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.

Can Twice-Daily Insulin Be Injected at Any Time of the Day?

I have questions regarding treatment of a 8-year old, male labrador retriever with poorly-regulated diabetes. He has been treated with once daily insulin (Vetsulin), administered once a day in the morning at 11 pm for the last 3 months. Despite insulin treatment, the dog remains hyperglycemic and glycosuric and if very thin.

The owner has a very odd work schedule, and he is not generally home in the early morning when the AM dose of insulin is generally given, so that's why the insulin shot is given in the late morning. I would like to put him on twice daily insulin; however, I was hesitant because the dog would have to get the two doses of insulin at 11 am and 11 pm if we are going to give the insulin at 12-hour intervals.

I have always assumed there was some sort of diurnal influence on blood glucose concentrations that mandated that we give the insulin first thing in the morning (6-8 am at time of breakfast) and then again in the early evening at dinner time. But when I actually dug out my physiology textbook and did not some on-line research, I didn't find any mention of this.

So my questions— is there any reason to not give him insulin injections at different times during the day? Why do we routinely start injections in the earlier morning— is just because that's when animals (and people) typically get fed?

My Response:

The problem of nocturnal hypoglycemia in human diabetics
In human patients treated with insulin (type 1 diabetes), nocturnal hypoglycemia is a well-recognized complication that can lead to major problems in regulation (1-7). Almost half of all episodes of severe hypoglycemia that develops in human patients occur at night during sleep. Such episodes of nocturnal hypoglycemia can be prolonged and can lead to seizures or coma in rare cases (7). In addition, this nocturnal hypoglycemia can lead to rebound hyperglycemia (Somogyi phenomenon) (1,8).

The problems of overnight hypoglycemia in human type I diabetes are further complicated by the dawn phenomenon (1,9,10). The dawn phenomenon is the combination of an initial decrease in insulin requirements between ~2400 and ~0300, followed by an increase in the insulin needs (and therefore, a tendency to develop hyperglycemia) between ~0500 and ~0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients (1,9,10).

Overall, this brings up the questions: does nocturnal hypoglycemia or the dawn phenomenon occur in dogs with diabetes?

Studies of canine diabetics
In a recent study, Mori and colleagues (11) monitored 5 diabetic dogs (treated with either NPH or insulin detemir) with a continuous glucose monitoring system (CGMS) over a 2-week period. They evaluated the daily glycemic profiles obtained with CGMS and compared glucose fluctuations between day- and night-time in these diabetic dogs. For data analyses, day-time was defined as 9:00 am-9:00 pm and night-time as 9:00 pm-9:00 am.

Using these glucose profiles, the investigators evaluated the following parameters: 1) the mean blood glucose concentrations (1- and 12-hr intervals); 2) the time spent in the hyperglycemic range (greater than 200 mg/dl); and 3) the time spent in the hypoglycemic range (less than 60 mg/dl). None of these parameters differed significantly between day-time and night-time in these insulin-treated dogs. 

Overall, this study confirmed that there are no differences in glucose fluctuations between day- and night-time, in diabetic dogs on a similar feeding regimen and insulin administration when monitoring carefully using CGMS. These studies also indicate that diabetic dogs do not frequently develop nocturnal hypoglycemia, unlike the situation in human patients with diabetes. Finally, dogs do not appear to develop the dawn phenomenon, as manifested by a morning surge in hyperglycemia, which again occurs in nearly all human diabetic patients.

Bottom line:

Based on these studies, there does not appear to be any physiologic reason why we must administer insulin injections first thing in the morning (with breakfast) and then again later at dinnertime. The reason we tend to give in the morning and evening is that most folks go to work during the day, not at night.

It doesn't matter when we give the insulin injections, but dogs almost always need twice-daily insulin injections, so we would want to give the injections about 12 hours apart. In this dog, I see no reason not to give insulin injections at 11 am and 11 pm if that schedule works best for the owner.

References:

1. Bolli GB, Perriello G, Fanelli CG, et al. Nocturnal blood glucose control in type I diabetes mellitus. Diabetes Care 1993;16 Suppl 3:71-89. 
2. Matyka KA. Sweet dreams?--nocturnal hypoglycemia in children with type 1 diabetes. Pediatr Diabetes 2002;3:74-81.
3. Yale JF. Nocturnal hypoglycemia in patients with insulin-treated diabetes. Diabetes Res Clin Pract 2004;65 Suppl 1:S41-46. 
4. Raju B, Arbelaez AM, Breckenridge SM, et al. Nocturnal hypoglycemia in type 1 diabetes: an assessment of preventive bedtime treatments. J Clin Endocrinol Metab 2006;91:2087-2092. 
5. Greenhill C. Diabetes: Nocturnal hypoglycemia is frequent in patients with type 1 diabetes mellitus. Nat Rev Endocrinol 2010;6:299. 
6. Ahmet A, Dagenais S, Barrowman NJ, et al. Prevalence of nocturnal hypoglycemia in pediatric type 1 diabetes: a pilot study using continuous glucose monitoring. J Pediatr 2011;159:297-302. 
7. Bay C, Kristensen PL, Pedersen-Bjergaard U, et al. Nocturnal continuous glucose monitoring: accuracy and reliability of hypoglycemia detection in patients with type 1 diabetes at high risk of severe hypoglycemia. Diabetes Technol Ther 2013;15:371 377. 
8. Nocturnal hypoglycemia as a cause of fasting hyperglycemia (Somogyi phenomenon). N Engl J Med 1988;318:1537-1538.
9. Campbell PJ, Bolli GB, Cryer PE, et al. Pathogenesis of the dawn phenomenon in patients with insulin-dependent diabetes mellitus. Accelerated glucose production and impaired glucose utilization due to nocturnal surges in growth hormone secretion. N Engl J Med 1985;312:1473-1479. 
10. Carroll MF, Schade DS. The dawn phenomenon revisited: implications for diabetes therapy. Endocr Pract 2005;11:55-64. 
11. Mori A, Kurishima M, Oda H, et al. Comparison of glucose fluctuations between day- and night-time measured using a continuous glucose monitoring system in diabetic dogs. J Vet Med Sci 2013;75:113-117. 

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

Vetsulin Insulin Updated and Approved For Release in USA

Merck Animal Health just announced that Vetsulin (porcine insulin zinc suspension) will again be available for distribution in the USA this week (1). This is welcome news, especially for dogs with diabetes mellitus that are not well regulated with other available insulin preparations, such as human recombinant NPH. Most authorities consider Vetsulin, known as Caninsulin outside the USA (2), to be the initial insulin of choice for treatment of dogs with diabetes mellitus (3-6). It can also be used to successfully manage cats with diabetes (7,8), but we have many other good options for treatment of feline diabetes.

As you may know, Vetsulin has had its share of problems in the last few years, which lead to the FDA having it withdrawn from the US market. All of these manufacturing issues have been resolved, and the FDA has re-approved the drug for release.

How is the "new" Vetsulin different than the original insulin product?

According to the company, the updated Vetsulin product has the same characteristics as the original insulin preparation, and the action in diabetic patients is expected to be the same as before. There have been no changes in the safety profile of Vetsulin for use in either dogs or cats.

The only difference in the Vetsulin itself is a slight change in the listed proportion of the short-acting amorphous fraction and long-acting crystalline fraction. The short-acting amorphous fraction is now listed as 35% (it was 30%), whereas the long-acting crystalline fraction is now reported as 65% (it was 70%).

Vetsulin will now be available only in 10-ml vials. The 2-5 ml vial formulation of Vetsulin has been discontinued.

Two important differences in the updated Vetsulin Package Insert: (9)

1. Prior to use, vials of Vetsulin should be shaken thoroughly (manually) until a homogeneous, uniformly, milky suspension is obtained. Foam on the surface of the suspension formed during shaking should be allowed to disperse before the product is used.
2. Vetsulin contents should be used within 42 days after the vial is first punctured.  

For the first new vials of Vetsulin that are released, the initial product dating will be only 12 months from the manufactured date. The company expects that Vetsulin will eventually have a 24-month shelf-life.

Additional information can be found on the Veterinary Home Page under the Product Update section (10). Also, see the package insert for full information regarding contraindications, warnings, and precautions (9).

Bottom line:

It's great to have Vetsulin, an FDA-approved insulin for use in both dogs and cats, back on the market. The company has done a great deal of work showing that Vetsulin is stable and effective, and they have made a few minor but good improvements in this insulin preparation.

Vigorous manual shaking of the Vetsulin? How will that impact accurate dosing?
We have all been taught that vigorous shaking will interfere with accurate dosing because of air bubbles that form when the insulin bottle is shaken (5,11). When the dose is drawn up, the insulin suspension may come out into the syringe together with lots of air bubbles.  In addition, we tend to worry that too vigorous shaking may damage the insulin protein structure itself. For these reasons, we generally instruct owners to gently roll the insulin vial than to vigorously shake it!

According to the company, the instructions are now to give the Vetsulin bottle a vigorous shake on initial use; then let it settle for a few minutes to let the bubbles rise before drawing up the dose. Upon subsequent insulin dosing, the bottle should only need a quick shake (less vigorous) to resuspend the insulin prior to drawing up the insulin dose.

Why this difference in vigorous shaking vs. rolling? I don't know, but I suspect it has something to do with the way the study was designed and input from the FDA. In any case, Merck Animal Health actually has done the studies to prove that this vigorous manual shaking does not interfere with the measured insulin concentration in the product (10).

Why was the proportion in the short-and long-acting insulin fractions changed? 
According to the company, the proportions of the short-acting amorphous fraction and long-acting crystalline fraction have not actually changed, as compared to the original Vetsulin product. Instead, the new stated ratio (65% long-acting and 35% short-acting insulin) represents a more accurate reflection of the actual composition of both the original and updated Vetsulin product (10).

Nevertheless, on a clinical basis, such a small change in the short- vs. the long-acting insulin fractions would not be expected to make any difference in the animal's glycemic control, even if the composition of the product did change slightly.

Vetsulin (porcine insulin zinc suspension), with it's 2 peaks of insulin activity

Must Vetsulin really be discarded after only 42 days? 
The Vetsulin product insert (9) clearly states that the product should be used within "42 days of first vial puncture."

Has the efficacy really been determined to decrease after 42 days?  The answer to that is no — it's almost certain that the potency of this preparation will extend many days (or even weeks) longer than this 42 days.  However, because Merck Animal Health only did the FDA studies for a period of 42 days, that's what they have been required to put on the package insert. But remember, in addition to efficacy, we must also worry about bacterial contamination secondary to repeated puncture of the insulin vial (11).

Why such a short expiration date? 
Again, for the first new vials of Vetsulin that are released, the initial product dating will be only 12 months from the manufactured date. This is not because the updated Vetsulin is unstable, but the FDA requires ongoing studies of the insulin's duration. The company expects that Vetsulin will eventually have a 24-month shelf-life (10).

Since we do not have to worry about Vetsulin disappearing again, at least anytime soon, I wouldn't recommend purchasing too many insulin vials now, since the initial "expiration" date will be only a few months.

References:

1. Vetsulin website. www.vetsulin.com
2. Caninsulin website. www.caninsulin.com
3. 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. 
4. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237. 
5. 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.
6. 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.
7. 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. 
8. Martin GJ, Rand JS. Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 2007;161:88-94. 
9. Vetsulin Package Insert. www.vetsulin.com/PDF/Vetsulin-Package-Insert.pdf
10. Vetsulin website: Veterinary Product Updates. www.vetsulin.com/vet/Product_Update.aspx
11. American Diabetes Association. Insulin administration. Diabetes Care 2001;24:1984-1987. 

More Information on the Discontinuation of the Vetsulin® Critical-Need Program (CNP)

Intervet/Schering-Plough Animal Health has announced it is discontinuing the VETSULIN® Critical-Need Program (CNP) effective immediately and will no longer provide VETSULIN® after the current supply is exhausted, which is expected to be the end of this month (February 2011).

Quality tests showed that the sterility of the most recent batch of VETSULIN® manufactured for the Critical-Need Program may be compromised by bacterial contamination.  This batch of VETSULIN® has not been released.  We therefore cannot supply the program and it is being discontinued.

See attached letters for more information (click on each letter to enlarge):

No Resolution to Problems in Shortage of Vetsulin

A new development in the ongoing Vetsulin recall situation. From the FDA website: http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm242368.htm

FDA Announces Upcoming Shortage of Vetsulin for Dogs and Cats in the Critical Need Program

February 4, 2011

The Food and Drug Administration (FDA) announced today an anticipated shortage of Vetsulin (porcine insulin zinc suspension), a product used to treat diabetes mellitus in dogs and cats. Vetsulin is manufactured by Intervet/Schering-Plough Animal Health and is only available to animals currently enrolled in the Vetsulin Critical Need Program.

In November 2009, FDA announced its concerns about the stability of Vetsulin, which may cause the product to have unpredictable onset and duration of action in dogs and cats treated with Vetsulin. At that time, FDA recommended that diabetic dogs and cats currently receiving Vetsulin be switched to other insulin products. In May 2010, Intervet/Schering-Plough Animal Health initiated the Vetsulin Critical Need Program, intended for a critical need dog or cat that, in the medical judgment of the pet’s veterinarian, could not be effectively managed on another insulin product.

In November 2010, Vetsulin intended for use in the Critical Need Program, failed critical manufacturing tests which are routinely conducted to assure consistency and quality of the drug. The tests showed that the sterility of the most recently manufactured batches of Vetsulin may be compromised by bacterial contamination. This batch of Vetsulin has not been released.

FDA has no evidence that Vetsulin currently on the market and being used under the Critical Need Program is affected. No adverse events consistent with bacterial infection in cats and dogs receiving Vetsulin have been reported to CVM under the current program.

Intervet/Schering-Plough Animal Health has indicated that it will be sending letters to owners of the pets enrolled in the Vetsulin Critical Need Program and their veterinarians. In those letters, the firm will be notifying veterinarians and pet owners of the upcoming shortage of Vetsulin and consequent discontinuation of the Vetsulin Critical Need Program. Owners of diabetic cats and dogs are encouraged to consult their veterinarian as soon as possible about transitioning their pets to other insulin products. Intervet/Schering-Plough Animal Health is planning to provide detailed instructions to veterinarians on how to manage the transition.