Recent guidelines from the American Diabetes Association (ADA) and others continue to emphasize the use of metformin as ‘first-line’ therapy in most patients with type 2 diabetes mellitus. However, when metformin monotherapy does not achieve adequate glycemic control, there remains considerable debate about which medication or medications should be added. In this 16-week, open-label, pilot study, 169 subjects with type 2 diabetes who had a hemoglobin A1C of at least 7.0% despite use of 1500-2550 mg daily of metformin were randomized to receive add-on therapy with either: colsevelam HCL 3.75 g/day, rosiglitazone 4 mg/day, or sitagliptin 100 mg/day. At study end, all 3 groups had modest, but statistically significant reductions in hemoglobin A1C (-0.3% with colsevelam, -0.6% with rosiglitazone, and -0.4% with sitigliptan. While rosiglitazone and sitigliptin were associated with modest increases in LDL-C, colsevelem use led to a 11.6% reduction in LDL-C. Both colsevelam and sitigliptin, but not rosiglitazone, were associated with a modest reduction in weight. Drug related adverse events were higher with colsevelam, mostly driven by gastrointestinal complaints. Limitations of this study include its small sample size, inclusion of mostly Hispanic subjects (with a large number of study sites in Mexico and Columbia), and open-label study design. Also, while colsevelam and sitigliptin were used at their maximum approved dose, a sub-maximal dose of rosiglitazone was used; while use of a higher dose of rosiglitazone may have led to greater reductions in hemoglobin A1C, it would have been unlikely to have had more favorable effects on LDL-C and may have been associated with greater weight gain. Despite these methodological short-comings, these data confirm what has been demonstrated with colsevelam in previous reports, namely that colsevelam, when added to metformin leads to modest reductions in hemoglobin A1C and unique favorable affects on LDL-C. As such, it may be a reasonable alternative add-on therapy in patients with type 2 DM, particularly when both hemoglobin A1C and LDL-C are modestly above goal. –Michael J. Bloch, M.D.