Glargine Insulin Is Expensive: Is Compounded Insulin an Acceptable Alternative?

After reading your last post about the escalating costs of insulin analogs, such as glargine and detemir, I wanted to ask your opinion about compounded insulin products. Compared to the human glargine preparation (Lantus), some compounding pharmacies offer a compounded glargine product at only about 25% of the regular price as sold by human pharmacies.

Any comments? Why not use these compounded insulin products?

My Response:

I would never use a compounded insulin product in my cat or dog patients unless there was absolutely not other option. I know it sounds tempting, but experience (especially with compounded PZI insulin), shows that the potency of these compounded insulin products can vary greatly from bottle to bottle (1). As we all know, it's difficult enough to regulate a diabetic cat without the additional variable of the insulin changing its potency every time the owner buys a new bottle. I feel that it’s far better to get manufactured FDA-approved insulin that has external quality control standards applied to it.

How insulin glargine is made (or how it should be!)
Making insulin glargine is not a simple process. Remember that glargine is an insulin analog (2). With insulin glargine, the chemical structure of the insulin protein is changed to make it have a relatively constant release over 24 hours with no pronounced peaks (at least in man).

So how do they make this insulin? Synthesizing human insulin is a multi-step biochemical process that depends on basic recombinant DNA techniques, and an understanding of the insulin gene (3-5). For insulin glargine and other insulin analogs, instead of synthesizing the exact DNA sequence for insulin, manufacturers synthesize an insulin gene where the sequence is slightly altered. These changes in resultant amino acid sequence are responsible for glargine's prolonged duration of action.

DNA carries the instructions for how the body works and one small segment of the DNA—the insulin gene— codes for the protein insulin. Manufacturers manipulate the biological precursor to insulin so that it grows inside simple bacteria. While manufacturers each have their own variations, this recombinant DNA process is the basis for manufacturing human insulin (Figure 1).

Figure 1: A diagram of the complicated manufacturing steps for insulin (from reference 4).

Quality control must play a very important aspect of insulin production (3-5). After synthesizing the insulin glargine, the structure and purity of the insulin batches are tested through several different methods. High performance liquid chromatography is used to determine if there are any impurities in the insulin. Other separation techniques, such as X-ray crystallography, gel filtration, and amino acid sequencing, may also be performed. Manufacturers also test the vial's packaging to ensure it is sealed properly. Manufacturing for human insulin must comply with National Institutes of Health procedures for large-scale operations. The United States Food and Drug Administration must approve all manufactured insulin preparation.

Practical and legal problems with using compounded insulin
As detailed above, making insulin entails a complicated manufacturing process, and I do not know how any compounding pharmacy could possibly produce a reliable insulin product. Compounded insulin products fall into a legally gray area that is the subject of current scrutiny by the FDA (6,7). It is important to recognize the limitations about safety, effectiveness, and stability of compounded insulin preparations.

Pet owners should be informed of the risks of failure associated with using a compounded insulin product. They should consent to therapy based on disclosure that the use of the insulin product is scientifically unproven (i.e., there are no published scientific papers concerning the use and effectiveness of compounded insulins).  Overall, it is the responsibility of the veterinarian to ensure the safety and therapy of any prescribed insulin treatment, including compounded insulin products — and failure to do otherwise places the patient and pet owner, as well as the veterinarian, at risk.

References:

1. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605. 
2. Owens DR, Griffiths S. Insulin glargine (Lantus). Int J Clin Pract 2002;56:460-466. 
3. Gebel E. Making insulin: A behind-the-scenes look at producing a lifesaving medication. Diabetes Forecast 2013;July issue. 
4. Website. How Products are Made: Insulin. 
5. Owens DR, Landgraf W, Schmidt A, et al. The emergence of biosimilar insulin preparations--a cause for concern? Diabetes Technol Ther 2012;14:989-996. 
6. Boothe DM. Veterinary compounding in small animals: a clinical pharmacologist's perspective. Vet Clin North Am Small Anim Pract 2006;36:1129-1173. 
7. Lust E. Compounding for animal patients: contemporary issues. J Am Pharm Assoc 2004;44:375-384.

Selecting the Best Insulin for Diabetic Cats when Cost Becomes Factor

I have an overweight (16 lb; 7.3 kg) male DSH cat who has been fairly well regulated on 3 units of glargine (Lantus) administered twice daily. He has been diabetic for over a year and has done well on a low-carbohydrate diet (less than 10% of calories as carbs).

However, the owner reports that the cost of glargine has risen again (now to just over $200 at our local pharmacy), so the owner wants to switch to another insulin preparation. Glargine has always been my first choice of insulin in diabetic cats so I'm not sure of which insulin would be the best (and cheapest) for this owner to switch to.

Any advice would be greatly appreciated. I'd still like to get this cat to go into remission, but I'm afraid that this will never happen if I stop the Lantus and change to another insulin preparation.

My Response:

The rising cost of all of the human insulin analogs, such as glargine and detemir, are indeed becoming a problem for many owners. If you and the owner decide to switch to another insulin preparation, you have 4 insulin preparations that could be considered (all should be given twice a day):

1. Levemir (insulin detemir), another long-acting human insulin analog
2. ProZinc (Protamine Zinc Insulin; PZI), a long-acting veterinary insulin preparation
3. Humulin N or Novolin N (NPH insulin), an intermediate-acting human insulin preparation
4. Vetsulin (porcine insulin zinc suspension; lente), an intermediate-acting veterinary insulin preparation

Cost comparison
Levemir (detemir): As far as cost, the retail price of Levemir will be about the same or even more than glargine (~$200 per vial), so that's not a good option for this owner.

ProZinc (PZI): A 10-mL vial of ProZinc insulin will be a bit cheaper than either a 10-mL vial of glargine or detemir. Most veterinarians will charge ~$125 - $150 for a vial of ProZinc, whereas both glargine and detemir will be ~$200 or more. That said, ProZinc is certainly not an inexpensive insulin preparation, especially when one considers that ProZinc is a U-40 insulin and each vial contains only 400 units of insulin. Since both glargine and detemir are U-100 insulins, a vial of these insulin preparations will contain 1,000 units of insulin. Therefore, the cost of ProZinc, at least per unit of insulin, turns out to be even more than the human insulin analogs.

Humulin/Novolin-N (NPH): The retail prices of an individual vial of NPH insulin (U-100) will vary widely depending on the pharmacy and its location. At the moment, the least expensive NPH product is Walmart's ReliOn brand (a Novolin insulin), which is sold at ~$25 per vial. However, most other pharmacies charge a retail price of $60 to $100 per vial.  So if you consider the cost per ml of insulin, NPH insulin would be the cheapest.  However, NPH insulin is also the least effective insulin in cats because of its very short duration, so I would not recommend this insulin in any cat, especially if excellent glycemic control or remission is the goal.

Vetsulin (porcine insulin zinc suspension): Vetsulin is available as a 10-mL vial of insulin in a U-40 insulin concentration. For veterinarians, the wholesale cost of the Vetsulin product is inexpensive (~$25 per vial). In most veterinary practices, the retail price of a vial of Vetsulin sold to pet owners will be approximately $50.

Therefore, the cost of a bottle of Vetsulin is similar or even less than the price of NPH insulin and costs much less (about 25-30%) than that of insulin glargine or detemir. But again, the total amount of insulin in a vial of NPH, glargine, and detemir (all U-100 insulins) is 1000 units, where a vial of Vetsulin (a U-40 insulin) contains 400 units, only 40% as much. So in the end, the client cost per unit of Vetsulin would be similar or slightly more than NPH but much less than Lantus, Levemir, or ProZinc.

Effectiveness of insulin preparations in cats
One must remember that it doesn't matter how much money we are saving if the insulin isn't working to control hyperglycemia and prevent ketoacidosis.

Most veterinarians would rank insulin glargine as the first choice of insulin in cats, then insulin detemir or PZI (not the compounded product (1), but FDA-approved ProZinc), then Vetsulin, then finally human NPH insulin as a very last choice (2-10). In my experience, all of the long-acting insulin preparations will show a similar effectiveness and remission rates (~35-50%), although individual cats may respond much better to one of these insulin products.

A number of studies have proven that Vetsulin will certainly control hyperglycemia in cats, especially if combined with a low carbohydrate diet (9,10). The remission rates for Vetsulin, on average, will not be as high as the long-acting insulins, but remission can certainly occur in cats on this insulin.

In this cat, however, remission of the diabetic state is highly unlikely. Most cats will go into remission within 3 months of starting insulin therapy (11-14). If the diabetic state has persisted for longer than 6 months, remission is highly unlikely. This is especially true in diabetic cats like your patient, in which an underlying cause of insulin resistance (i.e., obesity) is present.

Bottom Line

In this cat, given that remission has not occurred after 1-year of therapy with glargine and a low-carbohydrate diet, I would go with the least expensive insulin that will likely be effective in maintaining glycemic control and preventing ketoacidosis.  Overall, the best insulin fitting those criteria would be Vetsulin, which is relatively inexpensive and certainly would be more than adequate in most diabetic cats.

References:

1. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605.
2. Rand JS. Feline diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;133-147.
3. Marshall RD, Rand JS, Morton JM. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. J Vet Pharmacol Ther 2008;31:205-212.
4. Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg 2009;11:683-691. 
5. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
6. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
7. Norsworthy G, Lynn R, Cole C. Preliminary study of protamine zinc recombinant insulin for the treatment of diabetes mellitus in cats. Vet Ther 2009;10:24-28. 
8. Nelson RW, Henley K, Cole C. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. J Vet Intern Med 2009;23:787-793. 
9. Martin GJ, Rand JS. Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 2007;161:88-94.
10. Michiels L, Reusch CE, Boari A, et al. Treatment of 46 cats with porcine lente insulin—a prospective, multicentre study. J Feline Med Surg 2008;10:439-451.
11. Zini E, Hafner M, Osto M, et al. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med 2010;24:1314-1321. 
12. Reusch CE, Hafner M, Tschuor F, et al. Diabetes remission in cats: a review. Schweiz Arch Tierheilkd 2011;153:495-500.
13. Callegari C, Mercuriali E, Hafner M, et al. Survival time and prognostic factors in cats with newly diagnosed diabetes mellitus: 114 cases (2000-2009). J Am Vet Med Assoc 2013;243:91-95. 
14. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clin North Am Small Anim Pract 2013;43:245-249.

What's the Best Insulin for Diabetic Cats and Dogs?

With the reintroduction of Vetsulin (porcine insulin zinc suspension) to the U.S. market (1-3), I've received a number of questions concerning the use of this insulin in dogs and cats. Here are the major questions I've received:

• Is this the initial insulin of choice for dogs? 
• How about for cats? Should this be an insulin that we turn to for our newly diagnosed feline diabetics?  
• If we have a dog or cat that isn't responding well to the current insulin, should they be switched to Vetsulin?
• How will this insulin compare to NPH, glargine (Lantus), detemir (Levemir), or PZI (ProZinc) in cats or dogs?  How does the cost compare to these other insulin preparations?

Is this the initial insulin of choice for dogs?
In my opinion, the answer to that is yes, this is the initial insulin of choice for most dogs. Because it's composed of both short and long-acting insulin components, Vetsulin helps control postprandial hyperglycemia and has a longer duration of action than NPH in most dogs (4-7). The cost is approximately the same as NPH, but less than the insulin analogues (e.g., detemir and glargine). See more below, where I do my cost-comparisons for the various insulin preparations.

Is this the initial insulin of choice for cats?
A number of studies have proven that Vetsulin will certainly control hyperglycemia in cats, especially if combined with a low carbohydrate diet (<10% of calories) (8-11). However, the duration of action may be too short in some diabetic cats, and most feel that the longer acting insulin preparations (glargine, detemir or ProZinc) work better to maintain better control of hyperglycemia in cats (11-13).

Of course, maintaining glycemic control throughout the day is more important if diabetic remission is the goal (13,15,16)— if not, Vetsulin might be less expensive and certainly would be more than adequate in most cats (8-10).

If we have a dog or cat that isn't responding well to the current insulin, should they be switched to Vetsulin?
For diabetic dogs not regulated on NPH, the answer is a definite "yes." For cats that are on NPH, Vetsulin would certainly be a better choice, but switching to one of the  longer-acting insulin preparations (insulin glargine, detemir, or PZI) would be a better choice.

How will this insulin compare to NPH, detemir, glargine, or PZI in cats or dogs?  
In dogs, I generally use 3 insulin preparations: Vetsulin, NPH, and insulin detemir. Again, the main problem with NPH insulin in dogs is that the duration of action is too short, and many of these dogs will respond better to Vetsulin. Insulin detemir is the most potent insulin we have for use in dogs, with a longer duration of action (14), but it's much more expensive than either NPH or Vetsulin.

In cats, I never use NPH because of it's short duration, but I will sometimes use Vetsulin as an intermediate-acting insulin.  Most authorities would rank insulin glargine as the first choice of insulin in cats, then insulin detemir or PZI (not the compounded product (17), but FDA-approved ProZinc), then Vetsulin, then finally NPH as a very last choice.

How does the cost of Vetsulin compare to these other insulin preparations?
NPH insulin, insulin glargine, and insulin detemir are all available as 10-mL vials at a U-100 insulin concentration. The retail prices of an individual vial of NPH insulin, insulin glargine, and insulin detemir vary, depending on the pharmacy and its location. I checked out the prices today at my local Walmart, CVS, and Rite Aid pharmacies, and here are the range of prices I was quoted:

• NPH —$24.88 (Walmart's ReliOn brand) to $100.39 (CVS) and $107.99 (Rite Aid)!
• Glargine — $152.84 (Walmart) to $169.99 (CVS) and $188.99 (Rite Aid)
• Detemir — $160.32 (Walmart) to $190.99 (CVS)

Vetsulin (porcine insulin zinc suspension) is available as a 10-mL vial of insulin in a U-40 insulin concentration. The wholesale cost of the updated Vetsulin product is inexpensive ($23.97 per vial), similar to the original product. In most veterinary practices, the retail price of a vial of Vetsulin will be approximately $50.

Therefore, the cost of a bottle of Vetsulin is similar or even less than the price of NPH insulin and costs much less (about 25-30%) than that of insulin glargine or detemir.  But remember, the total amount of insulin in a vial of NPH, glargine, and detemir (all U-100 insulins) is 1000 units, where a vial of Vetsulin (a U-40 insulin) contains 400 units, only 40% as much. So in the end, the cost per unit of most of these insulins preparations woud generally turn out to be similar.

Therefore, the cost of all of these insulin preparations would be similar in most diabetic cats and smaller dogs receiving a typical daily dose of insulin (0.5-0.7 U/kg). Because the concentration of Vetsulin is 40 U/mL, owners of larger diabetic dogs, owner will often go through a bottle within a few days. In these dogs, if insulin resistance is present, it's sometimes cheaper to use a U-100 insulin, such as detemir.

However, the bottom line is clear: it doesn't matter how much money we are saving if the insulin isn't working. Instead, for most pet owners, it's more important use an insulin preparation that best controls the diabetic state. And for most diabetic dogs, that insulin would be Vetsulin, followed by insulin detemir.

References:

1. Peterson ME. Vetsulin Insulin Updated and Approved for Release in USA. Insights into Veterinary Endocrinology. April 17, 2013.
2. Vetsulin website. www.vetsulin.com
3. Vetsulin website: Veterinary Product Updates. www.vetsulin.com/vet/Product_Update.aspx
4. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682. 
5. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237. 
6. Nelson RW. Canine diabetes mellitus In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
7. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
8. Martin GJ, Rand JS. Pharmacology of a 40 IU/ml porcine lente insulin preparation in diabetic cats: findings during the first week and after 5 or 9 weeks of therapy. J Feline Med Surg 2001;3:23-30. 
9. Martin GJ, Rand JS. Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 2007;161:88-94. 
10. Michiels L, Reusch CE, Boari A, et al. Treatment of 46 cats with porcine lente insulin—a prospective, multicentre study. J Feline Med Surg 2008;10:439-451. 
11. Rand JS. Feline diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;133-147.
12. Marshall RD, Rand JS, Morton JM. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. J Vet Pharmacol Ther 2008;31:205-212.
13. Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg 2009;11:683-691. 
14. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci 2011;90:396-403.
15. Roomp K, Rand J. Intensive blood glucose control is safe and effective in diabetic cats using home monitoring and treatment with glargine. J Feline Med Surg 2009;11:668-682.
16. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
17. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. J Am Vet Med Assoc 2012;240:600-605. 
18. Drugstore.com. www.drugstore.com. (accessed 2006 Oct 3).
19. http://www.relion.com/diabetes/insulin

Insulin Glargine and Injection Pain in Cats

I have a 10-year-old neutered male diabetic cat that has been on 3 units of insulin glargine (Lantus) twice a day for 3 months. The cat's diabetes has responded very well. Over the past few days, however, the owner says that the cat has been in severe pain and appears to be very sensitive in the back area where the insulin injections are given.

The owner did her own research on-line and found information to suggest that Lantus can cause "shooting pain" in some human diabetics. Could this truely be a cause for the cat's pain, or are we most likely dealing with a hyperesthetic syndrome or an orthopedic problem?

They can not bring the cat to me for an exam for a couple of days. Do you have any other suggestions for insulin therapy if the owner decides that they want to stop the Lantus injections?

My Response:

In man, pain resulting from the injection of insulin glargine (Lantus) certainly can occur (1-3). In clinical studies of adult patients done by the manufacturer of Lantus, there was a higher incidence of treatment-emergent injection site pain in glargine-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%) (1).

The reason for the higher frequency of injection pain appears to be related to the fact that, unlike other insulins, insulin glargine is injected as an acidic solution with a pH of 4 (1-4). Careful investigation in children confirm that some individuals will indeed perceive more pain during subcutaneous injection of acidic insulin solutions than neutral insulin solutions (3).

If you decide that a change in insulin preparation is indicated in this cat, alternative, nonacidic, long-acting insulin options for cats include PZI (ProZinc) insulin and insulin detemir (Levemir) (4-9). Lente or NPH are also nonacidic insulins; however, both are intermediate-acting insulin preparations and may have a duration of action that is too short for the diabetic cat (10).

That all said, the pain you describe sounds like the cat's pain is constant and may not be related to the insulin or insulin injections at all. Again, this cat needs a good old physical examination to help sort out the underlying cause of the pain that the owner is describing.

References:

1. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-83.
2. LANTUS (insulin glargine injection), Sanofi-Aventis, Full prescribing information at http://products.sanofi.us/lantus/lantus.pdf
3. Karges B, Muche R, Riegger I, et al. Injection of acidic or neutral insulin and pain: a single-center, prospective, controlled, noninterventional study in pediatric patients with type 1 diabetes mellitus. Clin Ther 2006;28:2094-2101. 
4. Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. Vet Clin North Am Small Anim Pract 2010;40:297-307. 
5. Nelson RW, Lynn RC, Wagner-Mann CC, et al. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 2001;218:38-42. 
6. Norsworthy G, Lynn R, Cole C. Preliminary study of protamine zinc recombinant insulin for the treatment of diabetes mellitus in cats. Vet Ther 2009;10:24-28. 
7. Nelson RW, Henley K, Cole C. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. J Vet Intern Med 2009;23:787-793. 
8. Gilor C, Ridge TK, Attermeier KJ, et al. Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. J Vet Intern Med 2010;24:870-874. 
9. Roomp K, Rand J. Evaluation of detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Feline Med Surg 2012;14:566-572.
10. Marshall RD, Rand JS, Morton JM. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. J Vet Pharmacol Ther 2008;31:205-212. 

ProZinc (PZI Insulin) Supply Status: An Update

As most of you probably already know, ProZinc (PZI insulin), the only insulin preparation specifically made for use in diabetic cats (1,2), has been in short supply for the last few months (see my post about the shortage from last July).  It turns out that the problem has been a shortage of protamine, the protein which slows down the absorption of the PZI insulin and increases its duration of action.

The company that manufacturers ProZinc, Boehringer Ingelheim Vetmedica, had to apply to the FDA for approval to continue to make the insulin using a new source of protamine. The GOOD NEWS is that the company has been granted approval for the insulin formula using the new supplier of protamine. They are now ramping up production of the new ProZinc, but there is a one-month timeline from production to release of an insulin product.

Despite the shortage, current market conditions are better than they have been in awhile. There is still about 4 to 6 weeks of inventory in distribution warehouses at this time. So if you have cats doing well on ProZinc, it should no longer be a problem to obtain the insulin as needed.

References:

1. Nelson RW, Lynn RC, Wagner-Mann CC, et al. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 2001;218:38-42. 
2. Norsworthy G, Lynn R, Cole C. Preliminary study of protamine zinc recombinant insulin for the treatment of diabetes mellitus in cats. Vet Ther 2009;10:24-28. 

Temporary Shortage of ProZinc (PZI Insulin)

As most of you probably already know, ProZinc (PZI insulin) has been on backorder for the last couple of weeks.  It turns out that the problem is a shortage of protamine, the protein which slows down the absorption of the PZI insulin and increases its duration of action.

Hopefully, this shortage will be short-lived and ProZinc will be back soon.

Characteristics of Commercially Manufactured and Compounded PZI Insulin

Characteristics of Commercially Manufactured and Compounded Protamine Zinc Insulin

By J. C. Scott-Moncrieff, G. E. Moore, J. Coe, R. Lynn, W. Gwin, R. Petzold

Journal of the American Veterinary Medical Association 2012; 240: 600-605.

Background
Protamine zinc insulin is a long-acting insulin preparation commonly used for treatment of diabetes mellitus in cats (1-3) and, less commonly, in dogs (4). This insulin is combined with protamine (a protein extracted from salmon) and zinc to delay the absorption of injected PZI insulin and thus prolong its duration of effect (5). Therefore, for PZI insulin to work as expected, the insulin must be properly and carefully formulated with its 3 critical ingredients: protamine, zinc, and insulin (6).

Currently, an FDA-approved human recombinant PZI product (ProZinc, Boehringer Ingelheim Vetmedica, Inc) is commercially available for use in cats and has been reported to result in clinical responses comparable to those achieved with PZI of bovine and porcine origin (2,3). Because of the high cost of commercially manufactured PZI, alternative products have been made available to veterinarians by compounding pharmacies.

The purpose of this study by Scott-Moncrieff et al (7) was to evaluate the quality and consistency of several compounded PZI products and compare them to the commercially manufactured PZI insulin. Moreover, this study was designed to determine if compounded PZI would be as reliable as the commercially manufactured PZI product.

Objective
To evaluate and compare characteristics of a commercially manufactured protamine zinc insulin (PZI) product and PZI products obtained from various compounding pharmacies.

Design of study and 
sample collection
This was an evaluation study looking at 112 vials of PZI (16 vials of the commercially manufactured, FDA-approved PZI product and 96 vials obtained from 12 compounding pharmacies) purchased over an 8-month period.

Procedures
Validated methods were used to analyze 2 vials of each product at 4 time points. Appearance, endotoxin concentration, crystal size, insulin concentration in the supernatant, pH, total insulin and zinc concentrations, and species of insulin origin were evaluated.

Results
All 16 vials of commercially manufactured PZI met United States Pharmacopeia (USP) specifications. Of 96 vials of compounded PZI, 1 (1%) contained a concentration of endotoxin > 32 endotoxin U/mL, 23 (24%) had concentrations of insulin in the supernatant > 1.0 U/mL, and 45 (47%) had pH values below 7.1 or above 7.4; all of these values were outside of specifications.

Several vials of compounded PZI (52/96 or 54%) did not meet specifications for zinc concentration, and total insulin concentration in 36 (38%) of the vials was less than 90% of the labeled concentration.

Conclusions and clinical relevance
Only 1 of 12 compounded PZI products met all USP specifications in all vials tested. Use of compounded PZI insulin products could potentially lead to serious problems with glycemic control in veterinary patients.

My Bottom Line:

Protamine zinc insulin is a complex protein, requiring special expertise to manufacture. The long duration of PZI is attributable to the complexing of insulin with zinc and protamine in precise proportions to form a precipitate, which is released slowly from the subcutaneous tissues after injection (5,6).
It is easy to imagine why a compounding pharmacy may not be able to manufacture PZI insulin, especially insulin that is safe to use and consistent in concentration, onset of action, and duration of the insulin effect. To be honest, I find it more amazed that a compounding pharmacy could produce an insulin product that worked at all!

However, in this study by Scott-Moncrieff (7), a number problems were identified in compounded PZI preparations, included the following:

• Lack of an expiration date or lot number on the vial
• Lack of identification of the species of origin (bovine, porcine, or human)
• High endotoxin concentration
• pH below or above the recommended range
• Low total insulin concentration
• Zinc concentrations below or above acceptable limits
• Variability in insulin concentration among vials from a single compounding pharmacy
• Variability in insulin concentration among different compounding pharmacies that had the same labeled concentration
• Unacceptably high concentrations of insulin in the supernatant.

This study was not designed to identify the clinical consequences of these problems with the use of compounded PZI insulin in cats. However, such deficiencies would likely contribute to poor glycemic control in cats treated with compounded PZI. Other problems that may be seen would include changes in the onset and duration of insulin action, hypoglycemia due to inadvertent insulin overdosage, or fever due to endotoxin.

Based on the results of this study (7), it is clear that compounded PZI insulin cannot be recommended. Regulating diabetic animals is difficult enough without having to deal with variations in insulin quality and potency every time we buy a new bottle.  I believe that it’s best to use a FDA-approved insulin preparation that has external quality control standards applied to it.

 Remember, a bad insulin is almost worse than no insulin at all.

References:

1. Nelson RW, Lynn RC, Wagner-Mann CC, et al. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. Journal of the American Veterinary Medical Association 2001;218:38–42.
2. Nelson RW, Henley K, Cole C, et al. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Journal of Veterinary Internal Medicine 2009;23:787–793. 
3. Norsworthy GD, Lynn R, Cole C. Preliminary study of protamine zinc recombinant insulin for treatment of diabetes mellitus in cats. Veterinary Therapeutics 2009;10:24–28. 
4. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. Journal of Veterinary Internal Medicine 2012;26:109-115.
5. Scott DA, Fisher AM. Studies on insulin with protamine. Journal of Pharmacology and Experimental Therapeutics 1936;58:78–92. 
6. Brange J. Galenics of insulin, the physico-chemical and pharmaceutical aspects of insulin and insulin preparations. New York: Springer-Verlag Inc, 1987.
7. Scott-Moncrieff JC, Moore GE, Coe J, et al. Characteristics of commercially manufactured and compounded protamine zinc insulin. Journal of the American Veterinary Medical Association 2012;240:600-605.

Q & A: Will Lactulose Affect Blood Sugar Levels In Diabetic Cats?

My problem case is an 14-year old, male-neutered DLH cat that has been on a relatively high dose of lactulose (6 ml, bid) for chronic constipation for many years.

One month ago, he developed weight loss, an increase in appetite, and polydipsia. We diagnosed diabetes mellitus (he had severe hyperglycemia with glucosuria) and started him on insulin glargine (Lantus, Sanofi-Aventis). The owner has kept the cat on Hill's dry Science Diet, which the cat loves.

So far, the cat's glargine insulin dose is up to 4 U twice a day (0.9 units/kg), but he is not yet showing any improvement. His last blood glucose was still high at 381mg/dl, with marked glucosuria but negative ketonuria. A serum fructosamine was high at 630 μmol/L (normal <450 μmol/L). A blood glucose curve demonstrated persistent hyperglycemia throughout the day.

My questions are are 4-fold:

1. Does this cat have insulin resistance?
2. Would lactulose have any bearing on this high of blood glucose? Should I try stopping it to see if hyperglycemia improves on insulin therapy?
3. Should I change his insulin to PZI (ProZinc; Boehringer Ingelheim) or another insulin analogue?
4. Is his present diet acceptable?

My Response:

Lactulose is a synthetic, nondigestible sugar developed as a treatment for chronic constipation. It is a disaccharide formed from one molecule each of the monosaccharides fructose and galactose (see Figure 1).

Because it is not digested, lactulose passes unchanged to reach the colon, where it exerts its osmotic laxative effect.Therefore, the lactulose did not contribute to your cats diabetes since the "sugar" in lactulose is not absorbed. Similarly, the drug would not be an issue contributing to the lack of response to insulin therapy in this cat.

Structure of lactulose, a disaccharide

Recommended Steps in this Cat's Management:

1. Rule out urinary tract infection and other concurrent problems

• To start, I'd recommend a urine culture to rule out an occult urinary tract infection. Cat with diabetes are prone to developing urinary tract infections (UTI), so periodic urine cultures are a good idea.

2. Change to a high-protein, low-carbohydrate diet

• You should also consider switching this cat's diet to a good canned food diet — one with a composition that is low in carbohydrates (<10% of calories) and higher in protein (>40% of calories). By lessening the insulin resistance that is a hallmark of diabetes in cats, that diet change will make cats more sensitive to the effects of insulin. 
• Most of my diabetic cats are doing well on an over-the-counter canned food that are low enough in carbohydrates and high in protein content. Check out this website (binkyspage.tripod.com/canfood), which gives you a breakdown of the composition of the various prescription and over-the-counter diets. It turns out that many of the over-the-counter diets have a better composition of protein and carbohydrates than you might have thought — even better than many of the more expensive prescription diets. Very few of my diabetic cat patients require a prescription diet to fulfill their nutritional needs.
• Almost all dry food cat diets are much too high in carbohydrates and  too low in protein content. That is why I believe it's best to limit the amount of dry food that is fed to diabetic cats, or even better, not feed dry food at all.

3. Consider a change in insulin preparation

• Once you have excluded UTI as a cause of insulin resistance, I would change to a more appropriate "diabetic" diet. If no improvement in insulin dosage or glucose regulation is noted after 2-4 weeks, I would recommend switching from insulin glargine to another insulin preparation.
• If needed, I'd recommend a change to PZI (ProZinc), starting at a lower initial dose (e.g., 2 U, BID), and doing dose regulation as needed. I've now seen a few cats that could not be regulated on glargine do better on this insulin preparation.

References:

1. Rucinsky R, Cook A, Haley S, Nelson R, et al. AAHA diabetes management guidelines for dogs and cats. Journal of the American Animal Hospital Association 2010;46:215-224.
2. Frank G, Anderson W, Pazak H,  et al. Use of a high-protein diet in the management of feline diabetes mellitus. Veterinary Therapeutics 2001;2:238-246.
3. Rand JS, Fleeman LM, Farrow HA, eet al. Canine and feline diabetes mellitus: nature or nurture? The Journal of 2004;134(8 Suppl):2072S-2080S.
4. Nelson RW, Henley K, Cole C, et al. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Journal of Veterinary Internal Medicine 2009;23:787-793.

Q & A: Diabetic Cat on Compounded Insulin

I would like your advice on the use of compounded insulin. My patient is a 3.8 kg, 15-year old male diabetic cat that has been on compounded PZI insulin for the past 2 years.

Until recently, he was doing fine on 4 units of the PZI twice daily. However, the cat suddenly developed a severe hypoglycemic episode, which required a 2-day hospitalization stay for treatment at our emergency clinic. The owners brought him directly from the emergency clinic to my hospital; he is bright and alert, but the blood glucose concentration is now high at 458 mg/dl (normal < 150 mg/dl).   

So insulin therapy is being re-started, but I feel this cat should be on ProZinc, not the compounded PZI product. What would be in the best interest for this cat?  If I switch this cat from the compounded insulin, how do I go about it?

My Response:

ProZinc Insulin

I could not agree more about switching to ProZinc, the PZI insulin FDA-approved for use in cats (1).  I do not recommend ever using compounded PZI products because of the fact that potency can vary greatly from batch to batch (2).  It's difficult enough to regulate a diabetic cat without the additional variable of the insulin changing its potency every time the owner buys a new bottle. I feel that it’s far better to get manufactured insulin that has external quality control standards applied to it.

As far as the transition from compounded PZI to ProZinc, I would recommend dropping the ProZinc dose back down to 2 units BID. Then I'd wait a weeks and make additional dose adjustments based upon the cat's clinical status (activity, appetite, water consumption and urination) and a glucose curve, if you feel it's necessary.

In addition to the ProZinc, I'd recommend a good canned cat food — one with a composition that is low in carbohydrates (<10% of calories) and higher in protein (>40% of calories). By lessening the insulin resistance that is a hallmark of diabetes in cats, that diet change will make cats more sensitive to the effects of insulin. What are the owners feeding him now?

Follow-up:

His diet consists of dry Science Diet and Canned Friskies cat food. Are these diets acceptable? Do you think Hill's m/d would be a better choice?

My Response:

In my opinion, m/d is too high in carbohydrates for a diabetic cat.  A better prescription diet food is Purina DM. However, most of my diabetic cats are doing well on an over-the-counter canned food that are low enough in carbohydrates and high in protein content. It may be that the canned Friskies food that your patient is eating now is completely acceptable.

Check out this website (http://binkyspage.tripod.com/foodfaq.html), which gives you a breakdown of the composition of the various prescription and over-the-counter diets. It turns out that many of the over-the-counter diets have a better composition of protein and carbohydrates than you might have thought — even better than many of the more expensive prescription diets. Very few of my diabetic cat patients require a prescription diet to fulfill their nutritional needs.

As I discussed in other posts on diet management, almost all dry food cat diets are much too high in carbohydrates and  too low in protein content. That is why I believe it's best to limit the amount of dry food that is fed to diabetic cats, or even better, not feed dry food at all.

References:

1. Nelson RW, Henley K, Cole C, et al. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. Journal of Veterinary Internal Medicine 2009;23:787-793.
2. Scott-Moncrieff, JC. Comparison of the characteristics of PZI insulin obtained from different commercial sources. J Am Vet Med Assoc 2011 (in press)
3. Rucinsky R, Cook A, Haley S, Nelson R, Zoran DL, Poundstone M. AAHA diabetes management guidelines for dogs and cats. Journal of the American Animal Hospital Association 2010;46:215-224.
4. Frank G, Anderson W, Pazak H, Hodgkins E, Ballam J, Laflamme D. Use of a high-protein diet in the management of feline diabetes mellitus. Veterinary Therapeutics 2001;2:238-246.
5. Rand JS, Fleeman LM, Farrow HA, Appleton DJ, Lederer R. Canine and feline diabetes mellitus: nature or nurture? The Journal of 2004;134(8 Suppl):2072S-2080S.

Q & A: Addison's Disease in a Cat with Juvenile Diabetes

I have a 2-year old, male-neutered DSH cat who had had diabetes mellitus since 4 months of age. He has been very difficult to regulate, but his diabetic regulation and glucose control is much better since changing to ProZinc^®  insulin (Boehringer Ingelheim).

In the past, he has developed recurrent episodes of diabetic ketoacidosis. During each of these episodes, the cat had hyponatremia and hypochloremia. Because of these serum electrolyte changes and the fact that we are having trouble getting him to gain weight, I thought that Addison's disease should be ruled out.

I ran a baseline cortisol concentration 1 week ago, and the value was low at 0.7 μg/dl (reference range, 1.0-4.0 μg/dl). I did an ACTH stimulation test this week to rule out Addison's disease. For this test, I used cosyntropin (Cortrosyn^®) and administered a whole vial (0.25 mg or 250 μg), IV. The results of cortisol results before and after ACTH administration are as follows:

• 0 min (Pre-ACTH): 2.4 μg/dl (reference range, 1.0-4.0 μg/dl)
• 30 min (Post-ACTH): 5.3 μg/dl (reference range, 5.0-12.5 μg/dl)
• 60 min (Post-ACTH): 4.4 μg/dl (reference range, 5.0-12.5 μg/dl)

As you can see, the basal cortisol value is now completely within normal range, but both ACTH-stimulated cortisol values are low-normal. I don't understand why the baseline cortisol was so low 2 weeks ago but now it's so normal. But the response to ACTH stimulation still appears blunted.

Did I do the test correctly? Does this cat have Addison's disease or not?

My Response:

Both cortisol and ACTH are secreted in pulses throughout the day (episodic secretion) with peaks and valleys in hormone levels (1). So it would be very possible to take two serum samples for cortisol measurement just separated by just a few minutes and obtain two very different cortisol values. In my experience, cats tend to have lower basal cortisol concentrations than dogs, so the value of 0.7 μg/dl may be "normal," at least for this cat.

As far as this cat's blunted cortisol response to the cosyntropin (Cortrosyn^®)  injection, cats do not always respond as well as dogs (2,3), so I would consider this cat's ACTH stimulation test to be normal. Again, the post-ACTH peak serum cortisol concentrations tend to be lower in normal cats than the cortisol response seen in dogs. Because an low-normal cortisol response in a cat could be interpreted as severely blunted if the canine reference range is used, it is important for each laboratory to establish their own reference range values for cats. Obviously not all labs have actually done the work necessary to properly establish their own reference range values for all hormones, especially in the cat.

The bottom line: These results completely rule out Addison's disease.

Your protocol for performing the ACTH stimulation test in this cat is fine and certainly provided maximal adrenocortical stimulation, which is the goal of the ACTH stimulation test. Cosyntropin is the preferred ACTH preparation in cats, as it is in dogs. But let's talk more the best protocol for performing this test in cats, because there are some major differences between ACTH test protocols in cats and dogs.

First of all, the route of administration is very important in cats. In dogs, cosyntropin can be administered either IV or IM, with an equivalent cortisol response. In contrast, Cortrosyn should be administered IV to cats, because the adrenocortical response is more consistent and the peak cortisol is higher when given by that route. Given intramuscularly, the cosyntropin is not well absorbed in cats. In addition, giving cosyntropin by the IM route is painful for cats and therefore should be avoided.

Traditionally, it has been recommended that we collect post-ACTH cortisol samples at 30 and 60 minutes in cats to ensure detection of the peak cortisol response (4). However, this was based on the use of the intramuscular route of administration, where the peak cortisol response is lower and occurs earlier, generally at 30 minutes (4). By using the IV route of administration, the peak cortisol response in cats, as well as dogs, occur by 60 to 75 minutes after injection, so a sampling time of 60 minutes is recommended (2,3,5).

For many years, we have recommended administration of a relatively large dose of cosyntropin (125 μg per cat) to ensure an adequate and prolonged adrenocortical response in cats. However, it is clear that this 125-µg dose of cosyntropin, at least when administered IV, exceeds that needed to induce maximal adrenocortical stimulation in clinically normal cats, and that smaller doses can maximally stimulate the adrenal cortex (3,5).

A recent report evaluated the lowest feline dose of cosyntropin, based on body weight, that produced maximal cortisol secretion equivalent to that achieved with the standard dose of 125 μg per cat (5). In that study, the lowest cosyntropin dose that resulted in maximal cortisol response was 5 μg/kg and occurred at 60 to 75 minutes after IV cosyntropin administration. This 5 μg/kg cosyntropin dose is identical to that generally used in dogs for ACTH stimulation testing.

The bottom line: Low-dose ACTH stimulation testing with 5 μg/kg cosyntropin given IV followed by blood sample collection at 60 minutes in cats produced results equivalent to those produced by the traditional 125 μg per cat dose.

Lastly, let me comment about this cat's diabetes. Juvenile diabetes is extremely rare in cats (6,7). Most of these cats appear to have hypoplasia of the pancreatic islets, so almost all are life-long diabetics. Typically, cats and dogs with juvenile diabetes mellitus are extremely brittle, prone to ketoacidosis, and difficult to regulate. Therefore, I'm very pleased to learn that this diabetic cat is doing so well on the twice daily ProZinc insulin.

References:

1. Kemppainen RJ, Peterson ME. Domestic cats show episodic variation in plasma concentrations of adrenocorticotropin, alpha-melanocyte-stimulating hormone (alpha-MSH), cortisol and thyroxine with circadian variation in plasma alpha-MSH concentrations. European Journal of Endocrinology 1996;134:602-609.
2. Peterson ME, Kemppainen RJ: Comparison of intravenous and intramuscular routes of administering cosyntropin for corticotropin stimulation testing in cats. American Journal of Veterinary Research 53:1392-1395, 1992.
3. Peterson ME, Kemppainen RJ: Dose-response relation between plasma concentrations of corticotropin and cortisol after administration of incremental doses of cosyntropin for corticotropin stimulation testing in cats. American Journal of Veterinary Research 54:300-304, 1993.
4. Smith MC, Feldman EC. Plasma endogenous ACTH concentrations and plasma cortisol responses to synthetic ACTH and dexamethasone sodium phosphate in healthy cats. American Journal of Veterinary Research 1987;48:1719-1724.
5. DeClue AE, Martin LG, Behrend EN, et al. Cortisol and aldosterone response to various doses of cosyntropin in healthy cats. Journal of the American Veterinary Medical Association 2011;238:176-182.
6. Woods PJ, Panciera DL, Snyder PS, et al. Diabetes mellitus in a kitten. Journal of the American Animal Hospital Association 1994; 30:177-180.
7. Thoresen SI, Bjerkås E, Aleksandersen M, et al. Diabetes mellitus and bilateral cataracts in a kitten. Journal of Feline Medicine and Surgery 2002; 4:115-22.

To see more of my related posts on this topic, click on the links below:

• What ACTH Preparations Should Be Used For Stimulation Testing? 

• What's the Best Protocol for ACTH Stimulation Testing in Dogs and Cats?