Dr J David SpenceJ. David Spence, MD
A post-hoc analysis of patients with prediabetes has shown that pioglitazone (Actos, Takeda) use was associated with a significant reduction in stroke couple with myocardial infarction, and stroke alone.1

Ultimately, the risk of stroke and myocardial infarction was reduced by 40% and the risk of stroke alone was reduced by 33%.

The analysis from the IRIS trial showed that among 2885 patients, the 1456 patients treated with pioglitazone had a hazard ratio (HR) for stroke/myocardial infarction of 0.70 (95% CI, 0.56 to 0.88), and 0.72 (95% CI, 0.56 to 0.92) for stroke alone compared to the placebo group (n = 1429). Among those with good adherence (≥80%) to the antidiabetic agent (n = 644), HRs were 0.57 (95% CI, 0.39 to 0.84) for stroke and myocardial infarction, and 0.64 (95% CI, 0.42 to 0.99) for stroke alone.

“Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence,” the investigators, led by J. David Spence, MD, from the Stroke Prevention & Atherosclerosis Research Centre at the Robarts Research Institute of Western University, wrote. “Effects of pioglitazone were numerically greater among IRIS participants with prediabetes than in those without prediabetes; however, the differences were not significant.”

They added that the benefits appeared to outweigh the risks of fracture and fluid retention, which occurred in a serious fashion in 3.6% of patients (n = 23) in the pioglitazone group compared to 2.8% of patients (n = 23) in the placebo group, among those with good adherence. Weight gain of ≥10% occurred in 29.8% (n = 192) of those in the pioglitazone group compared to 12.0% (n = 97) of the placebo group. Edema occurred in 188 patients (29.2%) in the pioglitazone group compared to 175 patients (21.6%) in the placebo group. There was a slight but nonsignificant reduction in all-cause mortality, cancer, and hospitalization with pioglitazone, and no significant increase in heart failure.

Notably, Spence and colleagues acknowledged that one of the questions which arise from these data is whether or not patients can be chosen for pioglitazone therapy post-stroke or post-transient ischemic attack based on their prediabetes status, rather than their homeostatic model assessment of insulin resistance (HOMA-IR) score. Although, as the investigators wrote, insulin resistance is not commonly measured in clinical practice.

However, they shared their belief that “such a strategy is reasonable” and provided a trio of reasons as to why. First, that hemoglobin A1c (HbA1c) levels correlate well with measures of insulin resistance; second, that most patients with recent ischemic stroke and prediabetes have insulin resistance according to available literature, and third, in the IRIS trial, the HOMA-IR score was inversely and paradoxically correlated with the magnitude of treatment effect.

“If a criterion based on HbA1c results in administration of pioglitazone to patients with lesser severity of insulin resistance, our data suggest this may not diminish the benefit of pioglitazone,” they detailed. “Of course, the only way to provide a definitive answer would be to conduct a new trial with entry criteria based on HbA1c level rather than HOMA-IR score. An interim strategy might be to use pioglitazone for patients with a high threshold for HbA1c (e.g., 6.0%) to select patients with a very high probability of advanced insulin resistance.”

In an accompanying editorial, Leonardo Pantoni, MD, PhD, from the Department of Biomedical and Clinical Sciences at the University of Milan, pointed out that this study analysis adds to the known literature regarding the  strategies for secondary prevention of stroke and cardiovascular events in this high-risk population.2 Pantoni noted that this is especially so “if the results could be extended in the future to the population of patients with prediabetes without a history of stroke.”

Significantly, he pointed out that these data may have more of a direct impact on real-life practice due to its lack of a requirement of direct insulin measurement, “opening new horizons and offering new tools to the armamentarium of physicians” focused on using antithrombotic treatments and statins.

“However, it is noteworthy that the use of pioglitazone somehow struggles to be accepted among measures for the secondary prevention of stroke,” Pantoni wrote. He credited this struggle to a fear of other adverse effects of the therapy, which he noted carried “doubtful” evidence, as well as the cost of the drug. “In consideration of the magnitude of the beneficial effects outlined by the data presented by Spence et al and in other trials, this attitude should probably be changed,” he wrote.

Pantoni also suggested that this study is of interest due to the additional prospect of a similar therapeutic strategy and its role in the prevention of dementia, as insulin resistance, diabetes, and an increased risk of stroke are related to an increased risk of dementia, independent of one another. Thus, the possibility of targeting this high-risk population might represent an approach to prevent dementia linked with vascular brain changes, and “the availability of insulin-resistance drugs might represent an opportunity to test for preventing other forms of dementia that are not immediately linked with cerebrovascular events.”

“Surprisingly, the researchers involved in the fields of stroke and dementia continue to follow separate routes and do not talk too much to each other,” Pantoni concluded. “As a consequence, the composite end point of stroke and dementia is seldom used, although it is clearly of the utmost clinical relevance.”
REFERENCES
1. Spence JD, Viscoli Cm, Inzucchi SE. Pioglitazone therapy in patients with stroke and prediabetes: a post hoc analysis of the IRIS randomized clinical trial. JAMA Neurol. Published online February 7, 2019. doi:10.1001/jamaneurol.2019.0079.
2. Pantoni L. Potential new horizons for the prevention of cerebrovascular diseases and dementia. JAMA Neurol. Published online February 7, 2019. doi:10.1001/jamaneurol.2018.4406.