant combination of HbA1c- and LDL-lowering that in selected patients could be relevant as add-on treatment to other glucose-lowering drugs and a statin. Potential patients include those with renal impairment, and patients that are close to reaching their lipid and glycemic treatment goals but need further LDL and HbA1c reductions.

KEYWORDS:

• Bile acid
• bile acid sequestrant
• colesevelam
• glucose metabolism
• type 2 diabetes

Article highlights

• Colesevelam is a bile acid sequestrant used for treatment of dyslipidemia since 2000 and 2004 in the USA and Europe, respectively.

• In 2008, colesevelam was approved by the FDA as a glucose-lowering treatment for type 2 diabetes.

• The glucose-lowering mechanisms of colesevelam remain speculative and a range of mechanisms has been proposed, including stimulation of GLP-1 secretion from the enteroendocrine L cells.

• Since 2008, a variety of new glucose-lowering drugs has been approved for the treatment of type 2 diabetes; these have in general proved superior to colesevelam in terms of the balance among clinical efficacy, adverse events and price.

• Colesevelam remains to hold a potential as a glucose-lowering drug in selected patients, with special considerations to the modest efficacy and limiting side effects.

Declaration of interest

FK Knop has served on scientific advisory panels, been part of speaker’s bureaus for, served as a consultant to and/or received research support from Amgen Inc, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Gubra, MedImmune, Merck Sharp and Dohme, Norgine, Novo Nordisk, Sanofi, and Zealand Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.