'Incredibly Exciting': Diabetes Drug With CV Benefits

Hello. I'm Dr Anne Peters. Approximately 1 year ago I brought you news of the EMPA-REG trial.^[1] I was quite excited about the value of empagliflozin for reducing cardiovascular risk in patients with type 2 diabetes. Now, the US Food and Drug Administration finally agrees and has added a new indication for empagliflozin—to reduce cardiovascular death in patients with type 2 diabetes and known cardiovascular disease.^[2]

I believe this is the first cardiovascular indication for a diabetes drug. As I have said previously, I am quite excited that our diabetes drugs are having benefits for cardiovascular disease risk reduction.

This new indication was supported by data from the EMPA-REG trial. To review, EMPA-REG was a cardiovascular outcomes trial that compared empagliflozin with placebo in older patients with type 2 diabetes and existing cardiovascular disease. Empagliflozin is an SGLT-2 inhibitor, essentially a diuretic for glucose. These drugs increase glucose excretion in urine and thus lower blood glucose levels. As we have learned, empagliflozin also lowers the risk for subsequent cardiovascular events in people who have cardiovascular disease.

We are now convinced that these benefits are real.

In the EMPA-REG trial, 7020 patients were randomly assigned to one of three treatment arms: placebo; empagliflozin 10 mg; or empagliflozin 25 mg. They were then followed for three years. The investigators believed that the study would show that empagliflozin was safe for the heart, but it proved much more than this.

The study found a 38% reduction in cardiovascular disease mortality, a 32% reduction in overall mortality, and a 35% reduction in hospitalization for congestive heart failure in the patients who received empagliflozin. Those are huge benefits that began to be seen quite early on in the study, seemingly within a few months of patients starting the drug.

I do not know the true mechanism by which empagliflozin provides these cardiovascular benefits; many researchers are looking into this. But we are now convinced that these benefits are real, at least for empagliflozin. Studies are being conducted with other SGLT-2 inhibitors to see if the same is true with them.

Safety Considerations

All drugs have side effects. Empagliflozin is not indicated for patients with an estimated glomerular filtration rate (eGFR) below 45 mL/min/1.73 m², and in fact, some individuals have developed acute renal failure when started on empagliflozin. This is uncommon but does happen in those higher-risk patients who are more at risk for dehydration and may have more marginal renal function, even aside from diuretics.

For example, think of patients with an eGFR of around 55 mL/min/1.73 m²; they are taking diuretics, they may be older, they may be a little frail, they may be taking a nonsteroidal anti-inflammatory drug because their joints hurt. Those are the individuals with whom I am more cautious. In those individuals, I often will reduce the diuretic they are already taking, and perhaps use half of the lowest dose of empagliflozin when initiating the drug, to help patients become accustomed to the change in volume status and be sure they do well.

In the long term, patients on empagliflozin actually experience improvements in renal function. There is a reduction in the numbers of patients who develop significant renal disease, especially patients with preexisting proteinuria. Thus, we see a long-term benefit to using empagliflozin in patients with some degree of renal insufficiency. But one needs to be aware that initially, there can be some risk for acute renal failure.

In terms of other side effects, patients will urinate more often because this is a diuretic for glucose. There is also an increased risk for genital mycotic infections in both men and women. Patients need to be aware of this and be treated quickly should they develop any early signs or symptoms so that it does not progress into a more severe genital mycotic infection. I tell patients that this may happen, and in general, once forewarned, patients are actually able to get medical help quickly when they need it.

Dosing Strategy

In this trial, A1c reductions and cardiovascular outcomes were similar in patients who received the 25-mg dose and those who received the 10-mg dose. This leads me to believe that a 12.5-mg dose, or half of a 25-mg tablet, may be a good and potentially more cost-effective dose for some of our patients who cannot afford medications or have issues paying for their pills.

It is easier for patients to take a whole 10-mg tablet, but in settings where patients have to stretch their medication dollars, I have told them to split the 25-mg tablet and take it once a day. They seem to do well.

In summary, this new indication for empagliflozin is for cardiovascular disease risk reduction in our high-risk patients. It is incredibly exciting to have a diabetes drug that can provide this additional benefit.

I hope you will include this in your treatment of patients with type 2 diabetes, particularly those who have preexisting cardiovascular disease. Thank you.

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