Silvio Inzucchi, MD; Mark Harmel, MPH


May 11, 2016

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Last year, I was talking about "the search for the holy grail," the quest that diabetologists have been on for several decades to find a glucose-lowering strategy that would actually reduce cardiovascular events in patients with diabetes. As many of you know, glucose control by itself has a modest effect on cardiovascular events. Perhaps metformin from the pre-statin era has an effect on lowering the risk for myocardial infarction, but those data are far from robust. Year after year, we've seen multiple diabetes and cardiovascular outcome trials prove to be negative.

But last year, we reported the results of the EMPA-REG OUTCOME trial.[1] This is the first cardiovascular outcome trial involving a sodium glucose cotransporter 2 (SGLT2) inhibitor, and the one that we tested was empagliflozin. For the first time in a large cardiovascular outcome trial in type 2 diabetes patients at high cardiovascular risk, we demonstrated an 18% reduction in three-point major adverse cardiovascular events (MACE). The most striking finding was that this was primarily driven by an impressive 38% reduction in cardiovascular mortality, something that has never been demonstrated in any diabetes trial. In addition, we also found a 35% reduction in heart failure hospitalizations, which is an increasingly important outcome in patients with type 2 diabetes who have cardiovascular disease.

The field is now looking at these data to try to determine the optimal use of SGLT2 inhibitors, particularly with regard to the so-called algorithms that many groups have published over the years that position metformin as drug number one and then a variety of choices for drug number 2 in patients who need combination therapy.[2,3] A question that cardiologists and endocrinologists are struggling with is whether data from EMPA-REG could inform future guidelines and perhaps position the SGLT2 inhibitors as a favorite agent, at least for patients who have prevalent cardiovascular disease.

There is more good news. Our group reported the results of the Insulin Resistance Intervention After Stroke (IRIS) trial.[4] In this study, we demonstrated that 5 years of the thiazolidinedione (TZD) pioglitazone resulted in a significant reduction in stroke and myocardial infarction, both fatal and nonfatal, in almost 4000 patients who had a previous stroke or transient ischemic attack (TIA).

In the IRIS study, we did not look at patients with type 2 diabetes. We were focused on those with insulin resistance as denoted by the Homeostasis Model Assessment (HOMA) equation. We recruited patients with stroke or TIA who were found to be insulin resistant, but if they had diabetes, they were excluded from the trial. This study is very important because it confirms the potential antiatherosclerotic effect of this specific TZD, pioglitazone. It is also the first trial that has demonstrated that any glucose-lowering strategy could actually have a beneficial effect in people with dysmetabolism who don't yet have diabetes.

It's still unclear whether the metabolic effects of pioglitazone—reducing glucose and improving insulin resistance—were actually the drivers of the risk reduction. As many of you know, pioglitazone has been demonstrated to have direct vascular effects on the blood vessel wall. So, we could be talking about 2 different mechanisms: one related to the drug itself and its effect on improving insulin resistance, as well as decreasing diabetes rates that we also found in IRIS.

Obviously, the drug class has a lot of baggage associated with it in terms of side effects: fracture rates, edema, weight gain, etc. This is another study that—even though it's not a diabetes study—I'm hoping will inform future guidelines.

We just learned about a month ago that the LEADER trial, which is a cardiovascular outcome trial testing the safety and efficacy of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide, showed a positive effect on three-point MACE. This was just a top-line result. The data will be presented in June in New Orleans at the American Diabetes Association's Scientific Sessions.

It's quite surprising and encouraging that, after this desert of cardiovascular outcome benefits in diabetes trials, we now, over the span of less than a year, have two impressively positive studies. For the third, we don't know exactly what the risk reduction will be. We hope to learn more in June.

At least three drugs—empagliflozin, pioglitazone, and liraglutide—have cardiovascular benefits, at least in a subset of patients at high cardiovascular risk. So have we found the Holy Grail? I'm not sure yet. I think we're much further than we were when I spoke to you last April from ENDO 2015.

Editor's note: After the taping of this video, top-line results were released of the SUSTAIN-6 trial indicating that another diabetes medication—semaglutide—may also confer cardiovascular benefits. Semaglutide (Novo Nordisk) is a once-weekly GLP-1 agonist that has not yet been approved for use anywhere. The full results of the trial are expected to be presented sometime later this year.


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