TZD reduces ACS risk in insulin-resistant non-diabetic patients with prior stroke or TIA
Cardiac Outcomes After Ischemic Stroke or TIA: Effects of Pioglitazone in Patients with Insulin Resistance Without Diabetes
Epidemiological research showed that insulin resistance is associated with an increased risk for both myocardial infarction (MI) and stroke [1-3]. Moreover, it has recently been reported that insulin resistance was present in 63% of patients without diabetes after a recent ischemic stroke or transient ischemic attack (TIA) . It seems therefore interesting whether intervention of insulin resistance, eg. with thiazolidinediones (TZDs), reduces cardiovascular (CV) risk in patients without diabetes.
The PROactive trial showed that pioglitazone, a TZD, reduced the risk for a secondary outcome of CV mortality and non-fatal stroke by 28% in diabetes patients with a history of stroke . This research was extended by the insulin resistance intervention in stroke (IRIS) trial, in which effectiveness of pioglitazone was shown in patients with insulin resistance non-diabetic patients that recently experienced a stroke or TIA .
As pioglitazone has been shown to harbour coronary artery anti-atherosclerotic and possibly vascular stabilizing potential, the effect of pioglitazone on the incidence of acute coronary syndrome (ACS) was studied in a secondary analysis of the IRIS study with insulin resistant non-diabetic patients (n=3876). For this analysis, insulin resistance was defined by HOMA-IR >3.0.
- 5.1% experienced ACS: 0.1% with fatal MI, 3.1% with non-fatal MI and 9.1% with unstable angina. Of the 141 MI cases, 28 were ST-segment elevation MIs (STEMIs), 98 were non-STEMIs and 15 events could not be classified. 94 MIs were spontaneous (type I), 43 were due to myocardial oxygen supply/demand imbalance (type 2), 1 sudden death without biomarker ascertainment (type 3) and another one after percutaneous coronary intervention (type 4a).
- 99 ACS events occurred in 83 participants of the pioglitazone group and 126 events in 116 participants of the placebo group (HR 0.71, 95% CI 0.54-0.94, P=0.02). The effect of pioglitazone was similar among patients with and without impaired fasting glucose, among patients with HOMA values above and below the median and across different CV therapy groups. Pioglitazone was associated with a reduction in ACS events in patients without a history of coronary artery disease at baseline (HR 0.66, 95% CI 0.47-0.93). The effect was greater in patients without history of hypertension (HR 0.36, 95% CI 0.18-0.72) than in patients with a history of hypertension (HR 0.84, 95% CI 0.62-1.15, non-adjusted P interaction = 0.03).
- MI risk was non-significantly lower in de pioglitazone group (HR 0.73, 95% CI 0.51-1.03, P=0.08). However, these differences were significant for spontaneous type 1 MI (HR 0.62, 95% CI 0.40-0.96, P=0.03). On the other hand, there was no effect on type 2 MI.
- In a prespecified exploratory analysis, the effect of pioglitazone was greater in reducing risk for STEMIs, MIs with troponin increase >100x ULN or death (HR 0.50, 95% CI 0.28-0.88, P=0.02) compared to less severe MI events (HR 0.97, 95% CI 0.60-1.57, P=0.91).
In this secondary analysis of the IRIS trial, pioglitazone reduced the risk of ACS, particularly the most serious events, in insulin-resistant patients without diabetes after ischemic stroke or TIA. This was most evident for spontaneous type I MI, suggesting coronary artery plaque stabilization, and pioglitazone was more effective in preventing more clinically significant MIs.