Insulin u-500

Although insulin u-500 has been available since the 1950s, the use has sharply increased in only the past five years as a result of increasing rates of obesity and insulin resistance.

Insulin u-500 is a concentrated form of regular insulin, containing five times the units of insulin per mL as u-100.  Although it is a regular insulin, its pharmacokinetic profile may more resemble that of NPH;  a dose of u-500 may last up to 8 or even 24 hours. and there is a delay associated with the peak of action.¹  Although the total dose of u-500 may be more completely absorbed than large doses of u-100, there is a delay in absorption. ² 

There have been limited pharmacokinetic studies done.  Despite the availability of algorithms for the initiation of insulin u-500, much of the conversion may be trial and error. ¹  Pharmacokinetic reports have shown that a sharp rise in insulin concentration occurs 30 minutes after the dose is injected and peaks at 5 hours.  Insulin level will remain high even at 7 hours.  Insulin u-500 should be given 30 minutes before eating. ^2,3

Initiation of insulin u-500 is recommended for patients that are taking greater than 200 units of insulin daily and have not reached or have difficulty maintaining their goal A1c.  The total daily dose (TDD) of insulin should be added up.  If the patient’s A1c is less than 8%, 10-20% of the TDD should be subtracted. ^1,3

Insulin u-500 has both basal and prandial insulin properties.  On initiation, the TDD can be divided into three doses to be taken with breakfast, lunch and dinner although adequate glycemic control has also been achieved with the use of insulin u-500 in two divided doses.¹  If the TDD is 200-300 units, initiate a BID dosing regimen; 300-750, a TID regimen, and for doses 750-2000 consider dosing four times daily⁴.

Dividing the total daily dose²:  

BID dosing: Give 60% TDD qAM, 40% qPM

TID dosing:  Give 40-45% qAM, 30-40% at noon, and 20-30% qPM

no greater than 10% should be given at bedtime

Insulin u-500 acts more as prandial insulin in some patients, others more as basal; it is unclear if this is due to patient weight, insulin resistance, or the dose given^2,3.  The extent of peaking in insulin concentration has varied between studies.³

The patient should be followed every 2 weeks.  If over half of the blood sugar levels are 70-130, no dose change is needed.  If patient is experiencing hypoglycemic episodes, the dose can be decreased 25 units daily.  For fasting glucose levels of 130-200, the dose can be increased 25 units daily and for fasting glucose levels greater than 200, the daily dose may be increased 50 units. ¹

Insulin u-500 is associated with more weight gain than regular insulin.  For every 1% decrease in A1c, a 2kg increase in body weight can be expected³.  Despite the weight gain, patients will be a decreased risk of diabetic complications later on because of more tightly controlled blood sugar.  Weight loss should continue to be emphasized in patients taking insulin u-500.  Decreased weight will improve insulin sensitivity and may allow the patient to eventually step back down to using insulin u-100.  Weight gain with the switch to this insulin should be something assessed as part of the risks and benefits to starting insulin u-500. ^2,3

References:

1.  Ballani P et al.  Clinical experience with u-500 regular insulin in obese, markedly insulin-resistant type 2 diabetic patients.  Diabetes Care 2006; 29(11):2504-5.

2.  Daily AM et al.  Extreme insulin resistance: indications and approaches to the use of u-500 insulin in type 2 diabetes mellitus.  Curr Diabetes Rep 2011; 11:77-82.

3.  Segal AR et al.  Use of concentrated insulin human regular (u-500) for patients with diabetes.  American Journal of Health System Pharmacists 2010; 67:1526-35.

4.  Cochran E et al.  The use of u-500 in patients with extreme insulin resistance.  Diabetes Care 2005; 28(5): 1240-4.

Oral Xa inhibitors

Managing patients on warfarin therapy is an art.  There is a fine balance between achieving a supratherapeutic and subtherapeutic INR.  In addition to blindly making changes based on the INR reading, the practitioner must also take into account any changes in the patient's diet, missed doses, and any new medications among other considerations.  So far so Goude, right?

As previously covered in my entry on dabigatran, there is a demand for new oral anticoagulants that require less management and have less drug interactions than warfarin.  Dabigatran is a direct thrombin inhibitor, but there have also been a number of oral direct Xa inhibitors in development.

So where did the direct Xa inhibitors come from?  From heparin, which accelerates the inactivation of thrombin, Xa, and IXa.  Then came the low weight molecular heparins (enoxaparin, dalteparin, and tinzaparin).  The LWMHs are more selective for Xa, although they do have some anti-thrombin activity.  There is more grace with fondaparinux, which is a direct Xa inhibitor.  It is not reversible with protamine and it is specific for Xa inhibition.

Currently there are two Xa inhibitors in phase III trials in the U.S.: rivaroxaban and apixaban.

Rivaroxaban has already been approved in some European countries, but still has not been FDA approved.  For the criticism for the slow FDA approval process, I have only one thing to say: thalidomide.

Two of the major trials for rivaroxaban were the EINSTEIN and ROCKET-AF trials.  The EINSTEIN trial compared rivaroxaban to warfarin bridged by enoxaparin in the treatment of venous thromboembolism (VTE) and found that rivaroxaban prevented more events with no increased risk of bleed.  The ROCKET-AF compared rivaroxaban to warfarin for the prevention of VTE in patients with atrial fibrillation.  This trial has met the primary outcome, where rivaroxaban is non-inferior to warfarin, but superiority analyses have yet to be done.

A new multi-center RCT, AVERROES, was just published online in the New England Journal of Medicine comparing apixaban 5 mg BID to aspirin 81-324 mg in patients with atrial fibrillation that were unable to take warfarin.  Patients were followed for a year and the primary outcome was stroke or systemic embolism.

The trial was beautifully done and showed that apixaban reduced the risk of stroke or embolism in only a years time with no statistically significant increase in bleeding. 

On further inspection of the trial, I saw that 65% of patients taking aspirin were only taking 81 mg and about 26% were taking 162 mg.  I am more impressed that there was no associated increased risk of bleed compared to aspirin, rather than apixaban is more efficacious in stroke prevention than baby aspirin.

ARISTOTLE is an ongoing non-inferiority trial comparing apixaban to warfarin in patients with atrial fibrillation.  The results to this trial may offer more insight into apixaban than the AVERROES trial.

The ADVANCE trial(s) with apixaban were more impressive.  In this trial, apixaban was compared to enoxaparin for prophylaxis of VTE after a hip replacement.  Apixaban showed an absolute risk reduction of 2.5% with no increased risk of bleed.

Even if or when these drugs become FDA approved, it will take a lot more than FDA approval to replace warfarin.  Undoubtably the market is large; warfarin is difficult to manage, in some patients especially more than others.

Dabigatran, for example, still has a long way to go before it comes close to replacing warfarin.  Problems with dabigatran in clinical practice include high rates of dyspepsia, 30 day expiration, and high variability in absorption between patients.  Rivaroxaban has been shown to have a more predictable absorption between patients but it will be interesting to see what kinds of challenges for the medication may arise when/if it becomes available on the market.

One of the greatest questions with the new oral anticoagulants- dabigatran, rivaroxaban, and apixaban- is if they are more cost-effective than warfarin.  Are the costs of these medications off set by the decreased monitoring associated with them?

This is an exciting time for anticoagulation.  Unfortunately for now, we will just have to wait and see what happens.

This entry is also in reference to Jean-Paul Goude, whose work I have always admired, after being lucky enough to randomly buy his work "So far so Goude" at Club Monacco for $10... and it was worth every penny.


References:

Bauersachs R et al.  Oral rivaroxaban for symptomatic venous thromboembolism.  The New England Journal of Medicine 2010; 363:2499-2510.

O'Riordan M.  Off orbit? ROCKET-AF: rivaroxaban non-inferior to warfarin, but superiority analyses at odds.  The Heart 2010; available at http://www.theheart.org/article/1148785.do.  Accessed 02/23/2011.

Lassen MR et al.  Apixaban versus enoxaparin for thromboprophylaxis after hip replacement.  New England Journal of Medicine 2010; 363(26):2487-2498.

Connolly SJ et al. Apixaban in patients with atrial fibrillation.  The New England Journal of Medicine; published online 02/10/2011.  Accessed 02/21/2011.

Images by Jean-Paul Goude

People in Gallup like...

These six weeks have been a whirlwind.  I now have, not only a job for next year, I have my dream job.  I showed up in New Mexico exactly five weeks ago and bought a car on my second day here.  I knew what I wanted and planned accordingly.  In the week leading up to the residency selection, I thought,

My god, Vishnu Shiva and Brahma.  What am I doing?  I bought a car.  I jumped through hoops to register it in New Mexico.  What am I going to do if I don't get this?

But I got it.  I'm moving back to Gallup in July.

People are people no matter where you go.  I've lived in the bay area, Boston, and soon Gallup, New Mexico.  Despite the differences in geography, not only are we all human, we are all American.  But there are some interesting differences of interests between places.

For example, people in Boston like cranberries, rotaries, shell-fish (including lobster), the Red Sox, saying "wicked", and mis-prounouncing words in general.

So far, I've noticed that people in New Mexico are all about keeping their headlights on at all hours, looking at rocks, talking about rocks, biking, potlucks, large belt buckles, and anything silver and turquoise.  There is also much more of a "do it yourself" attitude out here.  I'm not sure if that is only representative of pharmacists in New Mexico, but my coworkers all like to brew their own beer, grow their own vegetables and hops, sew, and one of the pharmacists even mentioned wanting to start making his own soap.

I told him not to go all fight club on me.

I have a lot to learn about the history here.  I ask my 65 year old roommate a lot of questions.  I'm not really sure what he does.  He seems to maybe do something with park maintenance and was a pilot for a long time.  Maybe he still is one.  He was also telling me about some of the Navajo customs through his eyes.

We talked about medicine men.  He told me that he had found a religious set up of children's shoes, toys, feathers and rocks over the hill above the school that was meant to put a hex on the kids at the Rehoboth school.

He says,

You know, they're white when its better to be white and they're Indian when that works out better for them.  They come off with all this crap about caring for the land but I tell you what Marie.  You go to the res and see what they're doing with their land.  And all the crap about land ownership... jeez.  It makes me laugh.  They certainly believe it now.

Disheartening.

Gallup is on the eastern border to the Navajo Nation.  The largest reservation in the United States.  I can't say that cultures collide because the Navajo are mostly westernized today.  But if you dig a little, you most likely will be able to find some animosity on both sides.  Had history been different, the Navajo would probably have assimilated into western culture on their own.  The difference is that they were forced to.

My roommate told me that Navajo comes from the word for "horse thief".  Long ago the nation had called themselves Dine.  The people.  According to wikipedia, "Navajo" comes from "tewa navahu" or "fields adjoining a ravine".  Whatever the meaning of the word, the tribe recognizes themselves as "Navajo" today.

The Navajo also believe that if a person has something that they are not using, it is ok to take it to make use of it.  They also believe that if no one sees you take it, it is not stealing.  There are no words for "sin" and "forgiveness".

The Navajo language is not progressive.  New words are not made for new concepts of things; rather other words are used to describe the concept or item.  When I hear many Navajo translating for their grandmothers, I also hear English words mixed in.  Which isn't surprising.

The Navajo seem to have a good sense of humor about language.  My other roommate (a 29 year old male working at the Christian school) said that the direct translation of the word for "cell phone" is something like, "that thing that makes you walk up the hill".  Cell phone service is poor on the reservation.

What a culture emphasizes becomes apparent once you begin to learn the language.  I think learning some Swahili helped me to gain a better understanding of the cultures in East Africa.

At the present, I know two words in Navajo and I pronounce them poorly.  I have my work cut out for me.