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.

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