A study showed last year that the insulin-sensitizing drug pioglitazone reduces the risk for stroke in patients with recent ischemic strokes. A new secondary analysis of the trial results found that the patients most likely to benefit from the drug are the patients with the highest stroke risk.

Stroke is a major cause of death and disability worldwide. Patients that have survived an earlier ischemic stroke or transient ischemic attack (TIA) face a higher risk for recurrent strokes.¹ The presence of insulin resistance further increases the risk of cardiovascular events,² and a question has been whether modification of insulin resistance might reduce the incidence of stroke and myocardial infarction (MI).

Trial shows that pioglitazone reduces risk for new strokes

The Insulin Resistance Intervention After Stroke (IRIS) trial, a randomized, double-blind, placebo-controlled clinical trial, was designed to evaluate the effectiveness of pioglitazone, a peroxisome proliferator-activated receptor g (PPARg) agonist and potent insulin-sensitizing drug, in reducing the risk for stroke and MI among insulin-resistant, non-diabetic patients with a recent ischemic stroke or TIA.³ A report by Dr Walter Kernan and colleagues from the study demonstrated last year that pioglitazone reduces the risk of recurrent stroke and MI in these patients by about one-fourth, compared to placebo.⁴

Secondary analysis finds high-risk patients as best candidates for pioglitazone after stroke

A secondary analysis of the IRIS study, published this September in JAMA Neurology by Dr Kernan and colleagues, was conducted with the aim to identify those patients who were most likely to benefit from pioglitazone treatment.⁵ The patients were divided in two groups of equal sizes, above or below the median risk for stroke or MI within 5 years. Baseline features associated with stroke and MI risk, such as age, history of prior stroke, coronary artery disease, hypertension, current smoking, or aphasia were considered for the stratification. The analysis showed that patients with higher baseline risk for stroke or MI had a greater absolute benefit with pioglitazone treatment compared to lower-risk patients on pioglitazone. The 5-year risk for stroke or MI in high-risk patients was 14.7% in the pioglitazone group versus 19.6% in the placebo group (absolute risk reduction 4.9%), while low-risk patients had a 6.0% 5-year risk of stroke or MI in the pioglitazone group, compared to 7.9% in the placebo group (absolute risk reduction 1.9%). The difference in absolute risk reduction between the two risk populations (4.9% for high-risk vs. 1.9% for low-risk) is likely to be meaningful, although the study showed no difference in hazard ratios between the two populations (0.75 vs 0.77; P = 0.92). Dr Kernan and colleagues further calculated in the report that 21 high-risk patients would need to be treated for about 5 years to prevent one stroke or MI, compared with 53 patients with low risk.

High-risk stroke patients benefit the most, but have more bone fractures

The analysis further shows that patients with higher risk did also experienced less weight increase with pioglitazone than did low-risk patients, but had a higher rate of bone fractures. The authors conclude that patients at higher baseline risk for stroke or MI derive a greater absolute benefit from pioglitazone after an ischemic stroke or TIA, but also have an increased risk for fractures, compared to patients at lower risk.

In an editorial accompanying the study report in JAMA Neurology, Graeme Hankey, MD, of The University of Western Australia, notes that although the very elderly patients (above 80 years of age) have the highest risk of stroke and MI and may gain the most from pioglitazone therapy, they also have the highest risk of bone fracture.⁶ Thus, the patients with perhaps the biggest benefit are individuals between 70 and 79 years of age with a history of coronary artery disease, hypertension, and/or current smoking.

In summary, treating patients with ischemic stroke and insulin-resistance with pioglitazone is likely to reduce the occurrence of strokes, especially in patients at high risk for strokes or MI, but at the same time the risk of bones fractures increases. This means patients in the highest risk group may opt out of pioglitazone therapy, as the fracture risk may be too high for them.

References

1. Hankey GJ, ‘Long-term outcome after ischaemic stroke/transient ischaemic attack’, Cerebrovascular Diseases, vol. 16, Suppl.1, 2003, pp.14–19.

2. Kernan WN et al., ‘Insulin resistance and risk for stroke’, Neurology, vol. 59, no. 6, 2002, pp.809–815.

3. Viscoli, CM et al., ‘Pioglitazone for secondary prevention after ischemic stroke and transient ischemic attack: Rationale and design of the Insulin Resistance Intervention after Stroke Trial’, American Heart Journal, vol. 168, no. 6, 2014, pp.823-829.

4. Kernan WN et al., ‘Pioglitazone after Ischemic Stroke or Transient Ischemic Attack’, The New England Journal of Medicine, vol. 374, no. 14, 2016, pp.1321-1331.

5. Kernan WN et al., ‘Targeting Pioglitazone Hydrochloride Therapy After Stroke or Transient Ischemic Attack According to Pretreatment Risk for Stroke or Myocardial Infarction’, JAMA Neurology, doi:10.1001/jamaneurol.2017.2136, 2017.

6. Hankey GJ, ‘Which Patients With Ischemic Stroke and Insulin Resistance May Benefit From Pioglitazone Hydrochloride?’, JAMA Neurology, doi:10.1001/jamaneurol.2017.2142, 2017.