Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Aderonke Adeboye, PharmD, Mercer University College of Pharmacy

Researchers have found that patients who experience ischemic stroke or transient ischemic attack (TIA) are at greater risk for future cardiovascular events.2,3 It is stated that insulin resistance is seen throughout type 2 diabetes patients and in over 50% of patients without diabetes who experienced an ischemic stroke or TIA.4

Targeting insulin resistance as a means for prevention is suggested to be added to the standard of care after ischemic stroke or TIA.5 Per guidelines by the American Diabetes Association (ADA), thiazolidinediones are included in the classes of medications that improve insulin sensitivity.6 In type 2 diabetics, it is suggested that pioglitazone may reduce cardiovascular events including stroke.7,8

Title: Pioglitazone after Ischemic Stroke or Transient Ischemic Attack
Design Multicenter, double-blind, randomized, placebo controlled; N = 3,876
Objective Assess the hypothesis that pioglitazone would reduce the rates of stroke and myocardial infarction after ischemic stroke or TIA in patients without diabetes who have insulin resistance
Study Groups Pioglitazone (n = 1,936); placebo (n = 1,937)
Methods Patients where randomly assigned in a 1:1 ratio to receive either pioglitazone or placebo. Patients were titrated at 4 week intervals. At 12 weeks, patients received a 45 mg tablet of pioglitazone or placebo and were contacted every 4 months.

 

Duration 2005 – 2013
Primary Outcome Measure First fatal or nonfatal stroke or fatal or nonfatal myocardial infarction
Baseline Characteristics

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Characteristic Pioglitazone

(n = 1939)

Placebo

(n = 1937)

Demographics
Age (yr) 63.5 ± 10.6 63.5 ± 10.7
Male sex (%) 66.7 64.3
Black race (%) 11.4 11.8
Hispanic ethnic group (%) 3.9 3.7
Stroke (%)
At entry (%) 87.8 87.2
Previous (%) 12.7 12.5
Hypertension (%) 71.2 71.8
Coronary artery disease (%) 12.4 11.4
Body Mass Index (BMI) 29.9± 5.6 30.0± 5.3
Blood pressure (mmHg)
Systolic 133.2± 17.7 133.0± 17.3
Diastolic 79.4± 10.7 79.4± 10.5
Concomitant medication (%)
Statin (%) 82.5 82.4
Antiplatelet (%) 92.0 92.3
Oral anticoagulant (%) 12.0 10.8
Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) (%) 56.4 54.6
Diuretic (%) 30.1 27.6
Beta blocker (%) 31.8 31.7
Interval after index event
No. of days to homeostasis model assessment of insulin resistance (HOMA-IR) testing 56 (30-98) 56 (31-97)
No. of days to randomization 81 (51-121) 79 (52-121)
Results In an intent to treat analysis, the primary outcome of stroke or myocardial infarction occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (HR in the pioglitazone group, 0.76; 95% CI interval, 0.62 to 0.93; p = 0.007).
Adverse Events Common Adverse Events: weight gain >4.5 kg (52.2%), edema (35.6%), shortness of breath (17.6%)
Serious Adverse Events: hospitalization (46.8%), death (7.0%), incident of cancer (6.9%), bone fracture (5.1%), heart failure (2.6%)
Percentage that Discontinued due to Adverse Events: N/A
Study Author Conclusions The risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo.

The results from this study contrast prior studies that included type 2 diabetes patients.  The rate of the primary outcome of death, myocardial infarction, stroke, acute coronary syndrome, vascular surgery surgery, or amputation was not significantly lower among patients in the pioglitazone group than among those in the placebo group in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive trial). 7,8

It is known that due to activation of peroxisome proliferator-activated receptor gamma and alpha (PPAR-γ and PPAR-α), pioglitazone has favorable effects on insulin sensitivity, fat distribution, plasma glucose, lipid and protein metabolism, vascular endothelial function, and inflammation.  Researchers from this study are uncertain of the exact mechanism that attributed to the lower rates of of stroke and myocardial infarction in the pioglitazone group; however, enhancing insulin sensitivity may be the central benefit of pioglitazone. For future studies, exploring the additional mechanisms of pioglitazone and its impact post ischemic stroke or transient ischemic attack may provide more evidence for its use in this population.

References

  1. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016;
  2. Dhamoon MS, Sciacca RR, Rundek T, Sacco RL, Elkind MS. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology 2006;66:641-6.
  3. Johnston SC. Transient ischemic at- tack. N Engl J Med 2002;347:1687-92.
  4. Kernan WN, Inzucchi SE, Viscoli CM, et al. Impaired insulin sensitivity among non- diabetic patients with a recent TIA or ischemic stroke. Neurology 2003;60:1447-51.
  5. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the Ameriican Heart Association/American Stroke Association. Stroke 2014;45:2160-236.
  6. Approaches to Glycemic Treatment. Diabetes Care. 2016;39 Suppl 1:S52-9.
  7. Wilcox R, Bousser M-G, Betteridge DJ, et al. Effects of pioglitazone in patients with type 2 diabetes with or without pre- vious stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 2007; 38:865-73.
  8. Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macro- vascular events in patients with type 2 diabetes in the PROactive Study (PRO- spective pioglitAzone Clinical Trial In macroVascular Events): a randomised con- trolled trial. Lancet 2005;366:1279-89.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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