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Lantus

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Lantus
glargine by Aventis
long-acting analog
U100 Special, pH 4
Line new molecular entity
Also known as Glargine (generic)
Similar to  Levemir, PZI[1]
 ultralente, Ultratard (duration)
Action in cats  
  • varies by animal
  • onset variable,
  • asymmetric peak 5-14h
    (4-20 h as per Nelson)[2]
  • duration 9-24h
    (10-16 h as per Nelson)[3]
Action in dogs  
  • onset inconsistent,
  • peak 0.5 to 6 hours, inconsistent,
  • duration about 13hr but inconsistent-beef/pork PZI has longer duration
    (10-16 h as per Nelson)[4][5][6]
Use and Handling
Type clear
Shelf Life refrigerate, until date on package
When opened 28 days at room temp, up to 6 months when stored in the refrigerator (2C to 8C)[7]
In pen 28 days at room temp
Notes  
  • protect from light and heat
  • do not mix with other insulins
  • do not dilute
  • do not prefill syringe
  • discard if precipitate or cloudiness
  • discard if frozen
  • Do not use intravenously[8]
  • Do not use intramuscularly[9]

Lantus is the brand name for insulin glargine, an insulin analog made by Aventis[10]. Lantus is a very long-acting insulin (lasting up to 24 hours in humans) that uses pH reactions to form micro-precipitates under the skin, which create a time-release action.

Use in CatsEdit

Because of cats' faster metabolism, long-acting insulins like Lantus (and perhaps Levemir) are gaining a good reputation in veterinary research for regulating cats for a full 12 hours at a time, often better than some of their shorter-acting cousins.

Proponents of Lantus in feline use point out that it lasts a full 12 hours in many cats, has a very gentle onset, a negligible peak, and (some claim) less chance of triggering hypo or rebound than faster-acting insulins. The famous Queensland University studies[11] showed that a simple protocol (in a 24-hour monitored, veterinary environment, with a Low-carb diet) could bring many cats into remission in a few weeks.

Detractors say that Lantus lasts too long and causes too much overlap in some cats, whereas other cats don't achieve more than 9 hours' duration on a shot. Its action is very dependent on the individual cat's body. People have also noted that with Lantus it is difficult to time the next shot because its action often stops abruptly. Lantus is relatively expensive and poor availability in smaller vial sizes than 10mL.

The use of Lantus is still quite new in cats, and the collective wisdom on the best ways to do so is still being optimized. The standard protocol for Lantus has been developed by Dr. Rand at the University of Queensland in Australia[12]. In Germany, an Internet forum[13] has developed a tight regulation protocol for cats with Lantus or Levemir [14]. This latter protocol has been seen to work well and lead to remission or regulation in the majority of cats that have used it.

Felineinsulin analog
Feline insulin compared with bovine, canine/porcine, human, glargine (Lantus) and detemir (Levemir). Differences, alterations and additions shown for all 6 insulins.
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In cases where the duration is less than 12 hours, some cats (including Pumpkin) have had success with booster shots. In cases where the duration is more than 12 hours (e.g. Langu), caregivers need to learn to predict overlap and carryover effects. People trying to use Lantus as they would a shorter-acting insulin are often frustrated when attempting to adjust dosages based on preshot blood glucose levels. Lantus may well be an excellent choice for diabetic cats once the correct usage methods are established.

To that end, Absorption curves with Lantus in humans may be helpful to calculating carryover and overlap in cats. Absorption studies in humans[15]indicate that 24 hours after being injected, approximately 50% of the Lantus dose remained at the injection site; after 48 hours, the amount was about 20%. Cats seem to absorb and use Lantus about twice as fast as humans.

A 2008 University of Illinois study compared Lantus and Levemir in healthy cats. The result that Levemir had less variability than Lantus wasn't surprising, since these are what the human studies show. However, what has been seen with some people is that Levemir has less duration than Lantus; the feline studies show that in some cats, it's the direct opposite, with Levemir winning the duration race. Lantus was also found to have a faster onset than Levemir in some cats[16].

Use in DogsEdit

Dogs, on the other hand, do not fare as well with Lantus[17][18]. Using it for them means using the Lantus as a basal insulin with rapid or fast-acting insulins like Humulin R,Novolin R, Novolog[19] or Humalog as bolus insulin, given at mealtimes. This is how insulin-dependent people use it too. Most dogs receive insulin injections twice a day. Using Lantus would at least double the number of needed daily injections because of the need for the faster-acting insulin at each meal.

Dr. Rand, of Queensland Protocol fame[20], participated in another study[21], this time studying the effects of Lantus on dogs. The same 9 healthy dogs were tested with Lantus, beef/pork PZI and porcine (pork) lente insulin. It was concluded that Lantus does not lower blood glucose reliably in dogs; there was no consistent peak time or glucose lowering action, and 2 of the 9 failed to have any significant response at all. PZI was shown to significantly lower bg's with longest duration of action (about 19 hours); pork lente insulin began working faster but had less duration (about 10.5 hours).

(A recent study[22] was conducted regarding mixing Lantus and short-acting insulin in the same syringe. The results show that it did not decrease either insulin's effectiveness. There have been more studies like this regarding the combining of Lantus with short-acting insulins. All have been favorable, but the practice has yet to be approved by any regulating body and/or Aventis.)

Compare the study regarding mixing Lantus and short-acting insulin in the same syringe for humans and the information from the Lantus US patient information leaflet on the same procedure in dogs: "When Lantus and regular human insulin were mixed immediately before injection in dogs, a delayed onset of action and time to maximum effect for regular human insulin was observed[23]." The leaflet goes on to say that there was a slight decrease in the bioavailability[24] of both insulins--regular human insulin and Lantus--when both were mixed in the same syringe.

On the basis of the information above, it would appear that Lantus acts differently in dogs than in humans.

Usage and HandlingEdit

Glarginetap
Human time activity profile of insulin glargine (Lantus).
We hopeAdded by We hope

It's generally best for pet use to buy the smallest vials possible, which are 3ml insulin pen cartridges[25]. Cartridges may be used with regular syringes as in this pictorial.[26] Unfortunately 3ml cartridges may be hard to come by in your area.

More information about keeping Lantus past the Sanofi-Aventis stated 28 day "opened" period comes from the website ChildrenWith Diabetes[27]. The person posing the question uses only a small amount of Lantus daily, having most of the vial left at the end of the 28 day "opened" period. CWD's answer was that pharmaceutical manufacturers use the "worst case" scenarios when making these pronouncements. Keeping the insulin in the fridge gives it a longer opened life than non-refrigerated insulin. CWD went on to suggest the person might be able to keep his/her vial longer than 28 days, by keeping a good eye on blood glucose levels, replacing it when bg levels rise for no explainable reason.

Prof. Rand in Australia[28] and our German feline diabetes friends recommend storing opened Lantus pen cartridges in the refrigerator, protected from light, between 2 and 8 degrees C (36 to 46 F) and using them for up to six months. Of course if "snowflakes" are seen, the cartridge must be discarded.

Because of the pH action, Lantus is a bit more sensitive than other insulins -- it needs to have an (acidic) pH of 4 to work, and therefore may not be diluted, mixed with other insulins, or kept overnight in syringes. Lantus and another insulin may be used together in the same patient, but not from the same needle or at the same injection site.

This from Electronic Medicines Compendium in the UK, is of interest. Lantus[29] is to be stored at 2-8C, but once in use, pens and cartridges are not to be refrigerated. The information goes on to say that both cartridges and pens must be brought to room temperature 1-2 hours before their first use. Vials have no need for this treatment and are able to be stored refrigerated after opening.

Duration/variabilityEdit

White3
Insulin glargine (lantus) mechanism of action.
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People using Lantus who find that it doesn't last long enough to prevent dawn phenomenon sometimes use a small dose of either Lente or NPH in a separate bedtime injection. This seems to work well for them[30].

Some people do not have 24 hours duration from Lantus, having what's called an "afternoon phenomenon", where the Lantus taken at dinner the previous night appears to be waning before their next scheduled injection. This occurs even though they are using rapid-acting analog insulins for bolus meal coverage[31].

The Lantus prescribing information details a study in humans where it was compared to NPH insulin. The findings were that Lantus has a higher between patient (84%) variability than NPH (78%)[32].

Lantus is known to have a noticeable "hospital odor"[33] which sometimes may "ooze" from the patient, too. This is apparently normal. The odor is not from the insulin itself, but from the preservatives in it[34]. In this case, its the metacresol found in Lantus. Metacresol is present in all insulins except those in the Lente family and PZI.

Pens/CartridgesEdit

Aventis non-vialed delivery systems (cartridges, disposable pens) may have their own set of problems. Each of the Patient Insert Fliers (PIF) at EMC-UK contains a section entitled Problems with the Pen?[35][36] The section advises one to always keep some syringes on hand, saying that insulin may be drawn from the cartridges in this manner. A check of EMEA's (EU Drug Regulatory Authority) Lantus information shows Aventis applied for permission to change the rubber stopper for its 3ml cartridges in November, 2004, and for extending the shelf life of unopened product from 2 years to 3 years. A decision[37] was not rendered until November of 2005.

Same-syringe mixingEdit

(A recent study[38] was conducted regarding mixing Lantus and short-acting insulin in the same syringe. The results show that it did not decrease either insulin's effectiveness. There have been more studies like this regarding the combining of Lantus with short-acting insulins. All have been favorable, but the practice has yet to be approved by any regulating body and/or Aventis.)

Compare the study regarding mixing Lantus and short-acting insulin in the same syringe for humans and the information from the Lantus US patient information leaflet on the same procedure in dogs: "When Lantus and regular human insulin were mixed immediately before injection in dogs, a delayed onset of action and time to maximum effect for regular human insulin was observed[39]." The leaflet goes on to say that there was a slight decrease in the bioavailability of both insulins--regular human insulin and Lantus--when both were mixed in the same syringe.

Technical InformationEdit

The first alteration of human insulin for producing Lantus is found in the A insulin chain at position #21; where normally the amino acid Asparagine is found there, Glycine is substituted. The second modification takes place at the COOH terminus of the B insulin chain, where 2 arginine residues are added[40].

Addition of the 2 arginines at B-#30 and substituting glycine for the normal asparagine at position #21 on the A insulin chain, keeps the insulin in hexamer form[41].

Human insulin unaltered has a natural tendency to remain in hexamer form (self-associate); making these changes to the normal human insulin molecule produces an insulin which tends to remain in hexamer form even longer. Inhibiting the breakdown of the insulin hexamers into dimers and monomers means slower onset, peak and longer duration, as absorption takes longer.

Insulin hex di mon
Insulin hexamers (as produced by the body or injected) must break down into dimers and monomers to be absorbed[42].
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Figure3
Amino acid structure comparisons of human insulin and insulin glargine (Lantus).
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Insulin amino acid sequencesEdit


Amino Acid Sequence of Insulin Preparations[43]
Amino Acid Substitutions

 

  A-Chain Position  

B-Chain Position

Source
Species
A-8 A-10 A-21 B-28 B-29 B-30 B-31
B-32
Beef Ala Val Asn Pro Lys Ala N/A
Pork Thr Ilc Asn Pro Lys Ala N/A
Human Thr Ilc Asn Pro Lys Thr N/A
Aspart Thr Ilc Asn Aspartic Acid Lys Thr N/A
Lispro Thr Ilc Asn Lys Pro Thr N/A
Glulisine Thr Ilc Asn Pro Glu Thr N/A
Lantus (glargine) Thr Ilc Gly Pro Lys Thr Arg
Levemir(detemir) Thr Ilc Asn Pro Lys N/A Myristic Acid
Ala=Alanine Val=Valine Asn=Asparagine Pro-Proline Lys=Lysine Thr=Threonine Ilc=Isoleucine Glu-Glutamine Gly=Glycine

Insulin pharmacokineticsEdit

<center>Pharmacokinetics in Humans of Insulin Preparations[44]
Insulin Preparations
Onset (hr)
Peak (hr)
Duration (hr)
Rapid-Acting
R/Neutral
0.5 to 1
2.5 to 5
8 to 12
Lispro
0.25 to 0.5
0.5 to 1.5
2 to 5
Aspart
0.17 to 0.33
1 to 3
3 to 5
Glulisine
0.17 to 0.33
1 to 3
3 to 5
Intermediate-Acting
NPH
Isophane
1 to 1.5
6 to 14
16 to 24
Lente[45]
1 to 3
6 to 14
20+
70/30-30/70
0.5 to 1
2 to 12
24
50/50
0.5 to 1
2 to 12
24
Novolog 70/30 Mix
0.25
1 to 3
24
Humalog 75/25 Mix
0.25
0.5 to 1.5
24
Long-Acting
Ultralente[46]
6
14 to 18
18 to 24
PZI[47]
4 to 6
14 to 18
24 to 36
Glargine
1.1
N/A
24
Detemir
0.8 to 2
N/A
up to 24
These are human activity profiles. Animals, particularly cats, may differ significantly.

Studies: Lantus in CatsEdit

Studies: Lantus in DogsEdit

Medical and Vet information about LantusEdit

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ReferencesEdit

  1. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-Nelson-OSU Endocrinology Symposium-2006-Page 40
  2. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-OSU Endocrinology Symposium 2006-Page 40
  3. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-OSU Endocrinology Symposium 2006-Page 40
  4. University of Queensland-Pharmacodynamic & Pharmacokinetic Comparison of Glargine (Lantus), Protamine Zinc (PZI), Pork Lente Insulin in Dogs--Fleeman & Rand-2004
  5. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-OSU Endocrinology Symposium 2006-Page 40
  6. Evaluating Insulins for Companion Animals Abrams-Og ACVIM 2007
  7. Information On Use of Glargine in Diabetic Cats
  8. Intravenous Glargine (Lantus) & Regular (Neutral) Insulin Have Similar Effects on Endogenous Glucose Output and Peripheral Activation/Deactivation Kinetic Profiles--ADA-Diabetes Care-2002
  9. Early Hypoglycemia After Accidental Intramuscular Injection of Insulin Glargine-Diabetic Medicine (UK)-2005
  10. Lantus-Insulin Glargine Remedyfind.com
  11. Queensland University Studies
  12. Information On Use of Glargine in Diabetic Cats
  13. German Diabetes-Katzen Forum for Lantus and Levemir
  14. Tight Regulation with Lantus or Levemir in cats
  15. EMEA Scientific Discussion:Lantus
  16. Comparison of Lantus and Levemir in Healthy Cats 2008 ACVIM Oral Presentations-Page 30, Abstract #96
  17. Insulins-North American Veterinary Conference-2005
  18. Selecting an Insulin for Treatment of Diabetes Mellitus in Dogs & Cats-Nelson-OSU Endocrinology Symposium 2006-Page 40
  19. FDA Novolog New Drug Application--No Faster Action With Insulin Aspart & Dogs
  20. Queensland Protocol
  21. of Pharmacodynamics & Pharmacokinetics of Glargine (Lantus), Protamine Zinc (PZI), & Pork Lente Insulin Preparations in Dogs-Fleeman & Rand
  22. Using the Same Syringe for Lantus and Short-Acting Insulin
  23. US-FDA Lantus Patient Information Leaflet-Page 7
  24. Merck Veterinary Manual-Bioavailability
  25. Lantus 3ml Cartridges
  26. Photo essay showing syringes and cartridges used together including fine dosing.
  27. Keeping Lantus Beyond 28 Days After Opening
  28. Information On Use of Glargine in Diabetic Cats
  29. EMC UK Lantus Information
  30. Using Lantus & Lente/NPH at Bedtime
  31. Insulin Treatment and Type 1 Diabetes Topics--ADA-Diabetes Care-2006
  32. Lantus Prescribing Information-US
  33. FDMB Discussion--Lantus--"hospital odor"
  34. Disetronic.com (Manufacturer of insulin pumps)-Page 5
  35. Lantus Cartridges UK Package Leaflet-Problems With the Insulin Pen?
  36. Aventis Insuman Basal Cartridges:Problems With the Pen?
  37. EMEA Documents-Lantus
  38. Using the Same Syringe for Lantus and Short-Acting Insulin Pages 3 & 4
  39. US-FDA Lantus Patient Information Leaflet-Page 7
  40. Clinchem.org Alterations to Human Insulin Producing Insulins Glargine, Aspart & Lispro
  41. EMEA Scientific Discussion-Insulin Glargine-Lantus-Page1
  42. Insulin Dependent Diabetes-Dr. Ragnar Hanas-1999 (Page 5)
  43. Pharmacy Times-Guide to Insulin Preparations
  44. Pharmacy Times-Guide to Insulin Preparations
  45. Endotext.com-Insulin Pharmacology
  46. Endotext.com-Insulin Pharmacology
  47. NetDoctor-UK Hypurin Protamine Zinc
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