The current trend in human medicine is towards long-acting peakless insulin analogue preparations that aim to provide continuous basal insulin supplementation, and which are typically combined with administration at meal times of a rapid-onset, short-acting insulin preparation. This has resulted in many changes in the market for short- and intermediate-acting insulin products and their pre-mixed combinations. It is these products that are most likely to be useful for management of diabetes in dogs and cats, especially if the veterinary insulin preparations prove ineffective or are not available.
WHICH INSULIN PREPARATIONS HAVE BEEN WITHDRAWN?
Veterinarians must adapt to the withdrawal of several familiar insulin preparations. IDEXX Pharmaceuticals have recently withdrawn PZI-VET, which was a 40 U/ml bovine/porcine preparation of protamine zinc insulin registered in several countries for veterinary use. The loss of this product highlights the practical problems often associated with production of animal-sourced insulins. In the human market, all of the Lente and Ultralente insulin preparations were discontinued a number of years ago. There is a similar trend in the human market to withdrawal many of the older, human recombinant insulin preparations. For example, it appears likely that human recombinant regular insulin will be withdrawn in the near future.
WHICH PREPARATIONS ARE STILL AVAILABLE?
Porcine Lente Zinc Suspension
The only Lente insulin preparation now is Vetsulin (trade name in the USA) or Caninsulin (trade name elsewhere in the world), manufactured by Intervet Schering-Plough. This is a 40 U/ml porcine insulin zinc suspension specifically registered for veterinary use (Table 1).
Availability of Vetsulin in the USA has recently been severely limited by a FDA recall, as a result of their findings that he product may contain varying amounts of crystalline zinc insulin;1 however supply of Caninsulin elsewhere is unaffected and has been reliable for many years.
There is good evidence that this insulin product is effective for the treatment of diabetes mellitus in dogs and cats. (references 2,3,4) Lente insulin has an intermediate duration of action and is a combination of 30% short-acting Semilente insulin and 70% longer-acting Ultralente insulin. It is particularly suited to a twice-daily dosing regimen in diabetic dogs because the meal can be fed at the time of the insulin injection. This more dilute 40 U/ml veterinary preparation is advantageous for small dogs and cats, which might require a total insulin dose of only 1 or 2 U. Dosing is more simple and accurate if specific U-40 syringes are prescribed with this product.
Products containing 100% regular crystalline insulin (recombinant human insulin) are still available (100 U/ml) and have long been recommended for the management of diabetic ketoacidosis and ketosis in dogs. These include Humulin R (Eli Lilly) and ActRapid (Novo Nordisk). If these products are withdrawn from the human market, it will be necessary for veterinarians to switch to the newer short-acting insulin analogue preparations, such as insulin lispro or insulin aspart (Table 1).
Isophane (NPH) Insulin
Humulin N (Eli Lilly) and Novolin N (Novo Nordisk) are both recombinant human NPH insulin (100 U/ml) that have an intermediate duration of action (Table 1). The human NPH insulins are effective for the treatment of diabetes in dogs when administered twice-daily.5 These recombinant human NPH insulins do not work well in most cats and are NOT recommended.
Combinations of 70% Isophane (NPH) and 30% Regular Insulins
Humulin 70/30 (Eli Lilly) is still available in most countries. This is a 100 U/ml pre-mixed combinations of 30% short-acting and 70% intermediate-acting insulin (Table 1). Because it has a similar duration/action curve to Lente insulin, this insulin is well suited to a twice-daily dosing regimen in diabetic dogs where meals are fed at the same time as the insulin injections.
Recombinant Human Protamine Zinc Insulin
The release of ProZinc (Boehringer Ingelheim) provides a veterinary product to fill the gap in the market created by the discontinuation of PZI-VET, and efficacy of the new product (references 6,7) for treatment of diabetic cats is comparable to that of the discontinued product (reference 8). ProZinc is an FDA approved insulin and is available as a U-40 insulin concentration.
Protamine zinc insulin is not generally recommended as a first choice therapy for diabetic dogs as it has a less predictable action with a slower onset than Lente insulin or the 70% or 100% NPH preparations.
Short-Acting Lispro Insulin Preparations
Lispro insulin (Humalog, Eli Lilly) has been shown to be a safe and effective alternative to regular insulin for the treatment of diabetic ketoacidosis in dogs. Insulin Aspart (Novolog, manufactured by Novo Nordisk) and glulisine (Apidra, manufactured by Sanofi Aventis) are other short acting insulin analogs that could be used as an alternative to regular insulin (Table 1).
Lantus (Sanofi Aventis) is a long-acting synthetic insulin analogue developed for the human diabetic market to provide continuous basal insulin concentrations that inhibit hepatic glucose production. The therapeutic aim is to mimic the physiological pattern of insulin secretion of healthy subjects, and the basal insulin levels provided by these products are supplemented at meal times by administration of short-acting insulin preparations that act during the postprandial period.
Glargine insulin differs from standard insulins because it has been genetically modified, by replacing an asparagine with glycine and adding 2 arginine amino-acids to the c-terminal end of the molecule. This alters the pH solubility (isoelectric point) of the molecule, so that it is soluble at a pH 4 but insoluble at neutral pH (e.g., in the body). When glargine insulin is injected into the skin, it precipitates because of the pH change and forms insoluble microcrystals, which are slowly absorbed into the circulation. This constant release of small amounts of insulin prevents major peaks and troughs from developing. The formation of micro-precipitates and slow absorption are dependant on the acidity of glargine. Therefore, glargine cannot be mixed or diluted.
Insulin glargine is efficacious for the treatment of diabetes in cats. (references 9,10) Although there is very little information about the use of this product in dogs, it does not appear to work well in this species.
Levemir (Novo Nordisk) is another synthetic insulin analogue with long duration of action that is produced using recombinant DNA technology. The insulin molecule is modified by the addition of an acylated fatty acid chain that enables reversible binding to plasma proteins, from where it is released slowly into plasma.
Detemir results in a similar action profile as glargine, but appears to be more potent and may be longer-acting in some dogs and cats.
Mixtures of Short-Acting and Long-Acting Insulin Analogues
The latest insulin preparations released for the human market are pre-mixed combinations of a short-acting insulin analogue (ie, Lispro or Aspart insulin) with a longer-acting insulin analogue (ie. Lispro or Aspart Protamine Insulin). See Table 1 for more information.
Humalog Mix 75/25 (Eli Lilly) is marketed for human diabetics as an improved product that can be used twice-daily in replacement of Humulin 70/30 (reference 11). Compared with Humulin 70/30, Humalog Mix75/25 in human subjects has a more rapid and predictable onset of glucose-lowering activity, with greater reduction in postprandial glycemia when administered with a meal, and a similar duration of action.
There is currently no published information on the use of these new pre-mixed combinations for the management of diabetes in dogs or cats. At least in diabetic dogs, these insulins might be effective when administered twice-daily at the same times as meals. Based on the human data, it can be predicted that the risk of hypoglycemia might be greatest in the first 2 hours after injection in dogs and so it will likely be crucial that meals are always consumed at the time of injection.
- FDA CVM alert.
- 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;19:675-82.
- Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237.
- 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 10:439-51.
- 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.
- Norsworthy GD, Lynn RC. Clinical study to evaluate a new formulation of protamine zinc for treatment of diabetes mellitus in cats. J Vet Intern Med 22:729-730, 2008.
- Nelson RW, Henley K, Cole C. Efficacy of protamine zinc recombinant insulin for treating diabetes mellitus in cats. J Vet Intern Med 22: 730, 2008.
- Nelson RW, Lynn RC, Wagner-Mann CC, Michels GM. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 2001;218:38-42.
- 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
- Rand J. Editorial: glargine, a new long-acting insulin analog for diabetic cats J Vet Intern Med 2006;20: 219-20.
- Eli Lilly prescribing information.