Empagliflozin: A Transformative Approach to Diabetes?

By Thomas Crocker
Monday, May 1, 2017

A major trial demonstrated the glucose-lowering drug empagliflozin reduces cardiovascular morbidity and mortality in individuals with Type 2 diabetes and existing cardiovascular disease. Clinicians and researchers discuss how it does so and who is most likely to benefit.

Diabetes can as much as quadruple an adult’s risk of dying from heart attack, stroke or another form of cardiovascular disease, according to the American Heart Association. Cardiovascular disease is the leading cause of death for people with diabetes, and the medical community has long sought to reduce its effects on these patients — historically, without much success, according to Steven Nissen, MD, Chair of Cardiovascular Medicine at Cleveland Clinic.

“For a long, long time, there was a tremendous focus on lowering blood sugar,” Dr. Nissen says. “While it is certainly a good idea to lower blood sugar because it has effects on microvascular disease [associated with diabetes] — retinopathy, neuropathy, kidney disease — it turns out there is not a strong relationship between lowering blood sugar and a reduction in morbidity and mortality from macrovascular disease.”

The FDA-mandated EMPA-REG OUTCOME trial demonstrated that empagliflozin, one of a class of sodium-glucose cotransporter-2 inhibitors, was more effective than placebo in reducing cardiovascular-related complications and death in patients with Type 2 diabetes and established cardiovascular disease. More than 7,000 patients were randomized to receive empagliflozin or placebo once a day for about three years. Empagliflozin reduced cardiovascular death by 38 percent, and the study’s primary endpoint — death from cardiovascular causes, nonfatal heart attack or nonfatal stroke — by 14 percent. It also reduced hospital admissions for heart failure by 35 percent.

Empagliflozin is the first drug to lower glucose and improve cardiovascular outcomes, a breakthrough that earned it inclusion in Cleveland Clinic’s list of Top 10 Medical Innovations Most Likely to Be Game Changers for 2017.

“To have a drug that has this benefit of reducing both morbidity and mortality, particularly mortality ... is pretty impressive,” Dr. Nissen says. “Of all the things [clinicians] do for patients, living longer is the thing that’s first on people’s minds. Empagliflozin isn’t the first drug in this class, but it’s the first to show these benefits. There are three or four other drugs that work by the same mechanism that haven’t finished their trials yet. If it were the entire class that offered these benefits, that would be wonderful.”

Clear Mode of Action, Murky Mechanism of Benefit

Empagliflozin interferes with the kidneys’ reabsorption of glucose that they filter from the blood. The drug decreases glucose reabsorption by approximately 50 percent, which increases the amount of glucose that enters the urine, according to David M. Nathan, MD, Director of the Diabetes Center at Massachusetts General Hospital in Boston.

“This is essentially like putting a spigot for glucose in your kidney,” Dr. Nathan says. “You are kind of tapping off or draining off the glucose into the urine, which does have a modest effect on lowering blood glucose levels and long-term measures of glycemia, like the hemoglobin A1C assay. It’s like a diuretic for glucose, but when you put more glucose in the urine — and this happens in people with diabetes out of control — it draws with it water and electrolytes, like sodium and potassium, and so it depletes people of volume and some electrolytes.”

Why empagliflozin reduces cardiovascular disease morbidity and mortality is unclear. In the EMPA-REG OUTCOME trial, the drug did not reduce rates of nonfatal heart attack or nonfatal stroke, which led the researchers to conclude that the lower rate of cardiovascular death was responsible for the 14 percent reduction in the primary endpoint. According to one of the trial’s investigators, David Fitchett, MD, a cardiologist at St. Michael’s Hospital in Toronto and Associate Professor of Medicine at the University of Toronto, that factor, along with a decrease in cardiovascular disease mortality that the investigators observed within the first one to two months of the trial, likely means the mechanism of benefit is unrelated to a decrease in atherosclerosis.

“It is more likely that empagliflozin reduces cardiovascular mortality through the prevention of heart failure or its complications, either as a result of reduced loading or a metabolic process,” he says.

Pinpointing why the drug has a positive effect on cardiovascular morbidity and mortality, as well as investigating its potential efficacy in reducing risk of heart failure and complications of diabetes, such as nerve disease, are important avenues of exploration for the future, according to experts.

Limited Impact?

The FDA approved empagliflozin for Type 2 diabetes in 2014 and, last December, authorized its indication to reduce the risk of cardiovascular death for diabetes patients who have cardiovascular disease. Dr. Nathan says it is important for clinicians to remember empagliflozin has proved efficacious in a specific subset of diabetes patients.

“Based on the EMPA-REG OUTCOME trial and the previous studies that went along with it, empagliflozin hasn’t been shown to lower [cardiovascular] complications in most people with diabetes,” he says. “I would reserve this drug for people with Type 2 diabetes who have already had a heart attack or stroke and may need some extra lowering of their glucose because they’re not hitting their goals. That is the population the trial suggests will benefit.”