Observational follow-up of the PROactive Study: a 6-year update.

Erdmann E, Song E, Spanheimer R et al.
Diabetes Obes Metab. 2013 Jul 16. doi: 10.1111/dom.12180.

Background

The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study prospectively evaluates the effects of a thiazolidinedione on cardiovascular outcomes in high-risk patients with type 2 diabetes mellitus (T2DM) and pre-existing macrovascular disease [1]. Pioglitazone showed a non-significant 10% relative risk reduction for the primary composite endpoint (all-cause mortality, MI, acute coronary syndrome, cardiac intervention, stroke, major leg amputation, leg revascularization) and a significant 16% reduction for the main secondary endpoint (death, MI, stroke), after a mean follow-up of 34.5 months. Other composite macrovascular/mortality endpoints were also reduced upon pioglitazone treatment, as compared to placebo [2-4]. More bladder malignancies were however seen in the pioglitazone (n=14, 0.6%) arm than in the placebo-arm (n=5, 0.2%). Breast cancer was less common with pioglitazone (3 cases) versus placebo (11 cases).
 This article reports the results of a pre-specified 6-year interim analysis of a 10-year observational follow-up, in which patients are receiving normal medical care, without any specific study treatment. This study aims to investigate whether prior long-term treatment with pioglitazone has any effect on a composite outcome of all-cause mortality and macrovascular events and on the incidence of newly diagnosed malignancies. This analysis includes data from 1820 subjects previously receiving pioglitazone and 1779 previously on placebo.

Main results

• After a mean combined PROactive double-blind and 6-year follow-up period of 8.7 years, about 43% of subjects in both the former pioglitazone and placebo groups (no statistically significant difference) underwent a primary composite endpoint event. In the follow-up period alone, no differences were seen either (72.1 vs. 73.5 cases per 1000 patient years for pioglitazone and placebo respectively).
• Major leg amputation was seen significantly less frequent in the follow-up period after pioglitazone as compared to placebo. This was the only component of the primary endpoint that showed a statistically significant different between the two groups.
• In the follow-up period alone, nominally fewer bladder malignancies were seen in the subjects previously randomized to pioglitazone (n=10, 0.5%) than in subjects receiving placebo (n=17, 1.0%, RR: 0.57, 95%CI: 0.26-1.25), thus 0.9 vs. 1.6 cases per 1000 patient years.
  When considering the combined double-blind and follow-up periods, no difference in incidence of bladder malignancies was seen between the pioglitazone and placebo groups (RR: 1.06, 95%CI: 0.59-1.89, meaning a rate of 1.3 vs. 1.2 cases per 1000 patient-years).
• No bladder malignancies occurred in subjects who were randomised to pioglitazone and who subsequently received a thiazolidinedione during the follow-up period. No statistically significant different incidence was see between subjects who received any and no pioglitazone before the event (HR: 0.98, 95%CI: 0.55-1.77, P=0.959).
• No statistically significant differences were seen in the incidence of other malignancies between those in the pioglitazone-arm and those in the placebo-group, both during the follow-up or the combined period. 

Conclusion

Subjects who had previously received pioglitazone showed similar mortality and macrovascular morbidity rates after 6 years of follow-up to people randomised to placebo. Thus, the macrovascular effect of pioglitazone does not persist when there is no continued exposure to the drug. Furthermore, there are no long-term macrovascular safety issues 6 years after drug withdrawal, in high-risk patients with established macrovascular disease.

References

1. Dormandy JA, Charbonnel B, Eckland DJ, et al. PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macro- Vascular Events): a randomised controlled trial. Lancet 2005; 366: 1279-1289.
2. Erdmann E, Dormandy JA, Charbonnel B, et al.  The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J Am Coll Cardiol 2007; 49: 1772-1780.
3. Wilcox R, Bousser MG, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007; 38: 865-873.
4. Wilcox R, Kupfer S, Erdmann E; PROactive Study investigators. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: results from PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive 10). Am Heart J 2008; 155: 712-717.

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