Monday, November 8, 2010

Insulin Choices for the Diabetic Cat and Dog: Which is Best?

A multitude of new human insulin preparations are available, and the list changes almost every month as new products are continually being developed while others are withdrawn. Thankfully, the are still two veterinary insulin preparations registered specifically for use in dogs and cats (See Table 1). All products are potentially efficacious for the treatment of diabetes; however, there is only limited veterinary information on most of the recently released human products.

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WHICH INSULIN PREPARATIONS HAVE BEEN WITHDRAWN?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 IDEXX Pharmaceuticals have recently withdrawn PZI-VET, which was a 40 U/ml bovine/porcine preparation of protamine zinc insulin registered in several countries for veterinary use.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 For example, it appears likely that human recombinant regular insulin will be withdrawn in the near future.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.
Regular Insulin
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.
WHAT ARE THE NEW INSULIN PREPARATIONS?

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).


Insulin Glargine
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.
Insulin Detemir
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.


Table 1:


References:
  1. FDA CVM alert.
  2. 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.
  3. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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
  10. Rand J. Editorial: glargine, a new long-acting insulin analog for diabetic cats J Vet Intern Med 2006;20: 219-20.
  11. Eli Lilly prescribing information.

Monday, November 1, 2010

Diagnosis & Treatment of Thyroid Carcinoma in Cats

Hyperthyroidism in cats is most often associated with thyroid adenomatous hyperplasia or adenoma, with carcinomas accounting for only 2% to 3% of cases. While thyroid carcinoma in cats appears to be rare, many cases appear to go undiagnosed, at least in the earlier stages of disease. Diagnosing thyroid carcinoma is very important because standard treatment strategies for hyperthyroidism almost always fail to manage this malignant condition adequately.

Clinical Features of Thyroid Carcinoma in Cats

Most thyroid carcinoma in cats are functional and are associated with typical clinical and biochemical features of hyperthyroidism, such as polyphagia, weight loss, and restlessness. Non-secretory carcinomas also occur in cats and may represent up to a third of cats with thyroid carcinoma; such cats are euthyroid and usually present because of the incidental discovery of a moderate-sized to large cervical mass.

Whether the cat is hyperthyroid or euthyroid cannot, however, determine the carcinoma's capacity to take up and concentrate radionuclide. With thyroid scintigraphy, about half of euthyroid cats with thyroid carcinoma show some degree of radioisotope uptake, indicating that radioiodine may still be a useful treatment in a subset of these cats.

How to Distinguish Thyroid Carcinoma from Adenoma (Adenomatous Hyperplasia)

The clinical features of hyperthyroid cats with thyroid carcinoma are similar those of hyperthyroidism cats with benign adenoma (or adenomatous hyperplasia). Features that should increase one's suspicion for thyroid carcinoma include the following:

  • Larger-than-expected goiter; sometimes multiple, nodular thyroid masses
  • Long history of hyperthyroidism (> 2 years)
  • Extremely high serum T4 concentration (> 5 to 10-times the upper limit of normal)
  • Lack of response to high doses of methimazole or carbimazole (> 15-20 mg/day)
  • Failure or recurrence of hyperthyroidism after thyroidectomy or radioiodine therapy
  • Locally invasive or highly vascular thyroid tumor (usually noted at surgery)
  • Multifocal, irregular, and heterogeneous areas of increased radionuclide uptake with thyroid imaging
  • Signs of distant metastases on radiography or thyroid imaging (usually pulmonary)
In a few cats with thyroid carcinoma, however, very few of the above features will apply. Alternatively, it is possible for a cat with advanced benign disease to show some of the same features (e.g., large goiter, long history of hyperthyroidism, very high serum T4 value).

Thyroid carcinoma can be extremely variable on palpation (if in the cervical region), ranging from discrete solitary mobile nodules, to chains of tissue extending along the neck or fixed firm masses. Both benign and malignant thyroid tumors may become extremely large if cystic changes develop. Gross appearance at surgery, however, may be more informative since thyroid carcinomas frequently infiltrate local tissues and are highly vascular.

An inadequate response to conventional treatment in any hyperthyroid cat should raise the question of a possible thyroid carcinoma. For example, if hyperthyroidism is not controlled or quickly recurs after bilateral thyroidectomy or standard doses of radioiodine fail to cure the cat's hyperthyroidism, thyroid carcinoma must be considered.

Many cats eventually diagnosed with thyroid carcinoma had initially been controlled fairly well with antithyroid drugs. Although these drugs are typically effective in suppressing serum T4 concentration for variable periods, the daily dose requirement needed to control the hyperthyroid state gradually and progressively increases in these cats. Eventually, the thyroid tumor will grow to such a size that antithyroid drug therapy, no matter what the dose, no longer blocks T4 secretion from the large volume of carcinomatous tissue.

Scintigraphic features that can help distinguish malignant from benign thyroid disease include multiple and extensive areas of hyperfunctional thyroid tissue, a heterogeneous pattern of radioisotope uptake with irregular margins, linear multifocal patterns (suggestive of tumor extension along fascial planes), and uptake of masses within the cranial mediastinum. A recent review of scintigraphic findings in hyperthyroid cats, however, found that similar imaging changes are occasionally observed in cats with benign disease (Harvey et al. 2009). The identification of metastatic disease in thyroid carcinoma is complicated by the existence of ectopic thyroid tissue in up to 25% of cats. Hence, multiple areas of radioisotope uptake in the cervical or intra-thoracic locations (or both) could potentially reflect metastases or multiple primary tumors in ectopic sites.

Despite its limitations, thyroid scintigraphy remains a valuable and essential tool in evaluating a cat with suspected thyroid carcinoma. Thyroid imaging is the best means we have to assess tumor functionality and determine thyroid volume to assist in treatment planning with surgery or high-dose radioiodine.

Thyroid image performed in a 12-year-old cat with a 3-year history of hyperthyroidism.
This cat was no longer responsive to methimazole therapy. Notice the large multiple thyroid masses. Most of this cat's thyroid tumor was located within the thoracic cavity (the yellow horizontal line indicates the region of the thoracic inlet). For comparison, a thyroid scan from a normal cat is shown on the right.
Definitive Diagnosis of Thyroid Carcinoma
The only definitive way to confirm a diagnosis of thyroid carcinoma is by histopathologic examination. Pathological criteria for malignancy include extracapsular invasion, vascular invasion, cellular pleomorphism, and increased mitotic activity.

Definitive identification of thyroid carcinoma on histopathology generally necessitates excisional biopsy. Routine histopathology of the thyroid tumor should always be done after any thyroid surgery. Because many thyroid carcinomas are highly vascular, excision may be difficult and hemorrhage may occur; in these cats, it may not be possible to do a thyroidectomy, but one should at least attempt to obtain a biopsy for diagnosis.

Scintigraphy can be used adjunctively, especially in recognizing regional and distance metastasis. But again, scintigraphy alone cannot reliably distinguish whether the thyroid tissue is malignant since ectopic thyroid tissue commonly is found in cats with benign thyroid disease.
Interestingly, mixed adenoma and carcinoma tissue has been documented in some cats with thyroid carcinoma. This strongly suggests that, at least in some cats, thyroid carcinoma appear to arise from transformation of benign into malignant neoplasia.

Treatment of Cats with Thyroid Carcinoma

Radioiodine is considered the gold standard treatment for hyperthyroidism. It has the advantages of treating all hyperfunctional tissue, regardless of site (including ectopic thyroid tissue). In addition, there is no need for general anesthesia and treatment complications are minimal with radioiodine therapy. The efficacy of radioiodine is well established in cats with benign disease, with success rates of up to 94% reported (Peterson & Becker, 1994).

The use of radioiodine for treatment has also been reported in a limited number of cats with thyroid carcinoma. Higher 131I doses are required for cats with thyroid carcinoma (3-10 x higher than for benign disease), primarily because of the much larger tumor volume associated with carcinoma. In addition, at least in euthyroid cats with thyroid carcinoma, the malignant tissue appears less efficient at taking up and concentrating radioiodine. Therefore, higher administered 131I doses are needed in order to have enough 131I taken up by the tumor to destroy the carcinomatous tissue.

Most studies of cats with thyroid carcinoma have used an empirical high 131I dose of 30 mCi (1110 MBq). With this protocol, long-term prognosis is good with extended survival commonly achieved (Guptill et al. 1995; Hibbert et al. 2009).

In one recent study, 12 hyperthyroid cats with hypersecretory thyroid carcinomas were treated with high-dose radioiodine. Of these, treatment was successful in 11 cats, with complete resolution of hyperthyroidism and extended survival times (median 1,065 days). The remaining cat had a partial response.

Thyroid images of a cat with thyroid carcinoma before (left) and after (right) treatment
with high-dose radioiodine therapy. Notice that the thryoid carcinoma in this cat
has been completely destroyed.

The combination of surgical debulking followed by administration of high-dose radioactive iodine also has been reported to be successful in cats with thyroid carcinoma. This allows one to obtain thyroid tissue for histopathologic examination in order to confirm thyroid carcinoma. Because the total tumor volume is lessened by the debulking procedure, a lower 131I dose is generally needed to destroy the remaining tumor tissue. However, if excision biopsy is not possible, higher doses of 131I will be needed, necessitating a longer hospital stay. Unfortunately, many of these cats are not surgical or anesthetic candidates because of their severe, advanced, and uncontrolled hyperthyroidism.

Optimal treatment of non-secretory thyroid carcinoma remains unclear. Although some euthyroid cats treated with 131I have had least temporary remission of thyroid carcinoma, it is likely that these cats would respond better to a combination of surgery and external beam radiotherapy, similar to the management of canine thyroid carcinomas.

In conclusion, thyroid carcinoma is a relatively rare (but increasing common) cause of feline hyperthyroidism. Although there are many clinical and imaging features that suggest thyroid carcinoma, diagnosis can only be made by histopathologic examination of tissue. Treatment with high-dose radioiodine is clearly the best therapeutic option. Successful response to radioiodine is associated with prolonged survival times, comparable to those achieved in hyperthyroid cats with benign disease.

References

Broome MR. Thyroid scintigraphy in hyperthyroidism. Clin Tech Small Anim Pract 2006; 21:10-16. 

Chun R, Garrett LD, Sargeant J, et al. Predictors of response to radioiodine therapy in hyperthyroid cats. Vet Radiol Ultrasound 2002;43:587-591.

Cook SM, Daniel GB, Walker MA, et al. Radiographic and scintigraphic evidence of focal pulmonary neoplasia in three cats with hyperthyroidism: diagnostic and therapeutic considerations. J Vet Intern Med 1993;7:303-308.

Daniel GB, Brawnier WR. Thyroid scintigraphy In: Daniel GB, Berry CR, eds. Textbook of Veterinary Nuclear Medicine. 2nd ed. Harrisburg, PA: American College of Veterinary Radiology, 2006;181-199.

Guptill L, Scott-Moncrieff CR, Janovitz EB, et al. Response to high-dose radioactive iodine administration in cats with thyroid carcinoma that had previously undergone surgery. J Am Vet Med Assoc 1995;207:1055-1058.

Harvey AM, Hibbert A, Barrett EL, et al. Scintigraphic findings in 120 hyperthyroid cats. J Feline Med Surg 2009;11:96-106.

Hibbert A, Gruffydd-Jones T, Barrett EL, et al. Feline thyroid carcinoma: diagnosis and response to high-dose radioactive iodine treatment. J Feline Med Surg 2009;11:116-124.

Leav I, Schiller AL, Rijnberk A, et al. Adenomas and carcinomas of the canine and feline thyroid. Am J Pathol 1976;83:61-122.

Mooney CT, Peterson ME: Feline hyperthyroidism, In: Mooney C.T., Peterson M.E. (eds), Manual of Canine and Feline Endocrinology (4th Ed), Quedgeley, Gloucester, British Small Animal Veterinary Association, 2010 (in press)

Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. J Am Vet Med Assoc 1995;207:1422-1428.

Turrel JM, Feldman EC, Nelson RW, et al. Thyroid carcinoma causing hyperthyroidism in cats: 14 cases (1981-1986). J Am Vet Med Assoc 1988;193:359-364.