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IRIS: Pioglitazone lowers risk for CV events after ischemic stroke, TIA
In insulin-resistant patients who had a recent ischemic stroke or transient ischemic attack, treatment with the diabetes drug pioglitazone was associated with lower risk for stroke or MI compared with placebo, according to data reported at the International Stroke Conference.
“For the first time, a therapy directed at insulin resistance has been shown to prevent cardiac and cerebrovascular events for these patients,” Walter N. Kernan, MD, professor of medicine at Yale School of Medicine, said during a press conference.
Researchers for the double blind IRIS trial randomly assigned 3,876 patients with a history of recent ischemic stroke or TIA and insulin resistance (score > 3 on the homeostasis model assessment of insulin resistance [HOMA-IR] index) to receive the thiazolidinedione pioglitazone (Actos, Takeda) or matching placebo. Insulin resistance affects the majority of non-diabetic patients with ischemic stroke or TIA, according to Kernan.
Patients were enrolled at 179 centers in seven countries, including the United States. Those with diabetes, HF or bladder cancer were excluded from the trial. The cohort had a mean age of 63 years, 66% were men, 11% were black, mean BMI was 30 kg/m2 and mean NIH Stroke Scale score was 1.1.
Patients received an initial dose of 15 mg of pioglitazone daily or placebo, titrated to 45 mg daily if there were no drug-related adverse events such as new or worsening edema, shortness of breath, myalgia or excessive weight gain.
The primary outcome was time to first stroke or MI. According to results presented at ISC 2016, at 4.8 years of follow-up, 175 of 1,939 patients (9%) assigned pioglitazone developed first stroke or MI compared with 228 of 1,937 patients (11.8%) assigned placebo (HR = 0.76; 95% CI, 0.62-0.93; P = .007).
Overall, 3.8% of patients in the pioglitazone group and 7.7% in the placebo group developed diabetes (HR = 0.48; 95% CI, 0.33-0.69; P < .001), 5% vs. 6.6% developed ACS (HR = 0.75; 95% CI, 0.52-1.07; P = .11), 6.5% vs. 8% developed stroke (HR = 0.82; 95% CI, 0.61-1.1; P = .19) and 10.6% vs. 12.9% developed a composite of stroke, MI or serious HF (HR = 0.82; 95% CI, 0.65-1.05; P = .11). The researchers reported no significant difference in all-cause mortality during follow-up (pioglitazone, 7%; placebo, 7.5%; HR = 0.93; 95% CI, 0.73-1.17; P = .52).
In other results, pioglitazone was linked with a greater frequency of weight gain greater than 4.5 kg compared with placebo (52.2% vs. 33.7%; P < .001). Rates of edema (35.6% vs. 24.9%; P < .001) and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%; P = .003) were also more common in the pioglitazone group. Other serious adverse events included HF and incident cancer were similar between the treatment groups.
“Among insulin-resistant, non-diabetic patients with ischemic stroke or TIA, pioglitazone prevented stroke or MI, with an absolute risk reduction of 2.9% and relative risk reduction of 24%, and diabetes, with an absolute risk reduction of 3.9% and a relative risk reduction of 52%,” Kernan said.
Important next steps include further research to optimize the use of pioglitazone, including new strategies to minimize weight gain and assure bone health, and to identify other therapies that work on the same biological pathways, he said.
In a related editorial published in The New England Journal of Medicine, Clay F. Semenkovich, MD, from the division of endocrinology, metabolism and lipid research at Washington University in St. Louis, noted that “while the results of the IRIS trial might tempt clinicians to rush to prescribe pioglitazone,” he urged caution because the positive outcomes may have been related to the design of the trial. “Patients in the IRIS trial met strict criteria (including exclusion for HF) and were enrolled on the basis of standardized insulin assays. Patients had little neurologic impairments and the response to pioglitazone may be different among those with substantial deficits,” he wrote.
However, Semenkovich considers pioglitazone a “potentially important therapy for the secondary prevention of vascular events in appropriately selected patients with cerebrovascular disease.” The results of this trial “should stimulate the search for precision-medicine approaches to vascular disease,” he wrote. – by Tracey Romero
References:
Kernan W. LB 1. Presented at: International Stroke Conference; Feb. 16-19, 2016; Los Angeles.
Kernan WN, et al. New Engl J Med. 2016;doi:10.1056/NEJMoa1506930.
Semenkovich C. New Engl J Med. 2016;doi:10.1056/NEJMe1600962.
D isclosures: The trial was funded by the U.S. National Institutes of Neurological Disorders and Stroke. Kernan reports receiving no relevant financial disclosures. Semenkovich reports receiving grant support and personal fees from Merck, and personal fees from Ono pharmaceutical (Japan) and Sanofi/Regeneron outside the submitted work. In addition, he reports patents related to the use of chloroquine to treat metabolic syndrome and the use of an endogenous ligand for PPAR alpha to treat liver disorders.
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The IRIS trial evaluated the effect of double blind treatment with pioglitazone in 3,876 subjects with insulin resistance, but not diabetes (based on 2005 criteria), who had an ischemic stroke or TIA within the prior 6 months. Using current criteria, diabetes was present in 6% of subjects in the pioglitazone group and 6.7% in the placebo group. Insulin resistance was based on the HOMA-IR index, which requires measurement of plasma insulin level, which is not standardized. With these caveats, treatment with pioglitazone resulted in a 24% reduction in stroke or MI and a 52% reduction in diabetes over 5 years. This came at a cost of a higher rate of serious bone fractures, greater weight gain and higher rates of edema. Of 100 treated patients, three fewer would be expected to have a stroke or MI, but two more would have a bone fracture requiring surgery or hospitalization over 5 years. More than one-third of the strokes that occurred were severe (NIH Stroke Scale score greater than 4 points).
In addition to standardizing the assessment of insulin resistance, translating the results into clinical practice will require very careful patient monitoring and discussion with patients and individual consideration related to the tradeoff between benefits in reducing stroke and MI and complications associated with treatment.
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This is an important study because we now have another potential treatment for recurrent stroke prevention. This is a study that tested pioglitazone, a drug usually used in patients with diabetes. However, the patients in IRIS had insulin resistance. With prolonged use of the drug, it was shown that there was about a 24% relative reduction in recurrent stroke and MI, and an absolute risk reduction of about 3%. The results are substantial, considering that recurrent stroke prevention patients are being treated with a host of other recurrent stroke prevention medications. However, adverse events like weight gain and bone fractures have to be considered. Patients with osteoporosis and susceptibility to bone fractures will need to have a very detailed discussion about risks before consideration of going forward with this treatment. Unless bone health can be assured, risk for bone fracture could become a barrier to administration of this drug for recurrent stroke prevention.
A unique feature of the study was application of the HOMA-IR index for screening of insulin resistance. Clinicians may not be familiar with this index and another challenge may be that it is not currently readily available in many outpatient clinics and hospitals. Therefore, hospitals may need to adapt to a new practice, as may clinicians. We generally like to see replication of clinical trial results to make sure that we are dealing with valid findings. In relation to this well-done trial, another large-scale study is unlikely, based on cost.
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Pioglitazone administration to insulin-resistant nondiabetic patients after stroke has just been shown in the IRIS trial to be associated with reduction in stroke and in myocardial infarction. Why does this matter to those of us concerned with the treatment of diabetes?
Let’s start by recalling the findings of the PROACTIVE trial among diabetic patients (Dormandy JA, et al. Lancet. 2005;366:1279-1289). By focusing on patients with underlying cardiovascular disease, antiatherosclerotic effects of the thiazolidinediones become more prominent, and in this study the secondary combined endpoint of all-cause mortality, nonfatal MI and stroke was significantly decreased by 16% — quite similar to the 18% reduction in MI and stroke in IRIS. More importantly, and more comparable to the enrollment criteria of IRIS, among the 984 persons enrolled in PROACTIVE with prior stroke, there was a 47% reduction in recurrent stroke, and the same secondary combined endpoint was decreased by 28% (Wilcox R, et al. Stroke. 2007;38:865-873). Looking at an important manifestation of coronary atherosclerosis, a meta-analysis of seven randomized controlled trials involving 608 persons following percutaneous coronary intervention showed that the use of either rosiglitazone or pioglitazone was associated with more than a 50% reduction in need for repeat target vessel revascularization; similarly to IRIS, this risk was reduced among individuals with and without diabetes (Riche DM, et al. Diabetes Care. 2007;30:384-388).
Perhaps, then, we’ve erred overly in moving away from the use of the thiazolidinediones. Yes, IRIS showed the expected side effects: weight gain, edema and more frequent fracture, and the enrolled patients were carefully screened for risk of heart failure — and this is certainly important in considering the use of these agents today. But atherosclerosis remains a major cause of adverse outcome in diabetes. IRIS reminds us that the thiazolidinediones may be extremely important agents in avoiding these complications.
Perhaps (although this has not been definitely shown) the use of lower doses may be safer while preserving benefit. In appropriate persons who have existing CVD, then, part of our therapeutic approach may be to reconsider these agents.