The recent study by Raskin et al. (1) failed to emphasize three important points. In the study (1), the mean weight gain was 4.0 and 5.3 kg for the study groups given rosiglitazone 4 and 8 mg/day, respectively. No range of weight change or standard deviation was given, making it impossible to appreciate the maximum and minimum weight changes of this 26-week trial. It would be interesting to see if any factors predicted weight change for combination therapy. Furthermore, the authors failed to comment on the adverse health consequences of further weight gain in these obese study patients. Despite improved glycemia and other potential cardiovascular benefits of thiazolidinediones (2), at some point, weight gain, which is common, significant, and seen with all agents in this drug class when given with insulin, will probably outweigh any putative positive benefits. Also, because these drugs cause differentiation of preadipoctyes into adipocytes (3), it is possible that weight gain may be progressive with time in some patients. We do not consider weight increases of ≥10 kg unusual when thiazolidinediones with insulin are being used; in two of our patients, we saw weight increases of >40 kg. Intensive dietary intervention may be necessary to preclude this development in patients on insulin treatment concomitantly with a thiazolidinedione.

Edema was noted in 17 of 103 patients on insulin plus 8 mg rosiglitazone. Although edema is not considered to be a serious adverse event, it can be troubling for some patients. Expanded extracellular water is commonly seen with thiazolidinediones. Although echocardiographic studies in humans have failed to detect deleterious effects in the short term, the adverse cardiac effects seen in animal models (4) should give physicians some pause in their enthusiasm for these drugs. Perhaps exercise testing would be more confirmatory of the cardiovascular safety of these agents in the short term.

Finally, despite a therapeutic effect, the mean achieved HbA1c (8.5 and 7.9% for 4 and 8 mg/day rosiglitazone, respectively) is still much greater than the glycemic goals mandated by the American Diabetes Association (5). Although the combination of a thiazolidinedione and insulin is useful for the control of glycemia, it will nonetheless fail to achieve adequate glycemic control in many patients.

1.
Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J, the Rosiglitazone Clinical Trials Study Group: A randomized trial of rosiglitazone therapy in patients with inadequately controlled insulin-treated type 2 diabetes.
Diabetes Care
24
:
1226
–1232,
2001
2.
Parulkar AA, Pendergrass ML, Granda-Ayala R, Lee TR, Fonseca VA: Nonhypoglycemic effects of thiazolidinediones.
Ann Intern Med
134
:
61
–71,
2001
3.
Toseland CDN, Campbell S, Francis I, Bugelski PJ, Mehdi N: Comparison of adipose tissue changes following administration of rosiglitazone in the dog and rat.
Diabetes Obes Metab
3
:
163
–170,
2001
4.
Food and Drug Administration, Center for Drug Evaluation and Research: 73rd Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee, Bethesda, MD, April 22-23, 1999. Bethesda, MD, FDA,
1999
.
5.
American Diabetes Association: Standards of medical care for patients with diabetes mellitus.
Diabetes Care
24(Suppl. 1)
:
S33
–S43,
2001

Address correspondence to William L. Isley, MD, Saint Luke’s Lipid and Diabetes Research Center, MPI, Suite 128, 4320 Wornall Rd., Kansas City, MO 64111. E-mail: wisley@saint-lukes.org.

W.L.I. has received honorarium from Smith-Kline Beecham, who provides grant support to Saint Luke’s Lipid and Diabetes Research Center for the study of diabetes and hypertension drugs.