I thank Dr Sisam for his interest and remarks. 

Dr Sisam's comments underscore the challenges we face in maintaining long-term glycemic control in patients with type 2 diabetes mellitus (T2DM). As is mentioned in the March 2010 JAOA supplement, “Advances in Diabetes Management: Slowing Disease Progression,” loss of β-cell mass and decline in β-cell function, which lead to worsening glycemic control, are known to occur with disease progression in T2DM.¹ This β-cell failure is consistent with the increasing failure over time of monotherapy with sulfonylurea, metformin, or insulin to maintain glycemic control, as demonstrated in the United Kingdom Prospective Diabetes Study (UKPDS).² 

As Dr Sisam indicates, A Diabetes Outcome Progression Trial (ADOPT)³ showed that rosiglitazone slowed the rate of loss of β-cell function and improved insulin sensitivity to a greater extent than did either metformin or glyburide. However, declines in glycated hemoglobin over time were noted in all 3 of these monotherapy groups.³ 

Although declining β-cell function is a mechanism for progressive worsening of glycemic control in patients with T2DM, other mechanisms contribute to the underlying pathophysiologic condition, including impaired incretin response. Incretin-based therapies offer the advantage of addressing both of these mechanisms, thereby slowing disease progression by enhancing insulin secretion and suppressing glucagon release. Results of clinical trials with incretin-based therapies extending for as long as 3.5 years suggest some durability of treatment efficacy and safety, though these results are limited because of the relatively brief research periods, and further investigation is required.⁴ 

Several other areas of ongoing research, including β-cell survival, islet cell neogenesis, and therapeutics to demonstrate clinical durability, are certainly of interest.