Thursday, March 27, 2008

What Do You Know About Regular Insulin?

Just how much do you actually know about your insulin? Sadly, I am sometimes frightened about just how little some people who should know better actually know about the synthetic hormone they are injecting into their (or their child's) body. Even more troubling, however, is that when I ask them some basic questions, I am told "Oh, our CDE never told us that."

There is some very rudimentary information that anyone who uses insulin (or gives it to their child) needs to know. For example, you should always check what your pharmacist has given you before using it. What do you need to look for? Simply stated: Brand, Type and Strength, and maybe expiration (although as Allie Beatty has reported, the amount of toxic preservatives in your insulin and the fact that a majority of insulin sold today was probably made over a year ago and was imported and shipped across the Atlantic does kind of mitigate this issue slightly).

Insulin Is NOT A Drug, It's A Hormone

For most people, insulin is a type of hormone replacement (although for others it is hormone supplementation). Insulin sold in the U.S. is 100% synthetic (not of natural origin; prepared or made artificially), and to add to the confusion, analogs are not even insulin. There are no long-term studies evaluating the long-term impact of insulin analogs, all we know about them is their immediate impact on blood glucose levels. You may know that insulin can vary by brand, but its easy to see when you've received Novo Nordisk Novolog instead of Lilly Humalog (although, in truth, the brand name doesn't mean that either of these companies actually made it ... see here for details). Yet many people remain blissfully (and naïvely) unaware of the "older" insulin varieties, and oblivious to the fact that the human body makes only one type of insulin: regular.

Regular insulin, when secreted directly into the bloodstream by pancreatic beta cells, has a glucose-lowering action which is measured in just minutes compared to subcutaneously injected insulin, which even in the case the shortest acting insulin analogs, is still measured in hours. The simple fact is that subcutaneous injection of insulin was practical and convenient, but insulin was never intended to be administered subcutaneously. Regular insulin literally has several thousand years of proven efficacy across almost all species of animals.

It is therefore no accident that regular insulin is still the ONLY type of insulin available via IV administration, and that people going in for surgery will only be given only regular (at least while on the operating table). People without diabetes do not have Lantus, Levemir, Humalog, Novolog/Novorapid, Apidra or 70/30 coursing through their veins. So at the very least, you should know that if for some reason all of the Humalog, Novolog/Novorapid or Apidra were to disappear tomorrow, you (or your child) could survive quite fine on regular, and no, it does not mean certain complications, either. Furthermore, a number of meta-analyses studies have proven conclusively that insulin analogs do not deliver superior glycemic control over regular, yet we all seem to use them. Why? I would also add that the gold standard for insulin trials has been baselined against regular, but today, drug companies are trying to convince the FDA to abandon that standard in favor of rapid-acting insulin analogs the benchmark. But this is not a diatribe about insulin analogs, its merely meant to educate people about the most basic information they should already know.

How Potent Is Your Insulin?

Beyond the insulin type, you also need to check the strength or potency. Failure to do so could be a disaster. Consider that on December 13, 2005, a patient named Keith Scofield visited a Wal-Mart pharmacy in Frederick, MD and ordered Humulin R (U-100). Instead, he was allegedly given Humulin R (U-500), which is only available by pescription and contains is five times the strength of the insulin he requested. He reportedly injected that insulin on December 20, 2005, lapsed into a diabetic coma, and sadly, died on January 2, 2006, according to a lawsuit filed by his family. (That suit was reportedly settled during mediation without admission of liability or fault from the pharmacy, which happened to be Wal-Mart, see here for details)

Just what is insulin strength/potency? Well, the American Diabetes Association's Diabetes Forecast 2008 Resource Guide reports that all insulins come dissolved or suspended in liquids, but the solutions have different strengths. The most commonly used strength in the United States is U-100. That means it has 100 units of insulin per milliliter (also referred to as cc for cubic centimeter, which is an equivalent amount) of fluid.

But U-100 insulin was only introduced in the U.S. back in 1973. Prior to that, insulin was sold in different strengths, including U-80 (80 units per milliliter) and U-40 formulations (40 units per milliliter), so there was an effort made to "standardize" the potency sold in the U.S. to reduce dosage errors and ease doctors' job of prescribing for patients. But standardization did not eliminate the possibility of error, that burden really falls on the consumer -- but some people aren't aware of that.

The ADA's Diabetes Forecast 2008 Resource Guide also reports that the other strength available is U-500 insulin, which is five times more concentrated than U-100 insulin and is used infrequently. This form of insulin is only for people with marked insulin resistance who require doses of more than 200 units of insulin per day. However, as the prevalance of type 2 diabetes has grown, the use of U-500 has too, and many pharmacies now carry it for customers. A simple mistake by a pharmacy tech (as opposed to a licensed pharmacist) could happen quite easily.

Finally, the ADA 2008 Resource Guide also also notes that because different syringes are used for different insulin strengths, it's also essential that your syringes match your insulin. For example, because the syringes are calibrated to match the insulin preparation, you would need to adjust the drawn up amount accordingly if you ever had to use a different strength or potency of insulin.

U-500, Check. U-40 ... Wasn't That Discontinued in the 1970's?

Its worth noting that U-40 insulin is still widely available in the U.S. as a treatment for animals (dogs and cats) with diabetes. U-40 means that there are 40 units of insulin per milliliter of fluid. Note that some large U.S. pharmacy chains, such as Walgreens and CVS will happily fill prescriptions for pet prescriptions and often at a better price than your veterinarian. And, contrary to what we've been led to believe, highly-purified bovine and porcine insulin is still made in the U.S.A. and sold legally in the U.S. today, only it is marketed towards veterinarians and is by and large, U-40 strength. While Walgreen's may not carry pet insulin in the store regularly, they can usually have it in a day or two. But the U-40 strength is also more common in some other countries outside the U.S., so at least be familiar with it.

While U-100 may be the defacto standard in the U.S. today, the fact is that U-40 and U-500 aren't unheard of. But you cannot simply use a U-100 syringe with another strength of insulin. Let's say a patient was on 20 units of NPH, and the only insulin available was U-40, then they could use a U-100 syringe but would need to draw up 0.5 cc rather than 0.2 cc. Similarly, if you needed 20 units of regular but received U-500 instead, you would need to reduce your dosage to one-fourth the size, or just 5 units.

Could Color Coding Help Avoid Mixups?

There has been an inconsistent effort to address the confusion by color-coding different strengths of insulin, but beyond discussions and submissions to the FDA, nothing has happened.

In 1996, when the FDA approved Humalog, the manufacturer (Eli Lilly and Company) used a different color of the crimp and cap on Humalog vials and cartridges (magenta) to distinguish the product from Regular (Humulin R) but others did not adopt the scheme.

The International Diabetes Federation again discussed the issue of color-coding back in 2004, but nothing further ever happened with it beyond the discussion. One issue is that some people are color-blind and cannot distinguish variations in colors, therefore the products must also have basic information for consumers to properly identify them, therefore there has not been big a rush to move ahead.

Then, in 2005, the FDA held a meeting and solicited public comment on the "Use of Color on Pharmaceutical Product Labels, Labeling and Packaging", but few manufacturers other than Novo Nordisk responded (see here for Novo Nordisk's letter to the FDA on that topic). Apparently, it was not seen as urgent enough to move ahead with, so nothing was implemented.

While it does sound like it would be easier if every bottle or cartridge of rapid-acting analogs were magenta, whereas every bottle of long-acting analogs were say, red, and maybe blue for "old-style" insulins such as regular or NPH, the Food and Drug Administration apparently sees fast-tracking (see here for more on that) new drugs as more important than reducing errors.

But some mistakes are avoidable if we know what to look for. Now, let's get this on the CDE exam to make sure it is taught to everyone who uses insulin!


Anonymous said...

Scott, thanks for mentioning the benefits of Regular. Endos today think a patient is crazy to use it when so are "better" alternatives available. I find my control is so much more smooth when adding Regular to my mealtime dosing.

Minnesota Nice said...

Scott, when I was dx'd in '74 I always had to ask for "U100" - I'd forgotten about that.

I think I'm one of the few people who takes 3 insulins. In addition to my basal and meal coverage, I also take R to cover my dawn phenomenon. I get up at abou 2:30 a.m. to test and the R is timed just perfectly to cover the rise that I sometimes have.

My insurance will only pay for 2, so I pay for the R out of pocket - , and in the vial lifespan of a month usually only use about 40 units so I end up throwing a lot away.

It does its job, though, and I'm very thankful I discovered the trick.

Christine-Megan said...

Hormones ARE drugs, at least the ones you put in that your body doesn't make. Oxygen is considered a drug by med-pros.

Scott said...

It depends on your definition of "drug" ... if one uses the definition of drug to mean a chemical substance used in treating disease, then it is technically not even a "drug" but a biopharmaceutical because of the manner in which it is made. But I think this is more a debate over semantics; the fact is that it is essentially a replacement hormone normally found in the human body, and on that basis, there is not really a comparison to drugs like metaformin used in treating type 2 diabetes -- that's a chemical creation that exists nowhere in nature.

Anonymous said...

Insulin is the most dangerous drug in America, especially in the forms now being proffered. Hormones are highly bioactive and even a small error in miniscule a PPM dose can result in seizure, coma, or even death. What the insulin cartel doesn’t want you to know is that synthetic insulins are NOT just like what Mother Nature makes. If accurate adverse events reports were submitted for meta-analysis, I feel quite certain that synthetic insulins would be used sparingly, and only for those individuals who exhibited allergic reactions to natural insulins.

The theory proposed by our caregivers is that “faster is better” in order to cover post-prandial glucose elevation. Another way to say this is, “you can eat all the garbage (carbohydrates, empty calories) you want to; we have produced “insulins” that act quickly enough to offset the quick rise. The down-side to this sentiment is that the rise in insulin levels far outweighs the human body’s safety mechanism, which is telling the liver, “give me a burst of glucagon to solubilizes some stored carbohydrate so I can survive the excess insulin in the bloodstream.” The only reason natural insulins weren’t made by rDNA technology was that the natural hormone molecule was UNPATENTABLE. No one ever compared the beef/pork hormone molecule as a “standard” of insulin function and safety against the new synthetic molecules.

An analogous situation, folks, would be if automakers and oil companies decided that all vehicles with fuel efficiency exceeding 10 MPHG must be withdrawn from our roadways. Who would benefit from some a move?

Does anyone out there have connections or influence in the right places to have natural insulins made available—non-prescription, as they were in the past—as a human supplement in the manner of many enzymes sold by the nutraceutical industry? BTW, oxygen is sold as a drug because people CAN overdose; but there was another reason for this classification: it’s highly dangerous because of its explosive nature. Of course, you also know there are oxygen bars in some metropolitan areas where a regulated, safe form is available in the same manner we seek natural insulins.


Kristin said...

I live in Hungary and the standard here used to be U-40, but with January 1, 2008, they switched to U-100. Perhaps there is an attempt to standardize outside of the USA as well?

Scott K. Johnson said...

Great post SS.

Anonymous said...

The more I read the less I know. Does all this mean that the profiles given with lantas and nova rapid don't make life easier? Have all these "improvements" meant nothing?

Scott said...

Response to Anonymous: Fundamentally, it means that all of these so-called "improvements" have done virtually nothing to improve glycemic control, but they have done wonders for the drugmakers' bottom lines!

Anonymous said...

RHI is fantastic in IV form. But by subQ it's dirt slow. The analogues speed this up. Who wants to be on IV insulin all day? I don't, I'll take the analogue any day.

As an aside, Novolog is available for IV administration, although it makes little sense to use it that way, because insulin via IV is all the same. Just wanted to point out the factual error there.

The different analogues are attempts at altering the speed (slower-basal's, faster-bolus's) of administration through subQ to better mimic what the pancreas does. RHI will never do that via SubQ.

Scott said...

To my last "Anonymous" responder:

Thanks for your comments! A few responses. First, you note that "Novolog is available for IV administration". I do not find anything on file with the Food and Drug Administration (FDA) to verify the accuracy of this statement. It's 'possible that Novo Nordisk manufactures Novolog (insulin aspart rDNA origin) for IV administration and it may actually be approved in some countries, but to the best of my knowledge, it is not approved for IV admin in the U.S. Many people confuse the brand names Novolog and Novolin, as Novolin R is FDA approved for that use, but I see no evidence that Novolog is. Perhaps you can share some documents on file with the FDA to back that statement up, that would be appreciated!

As a follow-up to your last point, you stated "The different analogues are attempts at altering the speed (slower-basal's, faster-bolus's) of administration through subQ to better mimic what the pancreas does. RHI will never do that via SubQ."

With all due respect, you are incorrect, there is a Connecticut-based company called Biodel, Inc. which is now completing Phase III Human Clinical Trials for its FDA submission of VIAject, which is actually a version of RHI with already FDA-approved "additives" which alter the ADME (absorption, distribution, metabolism, and excretion) characteristics of RHI to work (at least according to the clinical trial results) faster than a rapid-acting insulin analogue such as Humalog (insulin lispro rDNA origin). Others have also doe similar things with RHI to prolong its ADME characteristics, although so far, only in a trial setting. It is entirely possible to alter the ADME characteristics without altering the genetic structure of the molecule itself.

I will spare you a diatribe about how numerous meta-analyses (conducted in the UK, Canada and Germany) of the the trials undertaken for insulin analogues have failed to demonstrate superiority over older-generations of insulin preparation in a clinical setting, but I assure you, the analyses have demonstrated that the trials in virtually all cases failed to demonstrate scientific proof of superiority.

Anonymous said...

Novolog's IV use is clearly stated in the prescribing information.

See section 2.4 in dosage and administration.

Scott said...

Thanks for the info ... since I don't personally use Novolog, I don't regularly read the package inserts, and they are often updated without much publicity. I can tell you, however, that rivals Humalog and Apidra are not currently approved for IV administration.

Still, the necessity seems lost for me. Regular works just fine (actually Schering Plough dominates the bags intended for IV administration) for IV administration and is far cheaper. But I can tell you that Novo has been very forthcoming about its desire to stop making regular and other original biosynthetic insulin formulations because they are no longer covered by U.S. patent law. In many markets around the world, all they'd have to do is stop marketing the product, but in the U.S. Lilly still controls a large share of old formulations (and they are growing that business on a worldwide basis) thus Lilly is the thorn in Novo's worldwide desire to "migrate" patients completely. Personally, I have an ethical problem, and commented to the FDA that regardless of what the drug companies think, the "standard" for clinical trials should never be against insulin receptor ligands (analogues) but against regular.

Aimee said...

I am curious, how could I take just Regular insulin only. I ordered NPH in Pork insulin from a Canadian company, but I will run out of mine before it gets to me. I am hoping to use just my regular until it gets here. Now after reading your post I wonder I could manage on Regular alone.

Scott said...

Hi Aimee, the best way to answer your question is to note that most people cannot use a single insulin variety alone unless they use an insulin pump. This is because basal insulin can be replicated with tiny deliveries of sub-unit increments each hour. Without that, unless your basal insulin requirements are next to nothing, you will probably require some type of long-acting insulin such as NPH (or you can use the Levemir or Lantus analogs for this purpose). For most people, a pump is probably the best option, and there are newer pumps that cost less than the traditional pumps, such as Insulet's Omnipod which may cost less if cost is an issue.