With commentary by senior study author Silvio Inzucchi, MD, professor of medicine and director of the Yale University Diabetes Center
That is important, since those with type 2 diabetes are at much higher risk of cardiovascular disease. About two of every three people with type 2 diabetes die of heart disease or stroke, the American Diabetes Association says.
In the new study, Jardiance helped prevent one in three cardiovascular-related deaths in patients with diabetes who had established heart disease, the researchers found. "We found that the risk for cardiovascular death was reduced by 38%, overall death [from any cause] by 32%, and hospitalization for heart failure by 35%,'' says Silvio Inzucchi, MD, professor of medicine and director of the Yale University Diabetes Center. He presented the findings at the meeting of the European Association for the Study of Diabetes (EASD) in Stockholm on September 17. The findings were also published Sept. 17 in the The New England Journal of Medicine.
"This is the first time that a diabetes drug has shown such a benefit in high-risk patients," Dr. Inzucchi says. "There were also no major safety signals [side effects] except for the known side effect of this class of increasing the risk of genital infections…''
Empagliflozin, or Jardiance, is in a class known as a SGLT-2, a sodium glucose cotransporter-2. It was FDA-approved in 2014. It can be given as a solo treatment or in combination with other diabetes drugs. Other drugs in the SGLT-2 class include Invokana (canagliflozin) and Farxiga (dapagliflozin), sometimes combined with other drugs. The SGLT-2 drugs lower blood sugar by causing the kidney to remove sugar from the body and excrete it in urine.
For the current study, the researchers assigned more than 7,000 patients with type 2 diabetes and a history of cardiovascular disease, such as a heart attack, to one of three groups. One group took 10 milligrams of the drug a day, another took 25 milligrams. A third group took a placebo pill daily.
The men and women were enrolled in the study from late 2010 through early 2013 and were followed for about three years.
The researchers looked at rates of non-fatal heart attacks, non-fatal strokes and death from cardiovascular disease as a combined outcome. The researchers did not find substantial differences between groups in the rate of non-fatal heart attack or non-fatal stroke, so the main ''driver'' of the risk reduction outcome was the reduction in death.
Funding for the study was from the drug's makers, Boehringer Ingelheim and Eli Lilly.
In May, 2015, the FDA issued a safety communication on SGLT-2 inhibitors, warning that they may lead to too much acid in the blood, a serious condition called ketoacidosis, which may require hospitalization. In the new study, one patient in the placebo group developed the condition, and four in the drug-treated groups did.
The study findings are called ''excellent news'' by Joel Zonszein, MD, director of the Clinical Diabetes Center at Montefiore Health System, the Bronx. He was not involved in the study but reviewed the findings.
It is, he says, ''the first drug for diabetes that demonstrates cardiovascular disease superiority—that is, a reduction in cardiovascular disease events." FDA draft guidance, issued in 2008, calls for new diabetes drugs to demonstrate cardiovascular safety. Other drugs, he says, have demonstrated neutrality—that is, they don't increase cardiovascular risk but nor do they decrease it.
The results were also noticed fairly quickly, Dr. Zonszein says. "Most of the studies we have with statins [and their effect on heart disease risks] show it takes about five years to see a significant change."
"We are still not sure about the mechanism," says Dr. Inzucchi of the new drug's actions. However, he adds that ''there are many theories. One thing we can say is that this is probably not mediated through glucose control alone."
"These are medications that work at the level of the kidney," Dr. Zonszein says. He calls it a water pill that causes loss of sugar, and that is part of the reason patients tend to lose excess weight on the drug, he says.
Cost is sometimes a barrier, both doctors agree. Jardiance is about $4,000 a year if no health insurance coverage is available. "Cost is always an important issue, and I have been concerned about the increasing prices of diabetes drugs for several years," Dr. Inzucchi says.
Some insurance companies are covering, says Dr. Zonszein, but the co-pays for patients may be higher for this than for some other drugs, he finds.
Dr. Zonszein reports serving on the speakers' bureau for Novo Nordisk and Takeda and is a consultant on an international level for Boehringer Ingelheim. Dr. Inzucchi reports consulting fees from Novo Nordisk and Intarcia and honoraria from other companies in such capacities and serving on the research program advisory board.