September 29, 2015

The Newly Approved Basal Insulin Tresiba's Label is Disappointing

We have been hearing for quite a while about the benefits of Novo Nordisk's new, longer acting basal insulin, Tresiba, whose approval was delayed for a year while the FDA waited for cardiovascular safety data .

Well, the FDA finally approved it last week. And lo and behold, none of the main claims that have been made for Tresiba until now appear in the official, FDA-sanctioned Prescribing Information (PI), A.K.A. "label."

You can read the whole PI/label here:

The hype was that Tresiba caused fewer hypos than existing basal insulins. If this is so, it is not demonstrated anywhere on the label. There were hefty hypo rates reported in 6 of the 7 studies summarized in the label. The percent of of people in these studies who had hypos where blood sugar dropped below 56 mg/dl via a blood sugar meter test were: 46.5%,  28.5%,  50%,  43.8%,  50.9%,  80.9% and 42.5%.  (Page 9 of the PI)

There is no way to directly compare these studies with studies of other basal insulins, as it is clear that there is really no way to compare any of these studies of Tresiba with any other study of Tresiba. When you have a range of outcomes from 28.5% to 80.9%, means and medians are worthless. There is just too much variation from study to study. So comparisons with studies of other insulins that would demonstrate superiority would have to be cherry picked. I am certain, of course, that they will be. Drug salespeople are extremely good at coming up with creative ways to promote drugs in ways that are not actually substantiated by existing research.

(It's worth noting that Toujeo's claims of causing fewer hypos were also removed from its U.S. when it was recently approved.  Toujeo is the latest incarnation of Lantus, which is being pitched as a "new" insulin though it is actually the same insulin molecule as is found in Lantus, just dressed up with a new pen and a new, higher price tag.)

The implication of the rest of the hype for Tresiba was that its longer action  would make it superior to Lantus, which currently dominates the niche for basal insulins. But oddly--and one has to assume the FDA insisted on this--the charts displayed from page 20 to page 24 of the PI clearly demonstrate that study after study found that patients on Lantus, be they Type 1s or Type 2s, saw better improvements in their A1c on Lantus than those on Tresiba. Lantus consistently achieved an improvement of  .1 to .2% in A1c.--i.e. if Tesiba lowered A1c on average to 7.1%, Lantus (called by its generic name, glargine, on the charts) brought its group down on average to 6.9%.

The reason for this may have to do with the way that Tresiba works. The chart showing the activity curve of Tresiba is worrisome. The insulin is active for 42 hours but the curve is far from flat. Since patients are told to inject it once a day, and furthermore told that they can inject it different times from day to day, the overlap between the previous day's insulin and the next day's insulin may be unpredictable.

We see from the comparison charts where Tresiba was matched with Lantus that despite the lower impact on A1c patients on Tresiba had to reduce their fast-acting insulin at meal times. This is undoubtedbly because of that very long tail of the previous day's insulin working in unpredictable ways.

The only real advantage with Tresiba is that it is available in a U200 concentrated form that will allow a single dose of up to 160 units. This is helpful for people with extreme insulin resistance who need huge doses and who, until now, had to take two or more shots of basal each day. But the population of those needing 160 units is small. For most people the main impact on them of switching to Tresiba will be that they or their insurer will be paying more for basal insulin while they will be likely to see less improvement in their control and a continuing possibility of experiencing serious hypos.

Another supposed benefit of Tresiba is that it can be mixed in the pen with fast acting Novolog, allowing it to be sold as a 70/30 insulin.  This 70/30 Tresiba/Novolog mix will be sold under the name Ryzodeg.

70/30 insulin is probably the worst form of insulin available, as putting basal and fast acting insulin into a single shot makes it impossible to match the dose of fast-acting insulin being given to the person's insulin resistance or to the the amount of carbs they eat at the meal that comes after their two daily shots. So this generic dosing of  meal-time insulin which occurs with 70/30 insulins guarantees the worst of both worlds. The choice is either more hypos or poorer control than is possible with dosing each meal separately for the rest. Insurers like it because they pay for only one prescription, not two. Some patients like it because it requires fewer shots. But no doctor who knows anything about insulin--or cares about his patients' long term outcome would prescribe this kind of insulin.

Nevertheless, you can expect to see plenty of advertising promoting this mixture of two insulins in one shot as a "convenience."  The main reason that Novo Nordisk is going to be selling Ryzodeg, of course, is not that it is good for patients. They introduced it because they know that that Lantus can not be mixed with a fast acting insulin--and Novo Nordisk is locked in a battle to the death for diabetes dollars with Sanofi, the maker of Lantus and Toujeo.

Keep in mind, both Tresiba and Toujeo come to the market under the shadow of the approaching launch of biosimilar glargine--Lantus equivalents which can be sold now since the Lantus patent has expired. For now, "can be sold" doesn't mean "will be sold." Sanofi is doing all it can to delay the day that cheaper but still effective basal insulins are available to American consumers. They just signed an agreement with Lilly, that will delay the launch of Lilly's biosimilar Lantus until 2017. This is what would be called "restraint of trade" anywhere that had real regulation of drug pricing and marketing (like, say, the EU, where biosimilar Lantus is already available). But here in the U.S. "free market" economics appear mean that companies are "free" to keep helpful drugs off the "market" as long as they pay off their big pharma peers--peers who will do the same for them in the future, to keep the profits high for both.

All of this is bad news for people with diabetes, of course, who are paying more than twice what they were paying for basal insulin just 8 years ago, while still contending with unexpected hypos. But their interests are overlooked since the business world appears to believe that the only important question about any new insulin is how much money can be extracted from those who are obliged to use it.

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!