Examining Cardiovascular Outcomes Trials

John Anderson, MD: When I look at cardiovascular outcomes trials, I try to think, “OK, look at them individually,” as I said, “look at them scientifically.” The FDA approval process will proceed as it always does. What does this mean for my patients? Which patients do I need to get on these medications? Let’s talk about a patient with cardiovascular disease who comes in and their A1C is great, but they’ve got heart failure or they have significant cardiovascular disease: I should be considering an SGLT2 inhibitor.

Obviously, empagliflozin is the drug that’s approved right now in the United States for that. I should be thinking about trying to get my patient, assuming renal function is OK and they can tolerate the medication, on empagliflozin, because the cardiovascular risk reduction doesn’t have anything to do with hemoglobin A1C. It’s outside of A1C lowering, and the indication is outside of A1C lowering. So, I feel an obligation to get my patients on this. If you’ve got a bunch of patients in your practice with cardiovascular disease and type 2 diabetes, if you put them all on empagliflozin—just according to the clinical trial data—you have to treat 49 of them to save 1 life in 3 years. That’s not 10 years; that’s not 15 years. That means in the next 3 years, you saved at least 1 life. Say you’ve got 150 of those patients, that’s 3 people who are still walking around.

These drugs need to be available to our patients. We’ll see what indications we get as these other trials are submitted. We now have an indication for liraglutide. Should I be thinking about how I get my patient who has type 2 diabetes on liraglutide to lower their risk? If I put myself in the patient’s seat, and I’m a pretty sick guy and I’ve got a lot of cardiovascular disease and diabetes, I’m going to be asking my provider, “Why can’t I get on this?” So, we need to make sure that they’re available.

The other thing that’s going to be important to see is a trial called CAROLINA coming up that will hopefully report out maybe in 2018. It is for linagliptin, which is a DPP-4 inhibitor. We’ve all seen that they’re neutral. It’s going to be neutral, but it’s versus glimepiride, a sulfonylurea. What if, for the first time, we see that the sulfonylurea is associated with increased cardiovascular risk? Are you going to make my patient with type 2 diabetes fail the less expensive medicine that has worse outcomes before I can get the more expensive, newer medicine that actually has cardiovascular prevention?

Those are the questions I think people need to struggle with. And the other part that I like to say is when you talk about the cost of medications, we need to think beyond the cost of the medication at the pharmacy window. Yes, glimepiride is inexpensive. How much does it cost to have hypoglycemia and a hip fracture? Or, what about my patient who got hypoglycemia? They were given it from another provider, got lightheaded one night, fell, had intracerebral bleeding, and was in the hospital for 7 days because of an episode of hypoglycemia. There are costs to the adverse effect profiles of some of these agents. So, I think payers, managed care companies, need to think carefully about looking at global costs and what’s best for these patients as we move forward.

I think the real question is, what does the future look like in terms of how these cardiovascular outcomes trials affect decision making and how we treat patients? I think this is a huge paradigm shift. One of the questions we don’t have answered, and probably are never going to have answered, is, “OK, with these SGLT2 inhibitors that showed benefit, these GLP-1 receptor agonist that showed benefit, perhaps the future drugs that are going to show benefit as well—all in cardiovascular patients, all in patients rich with cardiovascular disease—what does that say about my selection for the 45-year-old who comes in my office, new to diabetes, who needs something other than metformin?” Because you are never going to show a primary benefit. Nobody is going to enroll in a trial for 20 years, then stay there long enough to see if primary prevention actually works. And, by the time you do that, all these manufacturers who would be spending that kind of money are going to be generic anyway. I think it’s a really important question.

I go back to what I like to think about beyond just glycemic lowering. If I’ve got an agent that seems to have some sort of renal protection with it in terms of the SGLT2 class, and we seem to find that it has a benefit and cardiovascular risk reduction in patients with cardiovascular disease, it lowers blood pressure, and it lowers weight, why would I not just take that little leap of faith to say this is probably going to give cardiovascular protection for all of my patients with type 2 diabetes? You’re never going to get that indication. You’re never going to see that written anywhere, because no one is going to do the trial. But most of us who have seen these results coming in are thinking that there are much better choices for our patients, regardless of whether they have cardiovascular disease or not. It’s why at the top of the ACE [American College of Endocrinology] algorithm after metformin, you get GLP-1 receptor agonists and SGLT2 inhibitors as your number 1 and 2 choices. There’s a reason for it.

The classic CV [cardiovascular] outcomes trials as a whole are wrapping up in the next 2 to 3 years, because, unless I’m wrong, we don’t have a brand-new class of medications coming in. You’ll have a couple of new SGLT2 inhibitors. They may do cardiovascular outcomes trials, but they may not, especially if everybody thinks it’s a class effect. The real question is that in 2008, the FDA insisted that all new drugs for diabetes prove cardiovascular safety based upon a failed meta-analysis by [Steven] Nissen out of Cleveland Clinic. It turned out he was absolutely wrong, just like we said he was absolutely wrong. And now, you’re going to continue to make companies bringing forward new agents do these studies? This goes back to the consumer. These are expensive trials to do. These are publicly traded companies. They have a responsibility to their shareholders, so what do you think this is doing to the cost of medications?

You haven’t seen one trial yet that showed glaring danger. Yes, in a DPP-4 inhibitor there was some slight increase in hospitalization for heart failure, and most of us are questioning if that is a real effect or not. Do we continue to insist that companies do this? Or, do we let companies make the business decision of doing it on their own? I would urge the FDA to knock it off. I would urge them to say, as we’ve wrapped this up over a 10- or 12-year period of time, that the amount of money and expense of chasing our tails with this should be done, that we should let companies decide if they want to spend the money on these, and that they should not be mandated by federal government.

Some of the trials I’d like to see going forward are already going on. For example, studies looking at empagliflozin or canagliflozin in heart failure, and that’s heart failure with preserved ejection fraction, with reduced ejection fraction, with diabetes, and without diabetes. How about renal outcomes, such as the CREDENCE trial with canagliflozin? Empagliflozin is doing renal outcomes trials in patients with chronic kidney disease. Are we going to see for the first time in the next couple of years that these agents are going to be the first in 25 years, since ACE inhibitors and ARBs [angiotensin II receptor blockers], to be shown to actually slow the progression of renal disease in patients with type 2 diabetes? These are the trials I want to see. Heart failure trials where that’s the primary outcome, renal protection trials where that’s the primary outcome—where we can actually get on our soapboxes and talk about it in very broad sense with the community that takes care of our patients.