Don't overlook these 4 noteworthy advances in endocrinology

Advances in endocrinology are happening quickly, and four areas in particular merit our attention to ensure we are keeping up-to-date and providing the best care for our patients.

David S. Bruyette, DVM, DACVIM

ALTERNATIVES TO PZI VET

In April, IDEXX Pharmaceuticals announced the discontinuation of PZI Vet (a porcine-and bovine-source protamine zinc insulin). Consider these options for switching cats from PZI Vet to other insulin preparations:

• Vetsulin (Intervet), a porcine insulin zinc suspension originally approved for use in dogs, is now also approved for use in cats and is a U-40 insulin, like PZI Vet. I would start by giving the same dose of Vetsulin as you had been giving with PZI Vet. In addition, dosing guidelines can be found at www.vetsulin.com/PDF/Vetsulin_Dear_Doctor_Letter.pdf. If patients had been receiving PZI Vet once a day, I would prepare the owners for twice-a-day administration because it is unlikely that once-a-day dosing of Vetsulin will be sufficient. Reassess glycemic control seven to 10 days after the switch.

• Humulin N (Eli Lilly), a human recombinant NPH, is a U-100 insulin. I would start by administering the same dose of Humulin N as you had been giving with PZI Vet. As with Vetsulin, if the cat had been receiving PZI Vet once a day, I would prepare the owner for twice-a-day administration. Reassess glycemic control seven to 10 days after the switch.

• Glargine (Lantus—insulin glargine [rDNA origin] injection—Sanofi Aventis), a long-acting insulin analogue, is also a U-100 product. Although it is a viable option when switching from PZI Vet, I think it is unlikely to have any advantage over Vetsulin or Humulin N. The cost would also be greater. And in my opinion, while glargine is an excellent choice for treating diabetes in newly diagnosed cases, you won't see the same high remission response rate in cats with long-standing diabetes.

I do not recommend nor would I begin using compounded PZI insulin because clinical impression suggests that these preparations may result in poor or erratic glycemic control.

GLARGINE

As noted above, glargine is a good insulin option, particularly in cats in which diabetes has been newly diagnosed. The commercially available form of glargine, Lantus, is a human insulin analogue produced by recombinant DNA technology. The production organism is a nonpathogenic laboratory strain of Escherichia coli. Each milliliter contains 100 IU (3.6378 mg) insulin glargine.

At a pH of 4, Lantus is designed to be completely soluble at a neutral pH. After injection into the subcutaneous tissue in people, the solution is neutralized, and microprecipitates form and slowly release small amounts of insulin glargine, resulting in a relatively constant concentration over 24 hours.

A study presented at the ACVIM Forum in 2005 showed that eight of eight diabetic cats treated with glargine twice daily and fed a low-carbohydrate, high-protein diet were in diabetic remission within four months, and six of seven were still in remission at one year.1 My clinical experience has been similar, with more than 50% of cats newly diagnosed with diabetes experiencing remission within two to four months when receiving glargine and a low-carbohydrate, high-protein diet. The recommended starting dose is 0.5 U/kg twice a day if the initial fasting blood glucose concentration is > 360 mg/dl and 0.25 U/kg twice a day if the initial fasting blood glucose concentration is < 360 mg/dl.1

If you decide to use glargine in your diabetic feline patients, I suggest these tips:

• Do not dilute or mix glargine because it will affect pH.

• Keep glargine refrigerated. Once opened, the vial has a shelf life of four weeks at room temperature. I would discard any remaining glargine after eight weeks of refrigeration, pending further clinical data.

• After starting glargine, keep in mind that many cats have negligible decreases in blood glucose concentrations in the first three days: Do not increase the insulin dose. By day 10 after beginning glargine, most cats have good glycemic control.

• Obtain samples at time 0 (preprandial and preinsulin) and then every four hours for 12 hours or until the nadir (lowest glucose concentration) is observed. It is rare that a curve will need to be performed for a full 24 hours.

• Recheck the cat and perform a glucose curve one, two, three, and four weeks later and then as required.

• Use the preinsulin and nadir blood glucose concentrations obtained with in-house analyzers or at-home blood glucose monitors in conjunction with the cat's clinical signs to adjust the insulin dose and to monitor for diabetes remission.

TRILOSTANE

Canine hyperadrenocorticism has been most commonly treated with the adrenolytic drug mitotane (o,p'-DDD). However, mitotane has several side effects and is associated with a high frequency of relapses.

Trilostane is a synthetic, orally active steroid analogue. It can act as a competitive inhibitor of the 3-beta-hydroxysteroid dehydrogenase enzyme system and, thus, inhibit the synthesis of several steroids, including cortisol and aldosterone. This blockade is reversible and likely dose-related.

In the United Kingdom, trilostane is licensed to treat canine hyperadrenocorticism. Dechra Pharmaceuticals is pursuing U.S. FDA approval of trilostane for this condition.

Canine PDH

The efficacy and safety of trilostane in treating canine pituitary-dependent hyperadrenocorticism (PDH) were evaluated in a multicenter European study.2 Seventy-eight dogs with confirmed PDH were treated with trilostane for up to three years. Trilostane appeared to be well-tolerated by almost all the dogs. Two dogs developed signs and biochemical evidence of hypoadrenocorticism. One of these dogs recovered with therapy; the other dog died despite withdrawing trilostane and administering therapy. Two additional dogs died within one week of starting trilostane, but a direct link with the trilostane therapy could not be established in either case.

The study revealed that trilostane was nearly as effective as mitotane in resolving signs of hyperadrenocorticism such as polyuria, polydipsia, polyphagia, and skin abnormalities.2 These improvements were maintained as long as the dogs received adequate doses of trilostane. Only eight dogs that were treated with trilostane for more than two months showed poor control of clinical signs. Mitotane is effective in controlling clinical signs in about 80% of cases of PDH but has a higher percentage of side effects than trilostane does.3

Trilostane also caused a significant reduction in the mean basal and post-ACTH stimulation cortisol concentrations.2 These improvements were also maintained for the duration of the trial. Thirty-five dogs had at least one dose adjustment during the treatment period.

The mean survival time of all trilostane-treated dogs was 661 days.2 Direct comparison with mitotane is difficult as 65% of the dogs were still alive at censoring, so the mean survival time may be higher. In comparison, the mean survival time of mitotane-treated dogs is 810 to 900 days.4,5 A recent study comparing trilostane (administered twice daily) to mitotane (administered by using the nonselective adrenocorticolysis protocol) demonstrated a significantly longer median survival time in the dogs treated with trilostane (900 days) than in the dogs treated with mitotane (720 days).5

Canine adrenal-dependent hyperadrenocorticism

Only a few cases of adrenal-dependent hyperadrenocorticism have been treated with trilostane. A reduction in post-ACTH cortisol concentrations has been demonstrated, and survival times of more than two years have been achieved in some cases.6,7 Because of an insufficient number of documented cases, it is impossible to compare the long-term efficacy of trilostane with that of mitotane in treating adrenal-dependent hyperadrenocorticism. Trilostane is not cytotoxic, and it is likely to be inferior to mitotane in preventing and controlling metastatic disease. The value of trilostane for preoperative therapy before adrenalectomy has not been systematically examined. However, given the data above, trilostane might be an effective and safer alternative to ketoconazole in this respect.

Cautions

Trilostane should be given with food. In dogs receiving trilostane, only minor side effects, such as mild lethargy and decreased appetite two to four days from the start of therapy (potentially due to hypocortisolemia) and mild electrolyte abnormalities, are commonly seen. Overt hypoadrenocorticism seems to be a rare event, despite the marked decrease in serum cortisol concentrations found shortly after trilostane dosing. While sporadic cases of acute adrenal necrosis have been reported, this side effect is rare with trilostane. Keep in mind that mitotane works by inducing adrenal necrosis.

Trilostane can cause hyperkalemia through its aldosterone-inhibiting effect, so use caution if you administer it to a patient receiving a potassium-sparing diuretic. Trilostane may also potentiate the effect of angiotensin-converting enzyme inhibitors (again because of its aldosterone inhibiting effect), but no studies have evaluated this. No adverse drug interactions have been seen in dogs receiving trilostane and several nonsteroidal anti-inflammatory drugs, various antibiotics, insulin, or levothyroxine.

Monitoring

It is important to regularly monitor the clinical and biochemical effects of therapy and to adjust the trilostane dose to achieve optimal control. All ACTH stimulation tests must be performed four to six hours after trilostane administration and interpreted in light of the history and the findings of a thorough physical examination.

The long view

We need to continue to enhance our understanding of the etiopathogenesis of canine hyperadrenocorticism and eventually move beyond drugs that attack the end organ through adrenal enzyme inhibition (trilostane) or adrenocorticolysis (mitotane). It is likely that soon we will be able to address the primary cause by administering medications that alter gene expression, induce apoptosis, or decrease hormonal hypersecretion of ACTH from the pituitary gland. Potential therapies would include medications that include ligands for the peroxisome proliferator-activated receptor and retinoic acid receptors as well as medications that bind to somatostatin receptors. However, until that time, in my opinion, trilostane offers us the best option to manage dogs with moderate to severe signs of hyperadrenocorticism. At our hospital, we have treated more than 300 dogs with trilostane over the past five years, and it is our drug of choice for initial therapy.

RADIOIODINE THERAPY

Radioiodine therapy appears to be the safest and most effective therapy for hyperthyroidism in cats. Radioiodine may be administered intravenously, subcutaneously, or orally. While all routes appear effective, oral administration is discouraged because of the risk of human exposure and environmental contamination.

The largest radioiodine treatment safety and efficacy study involved 524 cats.8 Serum T4 concentrations remained high in 80 cats initially, but dropped within or below the reference range in all but eight cats by six months after radioiodine administration. Although many cats had low serum T4 concentrations after radioiodine treatment, only 11 cats required L-thyroxine therapy. Thirteen cats had a relapse of hyperthyroidism. Overall, 94% of the cats showed a good treatment response, and their median survival time was two years. A year after treatment, 89% of the cats were alive, and two and three years after treatment, 72% and 52% were alive, respectively. These percentages are important because pet owners may find this information on the Internet and erroneously assume that the cats die because of hyperthyroidism or its treatments. In reality, the cats die of senior diseases unrelated to hyperthyroidism.

Also keep in mind that cats with thyroid carcinoma are candidates for radioiodine therapy, especially after surgical debulking of neoplastic tissue.9 However, a higher percentage of these cats may require L-thyroxine supplementation after radioiodine treatment.

Feline hyperthyroidism can be treated safely, simply, and effectively with radioiodine therapy. Availability continues to increase as more and more centers become licensed. In addition, the cost of therapy has decreased, as routine scintigraphy appears not to be necessary to determine an effective radioiodine dose.10

David S. Bruyette, DVM, DACVIM, VCA West Los Angeles Animal Hospital, 1818 S. Sepulveda Blvd,West Los Angeles, CA 90025.

REFERENCES

1. Marshall RD, Rand J. Treatment with glargine results in higher remission rates than lente or protamine zinc insulins in newly diagnosed diabetic cats, in Proceedings. Am Coll Vet Intern Med Forum 2005.

2. Neiger R, Ramsey I, O'Connor J, et al. Trilostane treatment of 78 dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2002;150(26):799-804.

3. Kintzer PP, Peterson ME. Mitotane (o,p'DDD) treatment of 200 dogs with pituitary-dependent hyperadrenocorticism. J Vet Intern Med 1991;5(3):182-190.

4. Barker EN, Campbell S, Tebb AJ, et al. A comparison of the survival times of dogs treated with mitotane or trilostane for pituitary-dependent hyperadrenocorticism. J Vet Intern Med 2005;19(6):810-815.

5. Clemente M, De Andrés PG, Arenas C, et al. Comparison of non-selective adrenocorticolysis with mitotane or trilostane for the treatment of dogs with pituitary-dependent hyperadrenocorticism. Vet Rec 2007;161(24):805-809.

6. Eastwood JM, Elwood CE, Hurley KJ. Trilostane treatment of a dog with functional adrenocortical neoplasia. J Small Anim Pract 2003;44(3):126-131.

7. Benchekroun G, de Fornel-Thibaud P, Lafarge S, et al. Trilostane therapy of four dogs with metastatic secreting adrenocortical tumor, in Proceedings. Forum Am Coll Vet Intern Med 2007.

8. Peterson ME, Becker DV. Radioiodine treatment of 524 cats with hyperthyroidism. J Am Vet Med Assoc 1995;207(11):1422-1428.

9. 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(8):1055-1058.

10. Forrest LJ, Baty CJ, Metcalf MR, et al. Feline hyperthyroidism: efficacy of treatment with volumetric analysis for radioiodine dose calculation. Vet Radiol 1996;37:141-145.