How EMPA-REG Has Changed My Practice

Today I am going to discuss the results of the EMPA-REG trial.^[1] More importantly, I am going to talk about how they have changed my clinical practice. Just to review, for those of you who don't know the results or remember them, the EMPA-REG trial was one of the many cardiovascular outcomes trials that we did with new diabetes drugs. This particular cardiovascular outcomes trial compared the sodium glucose cotransporter 2 (SGLT2) inhibitor known as empagliflozin with placebo in patients with established cardiovascular disease. It was a big multicenter trial, and the results were released in Stockholm at the European Association for the Study of Diabetes meeting.

I can tell you that I have been in the audience at many diabetes meetings, and people are usually relatively unimpressed. When the results from EMPA-REG came up on the screen, not only did 5000 diabetologists gasp, we also cheered and applauded. Why was that? It was because this is the first time that we've had a diabetes drug that reduces the relative risk for both cardiovascular and all-cause mortality. This was staggering news to us because we have been plodding along, keeping glycated hemoglobin levels under control, and preventing microvascular complications from diabetes, but our patients remained at high risk for macrovascular disease.

In this study, empagliflozin showed a 38% relative risk reduction in cardiovascular mortality and a 32% risk reduction in all-cause mortality, largely driven by the reduction in cardiovascular mortality. This was very statistically significant and occurred in patients who already had cardiovascular disease and who were actually pretty well risk-modified. They were on statins, they were on angiotensin-converting enzyme inhibitors, and they were on aspirin. This was layered on top of all of those treatments that we already know, and it improved outcomes. It looks a lot like some of the statin trials in terms of reducing cardiovascular risk and mortality.

This was big news to me, and it caused a number of changes in how I look at treating diabetes. First of all, I have been an early adopter of SGLT2 inhibitors because I felt that they were quite effective on a number of levels. They lower glucose, they help with blood pressure, and they help patients lower weight. I have found them to be good adjuncts. Initially, I started using them as fourth-line therapy, and then I moved them up to third-line therapy. Lately, I have been using them as second-line therapy after metformin, or maybe third-line. They have moved up in my own personal algorithm of treatment. With the EMPA-REG trial, I am really convinced that there are additional benefits in addition to just lowering glucose.

Now, you may want to ask a very important question: Is this a class effect? The study made me feel confident in general that SGLT2 inhibitors are good drugs and that they are safe. In terms of the class effect, I'd love to believe that this is a class effect, but I can't know that until I have data from some of the other cardiovascular outcomes trials, which won't be available for another couple of years. For now, what I know is that empagliflozin produced this reduction in mortality, so empagliflozin is the one that I know can cause these benefits.

Clinically, if I am starting a patient who has established cardiovascular disease on an SGLT2 inhibitor, I put them on empagliflozin. That is what makes sense. That's what I know from this study, and that is what I do. If I have patients who are already stable on another SGLT2 inhibitor, I am not going to switch them. I think that if you are doing well, you probably don't want to mess with success. I just keep following them with what they are on. It is the higher-risk patients, the ones who look like the patients in this trial, who I think would benefit from starting empagliflozin, based on what we currently know. Again, this has made me feel more comfortable using these agents because I see the benefits.

There are still concerns; all drugs have side effects. In the EMPA-REG trial, stroke risk went the wrong way; it increased slightly. It wasn't statistically significant, but it went a little bit to the right on the forest plot, which means that there was a slight concern about stroke. This worried me a little because blood pressures went down in patients treated with empagliflozin, so you would expect stroke to go down as well. This is something that needs to be further explored, as do all of the mechanisms to this benefit. Many researchers are now working on some of these questions. I think this means that we can be very comfortable using this class of drugs, specifically empagliflozin, in patients with established cardiovascular disease.

Ironically, with most other medications, I will give them to a patient and say, "We'll know that it is working because your blood pressure will go down or because your blood sugar will go down." When I give them empagliflozin, I am very excited because of the benefits, and I say, "I am going to give you potentially longer life." They say, "How will I know?" And I say, "I have no idea, but the benefit is that it can reduce your risk for cardiovascular death."

In my heart, I know that I am finally using a diabetes drug that both reduces the risk for diabetes complications by lowering blood sugar and also potentially reduces the risk for cardiovascular mortality in my high-risk patients with type 2 diabetes. I couldn't be happier that I have this tool.

I think that it is very important to further explore this, but for now, the EMPA-REG trial was a great triumph for a diabetes drug. I am glad we have it to use for treating our patients.

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