Blood Glucose Curves and the Fractious Diabetic Cat

My problem patient is a 12-year old, DSH, female spayed cat with a 2-year history of insulin-dependent diabetes mellitus. She has been treated with glargine insulin at a variable dose, but typically between 1-3 units, BID. This cat will not eat canned food so we are feeding higher protein, lower carb dry foods (Hill's MD and Purina DM).

Six months ago, the cat was diagnosed with immune-mediated hemolytic anemia (IMHA) and was treated successfully with prednisolone and cyclosporine (Atopica). This led to development of insulin resistance and loss of diabetic control, but the cat did relatively well after raising the insulin dose to 6 units while on prednisolone. After a long and slow taper, the cat is now off all glucocorticoids for the last month, and the insulin dose is back down to 2 U, twice daily. The cat remains on Atopica, probably for life.

We have periodically done in-house blood glucose curves to adjust her insulin dose, but she becomes extremely fractious when hospitalized, and we can't really handle her (she bites, scratches, cries, and screams louder than any other cat I've ever had!). The owner does not care to check blood glucose at home, and given the cat's nature, I doubt if they could even do it. Since weaning her off the prednisolone, we have seen a couple of hypoglycemic readings on spot blood glucose checks so we are now worried that the current insulin dose may be too high.

Therefore a week ago, we performed a serial glucose curve on 2 units glargine, BID. The results were as follows:

• 6 am = Insulin given
• 8 am = 317 mg/dl
• 10 am = 376 mg/dl
• 12 noon = 352 mg/dl
• 2 pm = 299 mg/dl
• 4 pm = 229 mg/dl

We were a bit surprised by the high glucose concentrations during the day on this curve, but we increased glargine from 2 to 3 units BID based on the severe and persistent hyperglycemia. However, when I checked a spot afternoon blood glucose value yesterday, it was low-normal at 69 mg/dl. I rechecked another blood glucose reading 30 minutes later, and it was even lower at 57 mg/dl. Right or wrong, I put her back down to 2 units glargine BID and pm spot check in 1 week.

My main question is this: could this cat's in-hospital curve be leading us astray because she is so fractious? I am aware that spot checks aren't ideal. However, this cat is relatively easy to handle during a quick exam and single spot check, but she become so angry when hospitalized throughout the day.

What would you do? How do I adjust the insulin dosage in this cat? We've been trying to get the cat into remission but it's not looking good!

My Response:

Well, first the bad news: I can almost guarantee that this cat's diabetes will not go into remission, given the fact that she has been diabetic for 2 years. A number of studies have reported that diabetic remission, when it does occur, will generally happen within the first 6 months of diagnosis (1,2). In addition, the fact that she has concurrent disease and has been treated with glucocorticoids certainly hasn't increased her chances for remission.

The good news is that once we decide that diabetic remission is no longer our goal, then we can be more lax with our glucose regulation. Our goal for diabetic cats should then be 3-fold:

1. Control clinical signs of diabetes (e.g., weight loss, polyuria, polydispsia)
2. Prevent diabetic ketoacidosis
3. Avoid hypoglycemia

To do this, it's not really necessary to do the tight glucose regulation and frequent blood glucose monitoring that we would ideally do if we are trying to increase the odds for diabetic remission (3-5).

In fractious diabetic cats, I would never recommend doing serial blood glucoses to determine the best insulin dose. The release of catecholamines during this excitable state can absolutely increase the glucose readings during the curve (commonly referred to as stress hyperglycemia) (6). Overall, this means that all of the serial blood glucose curves you have done in this cat are most likely next to meaningless and that such testing should be stopped.

Spot glucose checks can't hurt, but as you say, they can be hard to interpret and may be misleading. If the blood glucose reading is low, you might want to decrease the insulin dose, but if the blood glucose is in the ideal range or high, you could still be overdosing the insulin.

In cats like this, I'd recommend that you adjust the insulin dose based on the presence or absence of clinical signs, including body weight and water intake (7).  If the owners can measure water intake at home, that can be a very sensitive way to help determine if more insulin is needed. If there are no clinical signs of diabetes and the weight is stable, the cat is probably adequately controlled. Monitoring an occasional serum fructosamine level can also help (8,9), as well as home measurement of urine glucose, if the owner can do it (7,19,11). A weekly check for urinary ketones can also be used to monitor for pending ketoacidosis, and become extremely important if anorexia, vomiting, or any other signs of illness develop.

Bottom Line:
In fractious cats, I would not recommend in-hospital blood glucose curves for monitoring. Stress hyperglycemia will give you results that are meaningless, and one could easily be misled into giving higher doses of insulin than are actually needed. This is especially true in cats with long-term diabetes that are unlikely to ever develop remission.

In cats like this case, I use a combination of clinical signs and blood/urine values, looking at the overall trend in results rather than the specific or individual values. For example, I don't use serum fructosamine concentration as the sole means of judging control, but I still think it is helpful as one piece of the puzzle. If it is high, that suggests that the insulin dosage may have to be increased; if the fructosamine value is low to low-normal, this may indicate overdosage and hypoglycemia.

Believe me, both your hospital staff and the fractious diabetic cat will all be better off with this approach!

References:

1. Gottlieb S, Rand JS. Remission in cats: including predictors and risk factors. Vet Clinics North America 2013: 43: 245-249
2. 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.
3. 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.
4. 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.
5. Nack R, DeClue AE. In cats with newly diagnosed diabetes mellitus, use of a near-euglycemic management paradigm improves remission rate over a traditional paradigm. Vet Q 2014; 34:132-136.
6. Rand JS, Kinnaird E, Baglioni A, et al. Acute stress hyperglycemia in cats is associated with struggling and increased concentrations of lactate and norepinephrine. J Vet Intern Med 2002;16:123-132. 
7. Miller E. Long-term monitoring of the diabetic dog and cat. Clinical signs, serial blood glucose determinations, urine glucose, and glycated blood proteins. Vet Clin North Am Small Anim Pract 1995;25:571-584. 
8. Crenshaw KL, Peterson ME, Heeb LA, et al. Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med 1996;10:360-364. 
9. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64-68. 
10. Bennett N. Monitoring techniques for diabetes mellitus in the dog and the cat. Clin Tech Small Anim Pract 2002;17:65-69. 
11. Cook AK. Monitoring methods for dogs and cats with diabetes mellitus. J Diabetes Sci Technol 2012;6:491-495. 

Top Clinical Endocrinology Research Abstracts, 2014 ACVIM Forum: Diabetes Part 3

Following last week’s post, this is the next installment of my review of the "top 12 list" of clinical endocrinology research abstracts presented at this year's American College of Veterinary Internal Medicine Forum.

As with last week's post, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health.  Rhett also serves as a consultant for the Animal Endocrine Clinic, so I talk to him almost every day about the more difficult cases I see in my practice.

In this post, we will review another of these "top 12" abstracts (finishing up with the diabetes abstracts). Next week, we will turn to the top clinical abstracts dealing with the adrenal gland, and then finish with disorders of the thyroid over the next 2 weeks. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Bertalan AV, Drobatz KJ. Hess RS. NPH and Lispro Insulin for Treatment of Dogs with Diabetes Mellitus. J Vet Intern Med 2014;28:1026.

Some dogs, treated with twice-daily NPH insulin and Hill's W/D diet, have postprandial hyperglycemia despite having clinically well-regulated diabetes mellitus (DM). The goal of this study was to determine whether postprandial hyperglycemia and fructosamine concentration can be decreased by adding lispro insulin to the treatment protocol.
      Six dogs were enrolled into this ongoing prospective study. Dogs were enrolled if they had clinically well-regulated DM while treated with NPH insulin and W/D q12 hours and if they had postprandial hyperglycemia defined as an increase in blood glucose concentration (BG) within two hours of NPH insulin administration and feeding. Fructosamine was quantified and BG was measured just before feeding and NPH insulin administration (T0), every 30 minutes for the first 2
hours (T30, T60, T90, T120), and every two hours thereafter for eight additional hours. Dogs were then treated at home with the same NPH insulin dose and W/D, but a separate lispro insulin injection of 0.1 Unit/kg SC was added to the NPH insulin and W/D protocol. Serial BG and fructosamine were measured two weeks later and compared to the original values using the Wilcoxon Signed Rank Test. Median [range] fructosamine (400 μmol/L [289–624 μmol/L]), and BG at T60 (313 mg/dl [187–376 mg/dl]) and T90 (239 mg/dl [166–332 mg/dl]) were significantly higher before lispro insulin was introduced compared to two weeks later (390 μmol/L [253–486 μmol/L]), p = 0.046, 117 mg/dl [42–307 mg/dl]), p = 0.028, and 94 mg/dl [48–197 mg/dl]), p = 0.028, respectively). 
      It is concluded that addition of lispro insulin to an NPH and W/D treatment protocol may significantly decrease fructosamine and postprandial hyperglycemia.

Comments— In this study, addition of a rapid-acting insulin analog (insulin lispro; Humalog, Lilly) to a standard twice-daily NPH insulin regimen appeared to improve glycemic control in dogs with clinically controlled diabetes. This finding is not unexpected, since it is well known that the administration of a short-acting insulin at time of meals will help lessen post-prandial hyperglycemia and lead to improved overall glycemic control in diabetic patients (1-4).

Rapid-acting insulin analogs— Although human recombinant regular insulin is still used as a short-acting insulin by most veterinarians, this insulin has been replaced for the most part with one of the more rapid-acting insulin analogs in human medicine (5-7). One of these newer rapid-acting insulin analogs is insulin lispro, which was the first commercially available insulin analog produced (6,7). Compared with regular human insulin, this insulin analog offers the advantages of faster subcutaneous absorption, an earlier and greater insulin peak, and a shorter duration of action. Although not used frequently in dogs, insulin lispro has been reported by this same group of investigators to be as effective as regular insulin in the treatment of ketoacidosis (8).

Long-acting insulin analogs and analog mixtures—Like human regular insulin, use of human NPH insulin is gradually being phased out and replaced with a mixture of rapid- and long-acting insulin analogs (5-7, 9-11). For example, newly diagnosed insulin-dependent human patients may be treated with a combination of once to twice daily injections of glargine (Lantus) or detemir (Levemir), together with a rapid-acting analog (e.g., insulin lispro or aspart) given at time of meals (11-14). Pre-mixed combinations of a short-acting synthetic insulin analog (i.e., lispro or aspart insulin) with a longer-acting insulin analog (i.e., lispro or aspart protamine insulin) are also commercially available as Humalog Mix 75/25 (Eli Lilly) or NovoLog Mix 70/30 (Novo Nordisk) (5,10). Both of these insulin analog mixtures are given twice daily with meals.

Time interval between insulin injection and meal intake— When a short-acting insulin (either human recombinant regular insulin or lispro) is added to the overall insulin regimen, it is standard protocol that the rapid-acting insulin be given shortly prior to ingestion of the meal (2-4,15,16). This allows enough time for the injected insulin to be absorbed into the circulation and blunt the post-prandial rise in blood glucose concentration. If the insulin injection is delayed until after the meal, severe post-prandial hyperglycemia may develop, which can lead to a clinical state resembling insulin resistance in some patients.

Most veterinarians fail to consider the importance of the time interval between insulin injection and meal intake when evaluating glycemic control in their diabetic dogs on standard insulin protocols. Whenever possible, I like to have my owners inject insulin (NPH, Vetsulin, or NPH/regular combinations) about 20-30 minutes before the dog eats, which allows enough time for insulin to to be partially absorbed and prevent severe post-prandial hyperglycemia (17).  With a more rapidly absorbed insulin, such as lispro, the timing between insulin injection and feeding can likely be shortened to less than 20 minutes. Of course, administering insulin injections prior to feeding is not always possible or even advisable, especially if the dog's appetite is poor or variable.

It is unclear what the time interval was between insulin injection and meal intake in this study by Bertalan et al., since it was not stated. If not given prior to feeding, however, the results might have been improved by using such a protocol.

The Bottom Line— In dogs with problem diabetes, addition of a short-acting insulin to the overall insulin regime may be helpful, especially in those dogs that experience severe post-prandial hyperglycemia.  The interval between insulin injection and meal intake must be taken into consideration when employing this protocol, and the addition of a short-acting insulin would likely be less effective when injected after eating. In any case, further research needs to be done on the effect on the timing of insulin injections and meals in dogs with diabetes mellitus.

Although insulin lispro works well in dogs, a major disadvantage of using any insulin analog, including lispro, is the high cost. All of the insulin analogs are approximately 3 to 5 times more costly than conventional human recombinant NPH, regular, or mixtures of NPH 70/30 insulins.

On a practical basis, there is little reason to use insulin lispro over human regular insulin in dogs, especially when you consider the great difference in cost. Premixed NPH/regular insulin is commercially available as Humulin 70/30 (Eli Lilly) or Novolin 70/30. Both of these commercial preparations contain a 100 U/ml pre-mixed combination of 30% short-acting (regular insulin) and 70% intermediate-acting insulin (NPH). In the USA, the cheapest place to purchase human regular, NPH, and 70/30 combinations is at Walmart, which sells these insulins as the ReliOn Novolin brand for around $25 per vial (19).

Another option, of course, is porcine lente insulin (Caninsulin or Vetsulin), which is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente, respectively) (20,21). Although more expensive than the ReliOn Novolin 70/30 insulin, Vetsulin is certainly much more cost effective than any of the insulin analogues. With either insulin preparation, I like to give the injection about 20-30 minutes prior to feeding to ensure that adequate insulin concentrations will be present in the circulation when the meal is absorbed to blunt the rise in blood glucose concentration and help better control the diabetic state (17).

References:

1. Brownlee M. Insulin treatment of diabetes. Hosp Pract 1979;14:85-94. 
2. Phillips M, Simpson RW, Holman RR, et al. A simple and rational twice daily insulin regime. Distinction between basal and meal insulin requirements. Q J Med 1979;48:493-506. 
3. Holman RR, Turner RC. A practical guide to basal and prandial insulin therapy. Diabet Med 1985;2:45-53. 
4. Zinman B. Insulin regimens and strategies for IDDM. Diabetes Care 1993;16 Suppl 3:24-28. 
5. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183. 
6. Campbell RK, Campbell LK, White JR. Insulin lispro: its role in the treatment of diabetes mellitus. Ann Pharmacother 1996;30:1263-1271. 
7. Noble SL, Johnston E, Walton B. Insulin lispro: a fast-acting insulin analog. Am Fam Physician 1998;57:279-286, 289-292. 
8. Sears KW, Drobatz KJ, Hess RS. Use of lispro insulin for treatment of diabetic ketoacidosis in dogs. J Vet Emerg Crit Care (San Antonio) 2012; 22:211-218.
9. Kalra S. Newer basal insulin analogues: degludec, detemir, glargine. J Pak Med Assoc 2013;63:1442-1444. 
10. Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs 2006;66:31-49. 
11. Hermansen K, Fontaine P, Kukolja KK, et al. Insulin analogues (insulin detemir and insulin aspart) versus traditional human insulins (NPH insulin and regular human insulin) in basal-bolus therapy for patients with type 1 diabetes. Diabetologia 2004;47:622-629. 
12. Ashwell SG, Gebbie J, Home PD. Optimal timing of injection of once-daily insulin glargine in people with Type 1 diabetes using insulin lispro at meal-times. Diabet Med 2006;23:46-52. 
13. Ashwell SG, Amiel SA, Bilous RW, et al. Improved glycaemic control with insulin glargine plus insulin lispro: a multicentre, randomized, cross-over trial in people with Type 1 diabetes. Diabet Med 2006;23:285-292. 
14. Lucchesi MB, Komatsu WR, Gabbay MA, et al. A 12-wk follow-up study to evaluate the effects of mixing insulin lispro and insulin glargine in young individuals with type 1 diabetes. Pediatr Diabetes 2012;13:519-524. 
15. MacGillivray MH, Mills BJ, Voorhess ML. Meal intolerance in type 1 diabetes mellitus: influence of time interval between insulin therapy and meal intake. J Med 1984;15:417-435. 
16. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010;12:173-177. 
17. Peterson ME. New development in the use of insulin mixtures and analogs for the problem diabetic. Proceedings of the 2013 American College of Veterinary Internal Medicine (ACVIM) Forum 2013;534-537.
18. Sawicki PT. Commentary: Does additional benefit justify additional costs of insulin analogues? BMJ 2011;343:d5858. 
19. ReliOn Insulins. http://relion.com/diabetes/insulin
20. Horn B, Mitten RW. Evaluation of an insulin zinc suspension for control of naturally occurring diabetes mellitus in dogs. Aust Vet J 2000;78:831-834. 
21. 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.

Escalating Costs of Insulin Glargine (Lantus): Can We Switch to Another Insulin?

My patient is a 14-year-old male Toy Poodle (weighing only 5 kg) that has been maintained on insulin glargine (Lantus; Sanofi-Aventis) for several years. Currently, the dog is receiving an insulin dose of 6 units twice daily and is doing well (i.e., no obvious polyuria, normal appetite with stable body weight). However, over the last few months, the price of Lantus has skyrocketed to over $250 for a 10-ml vial. The owner would like to switch to a more affordable insulin, if possible. At 12 units a day, she is going through a 10-ml vial of Lantus every 2.5 months or so.

My question is this: would another long-acting insulin —such as detemir (Levemir) or PZI (ProZinc)— be more cost-effective in this dog? Or would you suggest that I start over with an intermediate-acting insulin, such as NPH (Humulin N or Novolin N) or Vetsulin?

I did not start this dog on Lantus, but the owner claims that they had great difficulty in regulating him after his initial diagnosis. Therefore, I'm a bit hesitant to "rock the boat" when the Lantus seems to be doing the job. Do you have any ideas why the price has gone up so much over the last year or so?

My Response:

Long-acting insulins, such as glargine, are not commonly used in dogs with diabetes, although they can work fine to control clinical signs in some dogs (1-3). However, because these insulins have a less potent glucose-lowering effect than do more commonly used intermediate-acting insulins (NPH, Vetsulin), larger doses of the long-acting insulin preparation are often needed (1,2). Therefore, use of glargine or PZI (ProZinc) are generally cost-effective only in smaller dogs.

For example, notice that the daily glargine dose in this Toy Poodle is over 1 U/kg twice a day, which is in the expected dose range for a long-acting insulin in dogs (1-3). If this dog weighed 50 kg rather than only 5 kg, this would equate to a dose of 60 U twice a day, which means that we would go through a 10-ml vial of Lantus every two weeks or so! In contrast, most diabetic dogs on an intermediate-acting insulin can be well-regulated using doses of 0.5-0.7 U/kg per injection (4,5).

What's leading to the steady increase in the price for insulin glargine(Lantus)?
The drug maker Sanofi-Aventis has steadily raised its price of Lantus (insulin glargine) during the past 12 months, prompting angst among many pet owners and veterinarians alike. These concerns, of course, are inconsequential to Sanofi, since Lantus is FDA-approved for human diabetic patients (a huge market), and the insulin is not marketed for use in either dogs or cats.

Since I don't work for Sanofi-Aventis, I do not know what’s driving the escalating price increases that we have seen over the past few months. However, we do know that Sanofi's patent for Lantus expires in 2015, opening the market to competitors who can then release generic glargine insulins. Therefore, it is likely that Sanofi is trying to generate as much income as the company can from this branded insulin preparation before the patent expires and generic glargine preparations hit the market.

In support of that, it's known that Eli Lilly also has a generic equivalent in the works (6). Sanofi recently responded by suing Eli Lilly for alleged patent infringement (7). The lawsuit triggered a stay of approval by the FDA, delaying the release of Eli Lilly’s generic to mid-­2016.

However, Merck & Co. also recently announced that it's version of generic glargine is in the late stages of clinical trials (8). It's likely that Sanofi will also sue Merck in order to delay their release of a generic product too, but again, I don't know.

Do you understand why I sometimes hate using these human insulin analogs? We, as veterinarians, have absolutely no say or control in anything that is going to happen to price or availability, and it's certainly no use to complain. These companies don't market their products to us and really do not even want to know we use them in our patients.

Are other long-acting insulins less expensive than Lantus?
Unfortunately, when we look at the cost of other long-acting insulin preparations, the cost is not much cheaper than the current cost of Lantus, at least when we look at the cost per unit of insulin. The dose of ProZinc would likely be approximately the same as the glargine in this dog— at about $100 per 10-ml vial, the cost of ProZinc seems significantly less, at least at first glance. However, we must remember that each vial of ProZinc (a U-40 insulin) contains only 400 units of insulin, so this dog (on 6 units, twice a day) would need about one new vial per month. Since each 10-vial of Lantus contains 1,000 units, the cost per unit of insulin is about the same when these two insulin preparations are compared.

Insulin detemir (Levemir, Novo Nordisk) is another story. Although the cost of this U-100 insulin is equivalent to Lantus (about $250 per vial), this insulin is a very potent insulin when used in dogs (this is not true in cats). The average determir dose that most diabetic dogs require ranges from only 0.1-0.2 U/kg per injection — 5 to 10 times less that the average glargine dose needed for diabetic dogs (9,10).

That all said, I would hesitate to use detemir in this toy breed dog because of it's high potency. The calculated starting dose for a 5 kg dog would only be 0.5 U, and it's unlikely that more than 1 U per injection would ever be needed. As we all know, it's very difficult to measure 0.5 units of insulin accurately and overdosage might be expected. Because of its potent glucose-lowering effects, hypoglycemia is more common with detemir than the other longer-acting insulins.

Should a switch to an intermediate-acting insulin be considered?
Most diabetic dogs that we treat are not started on a long-acting insulin. In fact, use of an intermediate acting insulin, such as NPH or Vetsulin, are generally considered to be the insulins of choice when starting treatment for dogs with diabetes mellitus (4,5).

NPH is a much less expensive human U-100 insulin that is available at Walmart as their ReliOn brand of Novolin-N for only about $25 (11). Personally, I find that Vetsulin (Merke Animal Health) is a better choice than NPH in most dogs since it's a bit longer acting, and this insulin is also made by a veterinary company (Merck Animal Health) and licensed for use in dogs. As you know, the veterinarian cost for Vetsulin is around $30 per 10-vial, but, again, each insulin vial contains only 400 units rather than the 1000 units in each vial of NPH. Therefore, the cost is indeed a bit more for Vetsulin than NPH, at least when we look at the price of the Walmart ReliOn brand.

No matter what insulin we change to (ProZinc, Levemir, NPH, or Vetsulin), the dog will have to again be regulated. This may go very smoothly—but then again, this is a diabetic, it's always difficult to predict what is going to happen with certainty. I'd give the owner the pro's and con's of continuing the Lantus vs switching, but in the long-run, it may be best to stick with the Lantus and hope that the generic versions hit the market sooner than Sanofi would like!

References:

1. Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, et al. Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 2012;170:52. 
2. Maggiore AD, Nelson RW, Dennis J, et al. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 2012;26:109-115. 
3. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 2013;243:1154-1161. 
4. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med 2009;23:50-55. 
5. 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. 
6. Eli Lilly Press Release, Dec. 20, 2013. Eli Lilly and Company and Boehringer Ingelheim announce new drug application filing in the U.S. for new insulin glargine product. 
7. Reuters,  Jan 30, 2014. Sanofi sues Eli Lilly over patents for top-selling insulin drug.
8. Merck Newsroom.com, February 10, 2014. Merck and Samsung Bioepis Enter Collaboration Agreement to Develop and Commercialize Insulin Glargine Candidate for Diabetes.
9. Mori A, Sako T, Lee P, et al. Comparison of time-action profiles of insulin glargine and NPH insulin in normal and diabetic dogs. Vet Res Commun 2008;32:563-573. 
10. 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. 
11. ReliOn Insulins. http://relion.com/diabetes/insulin

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