There are three main findings in this report. The first and most robust is about stabilization of pancreatic β-cell function, an important determinant of deterioration to type 2 diabetes (2
). Measurements obtained during placebo treatment in the TRIPOD study established a natural history of declining β-cell function, manifested as a 33% fall in β-cell compensation for insulin resistance over a median of 4.6 years. That decline was stopped when women were placed on pioglitazone for 3 years and then removed from any acute drug effects for 6 months. Parallel analysis of data from women who had been on troglitazone in the TRIPOD study revealed no significant change in β-cell function in either study. In both cases, insulin resistance was ameliorated during periods of thiazolidinedione treatment but returned to baseline values when medications were stopped. These findings support an action of pioglitazone to stabilize β-cell function, as we previously observed for troglitazone in the TRIPOD study (7
The second main finding was the strong relationship between an initial reduction in insulin output and the risk of diabetes. As was true with troglitazone treatment in the TRIPOD study (7
), multivariate Cox regression analysis identified the change in IVGTT total insulin area when first measured during treatment as the strongest predictor of diabetes during pioglitazone treatment in the PIPOD study. Also consistent with the TRIPOD study, diabetes incidence rates revealed that they were lowest in the third of women with the greatest reduction in insulin output after 1 year of treatment and highest in the third of women with the smallest reduction after 1 year. Comparison to the analogous relationship among troglitazone-treated patients from the TRIPOD study revealed the same change in diabetes incidence for any initial change in insulin output, although there was a wider range of change in insulin output in the PIPOD study. Whether this wider range was due to differences between effects of the two medications or to the fact that measurements were made after a longer period of treatment in the PIPOD study cannot be determined. However, the striking comparability of the slopes of relationships in , combined with the fact that insulin sensitivity increased significantly during treatment only in women who did not develop diabetes, supports the concept that reducing insulin secretory demands through amelioration of insulin resistance can reduce the risk of diabetes, at least in high-risk Hispanic women.
The third main finding was a diabetes rate of 4.6% per year during treatment with pioglitazone for 3 years, followed by 6 months of postdrug washout. This rate is much lower than the rate of 12.1% per year observed during placebo treatment in the TRIPOD study. However, the interpretation of this finding is complicated by two factors. First, there was no parallel control group in the PIPOD study from which we could ascertain the expected rate of diabetes in the absence of treatment. Observation at a later stage relative to the index pregnancy and prior treatment of many subjects with troglitazone could have modified their inherent diabetes risk compared with the TRIPOD study. Second, drop outs in this highly mobile recent immigrant population precluded complete follow-up to ascertain diabetes status of all individuals. Baseline characteristics of drop outs were similar to women who completed follow-up save for slightly greater insulin resistance and slightly worse β-cell function. Both characteristics could indicate an increased risk of diabetes in the absence of treatment (15
), although neither was an independent predictor of development of diabetes in this study. The baseline differences do not indicate a reduced likelihood of protection from diabetes during thiazolidinedione treatment (7
), which could have been maintained in a standard clinical care setting in many subjects who dropped out of this study (e.g., subjects who moved away from the study site). We have no evidence to indicate that women dropped out because they developed diabetes. In the end, although we do not have strong evidence that incomplete follow-up biased our results in favor of apparent protection from diabetes, limitations in our study design limit the conclusions that we can draw about the impact of pioglitazone on the risk of diabetes in our high-risk patients.
Unlike β-cell function, which was preserved by treatment with both troglitazone (7
) and pioglitazone, insulin sensitivity measured remote from any acute effects of medication did not consistently change across the TRIPOD or PIPOD studies, even during periods that were characterized by weight gain. Testing conducted remote from medication use () allowed us to assess patterns of change independent of any acute drug effects. As expected, pioglitazone did increase insulin sensitivity while it was being taken (, 1-year change). In fact, the increase was twice as large in women who did not develop diabetes, an intergroup difference that did not approach statistical significance due to large variability of responses and the relatively small numbers of subjects. Changes in insulin sensitivity after 1 year of pioglitazone treatment were not independently predictive of diabetes. This finding was true in the TRIPOD study as well and was explained by a nonlinear relationship between insulin sensitization and reduced endogenous insulin requirements (7
). In both the TRIPOD and PIPOD studies, the latter change occurred in the presence of improved insulin sensitivity and was the variable that was most closely associated with a low risk of diabetes.
The potential clinical implications of our findings rest in part on their relationship to findings in the TRIPOD study. In that study, which was randomized and double blind in design, we observed an unequivocal effect of troglitazone to alter the natural history of progression to type 2 diabetes that was closely related to initial β-cell “rest” (7
). Both ethical and practical considerations led us to conduct the PIPOD study as an open-label follow-up study to the TRIPOD study. The well-characterized patterns of change in β-cell function that we observed during the TRIPOD study provided a robust outcome variable for an open-label follow-up study. Indeed, we view the stabilization of β-cell function in women who had been losing function during placebo treatment in the TRIPOD study to be the most important outcome of the PIPOD study. Continued stability of β-cell function in women from the troglitazone arm of the TRIPOD study is encouraging as well, although it is impossible to exclude a lingering effect of prior treatment with troglitazone. However, the fact that continued protection from new cases of diabetes was not observed after discontinuation of troglitazone in the Diabetes Prevention Program (16
) speaks against a prolonged protective effect of that drug. That protection from diabetes in the PIPOD and TRIPOD studies occurred in the presence of improved insulin sensitivity while subjects were taking study medication, and the fact that protection was most closely associated with initial reductions in insulin output, speaks strongly of a similar protective mechanism for the two drugs. Thus, our results are most consistent with a class effect of thiazolidinediones to lower insulin secretory demands, preserve β-cell function, and slow or stop progression to type 2 diabetes in one high-risk group. Whether similar effects will occur in other groups and whether weight gain induced by pioglitazone will limit the duration of protection in some patients, as suggested by differences in weight gain between groups that did and did not develop diabetes in the PIPOD study, remain to be determined.
In summary, 3 years of pioglitazone treatment given to Hispanic women with prior gestational diabetes was associated with stable pancreatic β-cell function and a relatively low rate of diabetes. The lowest rate of diabetes occurred in association with the greatest reduction in insulin secretory demands during the 1st year of treatment. These patterns from an observational study with an available thiazolidinedione drug suggest an effect on the pathobiology of diabetes that is similar to the effect observed in our randomized trial of troglitazone treatment in the same study cohort. Taken together, findings from these two trials support a role for thiazolidinedione drugs to modify the natural history of progression to type 2 diabetes in high-risk Hispanic patients. The optimal timing of treatment and the generalizability to other high-risk groups will require additional studies, some of which are currently underway.