September 18, 2015

Cutting through the Jardiance Study Hype: Be Cautious with this Drug!

Today's diabetes news is focusing on a study, published in the New England Journal of Medicine where the press release states:
Results after a median follow-up of about three years illustrated that patients receiving Jardiance had a 14-percent lower rate of the primary composite outcome than did those in the placebo group. Specifically, the drug was associated with a significant 38-percent lower rate of death from CV causes, while no significant difference was noted in the risks of non-fatal heart attack or non-fatal stroke. Meanwhile, patients treated with Jardiance also had significantly reduced rates of heart failure hospitalisations and death from any cause, with relative risk reductions of 35 percent and 32 percent, respectively.

If this is true, it would be logical for doctors to put all their patients with diabetes on this drug, but closer inspection of the actual published study made it very clear to me that it was far from true, and that the actual statistics had been heavily massaged to achieve the final numbers published.

Here's what the actual study reports:

1. The study was conducted only in people diagnosed with diabetes and established cardiovascular disease. That was defined as people who had already had a heart attack, stroke, stenting, unstable angina or a failed stress test.  So these were people who were already quite ill with heart disease. Not your average person with well-controlled diabetes.

2. The drug, Jardiance (Empaglifozin) did a poor job of lowering the blood sugar of these people, whose starting A1c ranged from 7% to 10%. "At week 94, the adjusted mean differences in the glycated hemoglobin level between patients receiving empagliflozin and those receiving placebo were -0.42 percentage points and -0.47 percentage points  respectively; at week 206, the differences were -0.24 percentage points  and -0.36 percentage points." The two numbers refer to the two doses.  At the end of the study the average A1c was 7.81 in those taking the drug. This suggests (though the standard deviation isn't given) so it is hard to know where the blood sugars clustered. This still means that means that a lot of people had A1cs north of 8%.

3. More people had fatal strokes while taking Jardiance than while taking the placebo. More people had nonfatal strokes while taking Jardiance than while taking placebo This data is on page 45 of the appendix to the study. More people taking Jardiance also had silent myocardial infarctions (heart attacks) on Jardiance than in the placebo group. More people were hospitalized for unstable angina on the lower dose of Jardiance than on placebo and the higher doses was pretty close to placebo.

4. Sub Group analysis showed that Blacks, people with better kidney function, people with A1cs over 8.5%, those with peripheral artery disease, and those on insulin did better on the placebo. (I.e. not taking the drug.) People over 65 were borderline for doing better on placebo.

5. A relatively small number of these people who were seriously impacted by cardiovascular disease actually died or had a serious adverse event in both groups. The actual difference in the number of deaths was an improvement of about 3% in the group as a whole--ie. out of every hundred 3 more people survived. This isn't trivial, but it is quite different from the inflated "risk" statistics being publicized that inflate the numbers.  Basically if you have serious heart disease and take this drug, your chance of having a heart attack or heart failure goes down, while your chance of having a fatal or nonfatal stroke goes up.

6. One quarter of those who participated in the trial dropped out. Many had adverse events, the most common of which was a genital infection (i.e. yeast.) These were much more common among women than men, and far higher in the group taking Jardiance than the placebo group. One in ten women on the drug had a significant genital infection. I have heard anecdotally that these infections are very painful and extremely hard to clear up, even after the drug is discontinued.

This suggests to me that if you have had a heart attack this might be a drug worth considering, though if you are concerned about stroke or have a history suggesting it is a possibility, you might want to avoid it.

But if you haven't been diagnosed with heart attack or stented, you might want to think twice and concentrate instead on lowering your A1c.  There is a clear cut relationship between A1c and heart attack risk and an A1c of 8% correlates to a much higher risk than one in the 5% range. You can't get to the 5% range with this drug, which is likely to lower your A1c a quarter of a percent. You can by cutting out carbs and, if that doesn't work because your beta cells no longer are making any insulin, finding a doctor who will give you an effective insulin regimen (basal and bolus.)

But as we all know, doctors are far too busy and overburdened to actually read this study and think through all the reported results. They will read newsletters that provide summaries instead. So all they will hear is that 38% risk improvement and the prescriptions will be written for everyone with Type 2 diabetes--and some for people with Type 1, as there is a movement afoot to promote this drug for Type 1, too.

This may end up causing unnecessary, life-destroying strokes in people who needed never have them.

Be careful!


@NaturalWorkwear said...

The fact that various endpoints that should be related (e.g. fatal stroke v. non-fatal, silent v. symptomatic MI) responded in different ways suggests to me that the results are a statistical anomaly. There is no a priori reason to think that this SGLT2 is any different than the others already on the market. Even in relatively large clinical trials these sorts of anomalies can happen -- it is the play of chance.