Cardioprotective Potential and Anti-Diabetes Medications

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The MD Magazine Peer Exchange "Improving Management of Type 2 Diabetes Mellitus" features a panel of physician experts discussing current best practices to treating and managing patients with T2DM that generally includes lifestyle modifications as well as medication. The mechanisms of action, patient selection criteria, and side effects for various oral medication classes are included in the discussion.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and an associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

The panelists are:

• Robert Busch, MD, director of clinical research in the Community Endocrine Group at Albany Medical Faculty Practice in Albany, NY
• Ralph DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center in San Antonio, TX
• Pamela Kushner, MD, clinical professor at UC Irvine Medical Center and director of Kushner Wellness at UC Irvine Medical Center in Los Alamitos, CA
• Jeffrey Miller, MD, professor of medicine and clinical director of the Division of Endocrinology and Diabetes at Jefferson Medical School in Philadelphia, PA

Peter L. Salgo, MD: At the risk of opening a Pandora’s Box of a 5-hour lecture, we can’t have time for that, what I’d like you to do is give me some of the current evidence regarding the potential for anti-diabetes medications that are in the pipeline or they’re relatively new to many practitioners, particularly the DPP4s and the SGLT2 inhibitors, specifically to be cardioprotective. What do we know about that?

Ralph DeFronzo, MD: If we go back to the UKPDS (United Kingdom Prospective Diabetes Study)—we have metformin in obese people, 342 people—there was a decrease in cardiovascular events. There’s been no follow-up study, and by today’s standards no one would accept this as a valid cardiovascular intervention trial. We have the PROactive study, which I personally think was a positive study—5238 patients in Europe, secondary prevention—showing a 16% decrease in the MACE endpoint, a very dramatic decrease in stroke which led the National Institutes of Health (NIH) to just complete a study in people who had had a recent stroke or TIA (transient ischemic attack).

Peter L. Salgo, MD: And, again, which drugs are these now?

Ralph DeFronzo, MD: Pioglitazone. There was a 27% decrease in stroke, according to a study done by the NIH by Dr. Inzucchi at Yale. I think that the evidence is that pioglitazone decreases cardiovascular events. We now have the SGLT2 inhibitor story with the EMPA-REG OUTCOME. It’s one in the class. I suspect it will turn out to be a class effect, but, right now, if I had someone who had a MI, stroke, or whatever, I’d go by evidence-based medicine that says they should be on empagliflozin. We’ll see this year at the ADA what the LEADER study shows. I said there would be about a 15% to 20% decrease. It would be significant and it would be across the board, a small decrease in MI, stroke, and cardiovascular mortality. I don’t know that is true, we’ll see. But, at least Novo Nordisk has come out and said it’s positive.

So, we have another class of drugs, the GLP-1s, for which there’s evidence. We now have some evidence of at least three classes, and you can put metformin it, you can put pioglitazone in it, you can put SGLT2, GLP-1. And, quite frankly, those would be the four classes from which I would be picking my combinations, and probably all of us have our own niche for the combination. But we probably all like to use one or more of those drugs in our patients, getting rid of the expense issue because that’s always...Patients can’t afford a medication, they’re basically on no medication.

Jeffrey Miller, MD: What do you think about bladder cancer with pioglitazone?

Ralph DeFronzo, MD: I think the issue of bladder cancer now has been put to rest. So, we have this 10-year study from Kaiser Permanente Northwest, no increase in hazard ratio for bladder cancer. And then about 3 months ago in Lancet Endocrinology Diabetes, for 1.1 million people—six different countries where there’s a national database—the hazard ratio for bladder cancer with rosiglitazone was, 1.00, and for pioglitazone, 1.01. So, to me, I think the evidence is pretty clear that even though in the United States the lawyers have crucified pioglitazone because of bladder cancer, it doesn’t cause bladder cancer. And this is, I think, a very important drug. If you don’t go above 15 to30 mg, you minimize the side effects and you get very good efficacy.

Pamela Kushner, MD: And I’ve had clinicians actually ask me, ‘Can I use a TZD with an SGLT2 because of this bladder cancer warning on some of the medications?’ And I say, ‘Fine, of course you can,’ and it’s a beautiful combination.

Ralph DeFronzo, MD: Absolutely. In fact, I’ve been encouraging the pharmaceutical companies that this is an important niche. Pioglitazone has gone generic. It’s now cheap, so I think we’ll start to see more use of it.

Jeffrey Miller, MD: I think we need to expand that we don’t give the audience the wrong information. I think you were referring, Dr. Kushner, to dapagliflozin and then pioglitazone. So, I think we need to say that the dapagliflozin data was specific for dapagliflozin, and there’s a big question mark. The pioglitazone appeared to be something more but now it has been put to rest. I think combo is probably not an issue.

Pamela Kushner, MD: Thank you, Jeff. I appreciate that clarification, and to go further back on that, I actually appreciate the fact that that drug was delayed getting to market because the FDA did an extensive review and it was not showing causality. So, we don’t want to leave negative impression of an SGLT2 that should not be there.

Ralph DeFronzo, MD: I want to emphasize this even further because I don’t want the audience going away with a misconception. What was the story with dapagliflozin? There were 10 cases of bladder cancer, one in the dapagliflozin group, one in the placebo group. But the randomization was 2:1, so it’s basically four-and-a-half cases of bladder cancer versus one. There’s no way you can do statistics on this. The majority of the patients, I think 8 or 9, had hematuria coming into the study. They should have never been in the study. And virtually all but one or maybe two of the patients developed the bladder cancer within the first year. If you take the most bladder cancer-toxic drug in the world—which is cyclophosphamide—it takes at least 7 years to see bladder cancer. And we now have a large experience in the United States, a large experience in Europe, and a signal for bladder cancer has not come up. It doesn’t mean that we should not be cognizant of this but I think that for now, the evidence does not support that this drug causes bladder cancer. And, most importantly, there’s no SGLT2 gene expression or receptor in the bladder, so how does it get there, how would it cause the problem? I feel comfortable using any of the three SGLT2 inhibitors. I think they’re all very, very good drugs and, in my opinion, really quite similar in their efficacy.

Pamela Kushner, MD: I would agree with you.

Peter L. Salgo, MD: So, now we come to the bottom line. We have all this data. We have all the cardiovascular risk data, the risk data that we’ve been addressing about bladder cancer. How does this data influence your treatment decisions? What drugs do you use knowing all of this?

Robert Busch, MD: Walking in the exam room with a patient and all-comers, they could take the medication. They don’t have heart failure, so they could be on a glitazone. They don’t have GFR (glomerular filtration rate) below 45, so they could be on an SGLT2. Their creatinine is okay, so they can be on metformin. And they don’t have pancreatitis in the past or medullary carcinoma of the thyroid, so they could be on a GLP-1. We have a tantalizing array of great drugs, no hypoglycemia with the cardiovascular benefits of, in the EMPA-REG study, a class effect. The benefits Dr. DeFronzo re-mentioned about pioglitazone in terms of the IRIS study that just came out, the offsetting of the ill effect of the weight gain or the edema by using the SGLT2 with a TZD. We have lots of great choices without hypoglycemia and with cardiac benefit. So, it’s pure pleasure to practice diabetes now. Yet, sulfonylurea is still the number 2 drug prescribed for diabetes after metformin despite all that.

Jeffrey Miller, MD: There’s one other medication, Dr. DeFronzo, you didn’t list on your CV protective list, and that is bromocriptine. You want to comment on it?

Ralph DeFronzo, MD: So, I actually was involved with Anthony Cincotta in the development of this drug. In early studies, we showed that it actually worked probably by improving insulin sensitivity in muscle, in liver. But the reductions in A1C really were modest. With an A1C of 8.6 or so, there was about a .5 or .6. I think myself and probably all of us here weren’t so excited about the glycemic control and then boom, here comes this 1-year study in which there’s like a 50% reduction in cardiovascular events. I don’t really understand from the mechanistic standpoint how bromocriptine would do this. We’re actually doing some studies to look at this now. I have to say I’m a little bit sort of shaken by the results. I honestly don’t know where to put bromocriptine. I personally don’t use much of it. I use the drugs that Dr. Busch uses, which are the low-dose TZDs, GLP-1 drugs with metformin, and the SGLT2 inhibitors. I think we really need another study with bromocriptine. You need to remember that this was more of a safety study. It wasn’t really designed with the approval of the FDA to get an approval for cardiovascular protection. So, we’re sort of in limbo.

Jeffrey Miller, MD: I think the issues are cost, number of tablets, and tolerability, side effects.

Ralph DeFronzo, MD: Yes, exactly. So, if you’re going to use it, one of the things is that when we put the package insert together, but the FDA wouldn’t allow it; it was very clear that about one-third of the patients absolutely do not respond, and you can see this by no change in the A1C at 3 months. If you’re going to use bromocriptine—and I know endocrinologists who do use it—if you will repeat the A1C at 3 months and there’s no benefit, you should stop the drug. That’s very clear even though it’s not in the package insert.