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Uncovering the Cardiovascular Effects of Pioglitazone

Is pioglitazone a viable option for patients with insulin resistance and recent stroke or myocardial infarction?

The use of thiazolidinediones (TZDs) has become part of the management of type 2 diabetes mellitus, mainly for Its physiological action that increases glucose uptake in peripheral tissues. However, concerns with kidney and cardiovascular risks have risen since the development of these agents. Out of all the agents within this class, pioglitazone is the only medication that is generally available due to its safety, tolerability, and lack of dose adjustments in patients with chronic kidney disease (CKD stages 2-5). Pioglitazone is metabolized mainly through the liver and recent evidence shows lower plasma concentrations in patients with CKD when compared to patients with normal renal function. However, there is inconclusive evidence in patients undergoing dialysis. The use of pioglitazone has been in debate due to concerns with cardiovascular risks and its ability to exacerbate heart failure signs and symptoms. Interestingly, some studies suggest an increased risk of bladder cancer development with the use of rosiglitazone and not pioglitazone, which has led researchers to believe that this risk is a medication specific effect and not a class effect. In ongoing research efforts, it was shown that there is no association between pioglitazone use and the risks of CV events or bladder cancer. Despite these recent debates over the use of TZDs and their potential risk, the IRIS study conducted by Kernan and colleagues further explores the CV risks associated with the use of pioglitazone.

The IRIS (Insulin Resistance Intervention after Stroke) study is an international, double-blind, placebo controlled trial that looked at 3,876 patients 40 years and older who had suffered from an ischemic stroke or transient ischemic attack (TIA) 6 months prior to the beginning of the study. It should be noted that patients with insulin resistance with no diabetes (HOMA-IR: 4.6-4.7 and A1c: 5.8%) were included in the study, whereas diabetic patients were excluded. Patients were randomly assigned to 15 mg of pioglitazone (n=1,939) or placebo (n=1,937). The study looked at stroke or myocardial infarction occurrence and the progression of diabetes. In addition to the side effect profile of the pioglitazone regimen.

According to the study results, out of those patients receiving pioglitazone, only 9% experienced stroke or myocardial infarction; 11.8% of those receiving placebo experienced stroke or myocardial infarction (HR 0.76; 95% CI 0.62-0.93; P=0.007). Consequently, those on the pioglitazone group (3.8%) had lower rates of progression into diabetes when compared to placebo group (7.7%) (HR 0.48; 95% CI, 0.33-0.69; P<0.001). It is also important to highlight that in this study, those patients receiving pioglitazone improved insulin sensitivity, blood pressure, glucose levels, triglycerides, HDL and C-reactive protein. Consequently, in a report Inzzucchi and colleagues explain these metabolic effects of pioglitazone in preventing diabetes occurrence. The exact mechanism of these findings is still unclear, but the authors conclude that gene transcription through PPAR-gamma activation improves endothelial function and inflammation, while promoting its known mechanism of action of improving glucose uptake by fat and muscle tissues.

Based on these results, the authors suggest that the benefits found in this study warrant closer monitoring in terms of the medication’s side effect profile. Bone density appears to be affected by pioglitazone therapy through osteoblastogenesis suppression. It was observed that those patients receiving pioglitazone had an increased incidence of hospitalizations and/or surgery due to bone fractures. Other notable side effects included weight gain and fluid retention. The latter becomes the main side effect of concern in patients with heart failure due to pioglitazone’s CHF worsening potential, thus warranting prescribers to take into account the risk-to-benefit ratio when initiating a patient on a pioglitazone regimen. The IRIS trial sets the foundation for other studies to take place. The use of TZDs, specifically pioglitazone, has always been reserved as second and third line options in patients with T2DM. With the current findings, pioglitazone can play a significant role in preventing cardiovascular complications in patients with insulin resistance and a history of TIA, stroke, or myocardial infarction. These findings can provide great benefit along with the insulin-sensitizing effects of diet, exercise, smoking cessation, reduced alcohol consumption, and other lifestyle modifications.

Practice Pearls:

  • Pioglitazone can help prevent recurrence of stroke and progression into diabetes in those patients with insulin resistance and recent cardiovascular events.
  • Bone mineral density should be closely monitored in patients taking pioglitazone due to high rates of bone fracture, hospitalizations, and surgeries.
  • The findings of the IRIS trial should be implemented in adjunct with lifestyle modifications.

Bath, P. M., J. P. Appleton, and N. Sprigg. “The Insulin Resistance Intervention after Stroke Trial: A Perspective on Future Practice and Research.” International Journal of Stroke (2016): n. pag. Web.
Davies, Melanie, Sudesna Chatterjee, and Kamlesh Khunti. “The Treatment of Type 2 Diabetes in the Presence of Renal Impairment: What We Should Know About Newer Therapies.” Clinical Pharmacology: Advances and Applications CPAA (2016): 61. Web.
Kernan, W.n., C.m. Viscoli, and K.l. Furie. “Pioglitazone After Ischemic Stroke or Transient Ischemic Attack.” Journal of Vascular Surgery 64.1 (2016): 260. Web.
Xu, Fei, Yonghui Dong, Xin Huang, Peng Chen, Fengjing Guo, Anmin Chen, and Shilong Huang. “Pioglitazone Affects the OPG/RANKL/RANK System and Increase Osteoclastogenesis.” Molecular Medicine Reports Mol Med Report (2016): n. pag. Web.

Researched and prepared by Pablo A. Marrero-Núñez – USF College of Pharmacy Student Delegate – Doctor of Pharmacy Candidate 2017 – University of South Florida – College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE