Levemir in Dogs

[We Hope]

Grace,

The Pet diabetes wiki has one case, Molly:

http://petdiabetes.wikia.com/wiki/Case:Miss_Molly

Molly has been using Levemir for over a year and is having good results. I don't see that Molly's person has left any contact information with the case information.

There are a lot of Levemir cases, but the rest are cats, who have a much faster rate of metabolism than either dogs or people. A cat can use NPH as quickly as a person or dog uses R/Neutral. A lot of the cats with wiki cases were switched from Lantus to Levemir with better results for quite a few coming from the Levemir as opposed to the Lantus.

http://petdiabetes.wikia.com/wiki/Ca...:Levemir_cases

Can suggest that you take a copy of the Rand-Fleeman Lente/NPH/PZI/Levemir protocol and go over it with your vet:

http://www.uq.edu.au/ccah/docs/diabetesinfo/link1.pdf

Being able to contact Molly's person would help a lot, I know! When Molly was Pet of the Month in October 2006, I believe they were at CDMB.

This is an older post where we were talking about Levemir:

Originally Posted by We Hope

Levemir was around with Novo for quite some time. When it was in the normal formulation other insulins use, 600 nmol/ml, nothing much positive happened with regard to its doing much about controlling blood glucose. Testing people with that formulation was a washout, just as the 1200 nmol/ml formulation of it was.

It was not until Novo increased the formulation to 2400 nmol/ml that Levemir began to show real promise as a marketable insulin.

http://www.emea.europa.eu/humandocs/.../093604en6.pdf

EMEA-Levemir-Scientific Discussion-Page 4

Product development and finished product

"Three formulations of finished product were used in clinical trials. Early clinical trials--Phase I and Phase II--were carried out with formulation A. Formulation B was used in later Phase I and Phase II trials, as well as early Phase II trials. Formulation C was used in late Phase I and Phase III trials and is the formulation intended for marketing.

"The concentration of active substance was increased from 600 nmol/ml (Formulation A--also the concentration of all other insulins) to 1200 nmol/ml (Formulation B) and finally to 2400 nmol/ml (Formulation C) as clinical trials in human subjects with diabetes revealed a higher molar requirement of insulin detemir (generic name for Levemir) compared to human insulin to obtain the same glucose lowering effect."

Page 6

"Contrary to other insulin analogues, insulin detemir was consistently less potent than human insulin in all in-vitro assays. Depending on the assay, the potency was 2-to 10 fold lower. In vivo, it was equipotent in dogs and pigs, 6 fold less potent in rats and > 15 times less potent in mice and rabbits, the species traditionally used to determine the biological potencies of insulins. In clinical studies, the molar potency of insulin detemir was approximately 1/4 that of human insulin, which is within the range observed in vitro. As one unit of human insulin equals 600 nmol, the applicant has defined 1 unit of insulin detemir as 24 nmol or 0.142 mg of the salt-free anhydrous protein (MW=5916.9). The lower potency of insulin detemir relative to human insulin is attributed to the myristic acid moiety being sufficiently close to the receptor recognition site to interfere with insulin receptor binding. As the binding site is not identical across species, the degree of interference may vary across species. Thus, in-vitro binding studies using human, rat, pig, and dog insulin receptors showed that insulin detemir had a relatively lower affinity to human and rat than to dog and pig insulin receptors. Another factor contributing to the observed species differences in potency in vivo is inter-species variations in the binding of insulin detemir to albumin and, consequently, in the volume of distribution and clearance relative to human insulin."

OK--a deep breath to sort out what's been said so far. When you test in vitro, it's not on living beings.

http://en.wikipedia.org/wiki/In_vitro

"In vitro (Latin for within the glass) refers to the technique of performing a given experiment in a controlled environment outside of a living organism; for example in a test tube. Many experiments in cellular biology are conducted outside of organisms or cells; because the test conditions may not correspond to the conditions inside of the organism, this may lead to results that do not correspond to the situation that arises in a living organism. Consequently, such experimental results are often annotated with in vitro, in contradistinction with in vivo."

According to preliminary tests done without involving any animals or people, studies showed that Levemir when formulated at the molar potency of other insulins, was less effective in people and rats than it was in dogs and pigs. They go on to say that it was equipotent (equally potent to human insulin) for dogs and pigs, but much less potent for humans and rats when used in vivo, a living being.

http://en.wikipedia.org/wiki/In_vivo

"In vivo (Latin for within the living) means that which takes place inside an organism. In science, in vivo refers to experimentation done in or on the living tissue of a whole, living organism as opposed to a partial or dead one or a controlled environment. Animal testing and clinical trials are forms of in vivo research."

But there are no details as to which formulation or formulations were equipotent in dogs and pigs when they were injected with it.

Guess we need to talk a little about insulin receptors and so on since they're mentioned here. Insulin receptors are a bit like locks, the "door" won't open when they're in "locked" position. To open the "lock", you need a "key", and it has to be the right key or the lock won't open and the door stays closed. When you have the right key for that lock, you can open the door (insulin receptor binding).

When the insulin you're using won't bind to the insulin receptor (wrong key for the door lock), the insulin cannot be used properly by the body because it can't "gain entrance" to do its job of lowering glucose. It's like having no key, knocking on the door or ringing the bell and whoever's on the other side won't let you in.

Pharmacokinetics--Page 6

"In rodents and subchronic dog studies, females tended to show higher Cmax (Maximum serum concentration (Cmax) ) and AUC (Area Under the Curve) values and exhibited more pronounced accumulation. Similar gender differences were not encountered in humans."

In this, I'd take subchronic to describe a dog who has had some exposure to the insulin on a somewhat regular basis.

Toxicology--pages 7

"Signs of systemic toxicity were limited to effects on plasma glucose, small decreases in serum protein and albumin, urea and magnesium and minor changes in a few organ weights, notable the liver in the rat and the adrenals in the dog. These findings, which were fully reversible, were also made in the NPH human insulin satellite groups and are therefore considered to be exaggerated pharmacodynamic effects."

Would take this to mean that upon ceasing the use of the insulin, the adverse effects reverted to normal. Also note that the preservatives in both Levemir and NPH are the same--phenol and meta cresol.

Levemir is suspended in the bloodstream by binding to albumin. Lantus is suspended by its creation of crystals under the skin after injection. While all other insulins are neutral pH, Lantus is acid pH in the vial. It depends on the reaction between its acid pH and the pH of your skin to create the subcutaneous crystals.

NPH insulin is bound to protamine for its suspension. The first longer-lasting insulin was Protamine Zinc Insulin which contains more protamine than NPH does and that's how it is longer lasting. Hagedorn, the Novo scientist, came up with them both--PZI first and then by reducing the amount of protamine in the formula, came up with the one that bears his name--Neutral Protamine Hagedorn.

Lente insulins are bound to zinc for their suspension; R/Neutral and the rapid-acting insulin analogs Novolog, Humalog and Apidra have no suspension at all.

There have been papers written suggesting that Levemir is no more effective than NPH insulin, that the big difference is the price tag between them. Others say that it's not a "true" once a day insulin like Lantus. What Sanofi-Aventis doesn't tell you is that for many people, Lantus isn't a once, but a twice-daily insulin. r-DNA Ultralente wasn't a once-daily insulin for quite a few people either, even though that's what the claim was.

Both Lantus and Levemir when used with faster-acting bolus insulins, mean that those injections will need to be given in separate syringes. Neither pharmaceutical company has done any work that's been released to the general public regarding combining their long-lasting basal insulin with bolus insulins; the official word as it stands is that combining any insulins with them may change the time action profile of the basal insulin.

Regardless of what insulin you're using right now, you won't see a true test of it until Ali's UTI is gone. You're not using a large amount of NPH at this point, and you could try simple "tweaks" by delaying the insulin shot by 30-45 minutes after food to see if that won't eliminate some of the "drops". Another "fix" for lows when insulin's peaking is to give a small snack shortly before that.

Welcome!

Kathy

Hope some of this might help!

Kathy

[grace.device]

Kathy, thank you for that protocol, I saw it in your previous message about 10 seconds after I posted

I think Patty sent me some info from Peggy (Molly's mom) about diet and the change to Levemir (decreasing effectiveness of the Lantus), but there wasn't too much else there. I know Breanne (Kramer's mom) from CDMB used Levemir once with her dog, and 1U was almost too much.

I am a little confused about the post you quoted - it said the 600nmol/cc detemir was equipotent in dogs (but less effective in humans), but now it is formulated as 2400nmol/cc for better efficacy in humans. Is real-world experience showing the 2400nmol forumulation to still be 4x as effective in dogs? I know the protocol says to use the same 0.5U/kg dosing as NPH, but between Kramer and Molly, it seems like it probably is more effective.

Grace

[We Hope]

Grace,

The real world insulin is sold in 2400nmol/cc formulation--four times as potent as the one they classed as equipotent for dogs. They worked with the insulin for years and until they discovered the 2400nmol/cc formulation, it was doing nothing really for people in their testing, and that's the population they intended to market it to.

Since you can't dilute either Levemir or Lantus according to both Novo and Sanofi Aventis, I'd say be cautious.

You or your vet might want to e-mail Dr. Rand asking about the 0.5 iu/kg starting dose indicated in the protocol:

j.rand@uq.edu.au

Kathy

[grace.device]

Sorry for the delay in updates, Rolo and I have been busy with insulin! She's switched over the Levemir now, and seems to be doing very well on it! Her bolus needs have dropped dramatically (from 0.5U to 0.1U) and I'm actually adding in some rice to her meals to keep her stable with the bolus (I can't accurately measure out less than 0.1U otherwise I'd just give her a smaller bolus). Her Levemir seems to be doing fairily well on 0.9U (a smidge under 1.0U), twice daily. 0.75U was not quite enough, and we were only getting 10hrs duration, and 1.0U had her dropping too low by 6hrs. I have a good magnifying eye piece that I use, though I think I will have to look into something even stronger so I can keep her dose consistent. We've had a few rough patches with rebound (on the 1.0U and a larger bolus) and some spikes when the duration of the Levemir ran out, but she seems to be setting in okay now. Fingers crossed that this keeps up!

Grace

[We Hope]

Grace,

Not sure if you can use this or not; page was written by members of the Feline Diabetes Message Board who've become experts in fine doses by necessity.

http://petdiabetes.wikia.com/wiki/Fine_doses

http://romlin.com/jock/SyringeFineGradations/

Fine Dose Pictorial Guide

What Steve's set up should look quite familiar; his Jock has been on Levemir for a long time.

HTH!

Kathy

[Patty]

Wow Kathy. That's really good info.
And the link that's given to the board on syringe accuracy for those small doses is very interesting to read: http://www.felinediabetes.com/phorum...php?22,1462377

I use BD syringes. I found, for me, they slide better than the Monoject/Relion ones. But I swear the top of the plunger is diagonal sometimes! Glad it's not just me that's seen this.

On the romlin.com site, I understand the amount in syringe. For the amount in tip are they talking from the neck of the syringe to the zero line? How do you vary the amount in there besides with an air bubble? I can't see the difference in amount of liquid in this space on the picture.

Glad you're working out the kinks Grace.

Patty

[We Hope]

Patty,

Think you need to ask Steve these questions because he's really VERY good in the "Art of Fine Dosing". When we started working on the Pet Diabetes Wiki in late 2005, Steve was living in Sweden. I understand that since then, he's now in London. The last e-mail address I have for him is this one:

http://petdiabetes.wikia.com/wiki/User:Steve_and_Jock

steveandjock at petabit dot com. (Done this way to prevent bots from harvesting it.) He hasn't changed the address for sending him diabetes case studies (You can do your own without contacting him.), so I'd believe he's still connected with petabit.com

http://petdiabetes.wikia.com/wiki/He...ing_Case_Study

Am not seeing anything further in a search of FDMB with "fine doses" so don't think he's added anything more there which isn't on the Fine Doses wiki page.

Those who are using either Levemir or Lantus at FDMB have also learned how to get the most "bang for their buck" when buying insulin. With most cats being smaller than dogs, the amount of insulin they use is considerably less and a vial of insulin will lose potency long before they're done with it.

So they buy their insulin in cartridge form because each cartridge is good for the expiration date stamped on the package if it's kept according to the maker's specifications and not opened. They draw their fine doses from individual 3ml insulin cartridges, getting the job done and saving quite a bit of money at it; you're not starting a 10ml vial of insulin and tossing most of it out because of potency issues this way.

Would give a try to the e-mail address above and see if it's valid. If not, he was last at his Wikipedia Page at the middle of April. You can leave him a message there by using the "Discussion" tab.

http://en.wikipedia.org/wiki/User:Steverapaport

Kathy

[grace.device]

Alright, after practicing for a looooong time last night with an old syringe and a bowl of water, I think I've mastered the microdoses. I successfully found a droplet size that is about 1/20th of a unit. I did it over and over (and over and over...) and consistently got 19-22 drops per unit. Rolo got 0.9U Levemir this morning, and 0.2U of the NovoRapid. It really feels like I'm giving her nothing when I push the plunger down but her BG numbers say otherwise. I feel much better about this - I tried to give 0.9U yesterday eyeballing it, but she was high 200s all day, and the duration was only 10-11hrs, so I know she got more like 0.75U. I've had to toss some of my syringes - for most of them, the plunger lines up well with the 0 line, but there are some that are crooked or have extra room above the 0 line, and given our tiny doses, they are obviously not going to be accurate enough. Hopefully we will start having more even numbers now that the doses are more accurate.

Grace

[grace.device]

I did try it with the Levemir this morning, and got the same size drop. I am thinking that as long as it is the same droplet size, it doesn't matter if it's insulin or water, it should be the same volume.

The drop I made was tiny, tiny, tiny! Maybe 3x the width of the needle, only. I tried to eyeball it yesterday, but it obviously didn't work out as planned. I played with the syringe for over an hour yesterday, lining up the plunger with a 1/2U mark, then just repeating the drops over and over. If I was using NPH I wouldn't go with such a tiny drop, but with the Levemir, i really think it makes a difference. 1/20th of a unit is about 1/5th of a NPH unit, so that's a big jump, really. I was doing 1/4U changes for Rolo and they were almost too big.

Rolo's going to my mom's for a whole month in July while I am on vacation, so she's going to have to get really good at measuring that drop. I'll make her practice and grade her!! I am actually hoping Rolo needs 1U exactly, then i wouldn't have to do any droplets, but it's not really that big of an issue.

Grace

[grace.device]

Just thought I would update everyone on Rolo. She is doing well with no change in insulin. I'm giving her 35g rice with every meal, which leaves me with a tiny rise 2hrs after eating (about 20-30 points) on 0.2U NovoRapid. When she gets more reguated I might decrease the rice a bit, but it's fine for now (I l like having some wiggle room while we continue to increase the Levemir).

Blood sugars yesterday were 227 at fasting, 209 @ 5hrs, 216 @ 10hrs, but then 362 @ 12hs. I have no idea why she gets that big jump between 10 and 12 hours, and it's definitely not the first time it's happened.

She does get a small snack at 5:15 when I get home from work (tiny piece chicken jerky and a few green beans), same snack that she gets at lunch. She didn't want her green beans yesterday, so if it's anything, it's the chicken causing her to spike. Otherwise, we're just not getting 12hrs duration out of our daytime dose (though she does fine overnight and we have good morning fastings).

I'm going to do a curve on Saturday (day 5 of the same doses) and leave out her evening snack to see if it's the snack or lack of duration causing the spike. If it's the snack, she'll just have to deal with green beans only. If it's duration, I'm not going to worry too much now since she'll probably need an increase in the Levemir anyway and that might increase her duration. When she gets to the right Levemir dose, if she still has duration problems, I will move up her dinner and adjust her NovoRapid dose so the bolus covers the gap (so 7:30am: breakfast, NovoRapid, Levemir; 5:30pm: dinner, NovoRapid; 7:30pm: Levemir). Or, I could go with breakfast/NovoRapid/Levemir at 7:30am and dinner/NovoRapid/Levemir @ 6:30pm if I am getting >12hrs with the evening dose and at least 11 with the daytime.

Does that sound like reasonable plan? I'm really happy with the Levemir otherwise, I'm seeing some real consistency that we've never had before.

Grace