Rationale and design of a clinical trial to evaluate metformin and colesevelam HCl as first-line therapy in type 2 diabetes and colesevelam HCl in prediabetes.

OBJECTIVE: The complications of type 2 diabetes mellitus (DM) can begin early in the progression from impaired glucose tolerance to type 2 DM. Metformin is recommended as initial drug therapy for managing hyperglycemia in type 2 DM. The bile acid sequestrant colesevelam hydrochloride (HCl) is approved in the United States for glycemic control in adults with type 2 DM. Colesevelam HCl improves glycemic control and reduces low-density lipoprotein-cholesterol in patients inadequately controlled on metformin-, sulfonylurea-, or insulin-based therapy. This trial is designed to evaluate whether initial therapy with metformin + colesevelam HCl provides greater glucose control and additional lipid and lipoprotein benefits, as compared to metformin alone in drug-naïve patients with type 2 DM, and whether treatment with colesevelam HCl has a beneficial effect on lipid and glucose levels in drug-naïve patients with impaired glucose tolerance and/or impaired fasting glucose (prediabetes).

RESEARCH DESIGN AND METHODS: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, drug-naïve patients with type 2 DM will be randomized 1 : 1 to metformin + colesevelam HCl or metformin + matching placebo, while those with prediabetes will be randomized 1 : 1 to colesevelam HCl or placebo, for 16 weeks of treatment. The primary efficacy endpoint will be change in glycosylated hemoglobin (HbA(1c)) in patients with type 2 DM and change in low-density lipoprotein-cholesterol levels in patients with prediabetes.

CONCLUSION: A potential limitation is that there is no direct comparator for the dual glucose- and lipid-lowering effect of colesevelam HCl in the prediabetes cohort. However, results of this trial will help to define the extent to which colesevelam HCl can help improve cardiometabolic risk factors for complications of type 2 DM in the first-line environment, and will also indicate the extent to which early intervention with colesevelam HCl can help to correct metabolic abnormalities associated with prediabetes.