Learning about Symlin, and Rejecting What I Learn

One of the biggest takeaways for me from the ADA Scientific Sessions was that I needed to learn about the magic drug everyone was talking about, Symlin. So, over the past week, I’ve been doing some reading, and this is what I’ve found:

Symlin (also known by the generic name pramlintide acetate) is Amylin Pharmaceutical‘s patented and commercially available synthetic analog of the naturally occurring endocrine hormone amylin.

Amylin is circulated throughout the body and helps to control post-meal glucose levels by impeding the release of glucagon from the liver and simultaneously slowing the rate of gastric emptying and subsequent intestinal uptake of carbohydrates. In short, amylin works in tandem with insulin to mitigate the effects of glucose that is ingested.

This close concert of amylin and insulin, however, does not stop with their joint functionality: amylin is made by the beta cells in the pancreas, and secreted in conjunction with insulin. And to all of us familiar with type 1 diabetes, this is where we say, “Alas and avast,” because, sadly, my body makes neither insulin nor amylin.

So that’s where Symlin comes in. Symlin has been available commercially for a number of years now, and an increasing number of type 1 and type 2 diabetics are augmenting their insulin-replacement-therapy with Symlin. The use of both hormones has been shown to reduce postprandial glucose spikes and reduce HbA1c measurements overall for patients, implying better glucose control.

I like this idea, and I want me some Symlin to replace my amylin.

But there’s a problem. Like insulin, Symlin can’t be taken orally. And it can’t be mixed with insulin in its synthetic formulation. So taking Symlin means either separate injections using something like Amylin Pharmaceutical’s Symlin Pen, or wearing a second pump to inject the hormone subcutaneously.

Some people I’ve spoken to say Symlin pumps work better, as they mimic more closely the natural flow of amylin throughout the body. But that would mean adding another hole to my already assailed body, and, frankly, I’m running out of space to stick things.

On the other hand, I’m not keen about the idea of injections either. Been there, done that, moved on. The thought of carrying around pen needles, and having to take shots before meals again… ugh. And ow.

So I’m back to square one, it seems. So much for Symlin.

Pause. Wait. Why isn’t anyone saying anything? This is where you’re supposed to say, “What, and give up that easily?”

And I respond, “Wait a minute, you’re right. Where’s my inner rebel when I need her?”

Take a look a few paragraphs up. Here’s what I said: “But there’s a problem. Like insulin, Symlin can’t be taken orally. And it can’t be mixed with insulin in its synthetic formulation.”

The skeptic in you should have complained at that point. You should have said, “Well, who says you can’t take it orally? Who says you can’t mix them?”

But that’s OK; I’ll say it for the both of us: Who says Symlin has to be such a pain-in-the-abdomen?

Claim 1: Symlin must be injected, and can’t be taken orally.
This one I can’t really get around; like insulin, Symlin needs to be circulating throughout the bloodstream in order to work properly, and science has not yet found a reliable way with either insulin or amylin to create a synthetic, oral version for type 1 diabetics. The complexities of digesting a drug that must in turn be used to monitor and manage the act of digestion have not yet been surmounted by the major drug players yet. Bummer.

Claim 2: Symlin and insulin cannot be mixed.
This claim gives us a bit more wiggle room. I’m not going to try drinking insulin or Symlin, but mixing them seems like it _should_ be an option, right? Figure out a standard ratio that works for me, include both in the pump reservoir, and use as if they were being simultaneously secreted by my stand-in pump pancreas?

So what’s the problem? People say the two shouldn’t be mixed. But who trusts an internet forum, right? Well, the prescribing information for Symlin says the two should not be mixed as well. Hm. But who trusts a drug company, right?

I look deeper, and find an American Journal of Health-System Pharmacy article from April 2005 called “Properties of pramlintide and insulin upon mixing.” Perfect. Written by a number of clinicians and directors at Amylin, this paper makes clear the issue with mixing Symlin and insulin:

“Pramlintide and insulin formulations interact primarily through their buffering systems. Most insulins have an isoelectric point in the range of 5–6 and are formulated at a pH of around 7. Pramlintide has an isoelectric point of >10.5 and is formulated at a pH of 4. The interaction of pramlintide and insulin formulations at different pHs (with different buffering capacities) potentially could result in precipitation of soluble insulin components or solubilization of crystalline insulin components. In vitro studies with pramlintide and short- and long- acting insulin formulations found substantial variability in insulin solubility when various quantities of insulin were mixed with fixed quantities of pramlintide.” (p. 821)

Darn. What does this mean? Synthetic insulin formulations, with the exception the long-lasting insulin glargine, like to live at a pH of about 7.4. This is because the isoelectric point of these synthetic insulins is about 5.4. The isoelectric point is the point at which the molecules of insulin in solution have no electric charge; at and near the isoelectric point, then, the insulin molecules are no longer active and ionic, and they become very stable. This stability, unfortunately, means that the insulin precipitates; the active insulin molecules bind and form a powder-like substance that falls out of the solution. The insulin molecules, no longer dissolved and distributed, cannot be absorbed or used by the body, and so the insulin is at worst useless and at best unpredictable.

By keeping insulin at a pH in the 7.0 – 8.0 range, then, manufacturers can ensure that that the insulin will not acidify and precipitate out of solution. This, clearly, is important to the potency and usefulness of insulin, but it makes mixing insulin with another solution that has a pH of 4.0 very questionable indeed.

In the 2005 study, mixing the two within a syringe that was used immediately seemed OK, and did not seem to decrease the solubility and absorption rates of the insulin, but the authors caution that the study did not test the many insulin types (just Regular and long-acting insulin), and that in vitro studies imply precipitation might occur, and that insulin’s pharmacokinetic properties are so variable according to person and environment that they can’t say for sure that the slightly longer time-to-max-effect of insulin in some of the trials was not caused by the mixing of insulin and Symlin (p. 821).

Plus, the study was conducted using syringe injections, which present a different set of problems than my hope of mixing the two in an insulin pump. The syringe concoction only has to last as long as it takes to inject and be absorbed by the body; mixing the two in a pump requires that the insulin remain soluble and uncorrupted for several days in the reservoir. Additionally, even a small amount of precipitation can have large effects in a pump, since the precipitated insulin can clog up tubing and infusion sites. In fact, though the prescribing information for both Humalog and Novolog says that “Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH,” they also specifically warn that the insulin “should not be diluted or mixed with any other insulin when used in an external insulin pump.”

Vive la resistance!
So, as many of us know from experience, insulin is a finicky little chemical, and does not like to have its pH changed. But, importantly, not all insulins are created equal; the pH sensitivity of different insulin formulations varies, according to the 2005 paper “Precipitation of Insulin Products Used for Continuous Subcutaneous Insulin Infusion.” (Note: this paper is written by chemists at Novo Nordisk; take it with a grain of salt if that’s your style.) The study compared the relative amount of precipitation at varying pHs for insulin aspart (Novolog), insulin lispro (Humalog), and Regular insulin. As you can see in the chart they produced, the solubility curve on each type of insulin is very steep; that is, there is a region in which they are not soluble at all, a region in which they are nearly entirely soluble, and then a very short region of transition between the two where the insulin is variably soluble. And, Novolog, Novo Nordisk’s own rapid-acting insulin, doesn’t start precipitating until a pH as low as about 6.0.

And here I run to the refrigerator, and check which brand of insulin I am issued by Kaiser. Novo Nordisk Novolog. Sweet. That gives me some leeway. I don’t like the idea of messing with the temperamental insulin’s pH, but if I’ve got from the neutral pH of 7.2 – 7.6 all the way down to the minimal allowable pH of 6.0, then perhaps, if I can bring up the pH of Symlin to between 6.0 and 7.0, then I can safely mix them.

So– the next set of questions– why is Symlin kept at such an acidic pH? Can it be safely kicked up a notch or two? What would that require?

I have begun to investigate these questions, and the preliminary answers are promising; but there’s more research to do before I advance to step two: Fun with Home Chemistry! And, if all goes well, step three: Karmel becomes her own lab rat! So, we’ll continue this conversation in the next installment of this Symlin saga.

Please note: I am not a doctor, or a medical professional, or even a chemist. The above is intended to be purely informational, and is based on my own research; it has not been independently verified, and is not medical advice.

Karmel Allison

Karmel was born in Southern California, diagnosed with Type 1 Diabetes at the age of nine, and educated at UC Berkeley. Karmel now lives in San Diego with her husband, where she is loving the sunshine, working in computational biology at the University of California, San Diego, and learning to use the active voice when talking about her diabetes.

Karmel Allison

Karmel was born in Southern California, diagnosed with Type 1 Diabetes at the age of nine, and educated at UC Berkeley. Karmel now lives in San Diego with her husband, where she is loving the sunshine, working in computational biology at the University of California, San Diego, and learning to use the active voice when talking about her diabetes.