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Saturday, February 16, 2019

Diabetes Drug, Pioglitazone, May Prevent Secondary Strokes

Target Audience and Goal Statement:
Cardiologists, neurologists, endocrinologists, primary care physicians
The goal of the study was to explore the effects of pioglitazone in patients with good adherence to the agent, as well as the intention-to-treat (ITT) effects of the drug in patients with prediabetes in the Insulin Resistance Intervention After Stroke Trial (IRIS) trial.
Question Addressed:
  • Was pioglitazone effective for secondary prevention in patients with stroke/transient ischemic attack (TIA) and prediabetes?
  • Was pioglitazone effective in patients with good adherence?
Synopsis and Perspective:
Thiazolidinedione drugs such as pioglitazone (Actos) are potent insulin sensitizers. In addition, pioglitazone is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, which means that it may have direct effects on the vascular endothelium and inflammatory cells that modulate the atherosclerotic process.

Pioglitazone’s anti-atherosclerotic and anti-diabetic effects observed in the 2016 IRIS trial (in which stroke was an index event for 87% of participants) add to promising earlier results from vascular imaging studies and outcomes from the prospective pioglitazone clinical trial in macrovascular events (PROactive). In the IRIS trial, pioglitazone reduced recurrent stroke or myocardial infarction (MI) by about one-fourth compared with placebo (9% vs 11.8%, HR 0.76, 95% CI 0.62-0.93), but raised the risk of weight gain, edema, and fractures.
But the results may have limited clinical application, as assessments were based on the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) score, which is not widely measured in routine practice. To enhance the potential real-world clinical benefit of IRIS results, J. David Spence, MD, of Western University in London, Ontario, and colleagues, performed a post hoc, exploratory subgroup analysis on stroke/TIA patients in IRIS who had prediabetes. Patients in the trial were randomized 1:1 to receive pioglitazone (15 mg per day titrated to 45 mg per day) or matching placebo over 3 months.
Prediabetes is defined by the American Diabetes Association (ADA) criteria as glycated hemoglobin (HbA1c) level of 5.7%-6.4%; or fasting plasma glucose level of 100-125 mg/dL (multiply by 0.0555 for mmol/L); or 2-hour glucose tolerance test result exceeding 140-199 mg/dL. Alternatively, the World Health Organization defines prediabetes as HbA1c of 6%-6.4% or fasting glucose level of 110 mg/125mg/dL. For the IRIS trial (2005-2013; mean follow-up is 4.8 years), patients were classified as having prediabetes based solely on the WHO criteria.
As with other trials, good adherence was defined as taking 80% or more of the protocol dose over the duration of the study (as measured by pill counts on returned bottles). Analysis focused mainly on this group, as pioglitazone could not be taken by about 10%-20% of patients because of fluid retention and weight gain, as Spence pointed out in an interview.
Recurrent fatal or nonfatal stroke, or MIs served as the primary outcome. Stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes were among the secondary outcomes.
Of the 3,876 initial study participants, 2,885 patients with prediabetes were included in this post hoc analysis, divided almost equally between pioglitazone and placebo groups. Mean age was 64. About 67% in the pioglitazone group and 64% in the placebo group were men. Patients showing good treatment adherence constituted 44.2% of the pioglitazone group and 56.7% of the placebo group. Mortality, cancer, and hospitalization were non-significantly reduced in the pioglitazone group; and there were significantly more participants with weight gain of 10% or more (29.8% vs 12.0%) and edema (29.2% vs 21.6%) taking the active drug.
For the “good adherence” group, hazard ratios for cardiovascular and metabolic endpoints were:
  • Composite of stroke and MI: 0.57, 95% CI 0.39-0.84
  • Stroke alone: 0.64, 95% CI 0.42-0.99
  • Acute coronary syndrome: 0.47, 95% CI 0.26-0.85
  • Composite of stroke, MI, and hospitalization for heart failure: 0.61, 95% CI 0.42-0.88
  • Progression to diabetes: 0.18, 95% CI 0.10-0.33
In the intention-to-treat analysis, the pattern was similar but differences (also in terms of hazard ratios) were less pronounced:
  • Composite of stroke and MI: 0.70, 95% CI 0.56-0.88
  • Stroke alone: 0.72, 95% CI 0.56-0.92
  • Acute coronary syndrome: 0.72, 95% CI 0.52-1.00
  • Composite of stroke, MI, and hospitalization for heart failure: 0.78, 95% CI 0.63-0.96
  • Progression to diabetes: 0.46, 95% CI 0.35-0.61
A small and nonsignificant reduction in all-cause mortality, cancer, and hospitalization with pioglitazone was observed, and the researchers did not observe a significant increase in heart failure. Adverse events reported for the ITT group followed the same pattern as for the ‘good adherence’ group.
Since this analysis was restricted to IRIS participants with higher HOMA-IR scores than other participants, the effectiveness of pioglitazone in participants with prediabetes and HOMA-IR scores less than or equal to 3 cannot be inferred from this study. Another study limitation was the fact that the diabetes endpoint was simply based on fasting glucose levels and patient reports. HbA1c testing was not performed after the baseline visit.
Source Reference: JAMA NeurologyFeb. 7, 2019; DOI:10.1001/jamaneurol.2019.0079
Study Highlights: Explanation of Findings
Among the 2,885 IRIS participants with prediabetes, the researchers observed a reduction in cardiovascular events and new-onset diabetes. The reduction was amplified in the “good adherence” group (≥80% of protocol dose taken), with risks for stroke/MI, stroke, and new-onset diabetes lowered by 40%, 33%, and 80%, respectively. These associations were greater than the ones found in the full IRIS trial cohort and occurred despite a high proportion of men and smokers, those with high diastolic blood pressure, and low high-density lipoprotein (HDL) cholesterol levels on average in this subgroup, Spence and colleagues wrote in JAMA Neurology.
These results are globally in line with the findings of the whole IRIS trial, noted Leonardo Pantoni, MD, PhD, of the University of Milan in Italy, in an accompanying editorial.
But a point not investigated in the study — and potentially of great interest — is that drugs like pioglitazone may help prevent dementia, Pantoni observed. “Prediabetes is a condition associated with the presence of abnormalities on brain imaging that are strong predictors of cognitive decline, such as lacunar infarcts and white matter hyperintensities,” he noted. “The possibility of targeting this high-risk population might represent an appropriate approach to also prevent dementia linked with vascular brain changes.”
And because diabetes is a risk factor for Alzheimer’s disease, “the availability of insulin resistance drugs might represent an opportunity to test for preventing other forms of dementia that are not immediately linked with cerebrovascular events,” he added.
Pioglitazone struggles to be accepted as a secondary stroke prevention treatment, which may stem from fear of adverse effects including bladder cancer and heart failure, Pantoni pointed out. The FDA confirmed a possible link between bladder cancer and pioglitazone in 2016, though a 2017 meta-analysis found no evidence of increased risk of heart failure with the drug. In IRIS, patients with heart failure or bladder cancer were excluded.

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