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!

June 23, 2015

Toujeo, a More Concentrated Version of Lantus Is Now Available

As most of you may know, Lantus, the most commonly prescribed basal insulin, saw its patent protection expire in February of this year. Several new competitors in the basal insulin niche are waiting in the wings, hoping to siphon off some of the $9 billion a year the French firm Sanofi has been earning from Lantus.

Two brand new basal insulins currently on deck are Novo Nordisk's Tresiba and a peglispro, from Lilly. Tresiba has been already available in Europe since 2013 but is not approved in the U.S.. It achieves similar blood sugar results as Lantus while claiming to produce fewer nighttime hypos.

Peglispro is not yet approved anywhere yet, and its approval appears to be getting delayed due to some troubling signs found in clinical trial data that suggest it may harm the liver and that it may cause more severe hypos than existing basal insulins.

Besides these new analog insulins, there is another kind of competitor ready to take away Lantus' market share: biosimilars. These are protein molecules that claim to be similar in action, though not identical in structure, to another drug. They are as close as we can get to a generic product with hormones like insulin.  Lilly, in partnership with Boehringer Ingelheim, has already received approval to market its biosimilar insulin glargine, Basaglar in Europe and has tentative FDA approval to market it in the U.S. though because of a patent dispute with Sanofi, it can't bring Basaglar to market in the U.S. until mid 2016. .

What is Toujeo?

To defend itself against this dramatic ramp up in competition, Sanofi has come out with its own "new" basal insulin, which it is calling Toujeo. However, Toujeo is not really a new insulin, as it uses the same molecule, insulin glargine, as Lantus. All that is different is that it now comes in a more highly concentrated form.  Regular Lantus is a U100 insulin, which means there are 100 units of the insulin in every 1 milliliter of solution. Toujeo, in contrast, is a U300 insulin. So there are 300 units in every milliliter.  This means you inject a smaller amount of fluid to get the dose of insulin you need and may change the speed with which the insulin is absorbed and how long it stays active.

This may be handy for people with Type 2 who use very large doses of insulin. However, it may not be easier on their wallets, since to keep people from giving themselves three times as much insulin as they need, Sanofi will only market Toujeo in pens, not the cheaper vials. The reason for this is that you would need to use a special U300 calibrated syringe to correctly dose U300 insulin. This would make possible terrible dosing mistakes, since someone accidentally using a syringe calibrated for U100 insulin with Toujeo would end up injecting three times as much Toujeo as they would need, a great way to cause a potentially fatal hypo. So to eliminate this possibility Toujeo will only be made available in pens calibrated to  dispense the expected dose.

If you are happy with Lantus, there is nothing to suggest that you need to switch to Toujeo. Though you can expect to see a heavy advertising campaign intended to make you think you should. Sanofi had hoped to market Toujeo in the U.S. with the claim that it caused fewer hypos than Lantus, but the FDA did not feel that the data they submitted proved this. So the only real selling proposition for Toujeo is that it makes dosing very large doses easier.

However, the European regulators did approve the claim that Toujeo caused fewer hypos than Lantus, so you can pretty much take your choice about who to believe. This kind of disagreement suggests to me that the difference in hypos between Lantus and Levemir is small enough that it could easily be due to the drug company tweaking the way it designed its comparison study and analyzed its data.

What About Tresiba?

If you are in Europe and want a more highly concentrated basal insulin, you can also get a pen version of Novo Nordisk's Tresiba that is U200, which allows you to inject 160 units in a single shot. Tresiba also comes in a U100 format.

Tresiba, unlike Toujeo is a truly new analog insulin  molecule, insulin degludec. Because it is new, and like all analog insulins is not quite identical to human insulin, its long term side effects have yet to be fully understood. This is why they F.D.A. has delayed approving it, out of concern that it might have a different profile in regard to cardiovascular effects.

The European label for Tresiba supports its claim to dramatically lower the incidence of nighttime hypos, which might be a strong selling point once it does get approved in the us.

People with diabetes have to hope that this injection of competition into the basal market will result in prices dropping to the benefit of consumers. But in the strange Alice in Wonderland world of Big Pharma this is far from guaranteed.  Worst case, some people fear, cheaper biosimilars that do not actually perform as well as branded basal insulins may be imposed on us by insurers who will treat them just like any other generic drug and refuse to pay the premium for a branded insulin if a biosimilar exists. If as some argue small chemical differences in these biosimilars keep them from actually duplicating the effect of the molecule they mimic, this could be a big problem going forward. Best case, some of the newer basals may perform better and insurers may cover them because they prevent those serious hypos. We'll know how it works out in another couple years.

June 9, 2015

The Latest Study "Proving" that Januvia Does Not Cause Pancreatic Cancer and Pancreatitis Does Not Prove This

As many of you know, a very disturbing study was published in 2013 that documented the pancreatic changes associated with Januvia. It is found here:

Marked Expansion of Exocrine and Endocrine Pancreas with Incretin Therapy in Humans with increased Exocrine Pancreas Dysplasia and the potential for Glucagon-producing Neuroendocrine Tumors. Alexandra E Butler et al. Published online before print March 22, 2013, doi: 10.2337/db12-1686. Diabetes March 22, 2013

You can read another discussion of what this study found HERE.

As soon as Dr. Butler's study came out, there was a rush to publish studies that supposedly refute it, funded, not so surprisingly by the companies who are earning billions of dollars from these highly profitable drugs.

The first such study was this one:

UPDATE 2-Doctors get good and bad safety news on diabetes drugs

This study claimed to find no sign of pancreatic disease with Onglyza.

This week, a larger, much more high profile study of Januvia was published in the New England Journal of Medicine in June of 2015. It was presented at the 2015 ADA conference which took place this past weekend and is being treated as if it removes all barriers to prescribing Januvia as it has supposedly dismissed all safety concerns about the drug.

This latest study is: Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. Jennifer B. Green, et al. NEJM, June 8, 2015DOI: 10.1056/NEJMoa1501352

Though the focus of the study was on cardiovascular outcomes, it was also reported as stating that there was no sign of more pancreatitis or pancreatic cancer in the group that took Januvia. This, apparently, is being interpreted as proving that these drugs do not cause these two conditions.

But the flaw in the reasoning used here is simple: Short term studies can't discover potentially fatal cancers that take a decade or more to be Detectable.

The first study only lasted 2 years, which is far too short a time for the changes in pancreatic architecture discovered by Dr. Butler to result in overt pancreatitis. The study just published in the New England Journal of Medicine study only lasted three years. But it would be quite possible to draw the same conclusion about the safety of smoking cigarettes if you limited your study to a three year period. 

Cancers of the pancreas take a long time to grow to where they are detectable, and by the time they are, they are almost always fatal. Pancreatic cancer is almost always symptom=free until it is too late for any treatment to keep the patient from dying within a few months. The patients in Dr. Butler's study who took Januvia and died with small precancerous tumors in their pancreases and abnormal cells throughout their pancreatic tissue had no symptoms suggesting anything was wrong with them. Had they been subjects in the studies listed above, they would have been considered to not have cancer because the only cases of pancreatitis or pancreatic cancer which were evaluated in these studies were those that produced symptoms.

The reason it is so hard to detect early cancers of the pancreas--or the damaging structural changes that lead to pancreatitis is that there is no way to study the cells of a living pancreas without destroying it. That is why Dr. Butler was forced to study the pancreases of people who have died of head injuries.

Any study that assures you that these drugs are not damaging the pancreas which does not examine pancreatic tissue is not conclusive. Given how cancers progress, it will take 10 years or more for the pancreatic tumors these drugs are capable of growing to cause the epidemic of pancreatic cancer deaths that I fear is coming. By the time the deaths appear, it will be too late to do anything.

Until someone shows you 10 years worth of data that show no significant increase in cases of either pancreatitis or pancreatic cancer in people taking any incretin drug, be very skeptical of studies claiming they are safe.

May 26, 2015

More Evidence that Gastric Bypass is NOT a Cure for Diabetes

There is so much money in selling gastric bypass that it is no surprise that surgeons have talked a lot of family doctors into believing that this risky operation will cure their patients of Type 2 diabetes. Now yet another study documents exactly how this is not true and what the real risks of the procedure are for people with diabetes.

 The study is reported here: Gastric bypass helps treat diabetes, but has risks. The actual study is found here: Roux-en-Y gastric bypass for diabetes (the Diabetes Surgery Study): 2-year outcomes of a 5-year, randomised, controlled trial

The meat of the report is in this statement: "'Some doctors had thought that gastric bypass could cure diabetes, but that did not happen for most of our patients,' said coauthor Dr. Charles J. Billington. 'Also unexpected was the extent of complications in the bypass patients,' said Billington, of the endocrinology and diabetes division at the University of Minnesota, Minneapolis."

Two years after the surgery, 75% of the people who had the surgery achieved A1cs below 7% (though exactly how much lower is not disclosed.) The serious side effects included severe infections and nutritional deficiency bad enough to produce fractured bones.

Note that this study only reported the results at 2 years after the surgery. The study is meant to last 5 years. By then, if their results are similar to others I've reported on in previous blog posts, most of the subjects with diabetes will have seen their blood sugars revert to diabetic levels. Some previous studies are reported here:
No, WLS Does NOT Cure Diabetes--Study By Doctor with Conflict of Interest


The REAL Truth about Gastric Bypass's Supposed "Cure" of Type 2 Diabetes

Contrary to what surgeons suggest, there is no permanent physiological change caused this surgery that heals diabetes. All it does is make it so that people can't eat very much carbohydrate at one time. As we know, the less carb you eat, the lower your blood sugar. By forcing people to eat less carb, the surgery will lower blood sugar.

But over time the stomach stretches out and people who have had this surgery but were not told the connection between carbohydrate intake and blood sugar levels will eat more carb and become diabetic again. But this time they will be diabetic with severe nutritional deficiencies, since this surgery prevents the normal absorption of important minerals and nutrients.

When assessing any claim for surgery, be aware that unlike drugs which must go through a lengthy process of clinical trials and FDA approval before they may be sold surgeries can be performed by any physician, with the only limiting factor being whether or not insurers will pay for them. Even when insurers won't pay for them, sleazy doctors can still do surgeries on patients willing to pay the bills themselves.

In this loosely regulated system, there is no control over what surgeons can claim about their surgeries and as we can see here, it takes many years until any studies are done to determine if any of the surgeons' claims are true.

There is no question that weight loss surgery does reduce weight, but if you are considering this risky surgery mainly to cure your diabetes, try cutting back on your carbs for six months first. How well you do with that approach will give you a very good idea of how well you'll do with the surgery--during the first year or two when you can't eat much carbohydrate even if you want to.

You can learn how to lower your blood sugar to normal levels with diet HERE.