Novel Strategies for Secondary Stroke Prevention - Exploring the Use of Pioglitazone Therapy Using a Mixed Methods Approach

Abstract

Pioglitazone, an oral thiazolidinedione (TZD), is used in the second- or third-line management of type 2 diabetes mellitus (T2DM). In addition, the Insulin Resistance Intervention after Stroke trial showed that pioglitazone reduced cardiovascular events in people with recent ischaemic stroke or transient ischaemic attacks who were insulin resistant but had no diabetes (relative risk reduction of 24%; 95% confidence interval (CI) 0.62-0.93; P=0.007; absolute risk reduction of 3%) versus placebo. Furthermore, with pioglitazone use, about half as many patients went on to develop diabetes. However, the net benefit of pioglitazone has been questioned because, with its use, the fracture rate increased by about a third (29% relative risk (RR); 2 to 5% absolute risk (AR)), many patients suffered substantial weight gain (55% RR; 6% AR) and there was an increase in peripheral oedema (43% RR; 10% AR). This means doctors are unsure about whether they should use pioglitazone. This is a much-discussed topic in the stroke community. This thesis addresses several areas concerning pioglitazone use after stroke. It aims to better characterise the risk of fracture, explore patient and clinician views regarding pioglitazone use and explore whether other new diabetes treatments could be similarly effective in people with strokes. The fractures, weight gain and peripheral oedema associated with pioglitazone use are important clinical issues. However, fractures are the most concerning. I performed a systematic review and meta-analysis of the fracture risk with TZD drugs following best-practice guidance. A search of the Cochrane Register of Controlled Trials, MEDLINE, EMBASE, the Web of Science and the trial registries (from their inception to Week 36, 2017) was performed. The updated searched was done in Week 10 in 2020. The grey literature was also searched. Published and unpublished studies comparing TZDs with placebo or other anti-hyperglycaemic drugs were included if they reported data on fracture occurrence. The search identified 860 studies. A total of 78 were included in this study as they satisfied the eligibility criteria. Thirty-four included trials had a high risk of bias, eight had unclear risk and 36 low risk. These studies had an overall high-to-moderate GRADE score of evidence. They included 39,568 participants on TZDs and 25,718 on comparators with 1,917 fracture events. The fracture risk was increased with TZDs (RR 1.35; 95% CI 1.24−1.48; P<0.00001; I2=10%) versus controls. In 14 trials comparing pioglitazone versus placebo (13,451 participants; 449 fractures), pioglitazone use increased fractures (RR 1.21; 95% CI 1.01−1.45; P=0.04; I2=32%). Both non-serious (RR 1.25; 95% CI 1.03−1.51; P=0.02; I2=53%) and serious fractures (RR 1.48; 95% CI 1.10−1.98; P=0.01; I2=24%) increased with pioglitazone use. In 13 trials comparing pioglitazone to anti-hyperglycaemic comparators (11,267 participants; 99 fractures), there was no increase in fracture risk (RR 1.08; 95% CI 0.73−1.59; P=0.70; I2=15%). Fracture risk increases occurred mostly in the spine (RR 2.13; 95% CI 1.28−3.55; P=0.004; I2=66%) and the lower extremities (RR 1.85; 95% CI 1.33−2.56; P=0.0002; I2=0%) with pioglitazone use. Increased risk was more evident in females (RR 1.56; 95% CI 1.20−2.02; P=0.0008; I2=0%) than in males (RR 1.10; 95% CI 0.84−1.43; P=0.49; I2=14%) with pioglitazone use. Pioglitazone use increases fractures, but this finding was mostly driven by studies that compared its use to placebo and by an increase in women. These data may help stroke clinicians decide whether to use pioglitazone in selected patients to guide further post-stroke trials. There are several new classes of antidiabetic drugs, some of which have been demonstrated to reduce cardiovascular risk. I assessed the effects of these therapies on the incidence of stroke via a systematic review and met