Selecting an Insulin for Treating Diabetes Mellitus in Dogs and Cats

From: The 30th Annual Royal Canin/Ohio State University Symposium for the treatment of small animal diseases: Endocrinology, October 2006, http://www.royalcanin.us/documents/OSUProceedings.pdf

Veterinarians often ask which insulin is the best for treating diabetes mellitus in dogs and cats. Unfortunately, this question is difficult to answer. All insulin types currently on the market have the potential to work well in some diabetic dogs and cats but not in others. Recommendations regarding the insulin of choice for treating diabetic dogs and cats are based on personal experiences and vary between clinicians. Some clinicians prefer NPH insulin while others prefer lente insulin for treating diabetic dogs. Some clinicians prefer PZI, some NPH, some lente, and some insulin glargine for treating diabetic cats. Which insulin is ultimately effective in a diabetic is unpredictable. The clinician’s role is to identify which type of insulin works best in the diabetic dog or cat currently being treated. Success with insulin therapy requires knowledge of currently available insulin preparations - their intended use, potency, trends regarding duration of effect, and potential impact of species of insulin origin on diabetic control.

Overview of Insulin Types. Commercial insulin is categorized by promptness, duration, intensity of action, and origin. Short-acting prandial insulins include regular crystalline (Humulin R®, Eli Lilly, Indianapolis, IN), insulin lispro (Humulog®, Eli Lilly) and insulin aspart (Novolog®, Novo Nordisk, Princeton, NJ). Regular crystalline insulin is a recombinant human insulin while insulin lispro and insulin aspart are insulin analogs. Recombinant DNA technology has been used to alter the amino acid sequence of the insulin molecule to alter the absorption characteristics of insulin lispro and insulin aspart following subcutaneous (SC) administration. The rate-limiting step in the absorption of human insulin is a hexamer formation of insulin molecules that occurs at high concentrations of insulin such as those obtained in the injectable fluid.1 After SC administration, the hexamers of insulin molecules slowly dissociate before absorption into the circulation occurs. By replacing certain amino acids in the insulin molecule, the tendency to self-associate into hexamers can be reduced without affecting the insulin-receptor kinetics. Insulin lispro is produced by inverting the natural amino acid sequence of the B-chain at B28 (proline) and B29 (lysine), and insulin aspart is produced by substituting aspartic acid for proline in position B28.2 As a consequence of these alterations, insulin lispro and insulin aspart exhibit monomeric behavior in solution and display a rapid absorption, faster pharmacodynamic action, and shorter duration of effect than regular crystalline insulin.3 Insulin lispro and insulin aspart are the current prandial insulins of choice for control of postprandial blood glucose concentrations in human diabetics and are typically administered prior to breakfast, lunch, and dinner. The role, if any, of these insulins for the home treatment of diabetes in dogs or cats remains to be determined.

Mixtures of short- and long-acting insulin have been developed in an attempt to mimic the increase in portal insulin concentrations during and immediately following consumption of a meal, thereby minimizing postprandial hyperglycemia. NPH insulin can be mixed with regular crystalline insulin and, if injected immediately, the regular insulin remains rapid-acting. Stable premixed 70% NPH/30% regular and 50% NPH/50% regular preparations are available (e.g., Humulin 70/30®, Eli Lilly and Co., Indianapolis, IN; Mixtard HM 70/30®, Novo Nordisk, Princeton, NJ). In my experience, these premixed preparations are quite potent, causing a rapid decrease in blood glucose concentration within 60 to 90 minutes of SC administration, and usually have a short duration of effect. I only use these insulin mixtures as a last resort when more conventional insulin preparations have been ineffective in establishing control of glycemia.

Types of insulin typically used for the home treatment of diabetes include intermediate-acting insulin (NPH, lente) and long-acting basal insulin (PZI, insulin glargine). NPH and PZI insulin preparations contain the fish protein protamine and zinc to delay insulin absorption and prolong the duration of insulin effect. Lente insulin relies on alterations in zinc content and the size of zinc-insulin crystals to alter the rate of absorption from the subcutaneous site of deposition. The larger the crystals, the slower the rate of absorption and the longer the duration of effect. Lente insulin contains no foreign protein (i.e., protamine). Lente insulin is a mixture of three parts of short-acting, amorphous insulin and seven parts of long-acting, microcrystalline insulin. Lente insulin is considered an intermediate-acting insulin, although plasma insulin concentrations may remain increased for longer than 14 hours following SC administration in some dogs.4

NPH (Humulin N®, Eli Lilly, Indianapolis, IN) is a recombinant human insulin, lente (Vetsulin®, Intervet, Millsboro, DE) is a purified pork-source insulin, and PZI (PZI Vet®, IDEXX, Westbrook, ME) is a beef/pork-source insulin with approximately 90% being beef-source insulin. Chronic administration of a foreign protein (i.e., insulin) has the potential to induce formation of circulating insulin antibodies; a problem which has been identified in diabetic dogs treated with beef-source insulin. Bovine insulin stimulates formation of insulin antibodies in 40% to 65% of diabetic dogs in which it is used.5-7 In contrast, development of insulin antibodies following chronic administration of recombinant human or porcine insulin to diabetic dogs appears uncommon6 and the prevalence of serum insulin antibodies causing problems with control of glycemia is uncommon in diabetic cats regardless of the species of insulin.8 Differences in the structure and amino acid sequence of the injected insulin relative to the native endogenous insulin influences the development of insulin antibodies. In a recent study evaluating insulin antibody formation in diabetic dogs treated with bovine insulin, the greatest anti-insulin antibody reactivity was directed against the whole insulin protein rather than the A- or B-chain.7 Serum insulin antibodies may affect the pharmacokinetics and pharmacodynamic response of the exogenously administered insulin. Antibodies may enhance and prolong the pharmacodynamic action by serving as a carrier, or they may reduce insulin action by neutralization.9,10 Antibodies may also have no apparent clinical effect on insulin dosage or status of glycemic control.2 In my experience, insulin antibody production in diabetic dogs can alter the duration of insulin activity and prolong its duration of action or have a deleterious impact on insulin effectiveness, ability to maintain control of glycemia and, in extreme cases, cause severe insulin resistance. The current PZI product on the market is predominately a beef-source insulin and is not recommended for diabetic dogs because of concerns for insulin antibody production.

Insulin glargine (Lantus®, Aventis Pharmaceuticals, Bridgewater, NJ) is a long-acting insulin analog that differs from human insulin by replacing asparagine with glycine at position A21 on the A-chain and adding two arginines to the C-terminus of the B-chain of the insulin molecule.11 These modifications result in a shift of the isoelectric point from a pH of 5.4 toward a neutral pH, which makes insulin glargine more soluble at a slightly acidic pH and less soluble at a physiological pH than native human insulin. As a consequence, insulin glargine forms microprecipitates in the subcutaneous tissue at the site of injection from which small amounts of insulin glargine are slowly released. In humans, the slow sustained release of insulin glargine from these microprecipitates results in a relatively constant con-centration/time profile over a 24 hour period with no pronounced peak in serum insulin. Insulin glargine is currently recommended as a basal insulin (i.e., sustained long-act-ing insulin used to inhibit hepatic glucose production) administered once a day at bedtime and used in conjunction with either prandial insulin analogs or oral hypo12glycemic drugs in human diabetics.In a preliminary study involving healthy cats, most of the pharmacokinetic and pharmacodynamic properties (i.e., onset of action, glucose nadir, time for blood glucose concentration to return to baseline, mean daily blood glucose concentration, and area under the 24-hour blood glucose curve) were similar for insulin glargine and PZI.13 In my experience, insulin glargine has a duration of effect ranging from 10 to 16 hours in most diabetic dogs and cats.

Insulin recommendations in newly-diagnosed diabetic dogs. In my opinion, recombinant human NPH and porcine lente insulin are the initial choices for treating newly-diagnosed diabetic dogs. My starting dosage for both types of insulin is 0.25 U/kg and I prefer to start with twice a day insulin administration because the overwhelming majority of diabetic dogs require NPH or lente insulin twice a day. Establishing control of glycemia is easier and problems with hypoglycemia and glucose counterregulation (i.e., Somogyi phenomenon) are less likely when twice a day insulin therapy is initiated while the insulin dose is low, i.e., at the time insulin treatment is initiated. A recent study evaluating porcine lente insulin in 53 diabetic dogs supports these recommendations.14 The starting dosage in the study was 1 U/kg once a day plus an additional 1 to 4 units depending on the size of the dog; a dosage which was too high as attested by the development of clinical signs of hypoglycemia in approximately 40% of dogs and identification of a blood glucose concentration less than 60 mg/dl in 36% of dogs in the study. Sixty-six percent of dogs required insulin twice a day to attain control of glycemia and the authors speculated that more dogs should have been treated twice a day. Finally, the median (range) insulin dosage required to attain control of glycemia was 1.09 (0.43 to 2.18 U/kg) and 0.75 U/kg (0.28 to 1.40 U/kg)in dogs receiving insulin once and twice a day, respectively; findings that support use of a low initial insulin dosage (i.e., 0.25 U/kg) in newly-diagnosed diabetic dogs.

Studies comparing the efficacy of recombinant human NPH versus porcine lente insulin have not been reported. Similarly, studies evaluating the efficacy of insulin glargine in diabetic dogs have not been reported. My experience with insulin glargine in diabetic dogs has been mixed and somewhat disappointing. I currently only use insulin glargine in poorly-controlled diabetic dogs where NPH and lente insulin are ineffective because of problems with short duration of insulin effect. I rarely use beef/pork-source PZI insulin in dogs because of the potential for development of insulin antibodies that may create problems with diabetic control. I consider using PZI in poorly controlled diabetic dogs where the poor control is caused by short duration of effect of NPH and lente insulin and insulin glargine is ineffective in improving control.

Insulin recommendations in newly-diagnosed diabetic cats. Diabetic cats are notoriously unpredictable in their response to exogenous insulin. There is no single type of insulin which is routinely effective in maintaining control of glycemia, even with twice a day administration. The initial insulin of choice ultimately is based on personal preferences and experiences. Commonly used insulin preparations for the long-term management of diabetic cats include NPH, lente, PZI, and insulin glargine. All have potential problems in diabetic cats. Although lente and NPH insulin are consistently and rapidly absorbed following subcutaneous administration, the duration of effect of lente and especially NPH insulin can be considerably shorter than 12 hours, resulting in inadequate control of glycemia despite twice a day administration. Although PZI is a longer acting insulin, the timing of the glucose nadir is quite variable and occurs within 9 hours of PZI administration in greater than 80% of treated diabetic cats. In one study, PZI significantly improved control of glycemia in newly-diagnosed diabetic cats and poorly-controlled diabetic cats previously treated with ultralente or NPH insulin.15 Comparison of efficacy between PZI and lente insulin has not been reported.

Insulin glargine is the longest acting commercially available insulin for treatment of diabetes in humans and is currently a popular initial choice by veterinarians for the treatment of diabetes in cats. A preliminary study identified better glycemic control and a higher diabetes remission rate in newly-diagnosed diabetic cats treated with glargine twice a day, compared with lente or PZI administered twice a day.16 Another study found no difference in glycemic control in diabetic cats treated with insulin glargine once a day versus diabetic cats treated with recombinant human lente insulin twice a day, and a higher diabetes remission rate in diabetic cats treated with recombinant human lente insulin.17 In my experience, the duration of effect of insulin glargine is quite variable, with the glucose nadir occurring as soon as 4 hours and as late as 20 hours after administration. Insulin glargine works well when given once or twice a day in some diabetic cats and does not work very well in others. Problems are usually related to duration of effect.

Currently, my personal preference for the initial treatment of newly-diagnosed diabetes in cats is PZI at an initial dose of one U per cat administered twice a day. Because the majority of diabetic cats require PZI insulin twice a day, I prefer to start with twice a day insulin therapy while the insulin dose is low to avoid problems with hypoglycemia and glucose counterregulation (i.e., Somogyi phenomenon). I switch to porcine lente insulin given twice a day if problems with prolonged duration of PZI effect develop and glycemic control can not be maintained with once a day PZI and I switch to insulin glargine given twice a day if problems with short duration of PZI effect develop. When using insulin glargine for the treatment of newly-diagnosed diabetic cats, I use an initial dose of one unit per cat administered once a day and switch to twice a day therapy if subsequent blood glucose evaluations support a duration of effect of 12 hours or less.

References

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