Insulin therapy in the dog and cat (Proceedings)

Insulin has become increasingly important in the treatment of dogs and cats with diabetes mellitus. Almost all dogs are classified with insulin-dependent or type 1 diabetes mellitus. Although up to 60% of cats are non insulin-dependent or type 2 diabetics at the time of diagnosis1 , early intervention with exogenous insulin is an important component to achieving remission and preserving the function of insulin-secreting beta cells. For this reason almost all of our diabetic dogs and cats will be treated with insulin so it is important to understand which insulin preparations are available and their utility in our canine and feline patients.

History

Insulin was first discovered in 1921. The original preparations were bovine and porcine pancreatic extracts. These formulations were short-acting, relatively dilute and impure. As a result, frequent administration and large volumes of insulin were required. Due to impurities, local reactions were common. Because beef and pork insulin differ from human insulin by 3 and 1 amino acids, respectively, many people developed insulin antibodies which resulted in variable and poor responses to these insulins in some diabetic people. Over time more concentrated beef and pork insulins were produced and purity improved. In the 1930's – 1950's it was discovered that the addition of protamine and zinc would cause crystallization of insulin and slow absorption. In the 1980's recombinant DNA technology led to the development of human recombinant insulin. The production of human recombinant insulin led to a dramatic decrease in the use of animal-origin insulin in man. The 1990's lead to the discovery of synthetic insulin analogues in an attempt to achieve better glycemic control.2

Ultra Short and Short Duration Insulins (Lispro, Aspart, Human Recombinant Regular)

Insulin analogues were developed to better mimic the basal-bolus requirements of man as well as improve consistency. The premise is that a more constant (basal) amount of insulin is produced by the pancreas as a result of glucose produced by the liver in between meals, i.e. in the fasted state. There is also a larger, more rapid increase (bolus) in insulin after meals as a result of post-prandial hyperglycemia.

Human recombinant regular insulin was the traditional 'bolus' insulin used separately or in mixed preparations with an intermediate insulin. Using regular insulin, peak insulin levels occurred at 60 minutes with a duration of up to 6 hours. This is because regular insulin exists as a hexamer (6 insulin molecules) that dissociates into dimers and monomers once injected subcutaneously. Monomers are the active form and required for absorption into the bloodstream. When given intravenously regular insulin rapidly dissociates to monomers so there is a more rapid onset and shorter duration. Because of the pharmacokinetics of subcutaneously administered human recombinant regular insulin in man, it is administered 30 to 45 minutes prior to eating. This was inconvenient so ultra short-acting analogues were developed that could be administered at the time of or 15 minutes prior to eating. Insulin analogues manipulate the amino acids sequences to alter absorption and dissociation. The ultra-short analogues achieved a more rapid onset, higher peaks and shorter duration. Insulin lispro (Humalog® - Eli Lilly & Co.) was created by switching proline-lysine to lysine-proline at the 28th and 29th positions on the beta chain of the insulin molecule. Insulin aspart (Novolog® - Novo Nordisk Laboratories) was created by the substitution of aspartic acid for proline at the 28th position on the beta chain. These substitutions prevent self-aggregation of the insulin molecules that can delay absorption.2

Ultra short acting analogues are not of any clinically significant benefit over human recombinant regular insulin in dogs and cats but may become important if we lose human recombinant regular insulin formulations. A single study in dogs reported that insulin lispro was comparable to regular insulin when given by continuous rate infusion to dogs with diabetic ketoacidosis.3

Intermediate Duration Insulins (NPH, Lente)

In 1946 Krayenbuhl and Rosenberg of Novo-Hagedorn Laboratories, following the work of Scott and Fisher (see PZI below), discovered that the addition of equal amounts of a protein derived from fish sperm, protamine, and regular insulin with a small amount of zinc prolonged the duration of insulin. This led to the development of Neutral Protamine Hagedorn (NPH). Neutral Protamine Hagedorn insulin is also referred to as isophane insulin due to its symmetrical structure and equal composition of regular insulin and protamine. This is the only human recombinant insulin that can be mixed with regular insulin because the regular insulin is not bound by the NPH so there is a short duration of effect derived from the regular and a longer effect from the NPH.1,2

Neutral Protamine Hagedorn must be given to cats and dogs twice daily. The peak is often too rapid and duration too short in both species, even with twice daily administration. This is particularly problematic in cats so this insulin is not routinely used in this species. Some dogs can be managed well with NPH and NPH mixes (70/30 = 70% NPH + 30% regular) with great success. The advantage of a mixed formulation would be in those dogs that have frequent post-prandial hyperglycemia with NPH administration. The regular insulin will help decrease or eliminate this problem.

In 1952 Hallas-Moller developed lente insulin when they discovered that the addition of zinc and an acetate buffer crystallized insulin and prolonged its duration. Lente insulin is actually 30% of short-acting semilente (not commercially available) and 70% long-acting ultralente. Initial preparations were beef/pork products because the pork insulin tends to be amorphous whereas the beef insulin crystallizes to a greater extent. The greater amount of zinc in lente insulin can lead to micro crystallization of any added regular insulin so they are not mixed.1,2

A pork lente insulin (Caninsulin® - Intervet/Schering Plough) is available as a U-40 preparation. Pork insulin is considered ideal for the dog because porcine and canine insulin are identical. Porcine lente has also been used successfully in cats for many years. The previously available FDA approved US equivalent, Vetsulin®, has been removed from the market due to problems with composition. It was found that Vetsulin® contained varying amounts of crystalline zinc which may cause a delay in onset and prolonged action. Although the insulin was found to be out of specifications established by Schering- Plough and the FDA it does not appear that most diabetic dogs and cats on this insulin are clinically affected. Currently the FDA allows Schering Plough to distribute a limited amount of Vetsulin® under a critical needs program for dogs and cats in which the veterinarian has determined that there is no other insulin that can be used to manage their diabetes effectively. Intervet's technical service department can be contacted at 1-800-224-5318 to enroll pets in this program.

Longer Duration Insulins (Glargine, Detemir, PZI)

In 1936 the work of Hagedorn, Scott and Fisher led to the development of protamine zinc insulin (PZI). Hagedorn discovered that the addition of various proteins, including protamine, could prolong insulin activity. Scott and Fisher also added the zinc and PZI was born.1,2

Eli Lilly & Co. manufactured PZI until 1991 at which time this insulin was unavailable commercially in the U.S. for several years. Commercial production resumed of a beef/pork formulation through IDEXX (PZI VET®) until 2008. There is still a limited supply of PZI VET® available through distributors but now a human recombinant PZI (Prozinc®) is available through Boehringer Ingelheim that has been shown to be effective in cats.4,5 Previous PZI formulations were primarily beef so there were concerns that dogs will develop antibodies against the beef component thus it has not traditionally been recommended in dogs. The use of human recombinant PZI in dogs has not been extensively studied. Despite being referred to as a long acting insulin, the majority of cats can not be regulated on once daily dosing. This is also a U-40 insulin.

More recently, long acting insulin analogues have been developed to more closely mimic the basal insulin secretion in man. Historically, the human recombinant intermediate insulins had to be given to people twice daily, which was inconvenient. Human recombinant insulins also showed patient-to-patient, interpatient and site variability in effect. For this reason the long-acting analogues such as glargine (Lantus® - Aventis Pharmaceuticals) and detemir (Levemir® - Novo Nordisk) were developed utilizing recombinant DNA technology.2

Insulin glargine was created by substituting a glycine amino acid for an asparagine at the 21st position of the alpha chain in the insulin molecule. Two arginines were also added to the beta chain. This results in an insoluble insulin molecule at a neutral pH. It is solubilized at an acidic pH and, once administered into the neutral subcutis, becomes insoluble to slow absorption. Glargine is relatively peakless, exhibits little patient-to-patient variability and can be given once daily in man. Because it is formulated in an acidic pH it can not be diluted or mixed without altering its pharmacokinetics.1,2

Glargine has become increasingly popular in cats with diabetes due to increased rates of diabetic remission (typically when accompanied by dietary modification) compared to lente and PZI insulin in newly diagnosed diabetic cats.6,7,8 Glargine has a longer duration than lente or PZI in cats and can be used once daily. Although many cats can be controlled with once daily administration, twice daily administration is believed by some to provide superior glycemic control and improve remission rates, particularly in newly diagnosed diabetic cats. The initial dose recommendations in cats are 0.5 U/kg BID if glucose is >/= 360 mg/dL and 0.25 U/kg if glucose is < 360 mg/dL. Because hypoglycemia is fairly common when instituting therapy, glucose curves (pre insulin then every 4 hours) are recommended for the first 72 hours when instituting therapy. Dogs have shown a less predictable response to glargine than cats so it is not as commonly used in this species. The recommended dose in dogs is 0.25 U/kg twice daily. Glargine can be stored in the refrigerator for 6 months. Additional information on glargine insulin can be found at www.uq.edu.au/vetschool/centrecah. Interestingly, a recent study has looked at the administration of intermittent intramuscular glargine with or without concurrent subcutaneous glargine insulin in cats with diabetic ketoacidosis and showed that it was effective in treating their disease.9

Insulin detemir is another long acting analogue created by the addition of a fatty acid moiety to position 29 of the beta chain of the insulin molecule. This fatty acid binds albumin in circulation and slows activity.2 There is limited experience with this analogue in dogs and cats. A study in a small number of poorly regulated and newly diagnosed diabetic dogs demonstrated improved glycemic control in all dogs with 46% of dogs well regulated.10 While no dose has been established for insulin detemir in dogs and cats, it is recommended to start cats utilizing the same guidelines as glargine but one study of long term use in cats found that the maximal dose was roughly 30% of the glargine dose form a previous study.11 Dogs are started on 0.1 to 0.2 U/kg twice daily.

Complications of Insulin Therapy

Persistence of clinical signs is common with insulin therapy. This may be a result of problems with the insulin itself, insulin under dosage, insulin over dosage or insulin resistance.

Insulin may be ineffective if it is stored, handled or administered incorrectly. Unused insulin is typically refrigerated. Once opened, it is often stored at room temperature when used in man. This led to the recommendation that insulin be replaced every 30 days due to potential loss of potency as well as microbial contamination. It is recommended that insulin for animals is stored in the refrigerator once opened. An important exception to this is insulin pens which should be stored at room temperature once opened. Refrigeration is thought to prolong potency and prevent contamination. The exact duration of maximum potency for most insulins is unknown. Some insulins contain crystals that if disturbed can lead to alterations in absorption and potency. For this reason insulin suspensions (NPH, PZI, lente) should not be shaken. It is typically recommended to administer insulin over the lateral thorax and flanks alternating sites. Skin over the neck and back may be thickened and insulin deposited intradermally affecting absorption. Animals can occasionally develop changes in the skin and dermis at the site of repeated injection and this might interfere with absorption. Dilute insulins can have variable potency so dilution should be avoided if possible. If diluting insulin, the diluent recommended by the manufacturer should be used.

Insulin under dosage should be suspected in a dog given < 1.0 U/kg/dose or a cat < 0.5 U/kg/dose with persistence of signs (weight loss, increased water consumption, increased urination).1 Clinical signs and high serum fructosamine and/or inadequate response on a blood glucose curve supports underdosage. Under dosage is more common in animals on once daily insulin as a result of short duration of effect.

Hypoglycemia is fairly common in diabetic dogs and cats that undergo insulin therapy but not all animals are symptomatic. With profound hypoglycemia (glucose < 65 mg/dL) diabetogenic hormones are released that result in increased glucose. Glucose may increase to over 400 mg/dl and remain increased for many hours to several days. This protective mechanism is blunted in some individuals resulting in hypoglycemia. Hypoglycemia is more common in newly diagnosed diabetics, cats with transient diabetes, animals given large increases in dose of insulin, patients on twice daily long-acting insulin, with increased activity and with decreased caloric consumption. Remember in cats, particularly new diabetics, it is common to revert to a non-diabetic state. This is the result of some endogenous insulin production or resolution of disease causing insulin resistance. Clinical signs of hypoglycemia include inappetence, lethargy, weakness, seizures and coma. Repeatedly negative urine glucose and a normal fructosamine are findings that should also raise suspicions of insulin overdosage and possible hypoglycemia.

Insulin resistance has classically been defined as poor or lack of glycemic control at >1.5 U/kg/dose in the dog and cat and most animals can be controlled on < 1 U/kg/dose.1 Transient insulin resistance can occur as part of insulin over dosage via the Somogyi phenomenon but may also occur as the result of insulin antagonistic drugs, diseases or conditions. Bacterial infections (in particular the oral cavity and urinary tract), pancreatitis, hyperadrenocorticism, drugs (e.g. glucocorticoids, progestins), hyperthyroidism (cat), stress (cat), and obesity are relatively common causes of resistance. Chronic inflammation, acromegaly (cat), hypothyroidism (dog), renal disease, liver disease, cardiac disease, glucagonoma, pheochromocytoma, exocrine pancreatic insufficiency, hyperlipidemia, and other forms of neoplasia have also been reported to cause insulin resistance. With insulin resistance, glucose curves may show little to no response to insulin or a response may be noted but excessive amounts of insulin required.

Insulin is a foreign protein that can result in anti insulin antibodies. Antibodies are thought to result from differences in conformational epitopes of insulin molecules. The formation of antibodies results in erratic changes in blood glucose, insulin resistance and poor glycemic control. In dogs and cats, antibodies to human recombinant insulin are uncommon and occur in less than 5%. Dogs do tend to develop antibodies to beef insulins, with an incidence as high as 45% with beef/pork formulations.1

Adjustments in Insulin Therapy

It is difficult to make general recommendations regarding insulin adjustments in dogs and cats. One of the most important determinants in insulin adjustment is clinical signs. It may take dogs and cats several days to adapt to the introduction of insulin. For this reason hyperglycemia should not be concerning in the newly diagnosed healthy diabetic and increases in maintenance insulin are not typically recommended earlier than one week after instituting therapy. Patients may be monitored after starting insulin therapy for hypoglycemia and appropriate reductions in insulin dose made. As stated previously, hypoglycemia is fairy common with initiation of glargine insulin in cats but clinical signs of hypoglycemia are rare. In general if hypoglycemia develops in dogs and cats, the dose of insulin is reduced by 25 - 50%. In some cases (e.g. Somogyi with excessive insulin doses) it may be advisable to revert to a recommended initial dose. Remember in cats diabetic remission is possible so in those on small amounts of insulin (</= 0.5 unit per dose) that develop hypoglycemia, discontinuation of insulin may be indicated. Diabetic remission is much more common in newly diagnosed diabetic cats and does not typically occur in the dog.

Traditionally diabetics have been monitored with clinical signs (primarily water consumption and urine production), glucose curves and serum fructosamine levels. Clinical signs continue to be important in evaluating a diabetic patient. A well-regulated animal should no longer be polyuric, polydipsic, polyphagic and maintaining (or gaining) weight.

The following discussion pertains to stable diabetics. A glucose is sometimes performed on cats initially placed on glargine or detemir for up to 72 hours because of the high incidence of hypoglycemia but in most instances curves are not performed earlier than 7 days after initiation of therapy. Curves are then performed every 7 to 14 days until a stable insulin dose has been determined. In-hospital glucose curves had long been the mainstay of diabetic monitoring. It is often difficult to get animals to mimic their lifestyle in the hospital including activity level and caloric consumption that may affect blood glucose levels. In-hospital glucose curves are particularly problematic in cats due to stress hyperglycemia. The impact of these factors can be minimized by having owners perform glucose curves at home. Glucose curves should consist of a pre-insulin/meal glucose and the nadir. The number of samples required varies patient to patient and with insulin types. With intermediate-acting, more potent insulins (NPH, lente), more glucose measurements may be necessary to determine the nadir because it can occur at various times and be quite dramatic over a shorter period of time. This is the basis for the traditional recommendation of glucose checks every 2 hours. For the less potent, 'peakless' insulins (glargine, detemir) a pre-administration glucose followed by measurements every 3 to 4 hours until the next insulin dose may be adequate. Glucose curves for diabetic ketoacidosis and sick diabetics require more intense monitoring than stable diabetics.

It is also important to remember that human glucometers are designed to measure venous blood glucose in people and are not necessarily accurate in dogs and cats. These glucometers also often read 30 mg/dl lower to protect diabetics from hypoglycemia. When utilizing glucometers calibrated for dogs and cats, there is a difference in recommendations made. The following are recommendations utilizing glucometers calibrated for dogs and cats. In general when using glucometer calibrated for dogs and cats, a pre-insulin glucose < 250 mg/dl and a nadir between 100 and 150 mg/dl are ideal. In the cat, a pre-insulin glucose < 250 mg/dl in the cat with a nadir between 100 and 150 mg/dl is desirable. Increases in the dog depend on the current dose and degree of glucose elevation but do not usually exceed 20 to 25% or 0.5 to 1 unit in the cat. Reductions are dependent on the nadir and presence of clinical signs but are typically approximate 50%. When weaning cats off insulin it is recommended they be gradually decreased to 0.5 units per dose and then insulin discontinued. Regarding duration, if giving twice daily insulin and the nadir occurs within 3 hours or the duration is < 8 hours a longer-acting formulation should be considered. If the duration is greater than 12 hours (nadir > 8 hours) the options are once daily administration or twice daily administration at a lower dose.

Fructosamine is a measure of glycated proteins in the serum and is a reflection of glucose levels over 2 to 3 weeks time.1 Fructosamine can also help eliminate concerns of stress hyperglycemia in cats but there are many factors that affect fructosamine so using them as a sole guide for insulin therapy is not recommended. Signs of hyperglycemia in the face of an elevated fructosamine should prompt a glucose curve to assess glycemic control.

References

Feldman EC, Nelson RW. Canine and Feline Endocrinology and Reproduction. Saunders. 2004.

Leahy JL, Cefalu WT eds. Insulin Therapy. Marcel Dekker, Inc. 2002.

Sears KW, Hess RS, et al. Use of lispro insulin for treatment of dogs with diabetic ketoacidosis. J Vet Intern Med 2009 May-June 23(3):696.

Norsworthy G, Lynn R. Preliminary study of protamine zinc recombinant insulin in the treatment of diabetes mellitus in cats. Vet Ther 2009 Spr-Sum 10(1-2):24-8.

Nelson RW, Henley K, et al. Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats. J Vet Int Med 2009 Jul-Aug 23(4): 787-93.

Marshall RD, Rand JS, et al. Treatment of newly diagnosed diabetic cats with glargine improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J feline Med Surg. 2009 Aug;11(8):683-91.

Boari A, Aste G, et al. Glargine insulin and high-protein-low-carbohydrate diet in cats with diabetes mellitus. Vet Res Commun. 2008 Sep;32 Suppl 1:S243-5.

Hall TD, Mahony O, et al. Effects of diet on glucose control in cats with diabetes mellitus treated with twice daily insulin glargine. J Feline Med Surg. 2009 Feb;11(2):125-30.

Rand JS. Glargine administered intramuscularly is effective for treatment of diabetic ketoacidosis. ACVIM Abstract # 51. 2010.

Ford SL, Rand J, et al. Evaluation of detemir insulin in diabetic dogs managed with home blood glucose monitoring. ACVIM Proceedings. 2010 p. 442.

Roomp K, Rand JS, et al. Evaluation on detemir in diabetic cats managed with a protocol for intensive blood glucose control. J Vet Intern Med 2009;23(3):697