Response to comments on: Nathan DM, Buse JB, Davidson MB et al. (2006) Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 49:1711–1721

To the Editor: We anticipated that our consensus algorithm [1, 2] would generate some controversy, but are pleased with the general level of appreciation expressed in the letters, albeit with some disagreements. P. E. Cryer specifically endorses the recommendation in our consensus algorithm to use insulin earlier in the treatment course of type 2 diabetes, but takes issue with the relatively low frequency of severe hypoglycaemia, defined as in the DCCT and compared with the rate in type 1 diabetes, that we cited [3]. As Dr. Cryer notes, our estimates were based on data from clinical trials aimed at normoglycaemia and achieving a mean HbA1c of ∼7% [3]. Dr. Cryer cites review articles, including some referenced by us, and other empiric studies—not controlled clinical trials—that suggest a much higher risk for severe hypoglycaemia in insulin-treated type 2 diabetes than we described. The reasons for choosing to use data from controlled clinical trials to establish the expected risk of severe hypoglycaemia with insulin therapy, rather than referring to the other clinical data referenced by Dr. Cryer, include the following: (1) more careful and uniform assessment of adverse events such as hypoglycaemia; (2) their use of consensus definitions established a priori; (3) their ability to compare frequency of hypoglycaemia among trials using ‘intensive’ therapy in type 1 and type 2 diabetes; and, perhaps most importantly, (4) their ability to examine the risk of hypoglycaemia in the setting of studies specifically aiming for and achieving glycaemic levels similar to those that we advocated. While we recognize that the selected cohorts and sometimes unrealistic setting of clinical trials may not accurately reflect what happens in clinical practice, we felt that the advantages noted above outweighed the potential problems associated with observational studies, and especially retrospective studies, that were cited in Dr. Cryer’s letter. Owing to space limitations, we did not include a comprehensive list of controlled clinical trials using insulin to achieve near-normoglycaemia with data supporting a relatively low rate of severe hypoglycaemia. However, we would draw attention to several large trials (a total of >1,400 participants), in addition to those cited in our original article, that utilized intermediate-acting insulin [4–6], long-acting insulin [5, 6], combinations of intermediate and rapidacting insulins [7], and insulin combined with oral agents [4, 6, 7], and documented low rates of severe hypoglycaemia (0–5 episodes per 100 patient-years) according to the DCCT definition. Moreover, large observational studies other than those cited by Dr. Cryer have noted rates considerably lower than those included in his table [8]. No one would argue that hypoglycaemia of any degree can be annoying and frightening for patients, and severe hypoglycaemia can potentially be life-threatening. However, we think that the best data, derived from the careful Diabetologia (2007) 50:231–233 DOI 10.1007/s00125-006-0527-6