In A First, A Diabetes Drug Saves Lives. But How?

Jardiance, a pill made by Boerhinger Ingelheim and Eli Lilly , is the first diabetes pill ever shown to prevent patients from dying of heart disease. It is a breakthrough result.

It’s also a big shock.

Jardiance’s benefit seems to have little to do with the medicine’s ability to lower blood sugar and treat diabetes, researchers say. Instead, Jardiance had a surprise result of reducing hospitalization for heart failure, when the heart becomes so weak that it cannot pump enough blood.

“It’s not because of hemoglobin A1C,” says Bernard Zinman, the University of Toronto endocrinologist who led the study, referencing the lab test used to measure high blood sugar. “I believe that the major effect is in the context of heart failure.”

8.3% of the 2,333 patients who received a placebo in the study died, compared to 5.7% of the 4,687 patients who got either of two doses of Jardiance. If we look at that as the rate of deaths per 1,000 patients per year, it drops 35% to 19.4 deaths per 1,000.

Patients who got Jardiance didn’t have fewer heart attacks, and there was a 24% increase in the risk of stroke – two more strokes per 1,000 patients per year. But the number of heart failure hospitalizations dropped 35% to 9.4 per 1,000 patients per year.

“This is an advance to be applauded, explored and hopefully replicated,” said James Stein, director of preventative cardiology at the University of Wisconsin’s medical school.

It’s also a result to be puzzled over and pondered. For years cardiologists have fretted that diabetes drugs, which lower high blood sugar levels, don’t seem to prevent heart attacks and strokes. They should, because high blood sugar levels damage blood vessels. Instead, concerns were raised that some diabetes medicines might increase rates of heart attack and stroke. That resulted in the Food and Drug Administration requiring that companies conduct studies like this one to test whether their medicines harmed the heart.

Steven Nissen of the Cleveland Clinic, who first proposed these studies, says that he always hoped that some of these medicines would prove to be helpful. “How many drugs have you covered in cardiovascular medicine over all these years that you have been covering medicine have produced that magnitude in benefit on death?” he said to me. “Unprecedented. Although there are some warts here I think mortality trumps everything.”

But nobody expected this result, least of all Boerhinger and Lilly. And the fact that the reason has to do with heart failure, not diabetes, complicates things further.

At first glance, admits Sanjay Kaul of Cedars Sinai Medical Center, the results are “too good to be true.” But there are several things that make it difficult to discount that Jardiance saved lives here, he says. The benefit was in death, which is sadly easy to measure. It was highly statistically significant. Most of all, the benefit occurred at two different doses of the drug, although it didn’t matter whether patients got the higher dose or the lower one. Kaul would still like to see another study, with Farxiga or another drug, replicate the result.

Jardiance has effects other than lowering blood sugar. It lowers blood pressure, and seemed to reduce waist circumference. It’s also possible that the older drugs given to diabetics had side effects that made the placebo do worse. Some information could come from the studies of related medicines, known as SGLT2 inibitors, including Johnson & Johnson’s Invokana and AstraZeneca’s Farxiga. But differences in the precise enzymes these drugs affect mean they may not all have the same effects. Right now, Lilly and Boehringer don’t yet have plans to further study Jardiance’s effect on heart failure.

Even with all the mystery, many doctors are likely to take the same stance as Robert Harrington, the chair of the department of medicine at Stanford. He says the stroke numbers are “worth watching” but that the benefits on cardiovascular death “trump” everything else. That could be good news for patients, good news for Lilly and Boehringer, and bad news for rival drug firms like Merck . But it will also leave many doctors prescribing a drug for its big benefit while wishing they had more proof – or knew exactly what the medicine is doing.

The fact that the study had been positive had already been revealed in a press release by the companies. The Jardiance results are published in the New England Journal of Medicine and are being presented at the annual meeting of the European Association for the Study of Diabetes in Stockholm, Sweden.

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