Saturday, October 11, 2014

Of lows and Lantus

Issues...

We've had a few issues recently that, I believe, are related to our Lantus...

Here's our average glycemic profile over the last 15 days. Even for someone like me who likes "good control", it seems we are running a bit low. "Lower your insulin!" would be the standard answer, except for the fact that we're using at a total dose of 0.58 U/kg (0.28 U/kg of Lantus and around 0.30 U/kg of Novorapid) - according to "Think Like a Pancreas, page 129", we are already at the very bottom of the dose for a "very active adolescent".

We have a few options here

  • increase the amount of carbs: in our meals (except that we aren't on a low carb diet)
  • lower the rapid insulin doses: that's a bit hard to fine tune when you are running a schema of 5-6-4 units and you are still getting a fair amount of post-meal spikes. Half units Insulin pens will hopefully be discussed during our next appointment.
  • lower the Lantus dose: that would be the sensible thing to do with any T1D who seems to be running low but...
There's also another reason why we should lower the Lantus dose: we do seem to have Lantus related lows (see arrow 1) starting around 10:30 PM and lasting until 1:30 AM well after the 6:30-7:30PM Novorapid has stopped its action. But, and that's a big but, starting at 3:00 AM, we have an dawn phenomenon so pronounced that 7:00 AM is actually the time of the day where our average is the highest (arrow 2). And that happens despite a frequent 4:30 AM corrective dose of 2 units that we give if the CGM indicates a value above 140 mg/dl at that time. That dawn phenomenon can only be tamed by higher doses of Lantus but those make the 10:30 PM to 30 AM lows even worse. This remains an open issue, to be discussed with our endos next month. Options seem to be
  • switch to Levemir
  • start pumping
  • delay the Lantus dose
  • split the Lantus dose 
The "split the Lantus dose" strategy is somewhat controversial. Exploring it led me to some interesting facts that illustrate the complex interactions of big pharma's interests, doctor's default attitudes and patient well-being.

What's the rationale for splitting the Lantus dose?

Lantus, introduced by Sanofi on the market in 2000, is an insulin analog that is supposed to be almost peakless and lasts for 24 hour. The often shown chart below, extracted from its FDA application (source), shows a very minor peak of activity, about 5 or 6 hours after injection which fits quite well with the lows we observe. The medical litterature also reports that around 10-15% of the patients on Lantus seem to experience more severe early night lows than others. But it is hard to be 100% certain as those studies predate widespread CGM use.

Interestingly enough, Novo Nordisk, the makers of Levemir seem to disagree a bit with that profile: according to the studies they cite, Lantus has a much higher peak at the 8 hours mark. (source)


In fact, there's a simple explanation for the long action profile of Lantus: a couple of arginine additions and the replacement of the terminal asparagine by glycine in one of the Insulin chains change its solubility at normal pH. Before the injection, Lantus has a pH of 4.0 (that's why it stings when injected). After the injection, the pH progressively rises and the Insulin analog is slowly released from the Zinc Chloride stabilized hexamers it has formed at low pH.

Assuming a simplified spherical model for the Lantus injection, it is obvious that release can not be perfectly even and is somewhat dose dependent. A bigger injection will start its life as a bigger sphere, with a bigger surface that will release less and less insulin over time as it shrinks (and conversely, release more Insulin at the start). That geometrical issue is the rationale for splitting the Lantus dose: instead of injecting one single large dose that has a bigger peak, inject two smaller ones that have smaller peaks. That "size of bolus" effect is also true for Levemir, see the chart below, where the dose dependent peak is quite visible. Unfortunately, I wasn't able to find a similar dose dependent profile for Lantus.


And that brings us back to our initial options list: splitting the Lantus dose logically makes sense and has been reported to be effective by many Internet users. However, since the main benefit of Lantus is that it only requires a single injection, we might as well go for two Levemir injections. This will eventually be discussed at our next appointment. 

Thoughts on big pharma, endos and common wisdom...

When I first enquired, based on our CGM data, about the possibility of a Lantus peak, the near Pavlovian response of our endocrinologist was "Lantus has no peak." That message has probably been so heavily hammered by Sanofi's marketing department since 2000 that is has become common wisdom (and to be fair, it was comparatively peakless in the 2000 context). However, both Novo Nordisk and user reported experiences paint a more nuanced picture. 

And here comes the icing on the cake: starting in 2015, Sanofi will not only agree that Lantus has a significant peak but will also have a solution for that peak: U300/Commercial Name Toujeo


And can you guess the reason behind their sudden change of mind? The welfare of diabetic patients?Well, maybe a bit. But not only. Remember, Lantus was introduced in 2000. It is Sanofi's cash cow, raking in €7.0bn ($9.0bn) per year. Other companies, such as Eli Lilly, are ready to jump on a slice of that cow, with cheaper analogs, when Sanofi's patents expire (November 2014 in Europe and February 2015 in US). Sanofi is now protecting its cow through lawsuits (automatic patent extension in the US until the case is resolved) and on the product front (rushed U300 approval in Europe). 

I am willing to bet that a lot of endos will soon be hammered by Sanofi's marketeers and re-conditioned to address an issue they were told, until now, was inexistent.

But you never know, it may incidentally address our small problem. Meanwhile, I might have another go at delaying the Lantus - it could be that its peak can be synchronized with the dawn phenomenon.




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