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-cell function.2 In ADOPT, the annual increase in glycated hemoglobin levels over a 4-year period in patients with newly diagnosed diabetes was greatest with glyburide, intermediate with metformin, and least with rosiglitazone. Our longitudinal data (for 2005–2006) from a nationwide general-practitioner database in Germany (Disease Analyzer)3,4 indicate similar findings. Among 12,304 patients with diabetes who were using oral antidiabetic drugs, the mean of the individual relative differences in glycated hemoglobin levels (those in 2006 divided by those in 2005) was 1.018 (95% confidence interval, 1.016 to 1.020). The mean relative difference in glycated hemoglobin levels was highest for glinides, followed by sulfonylureas, acarbose, metformin, and glitazones (Table 1). In multivariate logistic-regression analyses, the use of glitazones was associated with a significantly smaller increase in glycated hemoglobin levels than was the use of sulfonylureas, after adjustment for age, sex, the other oral antidiabetic drugs, health care use, and practice characteristics (P=0.007); the same trend was observed for metformin (P=0.048). Though all the oral antidiabetes drugs we studied are associated with progression of glycemia, our primary care data indicate the potential value of and need for new agents in the treatment of diabetes.2
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Wolfgang Rathmann, M.D., M.S.P.H.
German Diabetes Center
40225 Düsseldorf, Germany
rathmann{at}ddz.uni-duesseldorf.de
Karel Kostev, M.A.
IMS Health
60528 Frankfurt, Germany
Burkhard Haastert, Ph.D.
German Diabetes Center
40225 Düsseldorf, Germany
Mr. Kostev reports being an employee of IMS Health, a consulting company that received a grant from Eli Lilly, Germany, to carry out a database study of longitudinal changes in glycated hemoglobin values in patients with diabetes in primary care. Drs. Rathmann and Haastert report receiving consulting fees from IMS Health for this study.
References
Thus, the type of antihypertensive therapy subjects received in the trial conducted by Kahn et al. might have been a factor affecting the primary outcome and should have been documented as a baseline characteristic. Randomization according to this factor at the beginning of the study could have added sophistication to the study design and credibility to the results. Similarly, documentation of the use of aspirin therapy as prophylaxis against coronary artery disease in the three groups might have shed more light on the differences seen in the rates of cardiovascular events.
Amitabh Parashar, M.D.
Anjali Varma, M.D.
Carilion Clinic
Roanoke, VA 24018
aparashar{at}carilion.com
References
-cell function seems unwarranted. The three treatment groups started with similar baseline values for -cell function, determined with the use of homeostasis model assessment (HOMA 2), and at the end of the study there was no significant difference in the values between the rosiglitazone group and the glyburide group and only a small difference between the rosiglitazone group and the metformin group. The rate of decline in -cell function was greatest in the glyburide group because of an initial increase in -cell function according to HOMA 2; it does not represent the true state of -cell function. The stopping of all drugs or switching of all patients to a similar regimen for 3 months might have made clearer assessment possible.
Rajesh Garg, M.D.
Brigham and Women's Hospital
Boston, MA 02115
rgarg{at}partners.org
Dr. Garg reports receiving speaking fees from Merck and Novartis.
ADOPT is not a special case: only 20% of randomized studies of diabetes have reported important patient outcomes.1 We believe the time has come for a broad consensus on a standard set of important outcomes for patients in diabetes trials, like the Outcome Measures in Rheumatology (OMERACT) initiative,2 in order to improve the relevance of such evidence for clinical decision making.
Gunjan Y. Gandhi, M.D.
Victor M. Montori, M.D.
Mayo Clinic College of Medicine
Rochester, MN 55905
gandhi.gunjan{at}mayo.edu
References
Parashar and Varma correctly mention that antihypertensive agents have dissimilar effects on glucose metabolism. Table 2 of our article shows the percentages of subjects with concomitant use of various antihypertensive agents at some time during the study. There was no significant difference in the use of these medications among the three groups; thus, differential use cannot explain the differences in glycemia that we observed. Similarly, concomitant use of aspirin ranged from 31.6% of patients in the glyburide group to 33.0% in the metformin group and therefore also cannot explain the differences in outcomes.
The importance of the rate of loss of -cell function in determining the progression of type 2 diabetes is well documented.2 Garg is correct that -cell function according to HOMA 2 was similar in the rosiglitazone group and the glyburide group at baseline and after 4 years of treatment. However, since the two medications have different mechanisms of action and establishment of their maximal biologic effectiveness takes months, we prespecified that our analysis would commence at 6 months. From then on, the rate of change differed markedly between the two groups, which partly explains the greater durability of the lowering of glucose levels with rosiglitazone. Since insulin sensitivity is a critical determinant of -cell secretory demand,3 the similar -cell function according to HOMA 2 among patients receiving rosiglitazone and those receiving glyburide, with better insulin sensitivity among patients receiving rosiglitazone, indicates that at the end of the study, the cells of the patients receiving rosiglitazone were performing qualitatively better. With regard to the use of glucose-lowering medications before the study commenced, since no patients were taking these medications at the time of randomization, there was no need to discontinue their use or to use the same agent initially before switching to one of the three study treatments.
The primary care data reported by Rathmann et al. confirm our finding that glucose-lowering agents have differential effects in slowing the rate of progression of glycemia, providing support for our conclusion that the choice of initial monotherapy has to be guided by clinical efficacy along with a consideration of adverse events and costs. The challenge now is to develop new agents and approaches that can slow progression even more effectively.
Steven E. Kahn, M.B., Ch.B.
Veterans Affairs Puget Sound Health Care System
Seattle, WA 98108
skahn{at}u.washington.edu
Giancarlo Viberti, M.D., F.R.C.P.
King's College London School of Medicine
London SE1 9RT, United Kingdom
for the ADOPT Steering Committee
References
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