Pioglitazone and barriers to effective post-stroke comorbidity management in stroke survivors with diabetes
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* Hala Azhari
* Jonathan Hewitt
* Alexander Smith
* Martin O’Neill
* Terence Quinn
* Jesse Dawson

## Abstract

**Objectives:** To explore the barriers preventing pioglitazone use in stroke survivors and primary and secondary stroke care services.

**Methods:** A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its side effects (SEs) associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022.

**Results:** A qualitative grounded theory approached design was used to assess post-stroke diabetes treatments and to assess clinical applicability of pioglitazone as a preventive treatment to minimize its SEs associated. Three focus groups were established with 48 participants from Scotland and Wales health board centers during January 2019 to July 2022.

**Conclusion:** These strategies might allow greater treatment adherence by stroke survivors and increased confidence of the health care professionals in their practice. The findings suggest that further research will be needed to facilitate wider usage of pioglitazone in treating people with stroke and health education is necessitate when using diabetes drugs post-stroke.

**D**iabetes is a risk factor for the development of stroke with an incidence rate of more than doubling the risk of stroke recurrence.1 At present, there is no definitive evidence that intensive control of hyperglycemia improves the clinical outcomes of acute stroke.2 The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive)3 study demonstrated that the use of pioglitazone reduced the risk of recurrent strokes in patients with diabetes. Whether aggressive management of diabetes, using more frequently prescribed treatments, insulin or metformin, conveys stroke preventive benefits however remains unknown. Additionally, in the Insulin Resistance Intervention after Stroke (IRIS)4 study, the relative risk reduction of stroke with pioglitazone was 24% with a number need to treat of 36 versus placebo. These benefits are comparable to changes observed with aspirin5 and statins.6 It also reduced risk of developing diabetes and there was no increased risk of hemorrhagic stroke.7 The net benefits of pioglitazone however have been questioned, as it increased risk of peripheral edema, weight gain, heart failure (HF),8 and fracture9 associated side effects (SEs).

Although the European stroke guideline10 for long-term secondary prevention after transient ischemic attack or ischemic stroke stipulate that pioglitazone can be considered after a risk/benefit analysis, there is little data on the perspective of health care professionals and survivors with stroke concerning the benefits and potential SEs. Since the translation of early phase post-stroke diabetes management research will take time into later phase research translation. Gaining opinions from the health care professionals and stroke survivors’ data, are crucial to understand the current circumstances, will suggest innovative ideas to redesign the clinical practice of pioglitazone use post-stroke diabetes services.

The aimed of this study was to explore the views from the health care professionals and stroke survivors to help understand the barriers for the clinical applicability of pioglitazone Comorbidity Management Post-Stroke with a focus on Diabetes (COMPOSEd). Ultimately, to determine whether further research is needed.

## Methods

The protocol of the COMPOSEd study was approved by XXX Ethical Committee (XXX) with a reference of registration number (238470) in the UK Integrated Research Application System.

### Study design

The study used a qualitative method based on the approach of “grounded theory”11 to guide the design of focus groups (FGs) interpretation. The FGs interviews with the health care professionals and stroke survivors were conducted in the South Wales and Scotland hospitals. The interviews were directed by researchers experienced in qualitative methodology. In qualitative study, the point using of data saturation12 was determined the final number of FG interviews.

### Participants

The health care professionals and stroke survivors participated in individual FGs, received an information sheet, and provided written informed consent. The health care professionals were approached through special interest groups and professional networks with their direct care of patients with diabetes and stroke in the Wales and Scotland health board hospitals. A minimum of 2 individuals from each gender were surveyed (stroke and geriatric consultants, occupational therapists, diabetes specialists, clinical stroke nurses, and general practitioners). Stroke survivors with a history of diabetes were identified through clinical stroke care teams. A purposive sample was undertaken to achieve a range of age, gender, disability, and socioeconomic status.

### Study approach

Stroke survivor views were explored on the etiology of diabetes and stroke and on the strategies that can be used with pioglitazone to minimize weight gain and fractures SEs. Health care professionals’ views were explored on the barriers associated with the use of pioglitazone pre- and post-stroke and in mitigating its associated SEs to improve stroke outcomes in clinical practice.

### Format of the FGs

The FGs were formed to offer an opportunity for an in-depth exploration of participants’ perspectives. A series schedule of open-ended questions was prompted, digitally recorded, to encourage further discussion with participants. The participants were asked to express their views on the pre-stroke and COMPOSED in the primary and secondary services of stroke care. The meetings were conducted in neutral territory away from participants’ homes or hospitals. Participants had the opportunity to interact with others study participants or to respond individually in an un-structured discussed interviews at the end of each meeting.

### Analysis of the study data

The collection of FGs data and their analysis was performed with an iterative process. All interviews were anonymized, transcribed verbatim, and coded for qualitative analysis. A constant comparative analysis13 approach, using a grounded theory method, subsequently identified key points from the FGs interviews. Initially, the chunks of data were coded.14 The coded data comprised either of large text blocks or phrases that characterized health care professionals and stroke survivors’ regarding their knowledgeable views of pre-stroke and COMPOSEd. Coded data were then individually grouped into comparable related concepts and were formed to identify key theme and sub-themes. As groups were abstract categories, compared further, until the emerging of the core theme and sub-themes in each FG. Inconsistency was resolved with further discussion within the study team until an agreement was achieved on the final sub-themes.

We followed the Reporting of Qualitative Research checklist15 criteria to facilitate the decision-making use of this study.

## Results

During January 2019 to July 2022, 3 FG meetings with 48 participants were conducted (2 with health care professionals and one with stroke survivors). The interview meeting lasted 45 to 90 minutes. The health care professionals’ FGs had 32 participants from 2 health board centers in Wales and Scotland hospitals (4 stroke and geriatric consultants, 2 stroke trainee doctors, 3 occupational therapist, 2 diabetes specialists, 3 clinical stroke nurses, and 2 general practitioners). The patients FG had 16 stroke survivors’ participants from Glasgow hospital (8 men and 8 women), aged 53 to 79 years, who had hypertension and diabetes and had recovered from a stroke. The study participants baseline characteristics are explained in **Table 1**.

View this table:
[Table 1](http://nsj.org.sa/content/29/1/44/T1)

Table 1 
- Baseline characteristics of the participants included in the COMPOSEd study.

Details for participants’ themes and sub-themes are detailed in **Appendix 1**. In the stroke survivors’ FG, 3 themes (lack of stroke survivors’ awareness on the etiology of diabetes and stroke, lack of stroke survivors’ knowledge regarding advances in post-stroke diabetes management, and their decision making) and 2 sub-themes (diabetes and weight gain risk awareness and willingness, and diabetes and fracture risk perception and willingness) were identified. In the health care professionals’ FGs, 4 themes (barriers associated with pre-stroke and COMPOSEd, lack of health care professionals’ knowledge in post-stroke advance in diabetes treatments, future perspectives and clinical applicability of pioglitazone, and strategic plan to improve pioglitazone clinical practice in pre-stroke and COMPOSEd) and 2 sub-themes (weight gain and peripheral edema prevention strategies and fracture mitigation strategies) were identified.

## Discussion

The COMPOSEd study draws together the views of health care professionals and survivors with stroke to investigate the feasibility of pioglitazone use post-stroke. This study aimed to assess the trade-offs between the undesirable and desirable outcomes associated with pioglitazone as a preventive treatment post-stroke to analyze and capture the barriers to its adoption among primary and secondary stroke health care services.

The health care professionals’ views of the pioglitazone applicability in clinical practices are neutral. Their perceptions are multi-dimensional. Some avoid pioglitazone use owing to the greater treatment burden, while others do not have the knowledge of the chemotherapeutic advances in diabetes clinical studies post-stroke. These issues may be resolved through the use of knowledge, motivation, attitude, practice, and an outcomes framework.16 This may involve increased awareness and behavior change via recommendations and communications in clinical practice. Although health care professionals viewed some practical heterogeneity with chemotherapeutic advances in COMPOSEd, their preference is to devise optimal guidelines that combine flexibility with rigor for early screening of diabetes post-stroke. Additionally, a recommendation for this screening should be mentioned in the stroke survivor’s hospital discharge forms.

The association between stroke survivors’ willingness to accept treatment and their perceived risks associated is viewed as a significant concern. Their views on using pioglitazone are a choice between greater risks of weight gain and fractures or an improved in their long-term of stroke outcomes. The behavior of those stroke survivors reluctant to choose treatment may resonate with the loss of aversion phenomenon17—a tendency to favor avoiding loss over gaining benefits. Their preferences are to be monitored by health care professionals, who will observe for its early signs of SEs associated and will encourage survivors to engage in a rehabilitation program that will offer the caveat of being sensitive and flexible to the demand of their lifestyle.

This study highlights stroke survivors’ challenges in deciding whether they will adhere to a pioglitazone regimen, given the probability of peripheral edema, weight gain, and fracture SEs. Arguably, clear approaches can address these issues. Stroke clinicians must consider stroke survivors’ needs and abilities. In spite of the enhancement achieved in the IRIS4 and PROactive3 trials and the personalized medicine approach used in the IRIS4 trial, the successful amelioration of the excess risk of HF through dose reduction or discontinuation for IRIS stroke survivors who developed significant edema gives rise to hope. However, there is no clear consensus on the optimal approach post-stroke to alleviate weight gain or fracture associated with the use of pioglitazone. This makes it challenging to persuade survivors with stroke to accept pioglitazone use. The COMPOSEd study has produced strategies to optimize pioglitazone use and help decide the best treatment to be offered.

Peripheral edema represents a primary concern for health care professionals, while weight gain is a primary concern for stroke survivors in this study. The peripheral edema and weight gain SEs may be explained by increased subcutaneous adipose tissue mass, rather than increased visceral deposition.18 As a result, there is a tendency for plasma volume expansion and fluid accumulation owing to sodium retention,19 which increases the risk of HF if the levels of sodium are unchecked. In the IRIS trial,20 however, stroke survivors who gained weight had fewer rate of HF hospitalizations, improved glycemic controls, and lower rates of strokes recurrent than those with higher risk of HF or those with a normal-to-low body mass index.9 In the PROactive trial,21 HF rates independently correlated with increased the incidence risk of stroke related-mortality. The COMPOSEd study suggests following the IRIS4 recommendations to use safety algorithm to trigger the dose reduction with pioglitazone for substantial edema. However, this study varies from such a personalized medicine approach in that we aimed to target those stroke survivors with a low risk of peripheral edema and weight gain development and with the highest chance of benefiting from strokes prevention. We envisage employing an early cardiac echo test and B-type natriuretic peptide screening biomarkers,22 before and after the use of pioglitazone, to monitor those survivors at high risk of HF development along with a strict caloric diet restriction23 and exercise24 with a degree of flexibility to counteract the risk of weight gain. With these approaches, we hope to mitigate the fear of physicians and stroke survivors regarding the early use of pioglitazone post-stroke.

Participants’ FGs did not consider fracture to be a significant concern in prevention of stroke with the use of pioglitazone. Fractures may be explained by the increased bone resorption and decreased bone formation in mesenchymal bone stem cells, which accelerate bone loss.25 In the IRIS8 and PROactive26 trials, serious and non-serious fractures were observed among ill patients, with the majority of events were related to falls. However, neither study provided baseline data on falls nor measured the frequency of fracture-related stroke disability, which are major risk factors for fracture. Interestingly, a minority of patients with acute stroke in IRIS trial were on preventive treatments for fracture. The COMPOSEd study proposed to target people with the lowest risk of fractures and at the same time with the highest chance of benefiting from stroke prevention. This can be achieved by using the clinical scores of early fractures risk assessment (FRAX)27 to exclude those with the highest risk of fractures and falls28 and dual energy X-ray absorptiometry29 screening, with the use of fractures secondary prevention treatments such as vitamin D30 and bisphosphonates.31

### Implications for future research

The European32 and American33 guidelines are recommended a glycemic control of HbA1c level to be <7 % in ischemic stroke, but it is challenged the health care professionals to identify those stroke survivors with HbA1c at primary stroke centers. In this study, data on the implementation of HbA1c during rehabilitation phase of stroke emerged. Whether for an ongoing monitoring or early diagnosis, this appears to be a preferable solution for some health care professionals for early COMPOSEd. This raises the question whether a rigorous screening in stroke care can increase the possibility of detecting missing cases that appear soon after discharge and might lead to changes in their current managements.

To understand the clinical implications of pioglitazone, it is important to consider why it is utilized in post-stroke. The Council of UK Medical Research34 suggested that the acceptability of drug’s should be assessed to evaluates a complex intervention, with risks and benefits, as well as variability assessments in individual-level outcome. From the perspective of precision medicine,35 this study is unique from IRIS in that it aims to stratify stroke survivors whose will be most likely to benefit from the use of pioglitazone. Survivors with stroke have a doubled risk of fracture due to fall following an acute stroke.36 We address this however by using the proposed alternative therapy for fractures within the critical window of the first 6 to 12 months following a stroke and by excluding those at the highest risk of fractures at baseline. Such an approach could subsequently facilitate treatment decisions and allow survivors to adopt greater ownership of their stroke condition. For health care professionals, these approaches seem logical, although financial consideration was raised in term of their implementation. However, considering the vast expenses of the UK National health services for stroke survivors with comorbidities such as stroke and diabetes,37 it would be reasonable to accept these approaches for a secondary prevention of comorbidity post-stroke.

Education is essential for survivors with stroke who would welcome a sense of empowerment in managing their health needs, as well as for those in a state of flux between rejecting the guidelines and to adhering them. Given the variation in practice that emerged among health care professionals, it would be instructive to instill, through health education, a feeling of confidence in practices regarding when and which stroke survivors need to treat. Likewise, stroke survivors need simple guidance to adhere with the use of pioglitazone post-stroke. They need to be informed at what time they should be monitored for the SEs associated and under what conditions. Joint decision making involves stroke survivors is shown to increase the likelihood of compliance.38

The COMPOSEd study adopted several steps to understand the risks and benefits associated with the use of pioglitazone. Using inputs from the health care professionals’ and stroke survivors’ perspective and instituting appropriate health education would provide appropriate suggestions to incorporate into pioglitazone COMPOSEd and allow a flexibility in guidelines development.

### Strengths and limitations

To guarantee the best clinical outcome achievable with the available resources, as a theoretical framework for acceptability,39 the COMPOSEd study combined the insights of health care professionals and stroke survivors to explore the applicability of pioglitazone use. Although we ensured equal opportunities to the participants to respond to our FGs’ questions, our study may be subject to a dominant respondent bias, where some participants may have continuously dominated the talk and influenced their opinions of the other respondents. To increase the probability of experience diversity, the health care professionals were recruited from the primary and secondary Wales and Glasgow stroke centers. However, social desirability bias may exist, where the professionals would answer in a way they thought they should answer rather than what they would actually practice in clinical settings. Even though patients with stroke were recruited from a single hospital in Glasgow, theoretical saturation was assured,40 and may still recognize a pattern of clinical practices that could inform a design of future clinical study.

### Conclusion

The COMPOSEd study suggested exploring methods to reduce pioglitazone-associated SEs from the perspective of health care professionals and stroke survivors. Typically, stroke survivors felt that addressing stroke risk was more important than addressing weight gain or fracture treatment-related SEs. Health care professionals recommend exploratory approaches to mitigate the SEs associated with pioglitazone use, such as dose reduction, better selection of individual, early use of fracture preventive managements, and health care professionals monitoring for early SEs sign. These strategies would be beneficial in the advancement of care in the treatment of stroke survivors with diabetes post-stroke, might allow greater treatment adherence by them, and increase the confidence of health care professionals in their practice. Before the widespread use of pioglitazone, further research is necessitated to identify those stroke survivors for whom the risks might be acceptable with greatest stroke preventive benefits. The findings of this study inform the future of post-stroke trial design.

## Acknowledgement

*We would like to thank all the patients and physicians of the Acute Stroke Unit in Queen Elizabeth University Hospital in Glasgow, UK and Aneurin Bevan University Hospital Board – Research and Development at Wales, UK, for their willingness to help and eager participation in the COMPOSEd focus group study. We thank Pamela McKenzie, Belinda Manak, and Lesley Campbell in the Acute Stroke Unit at the Queen University Hospital in Glasgow, UK, helped in the digital recording and transcription of the focus groups study.*

## Footnotes

*   **Disclosure.** This work was supported by the Umm Al-Qura University at Makkah, Saudi Arabia, which is represented by the Saudi Arabian Cultural Bureau and Embassy in London and the National Health Service (NHS) Wales Stroke Implementation Group, which is sponsored by the NHS Greater Glasgow and Clyde in the UK (grant number UMU581). Authors have no conflict of interests, and the work was not supported or funded by any drug company.

*   Received May 31, 2023.
*   Accepted November 20, 2023.


*   Copyright: © Neurosciences

Neurosciences is an Open Access journal and articles published are distributed under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC). Readers may copy, distribute, and display the work for non-commercial purposes with the proper citation of the original work.

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