PracticeUpdate: Cardiology - Winter 2018

EXPERT OPINION 17

Clinically Relevant Data on Pioglitazone and CV Risk Reduction Interview with Silvio E. Inzucchi MD

these covariates together, we could explain about 50% of the benefit, but still, the major- ity of the benefit remains undisclosed. There was also a significantly reduced risk of progression to type 2 diabetes in the PPAR-gamma agonist-treated group. Can you shed any light on the possible mechanism or mechanisms behind this risk reduction? Well, here, I think, the data are more clear. Again, this is an insulin-sensitizing drug, and it’s been demonstrated in previous trials to reduce the progression from pre- diabetes to diabetes. So, in IRIS, we show that in this resistant cohort of patients there was greater than a 50% reduction in the progression to diabetes. Most of the benefit actually occurred in those patients that already had pre-diabetes. So the sense here is that by reducing insulin resistance, off-loading the beta cell, you will lead to less diabetes over time. Can the results of this trial be generalized to any PPAR-gamma agonist or just pioglitazone for those clinicians looking to prescribe a medication to patients with recent TIA or ischemic stroke? So pioglitazone, first of all, is not mar- keted in the United States for either insulin resistance or pre-diabetes. It’s only on the market for patients with diabetes, so this was really an exploratory investigation. The question is can it be extrapolated to other TZDs? First of all, pioglitazone is the only TZD in the United States that’s widely prescribed. Rosiglitazone had some con- troversy a number of years ago, and while it’s still available, is essentially rarely pre- scribed. I will say that when investigators have looked at the comparative benefits between pioglitazone and rosiglitazone, pioglitazone always seems to have some advantage over rosiglitazone, whether it’s based on cardiovascular risk in diabetes patients or on lipid parameters. So, I would say that we cannot extrapolate to any TZD.

The IRIS Trial provided evidence that using a PPAR-gamma agonist in patients with insulin resistance and a recent TIA or ischemic stroke would lower risk of a subsequent second stroke or MI. Can you briefly summarize the implications of these initial results? Well, this is a study looking at pioglita- zone, which is a thiazolidinedione, and our notion was to use this drug before patients develop diabetes because we were convinced that this drug had anti-ath- erosclerotic effects. So we recruited nearly 4000 patients with recent TIA or stroke, randomized them to pioglitazone or pla- cebo, and followed them for about 4 or 5 years, and what we found was a 24% risk reduction in future MI or stroke. I think the study confirms what we thought all along, that pioglitazone, the thiazolidinedione has potent anti-atherosclerotic effects. The benefits of using a PPAR-gamma agonist in this trial were clear, but the mechanism for the risk reduction of a vascular event was unclear. Has there been any progress toward determining the pathophysiology behind the reduced risk? Pioglitazone, a thiazolidinedione, is an insulin-sensitizing drug, and it has protean effects on multiple cardiovascular risk factors. Obviously, insulin resistance will improve; glucose levels drop a few points, as does blood pressure. There are benefi- cial effects on certain lipid parameters and CRP levels – a marker of inflammation also is reduced. It’s still not clear exactly which of those mechanisms actually translates to cardiovascular benefits. At this meeting, we presented a mediation analysis where we tried to determine which of the individual risk factor benefits from pioglitazone actually mediated the effect, and we couldn’t find a single change in any of these covariates that translated to the benefit. HDL cholesterol increases by a few points, and that seemed to mediate about 25% of the risk reduction, and there were minor contributions from blood pres- sure and triglycerides, glucose, as well as CRP. And as a composite when we put all of

Dr. Inzucchi is Professor of Medicine at the Yale University School of Medicine in New Haven, Connecticut, where he serves as the Clinical Chief of the Section of Endocrinology, Program Director of the Endocrinology and Metabolism Fellowship, and the Medical Director of the Yale Diabetes Center.

" There are beneficial effects on certain lipid parameters and CRP levels – a marker of inflammation also is reduced. It’s still not clear exactly which of those mechanisms actually translates to cardiovascular benefits. "

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VOL. 3 • NO. 3 • 2018