Patients with type 2 diabetes have a two-to-four-fold increased risk of fatal or non-fatal macrovascular events compared with those without diabetes. Whereas intensive glycaemic control decreases microvascular complications, such as retinopathy and nephropathy, its effect on macrovascular events is less certain. PROactive was a randomised, double-blind, placebo controlled outcome study of 5238 patients with type 2 diabetes and established macrovascular disease who were randomised to receive pioglitazone or placebo in addition to best standard of care.
Pioglitazone is an agonist of peroxisome proliferator activated receptor (PPAR) resulting in improved glycaemic control as well as effects on cardiovascular risk factors and various inflammatory markers. PROactive had a primary combination end-point of 7 different macrovascular events, including both disease and procedural endpoints, and principal secondary combination endpoint of death, heart attack and stroke. As previously reported, there was a 10% reduction in the primary end-point (P = 0.095) and a 16% reduction in the principal secondary end-point (P = 0.027).
The aim of this prespecified analysis was to compare the impact of pioglitazone on macrovascular events in patients who entered the PROactive study with or without a history of stroke > 6 months prior to randomisation.
Results
There were 984 (19%) patients with and 4254 patients without a prior history of stroke. Although there were some differences in baseline characteristics between these two categories, there were no differences within each category according to treatment allocation. Treatment duration averaged 34 months during which the incidence of stroke in the prior stroke group was 10.2% reduced to 5.6% by pioglitazone (HR 0.53, 95% CI 0.34 – 0.85, p = 0.009).
In patients without prior stroke the incidence of first stroke was 2.6% in placebo allocated patients and 2.8% for pioglitazone. (Table). All-cause mortality in the prior stroke group was 9.8% vs 9.5% and in the no prior stroke group 6.4% vs 6.2% for placebo vs pioglitazone treatment respectively.
Conclusion
In this subgroup analysis from the PROactive study, treatment with pioglitazone reduced significantly the risk of recurrent stroke in high risk patients with type 2 diabetes.
Robert Wilcox on behalf of Marie-Germaine Bousser, John Betteridge, Guntram Schernthaner, Valdis Pirags, Stuart Kupfer, John Dormandy, and the PROactive investigators.
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