Effect of pioglitazone on vascular events in post-stroke cognitive impairment: Post hoc analysis of the IRIS trial

Abstract

Background:

In stroke patients with insulin resistance (IR), post-stroke cognitive impairment (PSCI) is associated with higher risk of recurrent stroke, but the effect of pioglitazone on that risk has not been explored. The goal of this study was to compare the secondary stroke prevention effect of pioglitazone against placebo in patients with versus without PSCI.

Methods:

We studied patients enrolled in the Insulin Resistance Intervention after Stroke (IRIS) trial with a post-stroke modified Mini-Mental State Examination (3MS) cognitive assessment (mean time of assessment: 79 days post-stroke). We considered a baseline score of ⩽ 88 on the 3MS to indicate global PSCI, and domain-specific summary scores in the lowest quartile to indicate attention, language, memory, orientation, and visuospatial impairments.

Results:

In n = 3338 patients with IR, the effect of pioglitazone versus placebo on secondary stroke significantly differed by initial post-stroke global (interaction p = 0.0127) and memory impairment status (interaction p = 0.0003). Hazard ratios (HRs) were time-dependent such that, among those with either global or memory impairment, pioglitazone has an increasingly stronger protective effect at later timepoints. There was no statistically significant effect of pioglitazone among those without either global or memory impairment. The effect of pioglitazone versus placebo on myocardial infarction (MI) also significantly differed by global impairment status (interaction p = 0.030). Pioglitazone was protective among those with global impairment (HR = 0.23 [95% CI: 0.08, 0.71]) but not among those without (HR = 0.88 [95% CI: 0.59, 1.31]).

Conclusion:

These data indicate that pioglitazone treatment may be more effective at reducing risk of recurrent stroke and MI in stroke patients with PSCI. Simple cognitive testing 2–3 months post-stroke may identify patients for whom treatment would be most beneficial.

Keywords

Stroke post-stroke cognitive impairment recurrent stroke insulin resistance pioglitazone treatment effect modification

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References

El Husseini

Katzan

Rost

, et al. Cognitive impairment after ischemic and hemorrhagic stroke: a scientific statement from the American Heart Association/American Stroke Association. Stroke 2023; 54: e272–e291.

Schmidt

Power

Ciarleglio

Nadareishvili

and IRIS Study Group. Post-stroke cognitive impairment and the risk of stroke recurrence and death in patients with insulin resistance. J Stroke Cerebrovasc Dis 2022; 31: 106744.

De Havenon

Sharma

Falcone

Prabhakaran

Sheth

. Effect of intensive blood pressure control on incident stroke risk in patients with mild cognitive impairment. Stroke 2022; 53: e242–e245.

Kwan

Wei

Dowling

Power

Nadareishvili

. and SPS3 Study Group Cognitive impairment after lacunar stroke and the risk of recurrent stroke and death. Cerebrovasc Dis 2021; 50: 383–389.

Kernan

Viscoli

Furie

, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016; 374: 1321–1331.

Furie

Viscoli

Gorman

, et al. Effects of pioglitazone on cognitive function in patients with a recent ischaemic stroke or TIA: a report from the IRIS trial. J Neurol Neurosurg Psychiatry 2018; 89: 21–27.

Putter

Sasako

Hartgrink

Van de Velde

CJH

Van Houwelingen

JC.

Long-term survival with non-proportional hazards: results from the Dutch Gastric Cancer Trial. Stat Med 2005; 24: 2807–2821.

Chi

Chien

Chiou

. Alzheimer disease and risk of stroke: a population-based cohort study. Neurology 2013; 80: 705–711.

Zhang

Schwartz

Permana

Reaven

. Pioglitazone inhibits the expression of inflammatory cytokines from both monocytes and lymphocytes in patients with impaired glucose tolerance. Arterioscler Thromb Vasc Biol 2008; 28: 2312–2318.

10.

Rostamian

Mahinrad

Stijnen

Sabayan

De Craen

. Cognitive impairment and risk of stroke: a systematic review and meta-analysis of prospective cohort studies. Stroke 2014; 45: 1342–1348.

11.

De Havenon

Smith

Sharma

, et al. Improvement in the prediction of cerebrovascular events with white matter hyperintensity. J Am Heart Assoc 2023; 12: e029374.

12.

Nissen

Wolski

. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457–2471.

13.

Bouhlel

Derudas

Rigamonti

, et al. PPAR-gamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 2007; 6: 137–143.

14.

Grambsch

Therneau

. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika 1994; 81: 515–526.

15.

Jin

Chen

, et al. Comparison of the Mini-Mental State Examination and Montreal Cognitive Assessment executive subtests in detecting post-stroke cognitive impairment. Geriatr Gerontol Int 2017; 17: 2329–2335.

16.

Folsom

Rasmussen

Chambless

, et al. Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Diabetes Care 1999; 22: 1077–1083.

17.

Hong

Han

Park

. The insulin resistance by triglyceride glucose index and risk for dementia: population-based study. Alzheimers Res Ther 2021; 13: 9.

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