Acute Coronary Syndrome Risk Reduced With Pioglitazone in Insulin Resistance Post-Stroke

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Patients were assigned to placebo or pioglitazone, which was titrated for 8 weeks from 15 mg daily to a target dose of 45 mg daily.
Patients were assigned to placebo or pioglitazone, which was titrated for 8 weeks from 15 mg daily to a target dose of 45 mg daily.

Findings reported in Circulation show that pioglitazone lowered the risk of acute coronary syndromes (ACS) following ischemic stroke or transient ischemic attack (TIA) in patients without diabetes with insulin resistance.1

Insulin resistance is common in people with cardiovascular disease and has been linked with an elevated risk of myocardial infarction (MI) and stroke.2,3 For example, in the  2016 Insulin Resistance Intervention in Stroke (IRIS) trial (Clinicaltrials.gov identifier: NCT00091949), 63% of participants without diabetes who had recently suffered an ischemic stroke or TIA had insulin resistance.4

Two thiazolidinediones, pioglitazone and rosiglitazone, have been found to improve insulin sensitivity in patients with diabetes, and pioglitazone reduced the risk of cardiovascular mortality, MI, and non-fatal stroke by 28% (P =.047) in patients with diabetes and a history of stroke.5 In addition, the randomized double-blind IRIS trial demonstrated similar results in patients without diabetes.4

Other findings indicate that pioglitazone “reduces the progression of coronary atherosclerosis in patients with type 2 diabetes … reduces coronary inflammation, alters coronary plaque composition by reducing necrotic core, and prevents intimal hyperplasia after coronary stenting in patients with and without diabetes,” the researchers of the current study wrote.

They conducted a secondary analysis of the IRIS data to determine whether the drug decreased ACS in patients with insulin resistance. 

The sample consisted of 3876 patients with ischemic stroke (87.1%) or TIA (12.5%) across 179 centers in 7 countries. Approximately 12% of participants had a history of coronary artery disease. They were assigned to placebo or treatment with pioglitazone, which was titrated for 8 weeks from 15 mg daily to a target dose of 45 mg daily.  Follow-up occurred over a median 4.8 years.

The results of the analysis showed the findings listed below.

  • 225 ACS events, including 84 episodes of unstable angina and 141 MIs, including 28 (19%) with ST-segment elevation; 94 MI's (65%) were type 1 and 45 (32%) were type 2
  • Serum troponin of 10 to 100 times the upper limit of normal (ULN) in 49 of the MI patients (35%) and more than 100 times ULN in 39 (28%)
  • Pioglitazone reduced ACS risk (hazard ratio [HR]: 0.71; 95% CI, 0.54-0.94; P =.02) and type 1 MI risk (HR: 0.62; 95% CI, 0.40-0.96; log-rank P =.03), but not type 2 MI risk (HR: 1.05; 95% CI, 0.58-1.91; P =.87)
  • Pioglitazone also led to a lower risk of large MIs with serum troponin more than 100 times the upper limit of normal (ULN) (HR: 0.44; 95% CI, 0.22-0.87; P =.02), but not smaller MIs.

Along with the findings of earlier studies, the present findings “warrant consideration as clinicians weigh the potential benefits and risks of pioglitazone as a secondary prevention therapy in patients with insulin resistance and cardiovascular disease,” the researchers concluded.

Disclosures: Several of the study authors report that they have received grant support and/or consulting fees from various pharmaceutical companies.

References

  1. Young LH, Viscoli CM, Curtis JP, et al; IRIS Investigators. Cardiac outcomes after ischemic stroke or TIA: effects of pioglitazone in patients with insulin resistance without diabetes [published online February 27, 2017]. Circulation. doi:10.1161/CIRCULATIONAHA.116.024863
  2. Stubbs P, Alaghband-Zadeh J, Laycock J, Collinson P, Carter G, Noble M. Significance of an index of insulin resistance on admission in non-diabetic patients with acute coronary syndromes. Heart. 1999;82(4):443-447.
  3. Bartnik M, Rydén L, Ferrari R, et al; for the EHS Investigators. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on Diabetes and the Heart. Eur Heart J. 2004;25(21):1880-1890. doi:10.1016/j.ehj.2004.07.027
  4. Kernan WN, Viscoli CM, Furie KL, et al; for IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med. 2016;374(14):1321-1331. doi:10.1056/NEJMoa1506930
  5. Wilcox R, Bousser M-G, Betteridge DJ, et al; for the PROactive Investigators. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke. Results from proactive (prospective pioglitazone clinical trial in macrovascular events 04). Stroke. 2007;38(3):865-873. doi:10.1161/01.STR.0000257974.06317.49
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