New treatment paradigm should encompass cardiovascular outcomes: A discussion with Dr. Ismail-Beigi

Background:
Cardiovascular disease (CVD) is the principal cause of death in people with type 2 diabetes. Indeed, adults with diabetes are two to four times more likely to die from heart disease than adults without diabetes, according to the American Heart Association. Consequently, several major trials in the past decades—including UKPDS, VADT, ACCORD, and ADVANCE—investigated whether intensive blood glucose control could reduce cardiovascular events in patients with type 2 diabetes who had cardiovascular risk factors or established CVD.

“In aggregate, these trials enrolled nearly 27,000 patients with type 2 diabetes,” said Faramarz Ismail-Beigi, MD, PhD, one of the investigators in the ACCORD study. “At the end of the trials, none of them showed that strict glucose control made any difference in preventing cardiovascular disease—and in fact, in ACCORD, we found that there was an increase in cardiovascular deaths.”

In late 2008—based on questions raised about the cardiovascular safety of glucose-lowering rosiglitazone—the US Food and Drug Administration (FDA) issued a recommendation that all new drugs for type 2 diabetes should not have an “unacceptable increase in cardiovascular risk.”

Since that FDA guidance, and in the past two years in particular, several studies have reported results of newer medications—empagliflozin, pioglitazone, liraglutide, and semaglutide—that not only lower blood glucose but also show decreased cardiovascular-related mortality. However, current management guidelines have yet to catch up, Dr. Ismail-Beigi noted.

In light of these newer drugs that show improved cardiovascular outcomes, a recent paper by Dr. Ismail-Beigi and colleagues in the Journal of General Internal Medicine calls for a “paradigm shift” in the medical management of patients with type 2 diabetes. In this interview, Dr. Ismail-Beigi explains why a new paradigm is needed, what type of treatment is involved, and how it may result in better outcomes for patients with T2DM.

MDLinx: What do you mean by “paradigm shift” and what is it that you’re calling for?

Dr. Ismail-Beigi: If you look at all the treatment guidelines for type 2 diabetes—from the American Diabetes Association, from Canada, from Europe, from the Far East—the main topic of these guidelines is controlling HbA1c. By “paradigm shift,” we mean that we should pay attention and approve drugs that not only decrease the blood sugar but also decrease cardiovascular events and, hopefully, renal events.

MDLinx: Would that mean updating the recommended treatment guidelines?

Dr. Ismail-Beigi: Well, I think so. In the conclusion of our paper, we say that regulatory agencies as well as organizations that write guidelines should really reconsider whether these agents that improve clinical outcomes should be an additional treatment for patients with type 2 diabetes and cardiovascular disease.

MDLinx: To support this idea for a paradigm shift, your paper cites four trials—EMPA-REG, IRIS, LEADER, and SUSTAIN-6—as evidence of these improved clinical outcomes.

Dr. Ismail-Beigi: An SGLT-2 inhibitor was used in the first of those studies, pioglitazone in the IRIS study, and GLP-1 receptor agonists in the last two studies. In addition to those four trials that we reviewed, a new study called CANVAS was reported a few weeks ago at the meeting of the American Diabetes Association. That study showed that an SGLT-2 inhibitor, canagliflozin, decreased the risk of cardiovascular events, and it also had some positive renal effects. But about a third of the people did not have known cardiovascular disease. So for the first time, we see this class of drugs being given to patients who don’t have a history of heart attacks or strokes.

Also, there was another paper that came out a few weeks ago, the CVD-REAL study. This was an observational study with a huge population—309,000 patients—written by one of the authors of our paper, Dr. Mikhail Kosiborod and coworkers. Half of the patients were given an SGLT-2 inhibitor and half of them were given another glucose-lowering medication for comparison. The important thing is that only 13% had established cardiovascular disease, and yet there was about a 40% decrease in heart failure and a 51% decrease in all-cause mortality—just amazing results.

MDLinx: So, should these newer agents be given to all T2DM patients, or only to those with CVD?

Dr. Ismail-Beigi: At the moment, the evidence of the randomized trials indicates this treatment is for patients with type 2 diabetes who already have cardiovascular disease. Now, the CVD-REAL study is very strong evidence that these medicines could be given across the board, but it’s not a randomized trial. It doesn’t appear that the evidence for that is really strong enough yet. But for patients with type 2 diabetes and CVD, we should be thinking about giving these agents in addition to insulin, as well as giving these agents earlier and more frequently if we can.

It’s very important that we begin to think about how we should use these drugs so that our aim is not just to decrease blood glucose levels but also to see if we can actually reduce complications at the same time. This doesn’t mean that we stop treating high blood glucose—I’m not suggesting anything like that. We’ll still treat the patient’s total problems (including lifestyle changes, hypertension, dyslipidemia, and smoking cessation), but we can use these drugs that give you all these extra benefits. They’re going to be expensive, but I think there are very effective.

MDLinx: Are there any more of these drugs in the pipeline?

Dr. Ismail-Beigi: Yes, there are more GLP1-receptor agonists and more SGLT-2 inhibitors being developed. But, I’ll tell you what’s really missing are drugs like pioglitazone or rosiglitazone, for example. We were using these some years ago but they have fallen by the wayside because they have some side effects that we don’t like. But of all of the medications we have, those were the only two that specifically target insulin resistance, which is probably the underlying problem in all of this.

An interesting thing about the IRIS study was that it used pioglitazone in people who didn’t have diabetes but who’d had a stroke as evidence of a cardiovascular disease. And in these people, the incidence of new cardiovascular events was markedly lower, and of course it also prevented the development of type 2 diabetes. But that study was very important because it showed that if you attack the insulin resistance, you get benefits, and right now we don’t have many good medications that do that. But pioglitazone and rosiglitazone have side effects. Patients gained weight and nobody likes that.

MDLinx: So, you’d like a drug like pioglitazone but without the side effects?

Dr. Ismail-Beigi: Perfect. It would be my number one drug, absolutely. I’ll mix it up with metformin and take it twice a day. [laughs] That’s because I think the underlying pathophysiology in T2DM is insulin resistance—or what we call “insulin resistance.” In other words, the person doesn’t respond adequately to insulin, and they probably have endothelial cell problems, which also gives them atherosclerosis.

MDLinx: If the new paradigm you’re calling for does happen, what would be the result?

Dr. Ismail-Beigi: For one thing, if these newer and additive drugs work well, it may mean that we will use insulin later in the course of the disease rather than sooner. That is, if we can control the glucose and reduce cardiovascular events, we would not need to use insulin so soon. Because the safety margin is very low with insulin, the later we use it, the safer it will be for patients with type 2 diabetes.

Five years from now, under the new paradigm, we may use insulin much later in the disease when there’s not enough beta-cell function left, which would then reduce complications. Our biggest complication with insulin is hypoglycemic events, which lands people in the emergency room all the time and it’s a terrible thing to happen. So, with these newer drugs, it will also mean a longer and healthier life for these patients.

About Dr. Ismail-Beigi: Faramarz Ismail-Beigi, MD, PhD, is a professor of medicine at Case Western Reserve University and an endocrinologist at University Hospitals of Cleveland and Louis Stokes Cleveland VA Medical Center, in Cleveland, OH.

His article in the Journal of General Internal Medicine was not supported by any company.